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Single sign-on (SSO), tap-on-tap-off (TOTO) and virtual desktops (VD) are increasingly being used in hospitals to reduce the burden and risks of password management, but we know little about how these systems are used in practice. We aimed to understand whether, and if so, how and why a TOTO and VD solution supported clinical work in an emergency department (ED). Qualitative descriptive design comprising interviews (n = 17) and work observations (~ 7 h) with doctors and nurses in an Australian ED. Data collection and analysis were informed by the unified theory of acceptance and use of technology (UTAUT). Some participants perceived the TOTO-VD system as useful, however, most questioned the value of the system for ED work. Time to login was relatively long for the needs of the ED, which contributed to the system not being used as intended. Workarounds led to users being automatically logged out mid-task, which further contributed to clinicians' negative experience with the system. There appeared to be limited use for, and potentially new risks introduced with a VD solution, where ED clinicians perceived there to be redundant control of access to computers. The ED work context presented barriers to TOTO-VD adoption. The system did not support clinical work in an ED and so was worked around by clinicians. We recommend examining and understanding clinician work, including when and how computers are used and what systems are accessed, prior to implementation of any technological solution. Not applicable.

We report the case of a high-risk patient with candidemia and obstructive uropathy caused by renal fungal balls. Initial management with systemic antifungals and stenting was insufficient. Given the patient's dual antiplatelet therapy, we opted for flexible ureterorenoscopy utilizing a bendable ureteral access sheath with an integrated suction device. This enabled in toto removal of fungal balls and efficient clearance of a concomitant stone using laser lithotripsy. To our knowledge, this is the first report demonstrating in toto removal of renal fungal balls using suction-assisted URS in a high-risk patient, offering a minimally invasive alternative to PNL.

Tonsil stones or tonsilloliths are mineralised concretions in the crypts of palatine tonsils. They are usually small and asymptomatic. Sometimes, they can be recurrent, large in size and produce symptoms like a sense of foreign body in throat, mild pain and heaviness in throat and halitosis. In such cases, a surgical intervention may be required for permanent cure. We came across one such patient with massive tonsillolith which mimicked a peritonsillar abscess initially. Eventually, the large tonsillolith was surgically removed in toto. It measured 5.2 × 2.5 × 2.5 cm which makes it the largest tonsillar stone ever to be successfully removed till date.

Angiomyxoma is a rare, benign mesenchymal tumor rarely encountered in the infantile hard palate. This case report describes the presentation, diagnostic workup, and successful management of an angiomyxoma in an 11-month-old male infant. An 11-month-old male was presented to the ENT department with a slowly enlarging, asymptomatic palatal swelling first noticed at 9 months of age. Intraoral examination revealed a 2 cm × 2 cm, soft, nontender mass on the anterior hard palate. A contrast-enhanced computed tomography scan identified a well-defined, oval, heterogeneously enhancing cystic lesion (8 mm × 15 mm × 18 mm) with no bony erosion. The patient underwent complete surgical excision under general anesthesia. The lesion was excised in toto via an intraoral approach, revealing a well-encapsulated, gelatinous mass. Histopathological examination confirmed the diagnosis of angiomyxoma, showing spindle cells in a myxoid stroma with numerous thin-walled vessels. The postoperative course was uneventful, and the child resumed feeding normally. At the 6-month follow-up, there was no evidence of recurrence, and both functional and cosmetic outcomes were excellent. This case underscores that angiomyxoma, though rare, should be considered in the differential diagnosis of pediatric palatal masses. A combination of cross-sectional imaging and complete surgical excision is the cornerstone of management, leading to a favorable prognosis with low recurrence risk. RésuméL’angiomyxome est une tumeur mésenchymateuse rare et bénigne, exceptionnellement rencontrée au niveau du palais dur chez le nourrisson. Ce rapport de cas décrit la présentation clinique, le bilan diagnostique et la prise en charge chirurgicale réussie d’un angiomyxome chez un nourrisson de 11 mois de sexe masculin. Le patient a été adressé au service d’oto-rhino-laryngologie pour une tuméfaction palatine d’évolution progressive et asymptomatique, remarquée pour la première fois à l’âge de 9 mois. L’examen endobuccal a mis en évidence une masse de 2 cm × 2 cm, souple et indolore, localisée au niveau du palais dur antérieur. Une tomodensitométrie avec injection de produit de contraste a objectivé une lésion kystique bien limitée, ovalaire, à rehaussement hétérogène (8 mm × 15 mm × 18 mm), sans lyse osseuse associée. Le patient a bénéficié d’une exérèse chirurgicale complète sous anesthésie générale par voie endobuccale, permettant l’ablation en monobloc d’une masse bien encapsulée à contenu gélatineux. L’examen anatomopathologique a confirmé le diagnostic d’angiomyxome, révélant une prolifération de cellules fusiformes au sein d’un stroma myxoïde richement vascularisé par de nombreux vaisseaux à paroi fine. Les suites opératoires ont été simples, avec une reprise rapide de l’alimentation. Au recul de six mois, aucune récidive n’a été constatée, avec d’excellents résultats fonctionnels et esthétiques. Ce cas souligne que l’angiomyxome, bien que rare, doit être intégré dans le diagnostic différentiel des masses palatines pédiatriques. L’association d’une imagerie en coupe et d’une exérèse chirurgicale complète constitue le pilier de la prise en charge, offrant un pronostic favorable avec un faible risque de récidive.

Treatment with immune checkpoint inhibitors in colorectal cancer (CRC) has largely benefited patients with microsatellite instability-high (MSI-H) and not the larger proportion of patient with microsatellite-stable (MSS) tumors. This clinical dichotomy has fueled the view that high mutational burden is the dominant driver of tumor immunogenicity and that MSS CRC fails to respond because it is "antigen poor". To directly test this premise and define the origins of presented tumor antigens, we integrated HLA class I immunopeptidomics and matched RNA-seq from 26 primary CRC tumors spanning MSI-H and MSS subtypes. Using patient-specific canonical and cancer-specific proteogenomic databases, we identified 115,292 unique major histocompatibility complex (MHC)-associated peptides (MAPs) across 61 HLA alleles, with a mean of 9292 MAPs per tumor and no significant difference in MAP counts between MSI-H and MSS tumors. In toto, we identified 266 tumor antigens, all coded by unmutated genomic sequences, comprising 70 aberrantly expressed tumor-specific antigens (aeTSAs) and 196 tumor-associated antigens (TAAs). In our cohort, MSS tumors presented more TAAs and a comparable number of aeTSAs per tumor relative to MSI-H tumors. In TCGA-COAD stratified analyses (483 tumors), MSS tumors yielded more presentable aeTSAs and TAAs per patient than MSI-H tumors. Across both subtypes, aeTSAs arose predominantly from intronic translation, UTR usage, retroelement activation, and germline-like transcription, including recurrent aeTSAs from PIWIL1, L1TD1, and endogenous retroviral loci. Together, these data demonstrate that MSS CRC is not antigen poor and highlight noncanonical translation as a major, previously underappreciated contributor to the CRC immunopeptidome.

Malignant peripheral nerve sheath tumour (MPNST) is a rare, aggressive sarcoma with high mortality. MPNST can develop sporadically, after radiation therapy or in association with neurofibromatosis type 1 (NF1). The treatment is challenging especially if surgical removal is not possible. NF1 is an autosomal-dominant genetic disorder most often caused by a germline pathogenic variant in the NF1 gene and in rare cases a deletion of the NF1 gene. Patients with NF1 have a higher risk of developing several different cancers, of which MPNST is one of the most frequent. MPNST in individuals with NF1 often presents with large MPNST which are often not accessible for surgery. Several studies have shown that patients with NF1-associated MPNST (nfMPNST) have an overall inferior survival than those with sporadic MPNST (sMPNST). Despite this, NF1 status alone may not be a causative factor for poor prognosis, which might rather be due to the incidence of larger tumours, which are more challenging to resect in toto. A systematic research protocol was made using the PRISMA-P model and the review question and inclusion and exclusion criteria were defined using the PICO model. The study characteristics defined by PICO include patients with NF1 as the population of interest. The development of MPNST was considered as the intervention, patients with sMPNST were chosen for comparison and the primary outcome of interest was survival. The literature search was performed on 12 October 2024 and 4,394 studies were eligible for screening, of which 36 studies were included in this study. Meta-analysis of eight studies found NF1 status to be a risk factor for the survival of MPNST. The reported survival rates varied between studies, but the 5-year overall survival (OS) remained poor in general, Awith 15 studies showing a significantly inferior survival for nfMPNST. Only four studies have a worse survival for sMPNST, but none with a significant difference. The findings in this systematic review and meta-analysis of 36 studies indicates that patients with nfMPNST have a worse survival compared to sMPNST.

In the Forensic Collection of the Institute of Forensic Medicine in Belgrade there is an autopsy specimen of a man who underwent total reconstruction of the penis he had previously lost due to war injury, collected in the year 1929 by Professor Milovan Milovanović (1884-1948). The museum exhibit No. 453, labeled as Penis Arteficialis, is a specimen of in toto dissected male pubic region, including the grossly altered male external genitalia - the mechanical injury that completely destroyed the penis was partially overcome by a procedure of total phalloplasty: abdominal skin flap was used to create a bulky phalloid structure, with autologous rib cartilage fragment incorporated in its proximal part to provide sufficient rigidity for sexual intercourse. The procedure left an acquired hypospadia, since its inherent limitation was the inability to reconstruct the urethra through the artificial penis. The unaltered autopsy specimen was analyzed using multi-detector computed tomography and magnetic resonance imaging to reveal the complete anatomy of the pioneering total phalloplasty, while preserving the museum specimen. So, we demonstrated the essential elements of what was a successful reconstructive procedure of the time: the artificial penis with cartilage proximally embedded into the root portion of the erectile tissue, enabling stimulation, arousal, and rigidity, and the unobstructed urethra that opened on the skin below the neophallus. Milovanović sought to preserve this achievement in reconstructive surgery, and today, with imaging, we can directly observe the pioneering surgical approach to total penile reconstruction, appreciating its achievements and limitations in terms of morphology.

This article explores the cognitive foundations of Chinese writing by analyzing the earliest attestations on oracle bone and bronze inscriptions from the Late Shang (1250-1045 BCE) to the Western Zhou (1045-771 BCE) periods. Integrating palaeographic and cognitive perspectives, we show that metaphorical and metonymic devices of the visual type, through visual emphasis on key configurations (such as pars pro toto), conceptual extension of meaning, and organization of iconic core components, were crucial in shaping and anchoring the visual and semiotic architecture of the script. These cognitive mechanisms reveal a primacy of the visual structure of the script, supported by neuroscientific evidence of direct orthography-to-semantics mapping, with phonology acting only as a secondary refining mechanism. These findings challenge traditional phonocentric models of writing evolution and illustrate an internal developmental trajectory grounded on visual metaphor and metonymy that confirms, at last, the independent invention of Chinese writing.

The use of programmable nucleases has transformed genome editing and functional genomics. Clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) was developed such that targeted genomic lesions [usually DNA double-stranded breaks (DSBs)] could be introduced in vivo with ease and precision. In the presence of homology donors, these lesions facilitate high-efficiency precise genome editing (PGE) via homology-directed repair (HDR) pathways. Because DSBs can lead to genomic instability, however, a large amount of effort has been invested in methodologies (e.g., base editors) that only require nicking the chromosomal DNA on one strand. Indeed, we have demonstrated in human cells that oligodeoxynucleotide (ODN)-mediated PGE using nickase variants of Cas9 can proceed by at least two HDR subpathways termed synthesis-dependent strand annealing (SDSA) and single-stranded DNA incorporation (ssDI). Which pathway is utilized is determined by which chromosomal strand (sense or anti-sense/Watson or Crick) is nicked and by the strandedness (sense or anti-sense/Watson or Crick) of the donor ODN. While the mechanism of mammalian SDSA is moderately well understood, that of ssDI is not. To gain genetic insight into ssDI, we carried out a genome-wide CRISPR knockout screen to identify those genes which, when absent, enable increased ssDI. This screen identified the protein lysine methyl transferase (PKMT) Su(var)3-9, enhancer-of-zeste and trithorax (SET) domain bifurcated histone lysine methyltransferase 1 (SETDB1):activating transcription factor 7-interacting protein (ATF7IP) heterodimer and the downstream human silencing hub (HUSH) complex as strong negative regulators of ssDI. Consistent with their well-known biological effects, the negative regulation of ssDI by SETDB1/ATF7IP and HUSH was specific for transgenic reporters and for a HUSH-regulated single-copy gene, but was not observed at other (non-HUSH regulated) single-copy endogenous loci. In toto, these experiments underscore the profound impact that chromatin modifiers - and by extension, chromatin structure - have on PGE outcomes. Specifically, we have identified SETDB1/ATF7IP and the HUSH complex as major negative regulators of the HDR subpathway, ssDI, when the target is a transgene. These experiments are a proof-of-principle that chromatin can act as a potent barrier to genetic recombination and they strongly support the feasibility of extending similar chromatin modulating strategies to enhance PGE efficiency at endogenous single-copy loci.

Air pollution is the biggest environmental factor impacting the health of people worldwide contributing significantly to mortality. This study has been conducted to investigate the strategies of air pollution policies suggested by multilateral organisations to mitigate the adverse impact of air pollution on populations' health. This study was a qualitative document analysis of health policies and strategies related to air pollution. For this purpose, READ's 4-step approach (Ready material, Extract findings, Analyse data and Distil findings) was used. This approach entails systematic method for collating documents and extracting information from them. This was done with respect to air pollution and health policy studies at global, national and local levels. After extraction of related documents, the content analysis of the obtained documents was done. Cumulatively 12 documents were considered for analysis. In toto, 810 codes, 27 subcategories and 9 categories were extracted by content analysis. The categories included strategies for emission reduction, strategies for exposure reduction, strategies for education & communication, strategies for high-risk groups, strategies for research, strategies for capacity building, strategies for policymaking, implementation and enforcement, strategies for collaboration and coordination, and strategies for evaluation. Mitigating health impacts of air pollution needs to go beyond emission reduction at the sources of pollution. They could encompass comprehensive and holistic measures addressed to population affected by pollution. Health sector strengthening, policy advocacy by health sector, health sector awareness, policy enforcement and implementation through cross sectoral and geographical collaboration and coordination also needs to be the focus for improving the health of the population.

The Toto Bora trial tested whether a course of azithromycin reduced rates of re-hospitalization or death in the 6 months following hospitalization among Kenyan children. We hypothesized that azithromycin would reduce enteric bacteria and increase carriage of macrolide resistance in the subsequent 3 months. Kenyan children (1-59 months) hospitalized and subsequently discharged for non-traumatic conditions provided fecal samples before and 3 months after randomization to a 5-day course of azithromycin or placebo. Quantitative PCR identified enteropathogens and AMR-conferring genes in fecal samples. Generalized estimating equations assessed the impact of the randomization arm on pathogen and resistance gene detection, accounting for baseline presence and site. Among 1,393 baseline stools, 12.4% had at least one bacterial enteropathogen, 94.7% had at least one macrolide-resistance gene, and 92.6% had at least one beta-lactamase-resistance gene identified. At month 3, children randomized to azithromycin had a 6.1% higher likelihood of carrying a macrolide resistance gene compared to placebo (adjusted prevalence ratio [aPR], 1.06; 95% Cl, 1.04-1.08; PcO.OOl). Specifically, azithromycin randomization was associated with a higher relative prevalence of erm(B) (aPR, 1.09 [95% Cl, 1.04-1.15]; P=0.001), erm(C) (aPR, 1.23 [95% Cl, 1.14-1.31]; P<0.001), msr(A) (aPR, 1.14 [95% Cl, 1.04-1.25]; P=0.007), and msr(D) (aPR, 1.07 [95% Cl, 1.03-1.11]; P=0.001). There was no difference in overall bacterial pathogen prevalence (18.9% vs 17.3%) between randomization arms, but a slightly lower proportion of children had Shigella after randomization in the azithromycin arm (3% vs. 5%, aPR, 0.79 [95% Cl, 0.62, 1.01]; P=0.063). Azithromycin at hospital discharge was associated with higher carriage of macrolide-resistance-conferring genes in the post-discharge period compared with placebo, without significant declines in enteric pathogen carriage other than modest changes to Shigella. The potential benefits and risks of empiric azithromycin need to be considered, as children are increasingly exposed to this broad-spectrum antibiotic.

How embryos of different sizes generate reproducible body plans remains a central question in developmental biology. Do larger embryos contain more cells, or preserve conserved organizational principles that ensure robust tissue patterning independent of scale? Here, we address this question through whole-embryo quantitative mapping of cell number, tissue allocation, and spatial organization during early development in Xenopus. Using optimized in-toto 3D imaging, tissue clearing, and deep-learning for nuclei segmentation, we quantified cell numbers and reconstructed the spatial distribution of cells in early embryonic stages. Although X. laevis embryos exhibited substantially larger embryo volumes and higher total cell numbers than X. tropicalis, the proportional allocation of cells among ectoderm, mesoderm, and endoderm remained highly conserved between species. In addition, quantitative analysis of local cellular neighborhoods revealed striking conservation of spatial order, packing geometry, and large-scale tissue architecture despite major differences in embryo size and cellular density. Together, these findings demonstrate that early vertebrate embryos follow shared quantitative design principles in which embryonic scaling occurs without disruption of the underlying cellular blueprint of the body plan. Our study establishes a quantitative framework for comparing embryonic architecture across species and provides evidence that developmental organization is governed by conserved scale-invariant topological principles.

To describe the histological findings 7 weeks and 18 months after subretinal implantation of the PRIMA photovoltaic array in eyes with geographic atrophy. Comparative case series SUBJECTS: and controls: Four globes of two deceased study participants from the prospective PRIMAvera study were analyzed. The subretinal implant was removed after horizontal sectioning of the globe. Serial sections were performed and stained with hematoxylin-eosin, Masson trichrome as well as periodic acid Schiff for histopathologic analysis. Selected sections were immunohistochemically stained for CD68, CD163, GFAP, CD31, CK18, ARR3, RPBMS, and TRPM1. Both study and fellow eyes were analyzed. The histopathological analysis focused on the anatomical implant localization, wound healing processes, potential inflammatory reactions adjacent to the implant and at the retinotomy site, the development of retinal gliosis and retinal atrophy as well as a potential encapsulation. Both implants could be removed in toto without obvious retinal trauma. Histologically, the implants were located at the level of the outer plexiform layer, as intended, close to the inner nuclear layer. A tissue layer was identified beneath the implant, consisting of a basement membrane deposit and cellular components. A small rupture of Bruch's membrane was detected (in the globe with an 18 months follow-up) associated with localized subretinal fibrosis. At the implant-retina interface, there was only a minimal tissue response without pseudocapsule formation. Furthermore, no significant inflammatory response was detected. The retina overlying the implant was comparable to the fellow eyes in most areas, with limited focal atrophy of the inner retina 18 months after PRIMA implantation. At the retinotomy site, a full thickness scar was noted with mild atrophic changes in the implant insertion area. The wireless subretinal PRIMA implant demonstrated good biocompatibility with no significant encapsulation or surrounding inflammatory response. At seven weeks and eighteen months after implantation, retina overlying the implant was viable and layered as in control areas. Histopathologic analysis following innovative surgical techniques can provide important information in addition to in vivo findings.

Obesity prevalence continues to rise in the United States, with a disproportionate burden falling to West Virginia. To investigate the metabolic effects of region-specific dietary patterns, we developed the West Virginia Obesogenic Diet (WV-OD), a compositionally defined rodent diet based on nutritional analyses of meals consumed by obese individuals in the state. The WV-OD closely mirrors the macronutrient profile of the average American diet while incorporating regional features such as a greater sodium level and significantly less fiber. We compared the metabolic effects of the WV-OD to a matched control diet (WV-CD) and to a widely used high-fat diet (HFD, 60% of calories derived from fat) in male and female C57BL/6J mice. After 19 weeks, WV-OD-fed males exhibited weight gain and adiposity comparable to HFD-fed counterparts, along with glucose intolerance and hepatic triglyceride accumulation confirming the obesogenic and metabolically disruptive properties of the WV-OD. Unlike HFD-fed mice, WV-OD-fed males also displayed elevated circulating cholesterol and cholesterol esters without corresponding increases in hepatic total cholesterol. When compared to the HFD, the WV-OD did not increase uric acid or xanthine oxidoreductase (XOR) content of liver or circulation; however, both males and females on the WV-OD demonstrated trends towards elevated plasma uric acid. Interestingly, while exhibiting a similar caloric intake on either diet, the WV-OD females did not demonstrate significant fat accretion or metabolic dysfunction compared to females subjected to the 60% HFD. In toto, these findings: 1) establish the WV-OD as a regionally-grounded, yet broadly representative tool for modeling diet-induced obesity and metabolic dysfunction, 2) offer a physiologically relevant alternative to extreme-fat dietary models in preclinical research and 3) highlight sex-based differences in response to diet-induced obesity.

The RVLM (rostral ventral lateral medulla) region of the brainstem is implicated as a controller of both systemic and cerebral blood flow (CBF). Past studies leave open the question of how the RVLM stabilizes CBF in awake animals. Here, we focus on CBF regulation by the adenergic subpopulation of RVLM neurons (RVLMD&#x3b2;h). Hypoxic challenge increases the variability of the activity of RVLMD&#x3b2;h neurons along with increased CBF. Experimental photoactivation of RVLMD&#x3b2;h neurons leads to rapid vasodilation of pial arterioles across the cortical mantle and increased CBF, which is only then followed by an increase in cortical activity. No significant changes in systemic physiology are observed. Virus tracing establishes disynaptic pathways from the RVLM to neocortex with predominant relays involving the lateral hypothalamus and the zona incerta subthalamic nuclei. Chemogenetic inhibition of those nuclei led to a 70 % reduction in the ability of photoactivated RVLMD&#x3b2;h neurons to induce cortical vasodilation and increase CBF. In toto, these findings reveal a major RVLM subcortical pathway to drive transcortical increases in CBF and represent an adaptive mechanism to inform the cerebral vasculature about environmental shifts in pO2.

In mammals, the production of sex hormones is widely considered to depend on the interstitial lineage of the gonad, which differentiates into Leydig cells in males or theca cells in females. However, certain mammalian species evidence gonadal steroidogenic activity prior to the specialization of these interstitial lineages, suggesting that alternative cell types may assume this function. Here we reveal a previously unrecognized role for supporting-like cells (SLCs), which can act as a major steroidogenic lineage during mammalian embryonic development. Through comparative single-cell transcriptomics, steroidomics and in toto organ imaging we find that in rabbits, SLCs not only contribute to the formation of gonadal rete structures, as described for other mammals, but also differentiate into a steroid-producing population. The steroidogenic program of SLCs is initially activated in both sexes but selectively maintained in ovaries, whereas in testes it is progressively replaced by that of interstitially derived Leydig cells. Evolutionary comparisons indicate that SLCs may represent an ancestral lineage that is homologous to the steroidogenic cells of non-mammalian species, which also derive from supporting precursors and share expression of cell fate regulators such as PAX2/8 and TBX1. Altogether, our findings redefine current models of gonadal lineages, revealing an unexpected plasticity in sex differentiation and exemplifying how distinct cell types can converge on analogous functions during evolution.

Castleman disease constitutes a rare spectrum of conditions with rheumatologic, hematologic, and oncologic features. Orbital involvement is extremely rare with only several cases involving the lacrimal gland. This report describes Castleman disease in a 15-year-old patient who presented with progressive left eye bulging and intermittent periorbital pain. Neuroimaging demonstrated a well-defined, enhancing, homogeneous left lacrimal gland mass with decreased diffusivity, smooth bone remodeling, and anteromedial globe displacement, and no other systemic findings. The lesion was excised in toto and histopathology revealed features of hyaline vascular-type Castleman disease. This is the first reported case of Castleman disease in a pediatric patient with an isolated lacrimal gland lesion. It emphasizes the importance of considering Castleman disease among other lymphoproliferative diseases in the differential diagnosis for patients presenting with a well-circumscribed, homogeneous orbital mass associated with decreased diffusivity and bone remodeling.