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Salmonella enterica is a common foodborne pathogen that causes intestinal illness varying from mild gastroenteritis to life-threatening systemic infections. The frequency of outbreaks due to multidrug-resistant Salmonella has been increased in the past few years with increasing numbers of annual deaths. Therefore, new strategies to control the spread of antimicrobial resistance are required. In this work, we found that N-acetyl cysteine (NAC) inhibits S. enterica at MIC of 3 mg ml-1 and synergistically activates the bactericidal activities of common antibiotics from three-fold for ampicillin and apramycin up to1000-fold for gentamycin. In addition, NAC inhibits the expression of virulence genes at sub-inhibitory concentrations in a dose-dependent manner. The whole-genome sequencing revealed that continuous exposure of S. enterica to NAC leads to the development of resistance; these resistant strains are attenuated for virulence. These results suggest that NAC may be a promising adjuvant to antibiotics for treating S. enterica in combination with other antibiotics., Competing Interests: All authors declare that there is no conflict of interest., (Copyright: © 2025 Hamed 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.)

Introduction: Patients undergoing maintenance dialysis have a higher mortality rate compared to the general population. It is known that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have protective effects on the kidney; however, few studies have directly compared their impact on mortality in patients undergoing dialysis. This study aims to evaluate the effectiveness of ACEIs, ARBs, or their combination in reducing all-cause and cardiovascular mortality in maintenance dialysis patients., Methods: We systematically searched PubMed, Cochrane Central, Web of Science (WOS), and Scopus databases from inception until August 23rd, 2024. We included all observational studies and clinical trials that assessed the effectiveness of ACEIs versus ARBs or their combination on mortality outcomes, in patients with CKD on maintenance dialysis. We used Review Manager 5.4 for all statistical analyses., Results: Five observational studies, including 126,612 patients, met the eligibility criteria and were included in the final analysis. Among all patients, no statistically significant difference was found between ACEIs and ARBs in reducing all-cause mortality (RR: 1.12, 95% CI [0.98, 1.27], P = 0.10) or cardiovascular mortality (RR: 1.10, 95% CI [0.92, 1.33], P = 0.30). In patients on hemodialysis, ARBs were associated with a statistically significant reduction in cardiovascular mortality (P < 0.0001)., Conclusion: Our results suggest no differences between ACEIs and ARBs in reducing all-cause or cardiovascular mortality in maintenance dialysis patients. However, ARBs may reduce cardiovascular mortality more effectively in hemodialysis patients. Conducting randomized controlled clinical trials to validate our results is warranted., Competing Interests: Declarations. Conflict of interest: The authors declare no conflicts of interest. Ethical approval and Consent for publication: Not applicable. Human and animal rights: This article does not contain any studies with human or animal subjects., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Arthritis is characterized by the progressive degeneration of articular cartilage, and the avascular nature of cartilage limits its capacity for self-repair. Stem cells are considered a promising treatment option due to their multipotent differentiation potential. The aim of this work was to investigate the structural changes in the hyaline articular cartilage of the knee joint in a model of arthritis induced by complete Freund's adjuvant, and to assess intra-articular injection of bone marrow mesenchymal stem cells (BM-MSCs) through both histological and immunohistochemical study. Adult male albino rats were divided into four groups: group 0 (donor group), group I (control group), group II (arthritis group) and group III (BM-MSCs treated arthritis group). Samples were collected 2, 6 and 10 weeks after the onset of the experiment. Sections were stained with; hematoxylin and eosin, Safranin O fast green stain, Masson's trichrome stain and anti-MMP9 antibody. In Group II (arthritis group), the articular cartilage showed signs of degeneration, including chondrocyte extensive proliferation, fibrillations, fissuring, and denudation, with fibrous tissue covering the exposed surface. There was a significant decrease in cartilage thickness, collagen content, and proteoglycan levels. The integrated density of MMP9 in the cartilage was significantly increased compared to Group I (control group). In contrast, Group III (BM-MSCs-treated arthritis group) exhibited a continuous cartilage surface with no cracks or fissures. There was a significant increase in cartilage thickness, collagen content, and proteoglycan levels, while the integrated density of MMP9 was significantly decreased compared to Group II (arthritis group)., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval: All the steps took place in Mansoura Experimental Research Center (MERC), Faculty of medicine, Mansoura University, Egypt. The study was approved by Institutional Review Board (IRB), Faculty of Medicine, Mansoura University with a code number: MDP. 18. 06. 07. Informed consent: Not applicable. Consent for publication: Not applicable., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: Given the increasing frequency of drug-resistant bacteria and the limited progress in developing new antibiotics, it is necessary to explore new methods of combating microbial infections. Nanoparticles, particularly silver nanoparticles (Ag-NPs), have shown exceptional antibacterial characteristics; however, elevated concentrations of Ag-NPs can produce noticeable levels of toxicity in mammalian cells., Aim: This study examined the potential synergistic effect of combining a low dosage of Ag-NPs and anti-pseudomonas drugs against Pseudomonas aeruginosa (ATCC strain) and eleven clinical isolates from cystic fibrosis patients., Methods: The Ag-NPs were chemically produced by utilizing a seed extract from Peganum Harmala and characterized via ultraviolet-visible spectroscopy and scanning electron microscopy. The broth microdilution technique was utilized to investigate the minimum inhibitory concentration (MIC) of Ag-NPs and eight antibiotics (Piperacillin, Ciprofloxacin, Levofloxacin, Meropenem, Amikacin, Ceftazidime, Gentamicin, Aztreonam). The fractional inhibitory concentration index (FICI) was determined via the checkerboard method to evaluate the synergistic effects of Ag-NPs and various antibiotics., Results: The biosynthesized Ag-NPs were uniformly spherical and measured around 15 nm in size. When combined with antibiotics, Ag-NP produced statistically significant reductions in the amount of antibiotics required to completely prevent P. aeruginosa growth for all strains. The findings revealed that the MIC of Ag-NPs was 15 ug/mL for all strains which decreased substantially when administered with antibiotics at a dose of 1.875-7.5 ug/mL. The majority of Ag-NP and antibiotic combinations exhibited a synergistic or partially synergistic impact. This was particularly noticeable in combinations containing Meropenem, Ciprofloxacin, and Aztreonam (in which the FIC index was less than or equal to 0.5)., Conclusion: The findings revealed that combining Ag-NPs with antibiotics was more effective than using Ag-NPs or antibiotics in isolation and that combinations of Ag-NPs and antimicrobial agents displayed synergistic activity against the majority of strains assessed., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Al-Momani et al.)

Background: Compared with all other cancer types, Breast cancer (BC) among women has now exceeded them all as the primary reason for cancer worldwide. The BC represents 11.7% of all cancer cases and accounts for a predestined 2.3 million new cases. It is the fourth primary reason for cancer-associated deaths in women. With a staggering 200-400% increase in the relative incidence of BC in Egypt, there is an urgent need for new diagnostic or predictive markers., Purpose: The current investigation aims to explore the connection of the functional TNF-α -308 G > A (rs1800629) single-nucleotide polymorphism (SNP) with different breast cancer predictive indices., Methods: The ARMS-PCR method was used for genotyping TNF-α -308 G > A SNP. Three groups were recruited for the study: 79 patients with benign breast inflammation (BBI); 163 with breast cancer (BC) and 144 controls (C)., Results: The TNF-α -308 G > A SNP was distributed among different groups in a unique pattern; in the control group 63.9% of cases were in the GG, 34% were in the GA, and 2.1% were in the AA. The BC group had 14% GG, 79% GA, and 7% AA, while the BBI group had 24% GG, 76% GA, and 0% AA. The AA genotype and A allele represented a strong significant correlation with risk factors in the BC group (OR AA : 14.67 [95% CI = 3.78-56.91] and OR A : 0.27 [95% CI = 0.19-0.39], respectively; P < 0.0001) in contrast to the control group. However, in the BBI group, a strong significant correlation was noted with the GA genotype (OR GA : 5.93 [95% CI = 3.18-11.04] P < 0.0001). In the BC group, the AA genotype shows a significant increase in Nottingham Prognostic Index (NPI) in positive ER and PR in contrast to the relevant negative ones (P = 0.02 and 0.002, respectively). However, the GA genotype significantly increased NPI in positive Her2 and metastatic patients (P = 0.03 and 0.01, respectively)., Conclusion: This research is the first to correlate TNF-α -308 G > A (rs1800629) SNP in Egyptian BC patients. The A allele, GA & AA genotypes, and the Overdominant model of the TNF-α -308 G > A gene variants were recorded as prognostic risk factors for BC carcinogenesis., Competing Interests: Declarations. Conflicts of interest: The authors declare no competing interests. Ethical approval: Ethics Approval and Consent to Participate: The research received permission from the Institution Review Board IRB) of the Faculty of Medicine, Mansoura University, with the code number (R.22.031651R1.R2). Informed written consent was attained from all individuals who contributed to our work and agreed to the Helsinki Declaration. Consent to Participate: Informed approval was obtained from all contributors in the study. Consent for Publication: Participants signed an informed agreement regarding publishing their data., (© 2024. The Author(s).)

Background: Water temperature and feeding frequency are critical abiotic factors regulating the growth and immune function of aquatic organisms. This study investigated the effects of water temperature and feeding frequency on growth and immune function in Nile tilapia (Oreochromis niloticus) over two months. A total of 360 juvenile fish (average weight: 20.00 ± 1.26 g) were divided into six groups, each with three replicates, based on a combination of three water temperatures (26, 28, and 30 °C) and two feeding frequencies (either 1 or 2 meals per day)., Results: At 30 ºC and 28 ºC, water electrical conductivity and total dissolved salts increased, while total ammonia nitrogen and dissolved oxygen rose slightly in groups fed twice daily, with a significant interaction between temperature and feeding frequency. The group at 30 ºC with two meals per day showed the highest final body weight (FBW). The interaction between temperature and feeding frequency significantly influenced FBW, total feed intake, and body thickness. Fish at 30 ºC exhibited upregulated hepatic growth hormone receptor 1 and insulin-like growth factor 1, while those at 28 ºC with one meal per day, as well as those at 30 ºC regardless of meal frequency, also showed increased expression of hepatic fatty acid binding protein and intestinal cluster of differentiation 36. Fish at 30 ºC had upregulated leptin levels and downregulated cholecystokinin, while those at 26 ºC displayed the opposite trend, particularly with one meal daily. Higher temperatures significantly boosted serum IgM, superoxide dismutase (SOD), and lysozyme (LYZ) levels, with meal frequency also affecting malondialdehyde, IgM, and SOD levels. Additionally, 30 ºC enhanced the hepatic expression of mucin-like protein (muc), oligo-peptide transporter 1 (pept1), interleukin 1, nf-κB, complement C3, lyz, sod, catalase, and glutathione peroxidase, with twice-daily meals having a more pronounced effect. Conversely, 28 ºC with one meal per day upregulated some of these genes, such as muc, pept1, and sod., Conclusions: Overall, 30 ºC with two meals per day significantly improved the growth and health of juvenile Nile tilapia, while 28 ºC with two meals maintained satisfactory performance., Competing Interests: Declarations Ethics approval The study was conducted at the Department of Aquaculture, Faculty of Aquatic and Fisheries Sciences, Kafrelsheikh University, Egypt. It was reviewed and approved by Kafrelsheikh University’s Ethical Committee under approval number KFS-IACUC/176/2024. The study adhered to the regulations and ethical guidelines outlined in ARRIVE (https://arriveguidelines.org/). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

A long-standing challenge in human regulatory genomics is that transcription factor (TF) DNA-binding motifs are short and degenerate, while the genome is large. Motif scans therefore produce many false-positive binding site predictions. By surveying 179 TFs across 25 families using >1,500 cyclic in vitro selection experiments with fragmented, naked, and unmodified genomic DNA - a method we term GHT-SELEX (Genomic HT-SELEX) - we find that many human TFs possess much higher sequence specificity than anticipated. Moreover, genomic binding regions from GHT-SELEX are often surprisingly similar to those obtained in vivo (i.e. ChIP-seq peaks). We find that comparable specificity can also be obtained from motif scans, but performance is highly dependent on derivation and use of the motifs, including accounting for multiple local matches in the scans. We also observe alternative engagement of multiple DNA-binding domains within the same protein: long C2H2 zinc finger proteins often utilize modular DNA recognition, engaging different subsets of their DNA binding domain (DBD) arrays to recognize multiple types of distinct target sites, frequently evolving via internal duplication and divergence of one or more DBDs. Thus, contrary to conventional wisdom, it is common for TFs to possess sufficient intrinsic specificity to independently delineate cellular targets.

Most of the human genome is thought to be non-functional, and includes large segments often referred to as "dark matter" DNA. The genome also encodes hundreds of putative and poorly characterized transcription factors (TFs). We determined genomic binding locations of 166 uncharacterized human TFs in living cells. Nearly half of them associated strongly with known regulatory regions such as promoters and enhancers, often at conserved motif matches and co-localizing with each other. Surprisingly, the other half often associated with genomic dark matter, at largely unique sites, via intrinsic sequence recognition. Dozens of these, which we term "Dark TFs", mainly bind within regions of closed chromatin. Dark TF binding sites are enriched for transposable elements, and are rarely under purifying selection. Some Dark TFs are KZNFs, which contain the repressive KRAB domain, but many are not: the Dark TFs also include known or potential pioneer TFs. Compiled literature information supports that the Dark TFs exert diverse functions ranging from early development to tumor suppression. Thus, our results sheds light on a large fraction of previously uncharacterized human TFs and their unappreciated activities within the dark matter genome.

Brain tumor stem cells (BTSCs) are a population of self-renewing malignant stem cells that play an important role in glioblastoma tumor hierarchy and contribute to tumor growth, therapeutic resistance, and tumor relapse. Thus, targeting of BTSCs within the bulk of tumors represents a crucial therapeutic strategy. Here, we report that edaravone is a potent drug that impairs BTSCs in glioblastoma. We show that edaravone inhibits the self-renewal and growth of BTSCs harboring a diverse range of oncogenic mutations without affecting non-oncogenic neural stem cells. Global gene expression analysis revealed that edaravone significantly alters BTSC transcriptome and attenuates the expression of a large panel of genes involved in cell cycle progression, stemness, and DNA repair mechanisms. Mechanistically, we discovered that edaravone directly targets Notchless homolog 1 (NLE1) and impairs Notch signaling pathway, alters the expression of stem cell markers, and sensitizes BTSC response to ionizing radiation (IR)-induced cell death. Importantly, we show that edaravone treatment in preclinical models delays glioblastoma tumorigenesis, sensitizes their response to IR, and prolongs the lifespan of animals. Our data suggest that repurposing of edaravone is a promising therapeutic strategy for patients with glioblastoma., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Fuelled chemical systems have considerable functional potential that remains largely unexplored. Here we report an approach to transient amide bond formation and use it to harness chemical energy and convert it to mechanical motion by integrating dissipative self-assembly and the Marangoni effect in a source-sink system. Droplets are formed through dissipative self-assembly following the reaction of octylamine with 2,3-dimethylmaleic anhydride. The resulting amides are hydrolytically labile, making the droplets transient, which enables them to act as a source of octylamine. A sink for octylamine was created by placing a drop of oleic acid at the air-water interface. This source-sink system sets up a gradient in surface tension, which gives rise to a macroscopic Marangoni flow that can transport the droplets in solution with tunable speed. Carbodiimides can fuel this motion by converting diacid waste back to anhydride. This study shows how fuelling at the molecular level can, via assembly at the supramolecular level, lead to liquid flow at the macroscopic level., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The impact of LRRK2 variants on the risk of Parkinson's disease in Egyptians remains unknown. We examined 1210 Egyptians (611 PD patients and 599 controls) from 16 governorates across Egypt for 12 LRRK2 pathogenic variants. The p.Gly2019Ser was the only variant detected, with a prevalence of 4.1% in sporadic cases, 6.5% in familial cases, and 0.68% in controls. Among p.Gly2019Ser carriers, all were heterozygous bar one homozygous patient, and all shared the common haplotype 1. Demographics and UPDRS scores did not differ between carriers and non-carriers, with most patients being males and developed PD in their fifties. Young and Early-onset PD prevalence was 37.5% in carriers and 33% in non-carriers. Familial cases were 16.6% in carriers and 11.5% in non-carriers. This study affirms that like other Mediterranean populations, Egyptians with PD have a higher prevalence of the p.Gly2019Ser variant compared to the global average. LRRK2 inhibitors could be promising therapeutic options for further exploration in this population., (© 2024. The Author(s).)

This article investigates how mental health counsellors on helplines in Sweden deal with racism from callers who self-categorise as non-racialised. Previous studies have identified racism as a problem in health care interactions, but there is limited knowledge about the features of racialised talk and how staff respond. In this study, we use conversation analysis and membership categorisation analysis to examine racialised talk in 17 audiorecorded calls, a subset of 458 calls to suicide preventive helplines. The analysis shows that racialisation functions as a resource for callers to make sense of their mental health difficulties. This speaks to the complexity of responding to racism in a mental health setting, as counsellors must see to callers' needs, and calling out racialised talk may alienate callers. Call-takers manage this problem in three ways: (1) questioning racialised talk, (2) supporting the callers' stance in a way that makes it ambiguous if call-takers are coproducing racism or affiliating with callers' lives being difficult and (3) supporting callers' problems as mental health issues while resisting a potentially racist trajectory. The study offers direct insight into the workings of racism in health care and how practitioners can balance health care users' needs for support with an antiracist position., (© 2024 The Authors. Sociology of Health & Illness published by John Wiley & Sons Ltd on behalf of Foundation for the Sociology of Health & Illness.)

Background: Unintentional injuries are the leading cause of childhood injuries and result in thousands of deaths annually. However, children are at higher risk due to their increased curiosity and the time they spend at home. This study aimed to assess maternal knowledge regarding preventive measures for household injuries, including their frequency and severity., Method: Using an electronic, self-administered questionnaire, this cross-sectional study assessed the knowledge and awareness of 433 mothers of children aged 1 to 12 years in our population between March 22 and July 31, 2023. Participants' awareness levels were the main outcome., Results: Of the participants, 54% reported that their children had experienced domestic injuries. The most frequently reported injuries were falls, burns, and wounds caused by sharp objects. Moreover, more than 50% of the children needed to visit the emergency department, of whom 10% required hospitalization. Regarding the awareness level score, 55% of mothers had moderate knowledge of home-related injuries. Furthermore, attending first-aid courses and other health education programs predicted higher awareness scores among the mothers., Conclusions: More than half of the children in our study population had injuries that had occurred recently or in previous years. There was a significant discrepancy between the mothers' reported knowledge and their safety practices., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Unit of Biomedical Ethics Research Ethics Committee (REC), King Abdulaziz University issued approval 186-23. 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, Alhadrami et al.)

MicroRNAs (miRNAs) play crucial roles in physiological functions and disease, but the regulation of their nuclear biogenesis remains poorly understood. Here, BioID on Drosha, the catalytic subunit of the microprocessor complex, reveals its proximity to splicing factor proline- and glutamine (Q)-rich (SFPQ), a multifunctional RNA-binding protein (RBP) involved in forming paraspeckle nuclear condensates. SFPQ depletion impacts both primary and mature miRNA expression, while other paraspeckle proteins (PSPs) or the paraspeckle scaffolding RNA NEAT1 do not, indicating a paraspeckle-independent role. Comprehensive transcriptomic analyses show that SFPQ loss broadly affects RNAs and miRNA host gene (HG) expression, influencing both their transcription and the stability of their products. Notably, SFPQ protects the oncogenic miR-17∼92 polycistron from degradation by the nuclear exosome targeting (NEXT)-exosome complex and is tightly linked with its overexpression across a broad variety of cancers. Our findings reveal a dual role for SFPQ in regulating miRNA HG transcription and stability, as well as its significance in cancers., Competing Interests: Declaration of interests The authors declare no competing interests., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Introduction and Importance: GIST (Gastro Intestinal Stromal Tumor) treatment is surgical however surgical resection, especially for gGIST (gastric GIST), may be challenging due to location of tumor and the possible sequelae post resection., Case Presentation: We present a case of 66-year-old female presented for the management of gGIST. We opted for transgastric resection assisted by robot. The resection was with free surgical margins for a 4 cm GIST tumor low in grade., Clinical Discussion: Classical wedge resection of gastric tumors poses post-operative complications especially if the tumor is located near the cardia or pylorus. Various minimally invasive techniques were described aiming to avoid post-operative complications as in stenosis and gastric reflux., Conclusion: Minimally invasive transgastric resection of gGIST tumor seems to be worth of attention for it can prevent stenosis, hemorrhage and can preserve gastric tissue. Further studies need to be involved to endorse this technique., Competing Interests: Conflict of interest statement None., (Copyright © 2024. Published by Elsevier Ltd.)

Extracts of Salvia officinalis ( S. officinalis ) have been described to have many therapeutic properties. However, the effect of S. officinalis on copper sulfate toxicity has not been previously reported. The aim of this study was to investigate the toxicity of copper sulfate and the potential beneficial effects of S. officinalis aqueous infusion on proinflammatory response and antioxidant status. 56 male mice were used and equally divided into 6 groups: control group, copper sulfate treated group (40 mg/kg), S. officinalis aqueous infusion treated groups (200 mg/kg and 400 mg/kg) separately or in combination with copper. IL-6 (interleukine-6) and TNF-α (Tumor necrosis factor alpha) were assessed by Elisa. Catalase (CAT), superoxide dismutase (SOD) and acetylcholinesterase (AChE) activities, malondialdehyde (MDA) and oxygen peroxide levels were determined. Serum biochemical parameters were analyzed. Copper enhanced aspartate aminotransferase (AST), alanine aminotransferase (ALT) and Lactate dehydrogenase (LDH) (p < 0.05). Copper enhances significantly IL-6, TNF-α and MDA levels in liver and kidney and reduced CAT, SOD and AChE activities (p < 0.05). Aqueous infusion of S. officinalis at 400 mg/kg abolished copper-induced changes in AST and ALT activity. S. officinalis aqueous infusion at 200 mg/kg reversed copper-induced IL-6 in kidney and TNF-α in liver at both doses. S. officinalis aqueous infusion at 400 mg/kg restored SOD in kidney and CAT and AChE activities in both liver and kidney. S. officinalis aqueous infusion may be useful in partially ameliorating tissue disorders induced by copper exposure such as inflammatory response, oxidative stress imbalance and organ dysfunction through its phenolic compounds and higher antioxidant capacity.

Recent efforts to chart human brain growth across the lifespan using large-scale MRI data have provided reference standards for human brain development. However, similar models for nonhuman primate (NHP) growth are lacking. The rhesus macaque, a widely used NHP in translational neuroscience due to its similarities in brain anatomy, phylogenetics, cognitive, and social behaviors to humans, serves as an ideal NHP model. This study aimed to create normative growth charts for brain structure across the macaque lifespan, enhancing our understanding of neurodevelopment and aging, and facilitating cross-species translational research. Leveraging data from the PRIMatE Data Exchange (PRIME-DE) and other sources, we aggregated 1,522 MRI scans from 1,024 rhesus macaques. We mapped non-linear developmental trajectories for global and regional brain structural changes in volume, cortical thickness, and surface area over the lifespan. Our findings provided normative charts with centile scores for macaque brain structures and revealed key developmental milestones from prenatal stages to aging, highlighting both species-specific and comparable brain maturation patterns between macaques and humans. The charts offer a valuable resource for future NHP studies, particularly those with small sample sizes. Furthermore, the interactive open resource (https://interspeciesmap.childmind.org) supports cross-species comparisons to advance translational neuroscience research.

Optimizing fish performance depends on several factors, with dietary protein levels and rearing temperature playing important roles. In this study, Nile tilapia fingerlings (Oreochromis niloticus) weighing an average of 20.00 ± 1.26 g were divided into nine groups (in three replicates). Each group was subjected to different water temperatures (26 °C, 28 °C, and 30 °C) and received one of three dietary protein levels (20%, 25%, and 30%) for two months. Our findings indicate that higher temperatures, particularly at 30 °C, increased water electrical conductivity and total dissolved salts, especially noticeable in fish fed 25% or 30% crude protein (CP). Lower total ammonia nitrogen levels were observed at 28 °C with 25% CP, 30 °C with 30% CP, and 26 °C with 30% CP. Hepatic growth hormone receptor 1 and insulin-like growth factor 1 expression gradually rose with higher dietary CP percentages in fish at 26 °C but declined in those at 30 °C, albeit remaining higher than in the 28 °C groups with 25% CP. Fish at 28 °C showed the best final body weights and growth performance when fed 20% or 25% CP, with no significant difference between these groups. Hepatic leptin expression did not differ significantly among groups, but hepatic fatty acid binding protein expression notably increased in fish fed 30% CP at both 26 °C and 30 °C compared to those at 28 °C with 25% CP. Within the same temperature group, fish fed 30% CP exhibited higher globulin levels, particularly thriving at 28 °C or 30 °C. Hepatic mucin-like protein expression significantly increased across all groups, especially in fish at 30 °C with 30% CP compared to those at 28 °C with 25% CP. Hepatic lysozyme expression also increased notably in fish at 30 °C with 30% CP. Notable changes in superoxide dismutase, catalase, and glutathione peroxidase expression were observed, with the highest serum superoxide dismutase and catalase activities recorded in fish at 30 °C with 25% CP. Overall, dietary protein levels of 25% and 30%, combined with temperatures of 28 °C and 30 °C, yielded favorable outcomes, particularly favoring 28 °C with 25% protein., (© 2024. The Author(s).)

Single-cell analysis across multiple samples and conditions requires quantitative modeling of the interplay between the continuum of cell states and the technical and biological sources of sample-to-sample variability. We introduce GEDI, a generative model that identifies latent space variations in multi-sample, multi-condition single-cell datasets and attributes them to sample-level covariates. GEDI enables cross-sample cell state mapping on par with state-of-the-art integration methods, cluster-free differential gene expression analysis along the continuum of cell states, and machine learning-based prediction of sample characteristics from single-cell data. GEDI can also incorporate gene-level prior knowledge to infer pathway and regulatory network activities in single cells. Finally, GEDI extends all these concepts to previously unexplored modalities that require joint consideration of dual measurements, such as the joint analysis of exon inclusion/exclusion reads to model alternative cassette exon splicing, or spliced/unspliced reads to model the mRNA stability landscapes of single cells., (© 2024. The Author(s).)

This study focuses on developing a cost-effective Fe 2 O 3 catalyst from oilfield iron waste to create a floating heterogeneous photo-Fenton system with anatase/rutile(A/R) TiO 2 heterophase photocatalyst (cork-Fe 2 O 3 @A 1-x R x -TiO 2 ) for treating textile pollution in sunlight. Through controlling sol-gel (SG) microwave heating technique, the A/R ratio of A 1-x R x -TiO 2 crystal is tuned (A/R ratio = 1.13 and E g  = 3.02 eV) to improve adsorption-photocatalytic removal of anionic/cationic dyes with an apparent kinetic rate (k app ) of 0.0074 min -1 under UV-visible irradiation. The developed cork-Fe 2 O 3 @A 53.1 R 46.8 -TiO 2 floated system also outperforms the classical photo-Fenton with Fe/H 2 O 2 benchmark, showing a 2-fold enhancement in textile dye degradation (k app  = 0.216 min -1 and space-time yield (SY) of 1.7*10 -4  mol/E.g at pH 5.65) with high stability over four reuse cycles. The formation of Fe 2 O 3 @A 53.1 R 46.8 -TiO 2 Type-II heterojunction is confirmed by optical and electrochemical analyses, allowing the acceleration of direct electron transfer mechanism and oxidative degradation of dyes during photo-Fenton reaction. As a case study, the cork-Fe 2 O 3 @A 53.1 R 46.8 -TiO 2 system demonstrates a high capability for efficient mineralization of textile pollution in a real effluent, achieving 82 ± 2% reduction in the total organic contents at an operational cost of 2.61 $/kg.m 3 in sunlight. Thus, this research addresses challenges in conventional Fenton chemistry, iron waste recycling, and catalyst retention, offering new insights for sustainable treatment of textile effluents and environmental protection., 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.)

Research points to the existence of racial bias and beliefs among healthcare staff but does not explicate accounts of racialization in healthcare and the day-to-day utterances that have racializing effects excluding minoritized users' right to care. This study understands racism as structural and embedded in societies and institutions, including healthcare, as well as in interactions and talk. Through excavating accounts of healthcare staff's talk that devalues minoritized users, this study posits talk as reflective and constitutive of the dominant structure of racism within which it is situated. Drawing on qualitative interviews with 58 staff in Sweden, the study delineates three categories through which racialized talk differentiates between minoritized and majoritized users. These are: Characterizing minoritized users as 'bad' users, Characterizing minoritized users' health complaints as unworthy and finally, Devaluing minoritized users as justification for suboptimal and differential care. Healthcare staff accounts show that continuous racialization of minoritized users maintains existing power-relations representing Western users as civilized and non-Western users as uncivilized and problematic. Through reiteration, these practices of exclusion become invisible, normalized, and assume the status quo. It is imperative to address racialization as it has implications for the core ethics of healthcare., 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 Ltd.. All rights reserved.)

Introduction: In 2017, the Ministry of Health and Public Hygiene (MoH) of Burkina Faso designed and piloted a specimen transport system using the national courier services (La Poste BF) in 4 districts. Based on satisfactory performance indicators, the MoH set a vision aimed at scaling up this system to strengthen disease detection and surveillance of epidemic prone diseases across the country. This work describes the implementation process, performances, and lessons learned., Methodology: This work describes the implementation process, performances, and lessons learned. Under the leadership of the Directorate of Population Health Protection within the MoH, a stepwise approach was used to bring together multiple partners across sectors to develop the first needed documents including a guide, an implementation plan, Standard Operating Procedures, and data collection tools. Then, the execution phase included equipment purchase, trainings, and consensus on a financing mechanism. Key indicators were defined to allow performance monitoring., Result: The integrated biological specimen referral system (SITEB) was officially launched in January 2020 to transport human biological specimens of priority diseases including COVID-19 from district level to reference laboratories nationwide. As of December 31, 2022, La Poste BF transported 168,856 packages containing 206,314 specimens from all 13 regions. 99.66% of packages were delivered in <24 h as required, and 99.68% of specimens were in good condition at reception. COVID-19 specimens represented respectively 18% and 63% of samples transported in 2020 and 2021., Discussion: The political will combined with the experience gained during the pilot phase and the commitment and support from all stakeholders laid to the foundation of the effective implementation of this system. Collaboration between two government entities (MoH and Minister of Transport, Urban Mobility, and Road Safety) to benefit public health has led to reasonable pricing for sustainability. Although all documents integrate the "One Health" approach, the system ensures the transport of only human samples for now. Despite security constraints, Burkina Faso has successfully set up a system using the national postal service to ensure the routine transport of specimens for all diseases under laboratory surveillance including laboratory tests for HIV and TB from the district level to reference laboratories nationwide. This system has also proved to be useful and efficient in managing public health emergency., Competing Interests: Y-CA, MK, FT, and FA were employed by DAVYCAS International. AN was employed by Integrated Quality Laboratory Services (IQLS). The remaining 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. The reviewer AA declared a shared affiliation with the authors ED, RS, LR, AD, and RG-K to the handling editor at the time of review., (Copyright © 2024 Dama, Porgho, Ake, Yameogo, Gampini, Adjami, Nikiema, Kamate, Tarbangdo, Sawadogo, Sawadogo, Ouedraogo, Zerbo, Rahalison, Medah, Dahourou, Greco-Kone and Ake.)

Background: This study describes the utilization of the radial forearm free flap (RFFF) for the restoration of severe soft tissue deficiency involving the upper and lower eyelids in three patients., Methods: This study is a retrospective review of the senior authors' clinical records for patients who presented with periorbital defect and underwent reconstruction with RFFF between 2018 and 2022., Results: As a part of a comprehensive reconstructive surgery, we used the RFFF to deliver an ample amount of well-vascularized soft tissue. The flap's vessels were anastomosed to the ipsilateral facial vessels in all cases. Patients showed significant functional improvement, with complete eyelid closure achieved. No immediate postoperative complications were noted., Conclusions: RFFF demonstrated optimal outcomes in upper eyelid reconstruction., Competing Interests: The 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.)

Accurate quantification of transcript isoforms is crucial for understanding gene regulation, functional diversity, and cellular behavior. Existing RNA sequencing methods have significant limitations: short-read (SR) sequencing provides high depth but struggles with isoform deconvolution, whereas long-read (LR) sequencing offers isoform resolution at the cost of lower depth, higher noise, and technical biases. Addressing this gap, we introduce Multi-Platform Aggregation and Quantification of Transcripts (MPAQT), a generative model that combines the complementary strengths of different sequencing platforms to achieve state-of-the-art isoform-resolved transcript quantification, as demonstrated by extensive simulations and experimental benchmarks. By applying MPAQT to an in vitro model of human embryonic stem cell differentiation into cortical neurons, followed by machine learning-based modeling of transcript abundances, we show that untranslated regions (UTRs) are major determinants of isoform proportion and exon usage; this effect is mediated through isoform-specific sequence features embedded in UTRs, which likely interact with RNA-binding proteins that modulate mRNA stability. These findings highlight MPAQT's potential to enhance our understanding of transcriptomic complexity and underline the role of splicing-independent post-transcriptional mechanisms in shaping the isoform and exon usage landscape of the cell., Competing Interests: Competing interests The authors declare no competing interests.

In addition to the rabies virus (RABV), 16 more lyssavirus species have been identified worldwide, causing a disease similar to RABV. Non-rabies-related human deaths have been described, but the number of cases is unknown, and the potential of such lyssaviruses causing human disease is unpredictable. The current rabies vaccine does not protect against divergent lyssaviruses such as Mokola virus (MOKV) or Lagos bat virus (LBV). Thus, a more broad pan-lyssavirus vaccine is needed. Here, we evaluate a novel lyssavirus vaccine with an attenuated RABV vector harboring a chimeric RABV glycoprotein (G) in which the antigenic site I of MOKV replaces the authentic site of rabies virus (RABVG-cAS1). The recombinant vaccine was utilized to immunize mice and analyze the immune response compared to homologous vaccines. Our findings indicate that the vaccine RABVG-cAS1 was immunogenic and induced high antibody titers against both RABVG and MOKVG. Challenge studies with different lyssaviruses showed that replacing a single antigenic site of RABV G with the corresponding site of MOKV G provides a significant improvement over the homologous RABV vaccine and protects against RABV, Irkut virus (IRKV), and MOKV. This strategy of epitope chimerization paves the way towards a pan-lyssavirus vaccine to safely combat the diseases caused by these viruses.

Adult stem cells play a critical role in tissue repair and maintenance. In tissues with slow turnover, including skeletal muscle, these cells are maintained in a mitotically quiescent state yet remain poised to re-enter the cell cycle to replenish themselves and regenerate the tissue. Using a panomics approach we show that the PAX7/NEDD4L axis acts against muscle stem cell activation in homeostatic skeletal muscle. Our findings suggest that PAX7 transcriptionally activates the E3 ubiquitin ligase Nedd4L and that the conditional genetic deletion of Nedd4L impairs muscle stem cell quiescence, with an upregulation of cell cycle and myogenic differentiation genes. Loss of Nedd4L in muscle stem cells results in the expression of doublecortin (DCX), which is exclusively expressed during their in vivo activation. Together, these data establish that the ubiquitin proteasome system, mediated by Nedd4L, is a key contributor to the muscle stem cell quiescent state in adult mice., Competing Interests: The authors have no competing interests to declare., (© 2024 The Author(s).)

Social communication draws on several cognitive functions such as perception, emotion recognition and attention. The association of audio-visual information is essential to the processing of species-specific communication signals. In this study, we use functional magnetic resonance imaging in order to identify the subcortical areas involved in the cross-modal association of visual and auditory information based on their common social meaning. We identified three subcortical regions involved in audio-visual processing of species-specific communicative signals: the dorsolateral amygdala, the claustrum and the pulvinar. These regions responded to visual, auditory congruent and audio-visual stimulations. However, none of them was significantly activated when the auditory stimuli were semantically incongruent with the visual context, thus showing an influence of visual context on auditory processing. For example, positive vocalization (coos) activated the three subcortical regions when presented in the context of positive facial expression (lipsmacks) but not when presented in the context of negative facial expression (aggressive faces). In addition, the medial pulvinar and the amygdala presented multisensory integration such that audiovisual stimuli resulted in activations that were significantly higher than those observed for the highest unimodal response. Last, the pulvinar responded in a task-dependent manner, along a specific spatial sensory gradient. We propose that the dorsolateral amygdala, the claustrum and the pulvinar belong to a multisensory network that modulates the perception of visual socioemotional information and vocalizations as a function of the relevance of the stimuli in the social context. SIGNIFICANCE STATEMENT: Understanding and correctly associating socioemotional information across sensory modalities, such that happy faces predict laughter and escape scenes predict screams, is essential when living in complex social groups. With the use of functional magnetic imaging in the awake macaque, we identify three subcortical structures-dorsolateral amygdala, claustrum and pulvinar-that only respond to auditory information that matches the ongoing visual socioemotional context, such as hearing positively valenced coo calls and seeing positively valenced mutual grooming monkeys. We additionally describe task-dependent activations in the pulvinar, organizing along a specific spatial sensory gradient, supporting its role as a network regulator., (© 2024 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Aim: Fluoride-Amorphous Calcium Phosphate and Biomimetic Nano-Hydroxyapatite for Enamel Remineralization; An In-Vitro Study of Surface Microhardness and Composition., Material and Methods: Ninety-six extracted human premolars with sound buccal surface were divided using a randomization computer-generating software into four groups; Group I (control) sound untreated enamel, Group II (demineralized) demineralized to create white spot lesions, Group III (biom-n-HA) demineralized and then treated with biomimetic nanohydroxyapatite cream, and Group IV (F-ACP) demineralized and then treated using Fluoride-Amorphous Calcium Phosphate varnish. Each group was divided into two subgroups; subgroup "A" evaluated for mineral content using energy dispersive x-ray spectroscopy (EDX) and for surface microhardness using the Vickers microhardness test and Subgroup "B" evaluated for white spot lesion depth using a polarized light microscope (PLM)., Results: The highest microhardness (VHN) was found in the (F-ACP) group (mean=428.61±54.43) and then in the (Biom-n-HA) group (mean=408.11±70.16) followed by the (Control) group (mean=402.13±53.40) with no significant difference between them and finally in the significantly different (Demineralized) group (mean=256.99±45.83). The weight percentage of Ca (30.29±1.04 and 33.44±1.07) and Ca/P ratio (1.87±0.06 and 2.03±0.05) were significantly different between Group III and Group IV respectively. PLM measurements in Group II (198.83μm), Group III (60.17μm), and Group IV (26.33μm) were significantly different., Conclusions: Both the (Biom-n-HA) cream and the (F-ACP) varnish showed promising results for enamel remineralization. The increased enamel surface microhardness was consistent with the mineral content and the changes in the birefringence., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Hybrid polypyrrole (PPy) nanoparticles were prepared using a low-temperature oxidative polymerization process in an acidic solution with polyethyleneimine (PEI) as a template and amine source. The results showed that the nanoparticles have an amorphous structure in the X-ray diffractogram and exhibited good dispersibility in water, uniform size, and a specific conductivity ranging from 0.1 to 6.9 S/cm. The particle size could be tuned from 85 to 300 nm by varying the reactant concentration. Undoping the samples with sodium hydroxide (NaOH) solution altered the optical absorption properties and surface roughness of the particles. However, it did not affect the particle size. The nanoparticles also exhibited optical sensing properties based on their UV-vis absorption changes with the pH. Moreover, nanoparticles could have potential applications in gene delivery and bio-adsorption for contaminant removal. This work demonstrates a simple and effective method for preparing hybrid polypyrrole nanoparticles with controllable size, dispersibility, and conductivity for various nanotechnology, biotechnology, and environmental engineering purposes., (© 2024. The Author(s).)

Purpose: The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC)., Patients and Methods: The approval was based on the HRR gene-mutated (HRRm) population of TALAPRO-2, a randomized, double-blind trial that randomly assigned 1,035 patients with mCRPC to receive enzalutamide with either talazoparib or placebo. Two cohorts enrolled sequentially: an all-comer population (Cohort 1), followed by an HRRm-only population (Cohort 2). The independent primary end points were radiographic progression-free survival (rPFS) per blinded independent central review (BICR) in Cohort 1 (all-comers) and in the combined HRRm population (all HRRm patients from Cohorts 1 and 2). Overall survival (OS) was a key secondary end point., Results: A statistically significant improvement in rPFS by BICR was demonstrated in both the all-comers cohort and the combined HRRm population, with hazard ratio (HR) of 0.63 (95% CI, 0.51 to 0.78; P < .0001) and 0.45 (95% CI, 0.33 to 0.61; P < .0001), respectively. In an exploratory analysis of the 155 patients with BRCA -mutated ( BRCA m) mCRPC, rPFS HR was 0.20 (95% CI, 0.11 to 0.36). In the non-HRRm/unknown stratum of Cohort 1 (n = 636), the rPFS HR was 0.70 (95% CI, 0.54 to 0.89). OS was immature., Conclusion: Despite a statistically significant rPFS improvement in the all-comer cohort, FDA did not consider the magnitude of rPFS clinically meaningful in the context of the broad indication, combination treatment, and safety profile. Approval was therefore limited to patients with HRRm mCRPC, for whom there was a statistically significant and clinically meaningful improvement in rPFS and favorable OS results. This represents the first approval for the first-line treatment of patients with HRRm mCRPC.

Objectives: The purpose of this study was to assess the awareness of ototoxicity among medical doctors in Arar City, Saudi Arabia., Methods: This is a cross-sectional study based on a pre-formed validated questionnaire (Appendix) that included three sections covering participants' demographic data (three questions), their attitudes (five questions), and knowledge (13 questions) regarding drug-induced ototoxicity., Results: After obtaining their informed consent, 213 physicians from government and private sector health facilities in Arar were enrolled in the study. Interns and general practitioners represented 57.8% of the participants; consultants represented 17.8%. Only 71.8% of participants were interested in drug-induced ototoxicity, while 26.3% considered ototoxicity a rare complication. Approximately 90% of the participants were knowledgeable about the adverse effects of drugs on the vestibulocochlear system, and 26.7% reported having experienced cases of drug-induced ototoxicity in their practice. Participants showed an overall knowledge score about ototoxicity of 9.3±3.27 (out of 14). The knowledge score was significantly higher (p-value=0.0007) for participants with more years of clinical experience. The most widely known ototoxic drug for participants was frusemide (72.3%), followed by aminoglycoside (68.5%), while acetaminophen (44.1%) ototoxicity was the least known among participants., Conclusion: Awareness of drug-induced ototoxicity is satisfactory among physicians in the Northern Borders region. However, workshops about all types of drugs with ototoxic effects and the main lines for the management of drug-induced ototoxicity are recommended to increase awareness., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Elmorsy et al.)

Background Breast cancer remains a significant public health issue globally and is notably pervasive within the female population, representing a leading cause of concern. It poses a challenge across different age groups and is influenced by diverse risk factors that include genetic predispositions and various elements of lifestyle. Saudi Arabia, mirroring the global situation, has also seen its share of this disease's impact, prompting a closer look at the factors contributing to its prevalence. Educating the public and advocating for lifestyle changes are crucial steps in cancer prevention. With early-stage diagnosis and screening, many lives can potentially be saved. Our research is focused on understanding the level of awareness and preventative practices among women in the Northern Border region of Saudi Arabia. It seeks to explore the influence of familial history on knowledge and perceptions surrounding breast cancer, which could guide future educational and screening programs. Methods This cross-sectional study engaged 643 female participants, aged 18 and above, from the Northern Border region of Saudi Arabia upon their informed consent. Data were compiled via a structured questionnaire encompassing sociodemographic information, breast cancer knowledge, and preventive practices. Results The data disclosed that a significant majority (86%) recognized breast lumps as indicative of breast cancer, with 69.1% cognizant of hereditary risks. Awareness about lactation as a preventative strategy was noted in 76.7% of the participants, followed by 70.6% acknowledging the merits of a healthy diet. The study unveiled no substantial awareness disparity between individuals with or without a family history of the disease. Alarmingly, 80.4% had never sought a breast examination, and a parallel 83.7% had not undergone mammography. Conclusion The study sheds light on the heterogeneity in breast cancer awareness among women in Saudi Arabia's Northern Border region. Although the recognition of lumps and the preventative role of lactation is relatively high, there remains a deficit in comprehending additional symptoms, signs, and risk factors. The conspicuously low rates of breast cancer examinations and mammography underscore an urgent need for enhanced educational initiatives and a strategic push toward bolstering participation in regular cancer screenings., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Alanazi et al.)

Background: Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the chronic inflammation and cause of endothelial dysfunction (ED). Heart rate variability (HRV) is a marker of sympathetic and parasympathetic autonomic nervous system dysfunction. We investigated the association of lipid profile, inflammatory biomarkers, endothelial dysfunction, and heart rate variability in adolescents with T1DM among UAE population., Method: In this case-control study we recruited 126 adolescents (13-22 years) from Abu Dhabi, UAE (United Arab Emirates). Demographic, anthropometric, blood and urine samples were collected after an overnight fasting. HRV measurements were determined per Task Force recommendations. Independent t -test or Mann-Whitney U test and Pearson's Chi-squared test were used to compare groups. Adjusted conditional logistic regression model was used to identify the determinants independently associated with T1DM., Results: The mean ages in control (n = 47) and patient (n = 79) groups were 17.5 ± 4.6 and 18.6 ± 4.8 years, respectively. A family history of diabetes and waist and hip circumferences significantly differed between the groups (p = 0.030 and 0.010). The patients with T1DM exhibited significantly higher levels of atherogenic markers than control. Endothelial dysfunction biomarkers such as levels of sICAM-1 (p < 0.001), adiponectin (p < 0.001) and 25-hydroxyvitamin D (p < 0.001) were significantly different in the control group compared with those in the T1DM group. There was a significant difference in SDNN intervals, NN50, pNN50, and SD1/SD2 among the two groups. In adjusted analysis, total cholesterol (adjusted Odds Ratio (aOR): 2.78, 95 % CI:1.37-5.64; p = 0.005), LDL (2.66, 95%CI:1.19-5.92; p = 0.017), and triglycerides (5.51, 95%CI:1.57-19.41; p = 0.008) were significantly associated with developing T1DM. The HRV indicators were significantly associated with decrease odds of T1DM after controlling for SBP, BMI, and family history of DM., Conclusion: In this study, adolescents with T1DM showed a significant association with lipid profile, ED, and HRV compared with controls. Thus, an early attention to diabetes control is required to reduce the risk of cardiac autonomic neuropathy leading to various cardiovascular diseases., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Elhadi H. Aburawi reports financial support was provided by SHEIKH HAMDAN BIN RASHID AL MAKTOUM AWARD FOR MEDICAL SCIENCES. If there are other authors, they 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 The Authors.)

Purpose: The US Food and Drug Administration (FDA) approved elacestrant for the treatment of postmenopausal women or adult men with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), estrogen receptor 1 ( ESR1 )-mutated advanced or metastatic breast cancer with disease progression after at least one line of endocrine therapy (ET)., Patients and Methods: Approval was based on EMERALD (Study RAD1901-308), a randomized, open-label, active-controlled, multicenter trial in 478 patients with ER+, HER2- advanced or metastatic breast cancer, including 228 patients with ESR1 mutations. Patients were randomly assigned (1:1) to receive either elacestrant 345 mg orally once daily (n = 239) or investigator's choice of ET (n = 239)., Results: In the ESR1- mut subgroup, EMERALD demonstrated a statistically significant improvement in progression-free survival (PFS) by blinded independent central review assessment (n = 228; hazard ratio [HR], 0.55 [95% CI, 0.39 to 0.77]; P value = .0005). Although the overall survival (OS) end point was not met, there was no trend toward a potential OS detriment (HR, 0.90 [95% CI, 0.63 to 1.30]) in the ESR1 -mut subgroup. PFS also reached statistical significance in the intention-to-treat population (ITT, N = 478; HR, 0.70 [95% CI, 0.55 to 0.88]; P value = .0018). However, improvement in PFS in the ITT population was primarily attributed to results from patients in the ESR1 -mut subgroup. More patients who received elacestrant experienced nausea, vomiting, and dyslipidemia., Conclusion: The approval of elacestrant in ER+, HER2- advanced or metastatic breast cancer was restricted to patients with ESR1 mutations. Benefit-risk assessment in the ESR1- mut subgroup was favorable on the basis of a statistically significant improvement in PFS in the context of an acceptable safety profile including no evidence of a potential detriment in OS. By contrast, the benefit-risk assessment in patients without ESR1 mutations was not favorable. Elacestrant is the first oral estrogen receptor antagonist to receive FDA approval for patients with ESR1 mutations.

The plant homeodomain zinc-finger protein, PHF6, is a transcriptional regulator, and PHF6 germline mutations cause the X-linked intellectual disability (XLID) Börjeson-Forssman-Lehmann syndrome (BFLS). The mechanisms by which PHF6 regulates transcription and how its mutations cause BFLS remain poorly characterized. Here, we show genome-wide binding of PHF6 in the developing cortex in the vicinity of genes involved in central nervous system development and neurogenesis. Characterization of BFLS mice harbouring PHF6 patient mutations reveals an increase in embryonic neural stem cell (eNSC) self-renewal and a reduction of neural progenitors. We identify a panel of Ephrin receptors (EphRs) as direct transcriptional targets of PHF6. Mechanistically, we show that PHF6 regulation of EphR is impaired in BFLS mice and in conditional Phf6 knock-out mice. Knockdown of EphR-A phenocopies the PHF6 loss-of-function defects in altering eNSCs, and its forced expression rescues defects of BFLS mice-derived eNSCs. Our data indicate that PHF6 directly promotes Ephrin receptor expression to control eNSC behaviour in the developing brain, and that this pathway is impaired in BFLS., (© 2024. The Author(s).)

Propionibacterium acnes plays a critical role in the development of acne vulgaris. There has been a rise in the number of patients carrying P. acnes strains that are resistant to antibiotics. Thus, alternative anti-microbial agents are required. Zinc oxide (ZnO-NPs) and silver (Ag-NPs) nanoparticles can be used against several antibiotic-resistant bacteria. The impact of Ag-NPs and ZnO-NPs against two clinical strains of P. acnes , P1 and P2, and a reference strain, NCTC747, were investigated in this research. A chemical approach for the green synthesis of Ag-NPs and ZnO-NPs from Peganum harmala was employed. The microtiter plate method was used to examine the effects of NPs on bacterial growth, biofilm development, and biofilm eradication. A broth microdilution process was performed in order to determine minimal inhibitory (MIC) concentrations. Ag-NPs and ZnO-NPs had a spherical shape and average dimensions of 10 and 50 nm, respectively. MIC values for all P. acnes strains for Ag-NPs and ZnO-NPs were 125 µg/mL and 250 µg/mL, respectively. Ag-NP and ZnO-NP concentrations of 3.9- 62.5 µg/mL and 15-62.5 µg/mL significantly inhibited the growth and biofilm formation of all P. acnes strains, respectively. ZnO-NP concentrations of 15-62.5 μg/mL significantly inhibited the growth of NCTC747 and P2 strains. The growth of P1 was impacted by concentrations of 31.25 μg/mL and 62.5 μg/mL. Biofilm formation in the NCTC747 strain was diminished by a ZnO-NP concentration of 15 μg/mL. The clinical strains of P. acnes were only affected by ZnO-NP titres of more than 31.25 μg/mL. Established P. acne biofilm biomass was significantly reduced in all strains at a Ag-NP and ZnO-NP concentration of 62.5 µg/mL. The findings demonstrated that Ag-NPs and ZnO-NPs exert an anti-bacterial effect against P. acnes . Further research is required to determine their potential utility as a treatment option for acne.

Purpose: This article summarizes the US Food and Drug Administration (FDA) review of the data leading to approval of olaparib plus abiraterone for the treatment of patients with deleterious or suspected deleterious BRCA -mutated ( BRCA m) metastatic castration-resistant prostate cancer (mCRPC), as determined by an FDA-approved companion diagnostic test., Patients and Methods: Approval was based on the results from PROpel, a double-blind trial that randomly assigned 796 patients with mCRPC to abiraterone plus prednisone or prednisolone with either olaparib or placebo. The primary end point was radiographic progression-free survival (rPFS) per investigator assessment., Results: There was a statistically significant improvement in rPFS for olaparib plus abiraterone versus placebo plus abiraterone, with a median rPFS of 25 versus 17 months and a hazard ratio (HR) of 0.66 (95% CI, 0.54 to 0.81) in the intention-to-treat population. In an exploratory analysis of the subgroup of 85 patients with BRCA m mCRPC, the HR for rPFS was 0.24 (95% CI, 0.12 to 0.45) and the HR for overall survival (OS) was 0.30 (95% CI, 0.15 to 0.59). In an exploratory analysis of the subgroup of 711 patients without an identified BRCA mutation, the HR for rPFS was 0.77 (95% CI, 0.63 to 0.96) and the HR for OS was 0.92 (95% CI, 0.74 to 1.14). Adding olaparib to abiraterone resulted in increased toxicity, including anemia requiring transfusion in 18% of patients., Conclusion: In patients with mCRPC, efficacy of the combination of olaparib plus abiraterone was primarily attributed to the treatment effect in the BRCA m subgroup, the indicated population for the approval. For patients without BRCA m, the FDA determined that the modest rPFS improvement, combined with clinically significant toxicities, did not demonstrate a favorable risk/benefit assessment.

Visual attention can be guided by statistical regularities in the environment, that people implicitly learn from past experiences (statistical learning, SL). Moreover, a perceptually salient element can automatically capture attention, gaining processing priority through a bottom-up attentional control mechanism. The aim of our study was to investigate the dynamics of SL and if it shapes attentional target selection additively with salience processing, or whether these mechanisms interact, e.g. one gates the other. In a visual search task, we therefore manipulated target frequency (high vs. low) across locations while, in some trials, the target was salient in terms of colour. Additionally, halfway through the experiment, the high-frequency location changed to the opposite hemifield. EEG activity was simultaneously recorded, with a specific interest in two markers related to target selection and post-selection processing, respectively: N2pc and SPCN. Our results revealed that both SL and saliency significantly enhanced behavioural performance, but also interacted with each other, with an attenuated saliency effect at the high-frequency target location, and a smaller SL effect for salient targets. Concerning processing dynamics, the benefit of salience processing was more evident during the early stage of target selection and processing, as indexed by a larger N2pc and early-SPCN, whereas SL modulated the underlying neural activity particularly later on, as revealed by larger late-SPCN. Furthermore, we showed that SL was rapidly acquired and adjusted when the spatial imbalance changed. Overall, our findings suggest that SL is flexible to changes and, combined with salience processing, jointly contributes to establishing attentional priority., 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.)

Objectives: To compare the complications associated with cannulated hip screws (CHS) and dynamic hip screws (DHS) techniques., Methods: In this multicenter retrospective chart study, we reviewed the records and data of all patients operated upon by DHS or CHS for treatment of Garden type I and type II intracapsular non-displaced femoral neck fracture from January 2017 to December 2022. Patients with incomplete files or follow-ups of less than one year were excluded from the study., Results: The study enrolled 85 patients, 35 males, and 50 females, with a mean age of 72±5.4 for males and 70.6±7.6 for females. A total of 44 patients were operated upon with DHS, and 41 patients with CHS. The mortality rate of DHS was 15.9% and was 17.1% in the CHS group ( p >0.05). Non-union was recorded in 4.5% of the DHS group and 4.9% of CHS patients ( p >0.05). Avascular necrosis (AVN) was significantly higher in DHS (9.1%) than in CHS (4.9%, p <0.05). A revision was required in 15.9% of DHS patients and 14.6% of CHS patients ( p >0.05)., Conclusion: This study found that DHS was superior to CHS in AVN rate. However, there was no significant difference between both methods regarding mortality, revision, and non-union., (Copyright: © Saudi Medical Journal.)

Arid and semi-arid regions are characterised by extreme conditions including drought stress and salinity. These factors profoundly affect the agricultural sector. The objective of this work is to study the effect of drought and re-watering on leaf gas exchange, chlorophyll fluorescence and mineral nutrition in Pistacia vera and Pistacia atlantica . Water stress was applied to individuals of P. vera and P. atlantica for 23days, followed by rehydration for 7days. The results showed a clear reduction in water relations, leaf gas exchange and chlorophyll content in P. vera . Compared to P. vera , P. atlantica maintained less affected water status, total chlorophyll content, leaf gas exchange and chlorophyll fluorescence, stable Zn and Fe proportion, and even elevated K and Cu. The changes in the chlorophyll fluorescence parameter were manifested particularly at the maximal fluorescence (Fm). In contrast, no change was recorded at the minimal fluorescence (F0). After re-hydration, although water status was fully recovered in both species, stomatal conductance (gs), net photosynthesis (A ) and transpiration rate (E ) remain with lower values than the well-watered seedlings. P. atlantica was better adapted to drought stress than P. vera .

Background: Modified Release (MR) orally administered drugs products [Extended-Release (ER) and Delayed-Release (DR)] differ from Immediate-Release (IR) drug products in their drug release site and/or rate to offer therapeutic advantages. It is important to understand the biopharmaceutics factors that determine how a drug works in the gastrointestinal tract and the various pharmacokinetic properties that determine a drug's rate of absorption and release in the human body. To better understand the biopharmaceutics characteristics of ER and DR drug products, this study retrospectively analyzed submissions approved by the US Food and Drug Administration (FDA), from 2001 to 2021, and their corresponding review documents. This review work is expected to enhance the readers' understanding regarding the biopharmaceutics properties that supported approval of these products' ER claims, as per 21 CFR 320.25(f), and DR claims., Methods: A comprehensive search was conducted using the FDA's internal New Drug Application (NDA) database for ER and DR oral drug products approved between 2001 and 2021. The search yielded 87 ER applications (23 ER capsules and 64 ER tablets) and 21 DR applications (10 DR capsules, 11 DR tablets) for which electronic records were accessible. These products were analyzed for overall drug product design, dosing frequency compared to the reference (if applicable), degree of fluctuation, dissolution method, and alcohol dose-dumping., Results: Out of 87 total applications for ER drug products that were assessed, 62% of the ER tablets contained a polymer matrix formulation, and hypromellose (HPMC) was used in 50% of these products. 52% of the ER capsules consisted of polymer beads while about half of the DR drug products contained a non-bead formulation with a combination of polymers. The majority of ER drug products were found to have a reduction in dosing frequency and a decrease in the degree of fluctuation when compared to the IR reference product. The 13 ER drug products that exhibited an increase in degree of fluctuation exhibited general and pharmacodynamic benefits, such as reduced dosing frequency and reduced pill burden. The majority of DR formulations were developed to prevent drug degradation in the stomach, followed by to decrease potential stomach irritation, and lastly for localized release in the colon. The majority of ER drug products had 1:1 ratios of dissolution duration compared to dosing frequency (i.e., the majority of ER drug products had a dissolution duration of 24 h and were dosed every 24 h while those with a dissolution duration of 12 h were dosed every 12 h). The majority of ER applications had single-stage dissolution methods while most DR drug products used biphasic dissolution methods. All of the DR dissolution methods incorporated an acid stage of 2 h and a buffer stage with various timeframes. 53% the DR drug products had a ratio of dissolution duration to dosing frequency of 1:4 (e.g. a dissolution duration of 2 h to a dosing frequency of 8 h) or 1:8 (e.g. a dissolution duration of 2 h to a dosing frequency of 16 h). Of the ER tablets and DR drug products, 72% exhibited no alcohol dose-dumping under in vitro testing conditions. ER capsules, however, did not yield similar results-most of which exhibited alcohol induced dose-dumping. Alcohol dose dumping was mitigated by either in vivo studies or warnings on the drug product label., Conclusion: The results of this study help the reader understand the design, characteristics, and pharmacological advantages of the ER and DR drug products for patient benefit; as well as the regulations governing the FDA's assessment of ER claims., 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., (Published by Elsevier B.V.)

The present study aims to investigate how the competition between visual elements is solved by top-down and/or statistical learning (SL) attentional control (AC) mechanisms when active together. We hypothesized that the "winner" element that will undergo further processing is selected either by one AC mechanism that prevails over the other, or by the joint activity of both mechanisms. To test these hypotheses, we conducted a visual search experiment that combined an endogenous cueing protocol (valid vs. neutral cue) and an imbalance of target frequency distribution across locations (high- vs. low-frequency location). The unique and combined effects of top-down control and SL mechanisms were measured on behaviour and amplitudes of three evoked-response potential (ERP) components (i.e., N2pc, P1, CNV) related to attentional processing. Our behavioural results showed better performance for validly cued targets and for targets in the high-frequency location. The two factors were found to interact, so that SL effects emerged only in the absence of top-down guidance. Whereas the CNV and P1 only displayed a main effect of cueing, for the N2pc we observed an interaction between cueing and SL, revealing a cueing effect for targets in the low-frequency condition, but not in the high-frequency condition. Thus, our data support the view that top-down control and SL work in a conjoint, integrated manner during target selection. In particular, SL mechanisms are reduced or even absent when a fully reliable top-down guidance of attention is at play., (© 2023. The Author(s).)

Diabetes mellitus is a common metabolic disorder. About two-thirds of diabetic patients develop diabetic cardiomyopathy (DCM), which becomes a challenging issue as it severely threatens the patient's life. Hyperglycemia and the resulting advanced glycated end products (AGE) and their receptor (RAGE)/High Mobility Group Box-1 (HMGB-1) molecular pathway are thought to be key players. Recently, artemisinin (ART) has gained more attention owing to its potent biological activities beyond its antimalarial effect. Herein, we aim to evaluate the effect of ART on DCM and the possible underlying mechanisms. Twenty-four male Sprague-Dawley rats were divided into: control, ART, type 2 diabetic and type 2 diabetic treated with ART groups. At the end of the research, the ECG was recorded, then the heart weight to body weight (HW/BW) ratio, fasting blood glucose, serum insulin and HOMA-IR were evaluated. Cardiac biomarkers (CK-MB and LDH), oxidative stress markers, IL-1β, AGE, RAGE and HMGB-1 expression were also measured. The heart specimens were stained for H&E as well as Masson's trichrome. DCM induced disturbances in all studied parameters; contrary to this, ART improved these insults. Our study concluded that ART could improve DCM through modulation of the AGE-RAGE/HMGB-1 signaling pathway, with subsequent impacts on oxidative stress, inflammation and fibrosis. ART could therefore be a promising therapy for the management of DCM., (© 2023. The Author(s).)

In light of the numerous studies identifying post-transcriptional regulators on the surface of the endoplasmic reticulum (ER), we asked whether there are factors that regulate compartment specific mRNA translation in human cells. Using a proteomic survey of spatially regulated polysome interacting proteins, we identified the glycolytic enzyme Pyruvate Kinase M (PKM) as a cytosolic (i.e. ER-excluded) polysome interactor and investigated how it influences mRNA translation. We discovered that the PKM-polysome interaction is directly regulated by ADP levels-providing a link between carbohydrate metabolism and mRNA translation. By performing enhanced crosslinking immunoprecipitation-sequencing (eCLIP-seq), we found that PKM crosslinks to mRNA sequences that are immediately downstream of regions that encode lysine- and glutamate-enriched tracts. Using ribosome footprint protection sequencing, we found that PKM binding to ribosomes causes translational stalling near lysine and glutamate encoding sequences. Lastly, we observed that PKM recruitment to polysomes is dependent on poly-ADP ribosylation activity (PARylation)-and may depend on co-translational PARylation of lysine and glutamate residues of nascent polypeptide chains. Overall, our study uncovers a novel role for PKM in post-transcriptional gene regulation, linking cellular metabolism and mRNA translation., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Identifying the evolutionary origins of human speech remains a topic of intense scientific interest. Here we describe a unique feature of adult human neuroanatomy compared to chimpanzees and other primates that may provide an explanation of changes that occurred to enable the capacity for speech. That feature is the Prefrontal extent of the Frontal Operculum (PFOp) region, which is located in the ventrolateral prefrontal cortex, adjacent and ventromedial to the classical Broca's area. We also show that, in chimpanzees, individuals with the most human-like PFOp, particularly in the left hemisphere, have greater oro-facial and vocal motor control abilities. This critical discovery, when combined with recent paleontological evidence, suggests that the PFOp is a recently evolved feature of human cortical structure (perhaps limited to the genus Homo) that emerged in response to increasing selection for cognitive and motor functions evident in modern speech abilities., (© 2023. The Author(s).)

An educational intervention, based on qualitative evidence of racism in healthcare, is described. Using vignettes from a previous project, interviews were conducted to gather qualitative evidence of racism in healthcare settings from a wide range of healthcare staff in Sweden. From this interview material, case studies were devised that were subsequently presented to trainee healthcare professionals, in a seminar discussion. After the seminar, trainees responded to reflective questions. The order of work, as well as the materials used, are described. This intervention was successful in facilitating discussion about racism in an educational context, despite the difficult nature of these conversations for some participants.

The high antibiotic resistance of Pseudomonas aeruginosa (PA) makes it critical to develop alternative antimicrobial agents that are effective and affordable. One of the many applications of silver nanoparticles (Ag NPs) is their use as an antimicrobial agent against bacteria resistant to common antibiotics. The key purpose of this research was to assess the antibacterial and antibiofilm effectiveness of biosynthesized Ag NPs against six biofilm-forming clinically isolated strains of PA and one reference strain (ATCC 27853). Ag NPs were biosynthesized using a seed extract of Peganum harmala as a reducing agent. Ag NPs were characterized by Ultraviolet-visible (UV-Vis) spectroscopy and scanning transmission electron microscopy (STEM). The effect of Ag NPs on biofilm formation and eradication was examined through micro-titer plate assays, and the minimal inhibitory (MIC) and minimum bactericidal (MBC) concentrations determined. In addition, real-time polymerase chain reactions (RT-PCR) were performed to examine the effects of Ag NPs on the expression of seven PA biofilm-encoding genes (LasR, LasI, LssB, rhIR, rhII, pqsA and pqsR). The biosynthesized Ag NPs were spherically-shaped with a mean diameter of 11 nm. The MIC for each PA strain was 15.6 µg/ml, while the MBC was 31.25 µg/ml. All PA strains exposed to Ag NPs at sub-inhibitory concentrations (0.22-7.5 µg/ml) showed significant inhibitory effects on growth and biofilm formation. Biomass and biofilm metabolism were reduced dependent on Ag NP concentration. The expression of the quorum-sensing genes of all strains were significantly reduced at an Ag NP concentration of 7.5 µg/ml. The results demonstrate the extensive in-vitro antibacterial and antibiofilm performance of Ag NPs and their potential in the treatment of PA infection. It is recommended that future studies examine the possible synergy between Ag NPs and antibiotics., (© 2023. The Author(s).)

Aim: The aim is to illustrate and analyse reflections from graduate nursing students over their experience of discussing racism in healthcare in an educational intervention., Design: A qualitative, descriptive design was adopted., Methods: Data were collected through written reflections and analysed through content analysis. In total, 81 students participated in the intervention; 39 paediatric and 42 public health care nursing students. Of those, 27 participants gave consent to have their written reflections included in the study., Results: Three main categories were developed in the content analysis of student reflections: (a) the implicit embeddedness of racism in healthcare organization; (b) the effect of racism on interactions with patients; and (c) a growing awareness of one's own understanding of racism. This study indicates that student nurses discussed racism as relevant to understanding good clinical practice for the benefit of patients and work-based wellbeing of staff. This recognition of the organizational nature of racism warrants nursing leaders and managers to include racism as a social determinant of health in the undergraduate and graduate curricula to educate the next generation of nursing about racism., (© 2023 The Authors. Nursing Open published by John Wiley & Sons Ltd.)