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Transforming Growth Factor-beta (TGF-β) is a multifunctional cytokine that exerts its biological effects through a complex process of activation and signaling. Initially synthesized in an inactive form bound to latency-associated peptide (LAP), TGF-β requires release from the extracellular matrix via proteolytic cleavage or integrin-mediated activation to engage with its receptors. Once active, TGF-β binds to type II receptor (TβRII), which then phosphorylates and activates type I receptor (TβRI), triggering downstream signaling cascades, including both Smad-dependent and non-Smad pathways. These signaling cascades regulate key processes like cell growth, differentiation, migration, and immune response modulation, thereby influencing tumor development, progression, and treatment outcomes. This review discusses the complex signaling pathways of TGF-β in cancer, including its interactions with other signaling molecules and its involvement in epithelial-mesenchymal transition (EMT) and in evading immune surveillance. Moreover, dysregulated TGF-β signaling due to alterations in receptor expression, mutations in key signaling proteins such as TβRII and Smads, and aberrant activation of non-canonical pathways, contributes significantly to tumor aggressiveness, metastasis, and therapy resistance. The article emphasizes the potential of TGF-β as a diagnostic biomarker for cancer, highlighting its use in early detection, prognosis assessment, and monitoring treatment response. Additionally, it underscores various therapeutic strategies targeting TGF-β, such as small molecule inhibitors, monoclonal antibodies, immunotherapies, and evaluates their efficacy and limitations in preclinical and clinical settings. Finally, the review provides a comprehensive analysis of TGF-β's role as both a diagnostic tool and a therapeutic target, while also discussing the challenges and opportunities in targeting TGF-β signaling for improving cancer treatment outcomes., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

This paper describes the role of cardiovascular magnetic resonance (CMR) imaging in assessing patients with mitral valve disease. Mitral regurgitation (MR) is one of the most prevalent valvular heart diseases. It often progresses without significant symptoms, leading to left ventricular overload, dysfunction, frequent decompensated heart failure episodes, and excess mortality. Cardiovascular magnetic resonance assessment is recommended for MR when routine ultrasound imaging information is insufficient or discordant. A well-planned CMR can provide an in-depth assessment of the mitral valve apparatus, leaflet morphology, and papillary muscles. In addition, it can precisely inform the impact of MR on left atrial and ventricular remodelling. The review aims to highlight established and emerging techniques for morphological assessment, flow assessment (including regurgitation and stenosis), myocardial assessment, and haemodynamic assessment of mitral valve disease by CMR. It also proposes a simplified clinical flow chart for CMR assessment of the mitral valve., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Solution-processed oxide-based heterojunctions that work in diverse directions will be ideal alternatives for cost-effective, stable, and multifunctional devices. Here, we have reported a stable multilevel resistive switching (RS) at the solution-processed TiO 2 /ZnFe 2 O 4 heterointerface with endurance stability over 10 4 cycles and retention over 10 5 s. It can maintain the switching after dripping water onto the device, followed by drying at 100 °C and at an operating temperature of up to 200 °C. As the switching mechanism is governed by filamentary and interface-dominated charge conduction, our device shows additional tunability in the low resistance state (LRS) by changing environmental conditions. The inability to form filaments results in almost negligible switching under a vacuum or inert environment with an LRS loss. Meanwhile, the presence of reducing gas leads to a depletion layer lowering at the TiO 2 /ZnFe 2 O 4 heterointerface by removing the surface-adsorbed oxygen molecules that help filament conduction through the interface and, hence, a change in LRS. Furthermore, different reaction capacities of different reactive gas environments with the surface-adsorbed oxygen molecule lead to discrete ON-OFF ratios, presenting a pathway to identify several reactive vapors like ammonia, formaldehyde, and acetone at room temperature and presenting a new approach for integrating RS and room temperature gas sensing in the multifunctional device technology.

Background: Tuberculosis is a highly prevalent disease in India, while Histoplasmosis, an emerging disease, is often underreported due to limited resources in developing countries. Coinfection with both these organisms is rarely documented in immunocompetent host. Due to overlapping symptoms, it can be easily missed and treatment delays are not uncommon., Case Presentation: Here, we report a case of a 62-year-old male with a chronic history of intermittent fever and dry cough, splenomegaly, lymphadenopathy, and persistent pancytopenia. He was diagnosed with tuberculosis with cartridge-based nucleic acid amplification test (CBNAAT) positivity from a paratracheal lymph node biopsy. Simultaneously, a bone marrow biopsy revealed Histoplasmosis and the patient was started on dual treatment (Itraconazole and antitubercular drugs). After an initial response, the patient developed new space-occupying cerebral lesions. CSF histoplasma antigen was also positive. The reason for treatment failure was likely to be drug interaction (suboptimal levels of itraconazole due to rifampicin). The patient received liposomal amphotericin and subsequently put on a modified antitubercular treatment regimen to avoid interaction with itraconazole. At 2-month follow-up, the patient's condition significantly improved with a substantial resolution in CNS lesions., Conclusions: Histoplasmosis and tuberculosis have overlapping symptoms, diagnosing one does not preclude the possibility of other, even in non-HIV patients. Clinicians should also be vigilant about potential drug interactions., Competing Interests: Declarations Ethics approval and consent to participate This study did not require ethical approval. Consent for publication Written informed consent was obtained from the patient included in this report. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: To determine the feasibility of simultaneous multi-slice (SMS) real-time MRI (RT-MRI) at 0.55T for the evaluation of cardiac function., Methods: Cardiac CINE MRI is routinely used to evaluate left-ventricular (LV) function. The standard is sequential multi-slice balanced SSFP (bSSFP) over a stack of short-axis slices using electrocardiogram (ECG) gating and breath-holds. SMS has been used in CINE imaging to reduce the number of breath-holds by a factor of 2-4 at 1.5T, 3T, and recently at 0.55T. This work aims to determine if SMS is similarly effective in the RT-MRI evaluation of cardiac function. We used an SMS bSSFP pulse sequence with golden-angle spirals at 0.55T with an SMS factor of three. We cover the LV with three acquisitions for SMS, and nine for single-band (SB). Imaging was performed on 9 healthy volunteers and 1 patient with myocardial fibrosis and sternal wires. A spatio-temporal constrained reconstruction is used, with regularization parameters selected by a board-certified cardiologist. Images were quantitatively analyzed with a normalized contrast and an Edge Sharpness (ES) score., Results: There was a statistically significant 2-fold difference in contrast between SMS and SB and no significant difference in ES score. The contrast for SMS and SB were 13.38/29.05 at mid-diastole and 10.79/22.26 at end-systole; the ES scores for SMS and SB were 1.77/1.83 at mid-diastole and 1.50/1.72 at end-systole., Conclusions: SMS cardiac RT-MRI at 0.55T is feasible and provides sufficient blood-myocardium contrast to evaluate LV function in three slices simultaneously without any gating or periodic motion assumptions., (© 2024 The Author(s). Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

A highly efficient approach for synthesizing a supramolecular metallogel of Co(II) ions, denoted as CoA-TA, has been established under room temperature and atmospheric pressure conditions. This method employs the metal-coordinating organic ligand benzene-1,3,5-tricarboxylic acid as a low molecular weight gelator (LMWG) in DMF solvent. A comprehensive analysis of the mechanical properties of the resulting supramolecular Co(II)-metallogel was conducted through rheological investigation, considering angular frequency and thixotropic study. The hierarchical rocky network structure of the supramolecular Co(II)-metallogel was unveiled using field emission scanning electron microscopy (FESEM). Transmission electron microscopic (TEM) analysis showed rod-shaped structures via low-magnification high angle annular dark field (HAADF) bright field scanning transmission electron microscopic (STEM) imaging, while energy dispersive X-ray (EDX) elemental mapping confirmed its primary chemical constituents. The formation mechanism of the metallogel was examined via fourier transform infrared spectroscopy (FTIR) spectroscopy. The nature of the synthesized CoA-TA metallogel was affirmed through powder X-ray diffraction (PXRD) analysis. Furthermore, this study involved fabrication of Schottky diode structures in a metal-semiconductor-metal geometry based on cobalt(II) metallogel (CoA-TA), enabling observation of charge transport behavior. Remarkably, a resistive random access memory (RRAM) device utilizing cobalt(II) metallohydrogel (CoA-TA) demonstrated bipolar resistive switching at room temperature and under ambient conditions. The switching mechanism was investigated, revealing the formation and rupture of conductive filaments between metal electrodes that govern the resistive switching behavior. This RRAM device exhibited an impressive ON/OFF ratio (~ 414) and exceptional endurance over 5000 switching cycles. These structures offer great potential for diverse applications such as non-volatile memory design, neuromorphic computing, flexible electronics and optoelectronics. Their advantages lie in their fabrication process, reliable resistive switching behavior and overall performance stability., (© 2024. The Author(s).)

Aim. Melanized fungi were rarely studied for their antifungal resistance (AFR) or clinical outcome, despite rising incidence of melanized fungal ocular infections and AFR in general. We report the antifungal resistance patterns, clinical outcome and clinico-microbiological correlation in two commonly isolated melanized fungi from ocular infections, Curvularia lunata and Lasiodiplodia theobromae , at a tertiary eyecare centre in South India. Gap statement . Despite melanized fungi accounting for a significant proportion of ocular fungal infections in the Indian subcontinent, and despite there being a limited selection of effective antifungal agents available for these infections, the existing data and studies on these issues remain sparse. Therefore, this study aimed to investigate the prevalence of antifungal resistance in two of the most common melanized fungal pathogens in ocular infections, Curvularia lunata and Lasiodiplodia theobromae and correlate it with the treatment given and the clinical outcome in patients. Methodology. Electronic medical records provided the clinical data. Standard broth microdilution was performed for antifungal susceptibility testing (AFST) in 30 isolates (17 C . lunata and 13 L . theobromae ) for amphotericin B and natamycin (polyenes): voriconazole, ketoconazole, posaconazole, itraconazole and fluconazole (azoles) and caspofungin (echinocandin). Multidrug resistance (MDR) was defined as resistance to more than or equal to two classes of antifungals. DNA sequencing was performed for the isolates for species confirmation. The multivariate analysis was done for determining poor prognostic factors. Results. AFST showed highest susceptibility of study isolates for voriconazole (83.3% isolates), followed by natamycin (80%), fluconazole (80%), itraconazole (76.7%), ketoconazole (70%), posaconazole (66.7%), caspofungin (66.7%) and lastly amphotericin B (63.3%). All patients empirically received topical natamycin; additional oral ketoconazole/intraocular voriconazole was administered in select few. MDR was strongly associated with poor clinical outcome (multivariate analysis: P = 0.03, odds ratio = 7.8). All patients had microbial keratitis, one progressed to endophthalmitis. Additionally, therapeutic penetrating keratoplasty was required in 40% of cases. Globe salvage was possible in 80% patients, though good visual outcome was seen in only half of them. Both, anatomical and visual outcomes, were poor in 20% of patients. DNA sequencing showed C. lunata as the highest study species. Conclusion. C. lunata and L. theobromae showed varying in vitro antifungal susceptibility and clinical outcome in ocular infections. Voriconazole had significantly higher activity, while amphotericin B had lower activity in vitro for these melanized fungi. MDR isolates showed poorer clinical outcome.

A 67-year-old male presented to us with symptoms of postprandial abdominal pain for the last 3 months and was not able to take meals for the last month. The computed tomography (CT) angiogram showed complete occlusion in the coeliac artery (CA), superior mesenteric artery (SMA) and inferior mesenteric artery (IMA) with complete occlusion of infrarenal aorta and bilateral iliac arteries. While waiting for elective surgical mesenteric bypass, patient suddenly developed signs of peritonitis for which emergency surgery was done using a Dacron bifurcated graft 12 × 6 mm size. Inflow was taken from the supra coeliac aorta. At 6 months follow-up, the patient was doing well and the CT angiogram showed a patent graft. In our case, the challenge was from where to take inflow, as the patient's aorta was atherosclerotic and infrarenal aorta was completely occluded, and he was also not suitable for endovascular stenting. So, we decided to take inflow from the supra coeliac aorta and a distally mesenteric bypass was done. Although mesenteric ischaemia has very high morbidity and mortality rates, prompt and well-planned mesenteric bypass surgery can save both bowel and patients life as well., Competing Interests: Conflict of interestThe authors declare no competing interests., (© Indian Association of Cardiovascular-Thoracic Surgeons 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Repeat expansion disorders (REDs) are a devastating group of predominantly neurological diseases. Together they are common, affecting 1 in 3,000 people worldwide with population-specific differences. However, prevalence estimates of REDs are hampered by heterogeneous clinical presentation, variable geographic distributions and technological limitations leading to underascertainment. Here, leveraging whole-genome sequencing data from 82,176 individuals from different populations, we found an overall disease allele frequency of REDs of 1 in 283 individuals. Modeling disease prevalence using genetic data, age at onset and survival, we show that the expected number of people with REDs would be two to three times higher than currently reported figures, indicating underdiagnosis and/or incomplete penetrance. While some REDs are population specific, for example, Huntington disease-like 2 in Africans, most REDs are represented in all broad genetic ancestries (that is, Europeans, Africans, Americans, East Asians and South Asians), challenging the notion that some REDs are found only in specific populations. These results have worldwide implications for local and global health communities in the diagnosis and counseling of REDs., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

DNA binding protein from starved cells (Dps) is a miniature ferritin complex, which plays a vital role in protecting bacterial DNA during starvation to maintain the integrity of bacteria under hostile conditions. Several approaches, including cryo-electron tomography, have been previously implemented by other research groups to decipher the structure of the Dps protein bound to DNA. However, none of the structures of the Dps-DNA complex was resolved to high resolution to identify the DNA binding residues. Like other bacteria, Mycobacterium smegmatis also expresses Dps2 (called MsDps2), which binds DNA to protect it under oxidative stress conditions. In this study, we implemented various biochemical and biophysical studies to characterize the DNA protein interactions of Dps2 protein from Mycobacterium smegmatis. We employed single-particle cryo-EM-based structural analysis of MsDps2-DNA complexes and identified that the region close to the N-terminus confers the DNA binding property. Based on cryo-EM data, we also pinpointed several arginine residues, proximal to the DNA binding region, responsible for DNA binding. We also performed mutations of these residues, which dramatically reduced the MsDps2-DNA interaction. In addition, we proposed a model that elucidates the mechanism of DNA compaction, which adapts a lattice-like structure. We performed single-molecule imaging of MsDps2-DNA interactions that corroborate well with our structural studies. Taken together, our results delineate the specific MsDps2 residues that play an important role in DNA binding and compaction, providing new insights into Mycobacterial DNA compaction mechanisms under stress conditions., 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 Ltd. All rights reserved.)

GC-rich tandem repeat expansions (TREs) are often associated with DNA methylation, gene silencing and folate-sensitive fragile sites, and underlie several congenital and late-onset disorders. Through a combination of DNA-methylation profiling and tandem repeat genotyping, we identified 24 methylated TREs and investigated their effects on human traits using phenome-wide association studies in 168,641 individuals from the UK Biobank, identifying 156 significant TRE-trait associations involving 17 different TREs. Of these, a GCC expansion in the promoter of AFF3 was associated with a 2.4-fold reduced probability of completing secondary education, an effect size comparable to several recurrent pathogenic microdeletions. In a cohort of 6,371 probands with neurodevelopmental problems of suspected genetic etiology, we observed a significant enrichment of AFF3 expansions compared with controls. With a population prevalence that is at least fivefold higher than the TRE that causes fragile X syndrome, AFF3 expansions represent a major cause of neurodevelopmental delay., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Gynecological cancers, including ovarian, cervical, endometrial, and vulvar cancers, present significant challenges in diagnosis and treatment globally. The tumor microenvironment (TME) plays a pivotal role in cancer progression and therapy response, necessitating a deeper understanding of its composition and dynamics. This review offers a comprehensive overview of the gynecological cancer tumor microenvironment, emphasizing its cellular complexity and therapeutic potential. The diverse cellular components of the TME, including cancer cells, immune cells, stromal cells, and extracellular matrix elements, are explored, elucidating their interplay in shaping tumor behavior and treatment outcomes. Across various stages of cancer progression, the TME exerts profound effects on tumor heterogeneity, immune modulation, angiogenesis, and metabolic reprogramming. The urgency for novel therapeutic strategies is underscored by understanding immune evasion mechanisms within the TME. Emerging approaches such as immunotherapy, stromal-targeting therapies, anti-angiogenic agents, and metabolic inhibitors are discussed, offering promising avenues for improving patient outcomes. Interdisciplinary collaborations and translational research are emphasized, aiming to advance precision oncology and enhance therapeutic efficacy in gynecological cancers., 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.)

Purpose: Merozoites are the only extracellular form of blood stage parasites, making it a worthwhile target. Multiple invasins that are stored in the merozoite apical organelles, are secreted just prior to invasion, and mediates its interaction with RBC. A comprehensive identification of all these secreted invasins is lacking and this study addresses that gap., Experimental Design: Pf3D7 merozoites were enriched and triggered to discharge apical organelle contents by exposure to ionic conditions mimicking that of blood plasma. The secreted proteins were separated from cellular contents and both the fractions were subjected to proteomic analysis. Also, the identified secreted proteins were subjected to GO, PPI network analysis, and AI-based in silico approach to understand their vaccine candidacy., Results: A total of 63 proteins were identified in the secretory fraction with membrane and apical organellar localization. This includes various MSPs, micronemal EBAs and rhoptry bulb proteins, which play a crucial role in initial and late merozoite attachment, and majority of them qualified as vaccine candidates., Conclusion and Clinical Relevance: We, for the first time, report the secretory repertoire of merozoite and its status for vaccine candidacy. This information can be utilized to develop better invasion blocking multisubunit vaccines, comprising of immunological epitopes from several secreted invasins., (© 2024 Wiley‐VCH GmbH.)

One of the fundamental mechanisms developed by the host to contain the highly infectious and rapidly proliferating SARS-coronavirus is elevation of body temperature, a natural fallout of which is heat shock proteins over-expression. Here, for the first time, we demonstrate that the SARS-CoV-2 exploits the host Heat shock protein 70 (Hsp70) chaperone for its entry and propagation, and blocking it can combat the infection. SARS-CoV-2 infection as well as febrile temperature enhanced Hsp70 expression in host Vero E6 cells. Furthermore, heat shock or viral infection elevated the host cell autophagic response which is a prerequisite for viral propagation. In addition, Hsp70 protein demonstrated strong interaction with host Angiotensin-converting enzyme 2 (ACE2) as well as the receptor binding domain (RBD) of the SARS-CoV-2 Spike protein, indicating that interaction of Hsp70 with ACE2 and Spike protein may serve to protect them during febrile conditions. Suppressive and prophylactic treatment of Vero E6 cells with Hsp70 inhibitor PES, 2-(3-chlorophenyl) ethynesulfonamide (PES-Cl), abrogated viral infection more potently than the currently used drug Remdesivir. In conclusion, our study not only provides a fundamental insight into the role of host Hsp70 in SARS-CoV-2 pathogenesis, it paves the way for development of potent and irresistible anti-viral therapeutics., 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 B.V. All rights reserved.)

Next-generation immunotherapies have revolutionized cancer treatment, offering hope for patients with hard-to-treat tumors. This review focuses on the clinical applications and advancements of key immune-based therapies, including immune checkpoint inhibitors, CAR-T cell therapy, and new cancer vaccines designed to harness the immune system to combat malignancies. A prime example is the success of pembrolizumab in the treatment of advanced melanoma, underscoring the transformative impact of these therapies. Combination treatments, integrating immunotherapy with chemotherapy, radiation, and targeted therapies, are demonstrating synergistic benefits and improving patient outcomes. This review also explores the evolving role of personalized immunotherapy, guided by biomarkers, genomic data, and the tumor environment, to better target individual tumors. Although significant progress has been made, challenges such as resistance, side effects, and high treatment costs persist. Technological innovations, including nanotechnology and artificial intelligence, are explored as future enablers of these therapies. The review evaluates key clinical trials, breakthroughs, and the emerging immune-modulating agents and advanced delivery systems that hold great promise for enhancing treatment efficacy, reducing toxicity, and expanding access to immunotherapy. In conclusion, this review highlights the ongoing advancements in immunotherapy that are reshaping cancer care, with future strategies poised to overcome current challenges and further extend therapeutic reach.

Background: There is still considerable heterogeneity regarding which features of cryptoglandular anal fistula on magnetic resonance imaging (MRI) and endoanal ultrasound (EAUS) are relevant to surgical decision-making. As a consequence, the quality and completeness of the report are highly dependent on the training and experience of the examiners., Aim: To develop a structured MRI and EAUS template (SMART) reporting the minimum dataset of information for the treatment of anal fistulas., Methods: This modified Delphi survey based on the RAND-UCLA appropriateness for consensus-building was conducted between May and August 2023. One hundred and fifty-one articles selected from a systematic review of the literature formed the database to generate the evidence-based statements for the Delphi study. Fourteen questions were anonymously voted by an interdisciplinary multidisciplinary group for a maximum of three iterative rounds. The degree of agreement was scored on a numeric 0-10 scale. Group consensus was defined as a score ≥ 8 for ≥ 80% of the panelists., Results: Eleven scientific societies (3 radiological and 8 surgical) endorsed the study. After three rounds of voting, the experts (69 colorectal surgeons, 23 radiologists, 2 anatomists, and 1 gastroenterologist) achieved consensus for 12 of 14 statements (85.7%). Based on the results of the Delphi process, the six following features of anal fistulas were included in the SMART: Primary tract, secondary extension, internal opening, presence of collection, coexisting lesions, and sphincters morphology., Conclusion: A structured template, SMART, was developed to standardize imaging reporting of fistula-in-ano in a simple, systematic, time-efficient way, providing the minimum dataset of information and visual diagram useful to referring physicians., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction: Amphotericin B is a polyene antibiotic that is used as an off-label eye drop to treat fungal keratitis. Poor solubility, permeability and high susceptibility to hydrolytic degradation make it challenging to formulate a drug delivery system. Despite its drawbacks, it is a potent antifungal drug against Candida and other fungal species. However, it has not been explored much in ocular drug delivery. Hence, this review brings into focus the potential and increasing significance of Amphotericin B in ocular drug delivery., Areas Covered: In this review, we have systematically summarized the use of Amphotericin B in ocular diseases, the various formulation challenges for Amphotericin B, along with its off-label ocular usage, and stability concerns. The degradation mechanism of Amphotericin B in different conditions was discussed in this article as well., Expert Opinion: In the last few decades, several nanocarriers have been explored to improve the formulation challenges associated with Amphotericin B. Also, due to insufficient clinical studies and unknown toxicity profile, there is no US Food and Drug Administration (FDA) approved Amphotericin B formulation for ocular drug delivery. This review aims to offer thorough information about Amphotericin B in ocular drug delivery.

Background & Aims: Improvement in the nutritional status of patients with acute-on-chronic liver failure (ACLF) may lead to reduction in morbidity and mortality. This study assessed the impact of dietician-supported outpatient intensive nutrition therapy (OINT) on survival and frailty in patients with alcohol-related ACLF METHODS: Seventy patients with alcohol-related ACLF (Asia Pacific Association for the Study of the Liver [APASL] criteria) and frailty were randomized 1:1 to receive standard medical therapy (SMT) plus OINT (intervention) vs SMT (control) alone. The primary outcome was an improvement in survival at 3 months. Secondary outcome measures included improvement in frailty, prognostic scores, and hospitalization., Results: There was a significant improvement in overall survival in the OINT group as compared with the SMT group after 3 months of follow up (91.4% [standard error (SE), 4.7%] vs 57.1% [SE, 8.4%]; P < .00). On Cox regression model, inclusion in the intervention arm, baseline skeletal muscle index (SMI), and APASL ACLF Research Consortium (AARC score) were independent predictors of survival (P < .05). The liver frailty index (LFI) score also significantly improved in the OINT as compared with SMT (Δ-0.93; 95% confidence interval, -0.71 to 1.13 vs Δ -0.33; 95% confidence interval, -0.44 to 0.72; P < .00). The disease severity including MELD, MELD-Na, and AARC score showed a significant improvement in the OINT group as compared with the SMT group (P < .05). The patients in OINT group had lesser number of hospitalizations 6 (17%) vs 16 (45.7%) (P = .01) as compared with the SMT group., Conclusion: Outpatient intensive nutrition therapy significantly improves survival, frailty, and disease severity with a reduction in number of hospitalizations and supports the key role of nutrition in treatment of patients with alcohol-related ACLF., Clinical Trial Registry Number: ctri.nic.in/ CTRI/2022/01/039735., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Glyceraldehyde-3-phosphate-dehydrogenase (GAPDH; EC1.2.1.12) has several functions in Mycobacterium tuberculosis (Mtb) and the human host. Apart from its role in glycolysis, it serves both as a cell surface and a secreted receptor for plasmin(ogen) (Plg/Plm), transferrin (Tf), and lactoferrin (Lf). Plg sequestration by Mtb GAPDH facilitates bacterial adhesion and tissue invasion, while an equivalent interaction with host GAPDH regulates immune cell migration. In both, host and microbe, internalization of Tf/Lf-GAPDH complexes serves as a route for iron acquisition. To date, the structure of Mtb GAPDH or the residues involved in these moonlighting interactions have not been identified. This study provides the first known X-ray crystal structure of Mtb GAPDH. Through further mutagenesis and functional assays, we found that the C-terminal lysines of Mtb and human GAPDH affect enzyme activity and ligand binding. We also establish the stoichiometry of Plg, Tf and Lf interactions with the GAPDH tetramer. Lastly, molecular simulation studies reveal the interactions of the C-terminal lysine residues., (© 2024 Federation of European Biochemical Societies.)

Introduction: Takotsubo cardiomyopathy (TTCM) can occur in acute respiratory distress syndrome (ARDS) and a few cases in literature were reported to be associated with hemodynamic instability. All these patients were managed with venoarterial extracorporeal membrane oxygenation (VA-ECMO).Case presentation: We present two patients with ARDS-induced TTCM who were managed successfully with venovenous ECMO (VV-ECMO)., Conclusion: Ventricular function in both patients fully recovered three days after ECMO initiation, and they were subsequently weaned from ECMO once pulmonary function improved.

Introduction: Hospitalized patients with acute decompensation (AD) of cirrhosis are at risk of progressing to acute-on-chronic liver failure (ACLF), significantly increasing their mortality. The aim of this study was to identify key predictors and patient trajectories predisposing to ACLF., Methods: In this multicenter, prospective study spanning 2 years, clinical, biochemical, and 90-day survival data were collected from 625 patients with AD (European Association for the Study of the Liver criteria) across North, South, and East India. We divided the cohort into a Derivation cohort (DC: 318 patients) and a Validation cohort (VC: 307 patients). Predictive models for pre-ACLF were derived, validated, and compared with established scores such as model for end-stage liver disease (MELD) 3.0 and chronic liver failure Consortium acute decompensation., Results: Of 625 patients (mean age 49 years, 83% male, 77.5% with alcohol-related liver disease), 32.2% progressed to ACLF. Patients progressing to ACLF showed significantly higher bilirubin (10.9 vs 8.1 mg/dL), leukocyte counts (9,400 vs 8,000 per mm 3 ), international normalized ratio (1.9 vs 1.8), and MELD 3.0 (28 vs 25) but lower sodium (131 vs 134 mEq/L) and survival (62% vs 86%) compared with those without progression ( P < 0.05) in the DC. Consistent results were noted with alcohol-associated hepatitis, infection and hepatic encephalopathy as additional risk factors in VC. Liver failure at presentation (odds ratio: 2.4 [in DC], 6.9 [in VC]) and the 7-day trajectories of bilirubin, international normalized ratio, and MELD 3.0 significantly predicted ACLF progression ( P < 0.001). A new pre-ACLF model showed superior predictive capability (area under the curve of 0.71 in DC and 0.82 in VC) compared with MELD 3.0 and chronic liver failure Consortium acute decompensation scores ( P < 0.05)., Discussion: Approximately one-third of AD patients in this Indian cohort rapidly progressed to ACLF, resulting in high mortality. Early identification of patients at risk can guide targeted interventions to prevent ACLF., (Copyright © 2024 by The American College of Gastroenterology.)

(1) Background and Objectives : Flow assessment using cardiovascular magnetic resonance (CMR) provides important implications in determining physiologic parameters and clinically important markers. However, post-processing of CMR images remains labor- and time-intensive. This study aims to assess the validity and repeatability of fully automated segmentation of phase contrast velocity-encoded aortic root plane. (2) Materials and Methods: Aortic root images from 125 patients are segmented by artificial intelligence (AI), developed using convolutional neural networks and trained with a multicentre cohort of 160 subjects. Derived simple flow indices (forward and backward flow, systolic flow and velocity) and complex indices (aortic maximum area, systolic flow reversal ratio, flow displacement, and its angle change) were compared with those derived from manual contours. (3) Results : AI-derived simple flow indices yielded excellent repeatability compared to human segmentation ( p < 0.001), with an insignificant level of bias. Complex flow indices feature good to excellent repeatability ( p < 0.001), with insignificant levels of bias except flow displacement angle change and systolic retrograde flow yielding significant levels of bias ( p < 0.001 and p < 0.05, respectively). (4) Conclusions : Automated flow quantification using aortic root images is comparable to human segmentation and has good to excellent repeatability. However, flow helicity and systolic retrograde flow are associated with a significant level of bias. Overall, all parameters show clinical repeatability.

Diabetes mellitus (DM) is a global health concern, and dipeptidyl peptidase-4 (DPP-4) is a key therapeutic target. The study used three machine learning and deep learning models to predict potential DPP-4 inhibitors using a curated data set of 6,750 compounds. The models included support vector machine (SVM), random forest (RF), naive Bayes (NB), and multitask deep neural network (MTDNN). The MTDNN model demonstrated strong predictive performance, achieving 98.62% train accuracy and 98.42% test accuracy for predicting DPP-4 inhibitors and a correlation coefficient of 0.979 for training and 0.977 for the test data set, with low training and test errors while predicting corresponding IC 50 values. The MTDNN model predicted potential inhibitors using an external data set of FDA-approved drugs, identifying 100 compounds. Among these, five compounds stood out with promising molecular docking and dynamic profiles, suggesting their potential as repurposed drugs for targeting DPP-4 and offering hope for the future of diabetes treatment., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

GLH/Vasa/DDX4 helicases are core germ-granule proteins that promote germline development and fertility. A yeast-two-hybrid screen using Caenorhabditis elegans GLH-1 as bait identified BYN-1, the homolog of human bystin/BYSL. In humans, bystin promotes cell adhesion and invasion in gliomas, and, with its binding partner trophinin, triggers embryonic implantation into the uterine wall. C. elegans embryos do not implant and lack a homolog of trophinin, but both trophinin and GLH-1 contain unique decapeptide phenylalanine-glycine (FG)-repeat domains. In germ cells, we find endogenous BYN-1 in the nucleolus, partitioned away from cytoplasmic germ granules. However, BYN-1 enters the cytoplasm during spermatogenesis to colocalize with GLH-1. Both proteins become deposited in residual bodies (RBs), which are then engulfed and cleared by the somatic gonad. We show that BYN-1 acts upstream of CED-1 to drive RB engulfment, and that removal of the FG-repeat domains from GLH-1 and GLH-2 can partially phenocopy byn-1 defects in RB clearance. These results point to an evolutionarily conserved pathway whereby cellular uptake is triggered by the cytoplasmic mobilization of bystin/BYN-1 to interact with proteins harboring FG-repeats., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Background and Aims: Myokines are the muscle-derived hormones orchestrating muscle and systemic health. Their role in the progression of alcohol-associated liver disease (ALD) remains elusive., Methods: Three-hundred-one patients across the spectrum of ALD including fatty liver (FL, N = 13), compensated cirrhosis (CC, N = 17), non-acute decompensation (NAD, N = 95), acute decompensation (AD, N = 51) and acute-on-chronic liver failure (ACLF, N = 125) were recruited between 2021 and 2023. Plasma myostatin, decorin levels, nutritional status, handgrip strength (HGS), systemic inflammation, infection, ammonia, disease course and 30-day mortality were recorded., Results: Patients aged 48 years (IQR: 38-52) and 97.7% of males were enrolled. Myostatin was elevated while decorin was reduced in cirrhosis compared to without cirrhosis, and further in DC compared to CC (p < 0.001). A step-wise increase in myostatin and reduction in decorin was observed transitioning from NAD to AD to ACLF (p < 0.001). Myostatin was further increased and decorin was reduced along with the grades and organ failures in AD and ACLF (p < 0.001, each). Baseline decorin (AUC: 0.797) and its combination with MELD (AUC: 0.814) predicted disease resolution in AD and ACLF. Although, both myostatin (aOR: 18.96) and decorin (aOR: 0.02) could predict mortality, decorin was independent (aOR: 0.04) and additive to MELD (AUC of MELD+ log Decorin +  log TLC + HE-grade:0.815); p < 0.05 each. Myostatin increased and decorin reduced with inflammation, hyperammonaemia, malnutrition and HGS in AD and ACLF (p < 0.05, each)., Conclusion: Myokines are linked with malnutrition, fibrosis, systemic inflammation, organ failures, disease course and mortality in ALD. Decorin enhances the risk estimation of mortality of MELD in AD and ACLF. Therapeutic modulation of myokines is a potentially disease-modifying target in ALD., (© 2024 John Wiley & Sons Ltd.)

Purpose: To develop and validate a multiplex conventional PCR assay to simultaneously detect Cryptosporidium spp., Entamoeba histolytica, and Giardia lamblia in diarrheal samples as a rapid, cost-effective, and sensitive diagnostic tool for prevalent co-infections for improved diagnostic accuracy and efficiency in resource-limited settings., Methods: Stool samples collected from patients with gastrointestinal symptoms after taking written consent, processed via wet mount, iodine mount, and PCR assays. Cohen's kappa statistical analysis was done to test agreement., Result: Among 240 patients, 28.75% showed intestinal protozoa via Microscopy; Single-plex and multiplex PCR demonstrated 100% concordance, detecting 27.9%; confirmed by sequencing. Highest parasite positivity was observed in transplant and immunocompromised patients, with moderate to almost perfect agreement between microscopy and molecular methods., Conclusion: Multiplex-conventional PCR offers superior sensitivity and specificity over microscopy and 100% concordance with single-plex PCR, enabling rapid, cost-effective diagnosis of multiple parasites from single stool sample. Its adoption could revolutionize parasitic infection management in routine diagnostics., 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 Inc. All rights reserved.)

Purpose: Complex anal fistulas can recur after clinical healing, even after a long interval which leads to significant anxiety. Also, ascertaining the efficacy of any new treatment procedure becomes difficult and takes several years. We prospectively analyzed the validity of Garg scoring system (GSS) to predict long-term fistula healing., Methods: In patients operated for cryptoglandular anal fistulas, magnetic resonance imaging was performed preoperatively and at 3 months postoperatively to assess fistula healing. Scores as per the GSS were calculated for each patient at 3 months postoperatively and correlated with long-term healing to check the accuracy of the scoring system., Results: Fifty-seven patients were enrolled, but 50 were finally included (7 were excluded). These 50 patients (age, 41.2±12.4 years; 46 men) were followed up for 12 to 20 months (median, 17 months). Forty-seven patients (94.0%) had complex fistulas, 28 (56.0%) had recurrent fistulas, 48 (96.0%) had multiple tracts, 20 (40.0%) had horseshoe tracts, 15 (32.0%) had associated abscesses, 5 (10.0%) were suprasphincteric, and 8 (16.0%) were supralevator fistulas. The GSS could accurately predict long-term healing (high positive predictive value, 31 of 31 [100%]) but was not very accurate in predicting nonhealing (negative predictive value, 15 of 19 [78.9%]). The sensitivity in predicting healing was 31 of 35 (88.6%)., Conclusion: GSS accurately predicts long-term fistula with a high positive predictive value (100%) but is less accurate in predicting nonhealing. This scoring system can help allay anxiety in patients and facilitate the early validation of innovative procedures for anal fistulas.

Cancer ranks as the second leading cause of mortality worldwide, prompting extensive investigations into factors contributing to its development. Among these factors, genetic variations, known as genotypic polymorphisms, have been identified as significant influencers in the susceptibility to various types of cancer. Recent research has focused on exploring the connection between polymorphisms in the Long Non-coding RNA HOTAIR and cancer risk. However, the results from these studies have been inconsistent, leading to ambiguity and controversy. To address this uncertainty, we conducted a systematic analysis by gathering relevant studies from PubMed, EMBASE, and Google Scholar. Specifically, we focused on three well-studied polymorphisms within the HOTAIR lncRNA (HOTAIR rs920778 C > T, HOTAIR rs1899663 G > T, HOTAIR rs4759314 A > G) and their association with cancer risk. Our meta-analysis included data from 48 case-control studies involving 42,321 cases and 54,137 controls. The results of our updated meta-analysis revealed a significant correlation between HOTAIR rs1899663 G > T and HOTAIR rs4759314 A > G polymorphisms and overall cancer risk, particularly in the homozygous and recessive genetic models. Subgroup analysis further revealed that these associations were notably pronounced in the Asian population but not observed in the Iranian population. Furthermore, our findings underscore the potential of HOTAIR polymorphisms as diagnostic markers for overall cancer risk, particularly in gynecological cancers, precisely, HOTAIR rs1899663 G > T polymorphism in breast cancer. In conclusion, our systematic analysis provides compelling evidence that Long Non-coding RNA HOTAIR polymorphisms are linked to cancer risk, particularly in certain populations and cancer types, suggesting their potential clinical relevance as diagnostic indicators., (© 2024. The Author(s).)

Studies reveal variations in the in the origin, number, and branching patterns of the lateral circumflex femoral artery (LCFA). The present study aimed to document such variations and their potential clinical applicability. Thirty-two femoral triangles of 16 embalmed adult human cadavers were dissected to investigate the variation in the origin, number, and branching patterns of LCFA. The main branches of the LCFA were tracked independently for numerical variations in branching pattern. The distance between the origin of LCFA and mid inguinal point (MIP) was also measured in each case. LCFA was most commonly arising from profunda femoris (PF), followed by femoral artery (FA) and common trunk of the femoral artery (CFA). Duplication LCFA was observed in 15 (46.87%) limbs, in 5 (31.25%) cases duplication was only on right side, in 4 (25%) cases duplication was only on left side and in 3 (18.75%), duplication was bilateral. Cases with duplication of LCFA, showed numerical variations with descending pattern being the most common. The average distance of LCFA1 and LCFA2 from mid-inguinal point was 5.77±1.35 cm and 6.14±2.05 cm respectively. Detailed information regarding the occurrence of duplication will be great importance for surgeons, interventional radiologists, and other medical professionals performing procedures in the femoral region. Knowledge of variation of branching pattern of LCFA is utmost important as surgeons use the descending branch of the LCFA in bypass grafting and vascular reconstruction surgeries.

Background and Aims: Machine learning (ML) can identify the hidden patterns without hypothesis in heterogeneous diseases like acute-on-chronic live failure (ACLF). We employed ML to describe and predict yet unknown clusters in ACLF., Methods: Clinical data of 1568 patients with ACLF from a tertiary care centre (2015-2023) were subjected to distance-, density- and model-based clustering algorithms. Final model was selected on best cluster separation, viz. Silhouette width and Dunn's index (for distance- or density-based algorithms) and minimum BIC (for model-based algorithms). Cluster assignments, patient trajectories and survival were analysed through inferential statistics. Supervised ML models were trained in 70% data that predicted clusters in remaining 30% data followed by an temporal validation., Results: The cohort was male-predominant (87%), aged 44.3 years, with alcohol-associated hepatitis (62.9%) and survival of 50.5%. Due to poor performance of distance- and density-based algorithms and better explainability, the latent class model (LCM) was selected for exploration. LCM revealed four clusters with distinct trajectories, reversibility and survival (independent of MELD, CLIF-C ACLF and AARC scores). Cluster1 had patients with none/one organ failure and highest reversibility. Cluster2 had females with viral hepatitis and two organ failures. More-than-one acute precipitant, severity, infections, organ failures and irreversibility escalated from clusters 1 to 4. Circulatory and renal failures critically influenced cluster assignments. Incorporating clusters to CLIF-C ACLF, infection and ACLF definition improved the discriminative accuracy of CLIF-C-ACLF by 11%. Extreme gradient boost and decision trees could predict clusters with AUCs of 0.989 (0.979-0.995) and 0.875 (0.865-0.890). MELD, CLIF-C-OF, haemoglobin, lactate, CLIF-C-ACLF and ALT were critical variables for cluster prediction. Clusters with distinct survival were documented in a temporal validation cohort., Conclusions: ML for the first time could identify clusters with distinct phenotypes, trajectories and outcomes in ACLF. Stratification into clusters can address heterogeneity, guide prognosis, recruitment in trials, resource allocation and liver transplant discussions in ACLF., (© 2024 John Wiley & Sons Ltd.)

Cancer is a subject of extensive investigation, and the utilization of omics technology has resulted in the generation of substantial volumes of big data in cancer research. Numerous databases are being developed to manage and organize this data effectively. These databases encompass various domains such as genomics, transcriptomics, proteomics, metabolomics, immunology, and drug discovery. The application of computational tools into various core components of pharmaceutical sciences constitutes "Pharmacoinformatics", an emerging paradigm in rational drug discovery. The three major features of pharmacoinformatics include (i) Structure modelling of putative drugs and targets, (ii) Compilation of databases and analysis using statistical approaches, and (iii) Employing artificial intelligence/machine learning algorithms for the discovery of novel therapeutic molecules. The development, updating, and analysis of databases using statistical approaches play a pivotal role in pharmacoinformatics. Multiple software tools are associated with oncoinformatics research. This review catalogs the databases and computational tools related to cancer drug discovery and highlights their potential implications in the pharmacoinformatics of cancer., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The number of patients living with left ventricular assist devices (LVADs) has gradually increased in the past decade. Non-cardiac surgery (NCS) in patients with LVAD poses a unique situation with its inherent challenges., Aim: We conducted a comprehensive review to investigate the perioperative complications and mortality associated with emergent or elective NCS in patients with LVAD., Method: A comprehensive literature search for any papers referring to continuous LVAD patients with NCS. All publications with at least five durable LVAD patients who had NCS were eligible for inclusion., Result: Twenty articles matching our criteria were found and included in our study. This systematic review included 6,476 LVAD patients who underwent 6,824 NCS. There were 5-3,216 LVAD patients with NCS in each study. The median age was between 39 and 65 years, and most of the patients (78.8%) were male. Thirty-day postoperative mortality ranged from 0% to 60%. Eight studies reported no death within the 30 days of the operation. Common complications include gastrointestinal (GI) bleeding, intracranial bleeding, infection, acute kidney injury (AKI), urinary tract infection (UTI), stroke, sepsis, pneumonia, and VAD exchange. Emergent abdominal surgery had the highest (up to 60%) mortality rate, and vascular and neurological operations had the highest complication rates. Due to the diverse range of patients in each publication and the combination of outcomes presented in various publications, a meta-analysis was not conducted., Conclusion: In LVAD patients, noncardiac surgery may be performed effectively and safely. LVAD patients who undergo non-cardiac surgery may require more transfusions due to their complex coagulopathies. However, perioperative management of LVAD patients undergoing emergent NCS should be optimized to reduce mortality., Systematic Review Registration: https://osf.io/fetsb/., 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., (© 2024 Alamouti-Fard, Garg, Yazji, Brigham, Jacob, Wadiwala and Pham.)

Study Design: This study is a prospective observational study conducted over two years from December 2020 to March 2023 at the Department of Plastic and Reconstructive Surgery., Objective: To evaluate the outcomes of delayed reconstruction in patients with maxillectomy defects post-COVID-19 associated mucormycosis, focusing on safety, morbidity, and aesthetic results., Methods: Fifty patients with post-COVID-19 mucormycosis and maxillectomy defects without skin involvement were included. These patients underwent radical debridement and were treated with Amphotericin B followed by Posaconazole therapy until clinical and radiological resolution of the disease. Reconstruction was performed after a minimum of six months post-maxillectomy. Flaps used for reconstruction included the radial forearm free flap (RAFF), anterolateral thigh flap (ALT), and free fibula osteomyocutaneous flap, planned using a 3D-printed model. Follow-up was conducted weekly for the first month and monthly for the next two months, with semiannual visits thereafter., Results: Of the 50 patients, 42 % were male, and 58 % were female, with a mean age of 43 ± 8.75 years. Most patients (88 %) were diabetic. Maxillectomy defects were categorized as type IIA, IIB, IIIA, IIIB, and IV based on the Cordeiro classification. Four flaps (8 %) required re-exploration, with three salvaged. Complications included marginal flap necrosis (4 %) and oro-nasal fistula (2 %). The average hospital stay was six days, extended to ten days for re-explored cases. Flap dimensions varied with the largest being 62 cm² for the free fibula flap., Conclusions: Delayed reconstruction using free flaps in patients with post-COVID-19 mucormycosis maxillectomy defects without skin involvement is a safe approach with minimal morbidity. This method allows confirmation of disease resolution before major reconstructive surgery, resulting in excellent aesthetic and functional outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Introduction: Pain is the foremost complication of chronic pancreatitis (CP), affecting about 70% of patients. However, the pathophysiological understanding and management of CP-related pain is complex, likely as patients have diverse "pain phenotypes" responding differently to treatment. This study aims to develop a bedside test panel to identify distinct pain phenotypes, investigate the temporal evolution, and determine whether they can be used to predict treatment response., Method: The INPAIN study is an international, multi-center, observational, longitudinal cohort study comprised of 4 sub-studies. The studies will prospectively enroll 400 CP patients (50 without pain and 350 with pain) and 50 control subjects, conducting biannual observations for four years. The test panel is comprised of comprehensive subjective and objective assessment parameters. Statistical analysis strategies differ across the sub-studies. A model to predict treatment efficacy will be developed using various machine learning techniques, including an artificial intelligence approach, with internal cross-validation. Trajectories in pain parameters will be characterized by graphical analysis and mixed effect models., Discussion: The INPAIN study aims to comprehensively understand pain in CP through a test panel developed for routine clinical use. This tool has the potential to personalize treatments, improve clinical practice, enhance patient care, improve quality of life, and minimize treatment side effects., Competing Interests: Funding: Professor Asbjørn Mohr Drewes initiated this research project. Researchers behind this study declare no conflicts of interest. This study is economically supported by the INPAIN study sponsored by Aalborg University Hospital (“ForskningsKUBE”). This grant will be used to cover expenses related to equipment and salary for study personnel. Various funds will be applied to cover any additional financial expenses. Conflict of interest: The involved researchers will conduct the trial of general scientific interest without personal financial gain., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Ral-binding/interacting protein (RLIP) acts as a transporter that responds to stress and provides protection, specifically against glutathione-electrophile conjugates and xenobiotic toxins. Its increased presence in malignant cells, especially in cancer, emphasizes its crucial antiapoptotic function. This is achieved by selectively regulating the cellular levels of proapoptotic oxidized lipid byproducts. Suppressing the progression of tumors in human xenografts can be achieved by effectively inhibiting RLIP, a transporter in the mercapturic acid pathway, without involving chemotherapy. Utilizing ovarian cancer (OC) cell lines (MDAH2774, OVCAR4, and OVCAR8), we observed that agents targeting RLIP, such as RLIP antisense and RLIP antibodies, not only substantially impeded the viability of OC cells but also remarkably increased their sensitivity to carboplatin. To delve further into the cytotoxic synergy between RLIP antisense, RLIP antibodies, and carboplatin, we conducted investigations in both cell culture and xenografts of OC cells. The outcomes revealed that RLIP depletion via phosphorothioate antisense led to rapid and sustained remissions in established subcutaneous human ovary xenografts. Furthermore, RLIP inhibition by RLIP antibodies exhibited comparable efficacy to antisense and enhanced the effectiveness of carboplatin in MDAH2774 OC xenografts. These investigations underscore RLIP as a central carrier crucial for supporting the survival of cancer cells, positioning it as a suitable focus for cancer treatment., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

BACKGROUND Pheochromocytoma, a rare catecholamine-secreting tumor, often presents with paroxysmal or sustained hypertension, tachycardia, headache, and diaphoresis. Timely diagnosis is essential to prevent adverse complications. Less common presentations include pheochromocytoma crisis, with severe neurological and cardiac complications. CASE REPORT We report a unique case of a 25-year-old woman who initially presented with pheochromocytoma-induced hypertensive encephalopathy and acute coronary syndrome. Echocardiography revealed takotsubo-like cardiomyopathy, and magnetic resonance imaging of the brain revealed posterior reversible encephalopathy syndrome. Initial treatment focused on controlling her blood pressure and supporting cardiac function. Due to her recovering from immediate crisis and absence of further symptoms, the patient refused further follow-up. However, she eventually experienced another episode of hypertensive crisis 2 years later. Subsequent investigations with 24-h urine tests revealed elevated vanillylmandelic acid levels (7.93 mg/24 h), normetanephrine (2638.72 µg/24 h), and nor-metanephrine to creatinine ratio (3546.67) and normal urine metanephrine levels (195.92 µg/24 h) and metanephrine to creatinine ratio (263.33). Contrast-enhanced computed tomography of the abdomen revealed a 4.3×3.1×4-cm mass in the right adrenal gland. A DOTATATE positron emission tomography scan revealed a 3.9×4.3×2.7-cm localized right adrenal pheochromocytoma. Biochemical testing and adrenal imaging revealed a previously undiagnosed pheochromocytoma. Following targeted medical therapy and right adrenalectomy, the patient achieved complete resolution of her hypertension and associated symptoms. CONCLUSIONS Our case is a unique simultaneous presentation of posterior reversible encephalopathy syndrome and takotsubo-like cardiomyopathy, highlighting the importance to consider pheochromocytoma in acute neurological and cardiac presentations, even in the absence of typical symptoms.

The synthesis of sulfur-doped exfoliated graphitic carbon nitride (S-gCN) photocatalyst was achieved by the implementation of a two-step calcination technique. The XRD results revealed that all the fabricated photocatalytic materials were crystalline in nature. The inclusion of 5% sulfur in gCN led to a conspicuous escalation in the surface area of photocatalyst, rising from 10.294 to 61.185 m 2 g⁻ 1 . Morphological scrutiny of the samples using FE-SEM revealed that pristine gCN exhibited tightly stacked small nanosheets, whereas inclusion of sulfur and exfoliation resulted in generation of loosely distributed large nanosheet. Furthermore, the inclusion of sulfur also induced a shift in the energy band gap (Eg) from 2.81 eV to 2.63 eV, making it felicitous for investigation as proficient visible light photocatalyst. Additionally, the photoluminescence photo-induced charge carrier recombination behavior revealed a reduced peak intensity for 5% S-gCN compared to other synthesized compositions. This observation can be directly linked to the minimized electron-hole pairs recombination during photocatalysis, underscoring its superior photocatalytic performance. Our findings revealed that the 5% S-gCN photocatalyst exhibit the most promising attributes, it degraded Tetracycline drug, Chlorpyrifos pesticide and Eriochrome Black T dye under visible light irradiation almost ∼4 times more efficiently than pristine gCN. Additionally, exceptional visible light photocatalytic antibacterial efficacy was also perceived by 5% S-gCN against S. aureus bacteria. Overall, the present research sheds light on how doping and exfoliation interact to modify the structure and catalytic properties of gCN, paving the way for the development of outstanding performance, visible light-responsive efficient photocatalysts for environmental restoration., 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 Ltd. All rights reserved.)

The UK food system is distorted by inequalities in access, failing the people most in need, yet it should provide access to safe, nutritious affordable food for all citizens. Dietary patterns are associated with socio-demographic characteristics, with high levels of diet-related disease mortality attributed to poor dietary habits. Disadvantaged UK communities face urgent public health challenges, yet are often treated as powerless recipients of dietary and health initiatives. The need for food system transformation has been illustrated within recent UK government policy drivers and research funding. The Food Systems Equality project is a research consortium that aims to 'co-produce healthy and sustainable food systems for disadvantaged communities'. The project focusses on innovating food products, supply chains and policies, placing communities at the centre of the change. Tackling the above issues requires new ways of working. Creative approaches in food research are known to empower a wider range of individuals to share their 'lived food experience' narratives, building relationships and corroborating co-production philosophies, thus promoting social justice, and challenging more traditional positivist/reductionist 'biomedical' approaches for nutrition and food studies. This review paper critiques the use of community-centric approaches for food system transformation, focusing on one, a community food researcher model () as an exemplar, to highlight their utility in advocating w ith rather than for less affluent communities. The potential for creative methods to lead to more equitable and lasting solutions for food system transformation is appraised, consolidating the need for community-driven systemic change to foster more progressive and inclusive approaches to strengthen social capital. The paper closes with practice insights and critical considerations offering recommendations for readers, researchers, and practitioners, enabling them to better understand and apply similar approaches.

Androgen receptor (AR), a steroid receptor, plays a pivotal role in the pathogenesis of prostate cancer (PCa). AR controls the transcription of genes that help cells avoid apoptosis and proliferate, thereby contributing to the development of PCa. Understanding AR molecular mechanisms has led to the development of newer drugs that inhibit androgen production enzymes or block ARs. The FDA has approved a small number of AR-inhibiting drugs for use in PCa thus far, as the identification of novel AR inhibitors is difficult, expensive, time-consuming, and labor-intensive. To accelerate the process, artificial intelligence (AI) algorithms were employed to predict AR inhibitors using a dataset of 2242 compounds. Four machine learning (ML) and deep learning (DL) algorithms were used to train different prediction models based on molecular descriptors (1D, 2D, and molecular fingerprints). The DL-based prediction model outperformed the other trained models with accuracies of 92.18% and 93.05% on the training and test datasets, respectively. Our findings highlight the potential of DL, particularly the DNN model, as an effective approach for predicting AR inhibitors, which could significantly streamline the process of identifying novel AR inhibitors in PCa drug discovery. Further validation of these models using experimental assays and prospective testing of newly designed compounds would be valuable to confirm their predictive power and applicability in practical drug discovery settings.Communicated by Ramaswamy H. Sarma.

Bipolar disorder is a mood-related disorder, which can be portrayed as extreme shifts in energy, mood, and activity levels which can also be characterized by manic highs and depressive lows that can be often misdiagnosed as unipolar disorder due to primitive diagnostics techniques based on clinical assessments as well as diagnostic complexities arising due to its heterogeneous nature and overlapping symptoms with conditions like schizophrenia. leading to delays in treatment Strong evidence in support of genetic and epigenetic aspects of bipolar disorder, including mechanisms such as compromised hypothalamic-pituitary-adrenal axis, immune-inflammatory imbalances, oxidative stress, and mitochondrial dysfunction are found. Moreover, some previous research has already stated the role of genes like CITED2, NUDT4, and Arl8B in these processes. The primary goal of this study is to investigate the involvement of the genes in exploring and validating their potential as biomarkers for bipolar disorder. In silico tools like MutationTaster, PolyPhen2, SIFT, GTEx, PhenoScanner, and RegulomeDB were used to perform mutational and gene expression analyses. Results revealed potentially dangerous mutations caused in CITED2, NUDT4, and Arl8B, those which can have diverse outcomes. RegulomeDB, GTEx, and PhenoScanner reveal the involvement of these genes in various brain regions highlighting their relevance to bipolar disorder. This analysis suggests the potential utility of CITED2, NUDT4, and Arl8B as diagnostic markers hence shedding light on their roles to elaborate the molecular range of bipolar disorder. The study also contributes to providing valuable insights into the genetic and molecular basis of bipolar disorders., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The growth hormone-insulin-like growth factor (GH-IGF-1) axis and its impairment with sarcopenia, frailty, bone health, complications, and prognosis are not well characterized in cirrhosis., Methods: We investigated the adult decompensated cirrhosis out-patients at a tertiary care institute between 2021 and 2023 for serum GH and IGF-1 levels, and associated them with sarcopenia (CT-SMI in cm 2 /m 2 ), liver frailty index (LFI), osteodystrophy (DEXA), clinical decompensations (overall, ascites, encephalopathy, infection, and bleed), and survival up to 180 days., Results: One-hundred-seventy-two patients, 95% males, aged 46.5 years (median). log IGF-1 levels were negatively associated with sarcopenia, osteodystrophy, LFI, CTP, and MELD-Na score ( P  < 0.05 each). Patients with low IGF-1 levels had a higher incidence of complications (overall, ascites and encephalopathy) than those with intermediate, and high IGF-1 levels ( P  < 0.05 each). Both log IGF-1 (AUC: 0.686) and MELD (AUC: 0.690) could predict 180-day mortality ( P  < 0.05, each). Adding log IGF-1 with MELDNa further improved discriminative accuracy of MELDNa (AUC: 0.729) P  < 0.001. The increase in IGF-1 on follow-up was associated with better survival and fewer complications., Conclusion: Reduced IGF-1 levels reflect sarcopenia, frailty, and osteodystrophy in cirrhosis. Low IGF-1 are associated with severity, development of decompensations, and mortality., (© 2024 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Alzheimer's disease (AD) is a neurodegenerative disorder marked by significant loss of central cholinergic neurons. This progressive deterioration leads to cognitive dysfunction and impaired motor activity, culminating in the brain cell's death at the later stages of the disease. The approved drugs for AD are limited to providing symptomatic relief for an initial period due to the multifaceted etiology of the disease. Several studies have demonstrated that rivastigmine (RIV) is a selectively potent inhibitor of butyrylcholinesterase and devoid of antioxidant, Aβ, and tau protein aggregation inhibition and anti-inflammatory properties. Therefore, to address these issues associated with RIV, novel rivastigmine-based molecules were rationally designed, synthesized, and evaluated in various in-vitro and in-vivo AD models. In in-vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition studies revealed that 3q & 6e as promising leads (AChE, IC 50 1.72 ± 0.15, 0.91 ± 0.016 μM, BChE, IC 50 6.69 ± 0.28 μM, 1.19 ± 0.026 μM, for 3q & 6e, respectively). The computational studies (molecular docking and dynamics) further corroborated the in-vitro studies. Further, 3q and 6e were found to be potent antioxidants in the DPPH assay (IC 50 16.15 ± 1.05 & 15.17 ± 0.07 μM, for 3q & 6e, respectively). Interestingly, 3q, and 6e could effectively inhibit self-induced full-length tau and Aβ 1-42 aggregation. Treatment with 3q & 6e inhibited microglial activation by attenuating ROS release and mitochondrial damage. Further, 3q & 6e also suppressed NLRP3 inflammasome and NF-κB expression levels in microglial cells and halted the release of pro-inflammatory cytokines in human microglial cells. Finally, 3q & 6e were found to be efficacious in reversing the scopolamine-induced memory impairment in the Morris water maze test. The expression of various neuroprotection markers, such as BDNF and TRKB, was significantly overexpressed compared to the disease control group., 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.)

Aim: To identify and know the antimicrobial sensitivities of the aerobic bacteria in patients with acute otitis externa (AOE)., Materials and Methods: Sixty-six patients of acute otitis externa were prospectively analysed at a tertiary care centre in North-India from May 2021 to April 2022. Samples for culture and sensitivity were sent to the microbiology department and the results analysed., Results: A total of 50 samples yielded positive results for bacterial cultures. The gram-negative isolates were 60%, and the gram-positive were 40%. Pseudomonas aeruginosa was the most common organism isolated overall (48%), followed by Staphylococcus aureus (36%). Pseudomonas aeruginosa isolates were found to be most susceptible to piperacillin + tazobactam and imipenem (100%), followed by cefepime (91.67%) and ciprofloxacin (87.5%) while the Staphylococcus aureus isolates were found to be most susceptible to linezolid (100%) and doxycycline (94.44%), followed by clindamycin (88.89%)., Conclusion: Causes of bacterial diversity and their varied anti-microbial sensitivities and increasing antimicrobial resistance due to inadvertent use of antibiotics over time has caused change in susceptibility of bacteria. It therefore becomes essential to periodically assess the microbiological flora so as to provide quality and cost-effective treatment to the patient population presenting with AOE., (© Association of Otolaryngologists of India 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)