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Objetivos: Los datos sobre la supervivencia y los factores de riesgo del adenocarcinoma ampular son limitados debido a su rareza. Este estudio buscó comparar el subtipo intestinal y el subtipo pancreático-biliar en pacientes con adenocarcinoma ampular. Métodos: Análisis retrospectivo de hallazgos clínicos y patológicos y la supervivencia de 184 pacientes con adenocarcinoma ampular tratados entre 2007 y 2018. Resultados: El subtipo pancreático-biliar tuvo una mayor prevalencia de ictericia antes de la operación y un tamaño de tumor mayor, y una peor diferenciación, que el subtipo intestinal. La invasión perineural fue más frecuente en el subtipo pancreático-biliar, con una mayor prevalencia de linfonodos disecados positivos y un estadio avanzado de la enfermedad. Los pacientes del subtipo pancreático-biliar tuvieron una supervivencia libre de enfermedad y una supervivencia general peores que los pacientes del subtipo intestinal. No se encontró ningún beneficio de la quimioterapia adyuvante en pacientes del subtipo intestinal o pancreático-biliar. No hubo diferencia significativa en las regiones recurrentes. Conclusión: El subtipo pancreático-biliar mostró una tasa de recurrencia y una tasa de supervivencia general peores, con características patológicas más desfavorables que el subtipo intestinal.

Abstract Background The purpose of this study was to examine the correlation between fasting blood glucose and new-onset hypertension and examine any synergistically effect modification with multiple risk factors. Methods We conducted post-hoc analyses of repeated-measures data in the original Dongzhi osteoporosis cohort study. In total, 3985 participants without hypertension aged 25–64 years were included in the current analyses. Generalized estimating equation models were used to assess the relationship between fasting blood glucose and risk of new-onset hypertension after adjusting for pertinent covariates and autocorrelations among siblings. Results 393 men (19.4%) and 398 women (20.3%) without hypertension at the baseline developed hypertension by the end of the study period. Compared to lower baseline fasting blood glucose levels (Q1–Q3:

Human dental pulp stem/stromal cells (hDPSCs) derived from the permanent secondary dentition are recognised to possess certain advantageous traits, which support their potential use as a viable source of mesenchymal stem/stromal cells (MSCs) for regenerative medicine-based applications. However, the well-established heterogeneous nature of hDPSC subpopulations, coupled with their limited numbers within dental pulp tissues, has impeded our understanding of hDPSC biology and the translation of sufficient quantities of these cells from laboratory research, through successful therapy development and clinical applications. This article reviews our current understanding of hDPSC biology and the evidence underpinning the molecular basis of their heterogeneity, which may be exploited to distinguish individual subpopulations with specific or superior characteristics for regenerative medicine applications. Pertinent unanswered questions which still remain, regarding the developmental origins, hierarchical organisation, and stem cell niche locations of hDPSC subpopulations and their roles in hDPSC heterogeneity and functions, will further be explored. Ultimately, a greater understanding of how key features, such as specific cell surface, senescence and other relevant genes, and protein and metabolic markers, delineate between hDPSC subpopulations with contrasting stemness, proliferative, multipotency, immunomodulatory, anti-inflammatory, and other relevant properties is required. Such knowledge advancements will undoubtedly lead to the development of novel screening, isolation, and purification strategies, permitting the routine and effective identification, enrichment, and expansion of more desirable hDPSC subpopulations for regenerative medicine-based applications. Furthermore, such innovative measures could lead to improved cell expansion, manufacture, and banking procedures, thereby supporting the translational development of hDPSC-based therapies in the future.

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Abstract Objectives The purpose of this study was to determine the relationship between protein-coding RNA (messenger RNA, mRNA) and long noncoding RNA (lncRNA) expressed in vascular endothelial cells (VECs) in keloids by reanalyzing Gene Expression Omnibus (GEO) microarray chip data. Materials and methods The GSE121618 database and clinical information of these samples were downloaded and reanalyzed by the R language package. Expression differences in mRNA and lncRNA between keloids and normal skin were calculated. GO/KEGG enrichment analysis was conducted to determine the function of these genes, and an interaction network of lncRNAs–mRNAs was constructed. Magnetic Sorting of VECs and qRT-PCR were used to verify these bioinformatic results. Results The expression of three hundred and five mRNAs in the keloid group was significantly different from that in the normal group, and 98 lncRNAs were different, 21 of which were upregulated and 118 of which were downregulated. The hub relationship between the upregulated lncRNA‒mRNA interaction was lncRNA LINC01546–RASAL3/COL13A1, while the downregulated hub was lncRNA LOC101929787–PRKAA2/KRT71/SSTR1. qPCR verification result showed no obvious statistical differences. Conclusions Through the in-depth mining of keloid microarray data using bioinformatic methods, we speculated that VECs can affect the development and progression of keloids by epigenomic regulation via lncRNA‒mRNA interactions.

Abstract Metal halide perovskites are attractive for optoelectronic applications, but the existing solution-based synthetic methods rely on hazardous solvents and lack reproducibility. To overcome these challenges, solvent-free mechanochemical synthesis of perovskites can be conducted, although traditional opaque ball milling equipment hinder real-time monitoring of the reaction progress. Herein, mechanochemistry was performed with time-lapsed in situ (TLIS) measurements to elucidate the optical properties during the synthesis. The TLIS spectrometer enabled real-time observation of the impact of varying the compositions on the absorption properties of formamidinium/methylammonium lead iodide (FA x MA1-x PbI3, x = 0 to 1) and facilitated optimization of the synthesis duration. Moreover, we can accelerate the evaluation and directly observe the effects of different synthetic strategies for enhancing the photoluminescence quantum yield and stability of the perovskites, providing near-infrared (NIR) emitting tin-based perovskites FASnI z Br3-z (where z = 0 to 3) with core-shell structures. Intriguingly, halide ion migration was deduced in lead-free double perovskites Cs2Na y Ag1-y BiCl6 (y = 0 to 1.0) at room temperature during aging after mechanochemical activation. Our work provides insights into the mechanochemistry of compounds with low thermodynamic barriers.

Abstract Schwannomas are tumors that originate from the glial cells of the nervous system and can occur on myelinated nerve fibers throughout the body, especially in the craniofacial region. However, pancreatic schwannomas are extremely rare. We report a case of a pancreatic schwannoma that was difficult to differentiate from other pancreatic tumors preoperatively. A 44-year-old female patient was found to have a pancreatic mass on Computed Tomography imaging and the preoperative diagnosis was a pancreatic solid pseudopapillary neoplasm. Meanwhile, the patient had type 2 diabetes and the blood glucose was controlled at 8-15mmol/L by taking oral antidiabetic drugs. During exploratory laparotomy, an 8 cm × 7 cm × 4 cm mass was discovered in the middle part of the pancreas. Considering the preoperative diabetes, the patient underwent a central pancreatectomy (CP) and Roux-en-Y pancreaticojejunostomy. Postoperative histopathological examination confirmed the diagnosis of a pancreatic epitheloid schwannoma. After surgery, the patient developed Grade B pancreatic fistula, which disappeared after treatment. At the same time, the patient’s blood glucose remained basically stable by insulin therapy, which was adjusted to oral antidiabetic medications in about 40 days after surgery. At a 32-month follow-up after discharge, no tumor recurrence was observed, and the patient’s blood glucose was controlled below 11.1mmol/L with only oral antidiabetic drugs. The radiological diagnosis of pancreatic schwannomas lacks specific features, and diagnosis primarily relies on histopathological examination and immunohistochemical testing. Although pancreatic schwannomas are extremely rare, they must be differentiated from other solid or cystic pancreatic lesions. For patients with pancreatic schwannoma and diabetes, CP may represent a favorable surgical option.

Abstract Quantum entanglement uncovers the essential principles of quantum matter, yet determining its structure in realistic many-body systems poses significant challenges. Here, we employ a protocol, dubbed entanglement microscopy, to reveal the multipartite entanglement encoded in the full reduced density matrix of the microscopic subregion in spin and fermionic many-body systems. We exemplify our method by studying the phase diagram near quantum critical points (QCP) in 2 spatial dimensions: the transverse field Ising model and a Gross-Neveu-Yukawa transition of Dirac fermions. Our main results are: i) the Ising QCP exhibits short-range entanglement with a finite sudden death of the LN both in space and temperature; ii) the Gross-Neveu QCP has a power-law decaying fermionic LN consistent with conformal field theory (CFT) exponents; iii) going beyond bipartite entanglement, we find no detectable 3-party entanglement with our two witnesses in a large parameter window near the Ising QCP in 2d, in contrast to 1d. We further establish the singular scaling of general multipartite entanglement measures at criticality and present an explicit analysis in the tripartite case.

Aims: To assess the effectiveness of an unsupervised home‐based pulmonary rehabilitation with self‐management program in patients with chronic obstructive pulmonary disease (COPD). Background: A few recent studies have shown that unsupervised home‐based pulmonary rehabilitation can improve the clinical outcome of patients with COPD. More studies are needed to prove its benefits. Design: This study used a quasi‐experimental design. Methods: Seventy‐two admitted COPD patients were assigned to experimental group or control group through purposeful sampling. Data were collected from March 2016 to November 2017 in the Thoracic Intensive Care Unit of a Medical Center in Taiwan. The Medical Research Council dyspnea scale, the COPD Self‐Efficacy Scale and the Clinical COPD Questionnaire were measured before education and at the first, second and third months after discharge. Results: The Medical Research Council dyspnea scale and COPD Self‐Efficacy Scale results in the experimental group were significantly improved compared with the control group in the third month after discharge. The Clinical COPD Questionnaire score continued to improve in both groups in the third month after discharge, and there was no difference between the two groups. Conclusion: A short‐term unsupervised home‐based pulmonary rehabilitation with self‐ management program had significant benefits for patients with COPD. The long‐term effects need to be confirmed. Summary statement: What is already known about this topic? The literature emphasizes the importance of alternative supervision of home‐based pulmonary rehabilitation rather than center‐based pulmonary rehabilitation for patients who find this inconvenient to access.Few studies have shown that unsupervised home‐based pulmonary rehabilitation can improve the clinical outcome of patients with chronic obstructive pulmonary disease (COPD). What this paper adds? This study demonstrates that a short‐term unsupervised home‐based pulmonary rehabilitation with self‐management program can improve dyspnea during physical activity, self‐care efficacy in certain activities and quality of life after discharge in patients with COPD. The implications of this paper: The findings of this study can be used as the basis for providing a short‐term unsupervised home‐based pulmonary rehabilitation with self‐management program for patients with COPD after discharge.We recommend that patients with COPD undergo unsupervised home‐based pulmonary rehabilitation with self‐management for 3 months after discharge, especially if regular hospital visits for this are not convenient.The effect of longer‐term unsupervised home‐based pulmonary rehabilitation can be further studied in the future. [ABSTRACT FROM AUTHOR]

Abstract Nocturnal hypoglycemia is a critical problem faced by diabetic patients. Failure to intervene in time can be dangerous for patients. The existing early warning methods struggle to extract crucial information comprehensively from complex multi-source heterogeneous data. In this paper, a deep learning framework with an innovative dynamic attention mechanism is proposed to predict nocturnal hypoglycemic events for type 1 diabetes patients. Features related to nocturnal hypoglycemia are extracted from multi-scale and multi-dimensional data, which enables comprehensive information extraction from diverse sources. Then, we propose a prior-knowledge-guided attention mechanism to enhance the network's learning capability and interpretability. The method was evaluated on a public available clinical dataset, which successfully warned 94.91% of nocturnal hypoglycemic events with an F1-score of 96.35%. By integrating our proposed framework into the nocturnal hypoglycemia early warning model, issues related to feature redundancy and incompleteness were mitigated. Comparative analysis demonstrates that our method outperforms existing approaches, offering superior accuracy and practicality in real-world scenarios.

Axolotls are known for their remarkable regeneration ability. Exploring their transcriptome provides insight into regenerative mechanisms. However, the current annotation of the axolotl transcriptome is limited, leaving the role of unannotated transcripts in regeneration unknown. To discourse this challenge, we exploited long-read sequencing technology, which enables direct observation of full-length RNA transcripts, greatly enhancing the coverage and accuracy of axolotl transcriptome annotation. By utilizing this method, we identified 222 novel gene loci and 4775 novel transcripts, which were quantified using short-read sequencing data. Through the inclusive analysis, we discovered novel homologs, potential functional proteins, noncoding RNAs, and alternative splicing events in key regeneration pathways. In particular, we identified novel transcripts with high protein-coding potential implicated in cell cycle regulation and musculoskeletal development, and regeneration were identified. Interestingly, alternative splice variants were also detected across diverse pathways critical to regeneration. This specifies that these novel transcripts potentially play vital roles underpinning the robust regenerative capacities of axolotls. Single-cell transcriptomic analysis further revealed these isoforms to predominantly exist in axolotl limb chondrocytes and mature tissue cell populations. Overall, the findings significantly advanced consideration of the axolotl transcriptome and provided a new perspective for understanding the mechanisms of regenerative abilities of axolotls.

Introduction: Management of aortic stenosis (AS) in patients with chronic kidney disease (CKD) may often be overlooked, and this could confer poorer outcomes. Methods: Consecutive patients (n = 727) with index echocardiographic diagnosis of moderate to severe AS (aortic valve area

The solid backfilling mining method has great advantages in handling coal-based solid waste and controlling surface subsidence, but its low backfilling efficiency, long succession time and high labour intensity constrain the development of green backfilling mining. Aiming at the endogenous driving force of solid backfilling technology upgrading, the urgent demand of industry development and the inevitable trend of mine intelligent construction, the solid intelligent backfilling method analysed by video AI algorithm is proposed. Initially, this paper examines the essence and challenges of intelligent solid backfilling methods, establishes the system framework for analyzing the intelligent solid backfilling mining method using video AI algorithms, elucidates the operational principles and implementation process of the video AI algorithm, and outlines the capabilities that can be achieved through this algorithm. It analyzes the influencing factors on key backfilling equipment under different geological conditions. The hydraulic support framework modeling was conducted using Creo to simulate its movement in various working conditions; corresponding control criteria and paths were provided, along with a designed control algorithm flow for key backfilling equipment across different processes. Based on the characteristics of video algorithms and their pros and cons, an image recognition algorithm is initially chosen; after training and adjusting the model, optimal algorithms and corresponding parameters are determined. Through an analysis of application effects on an coal mine fill surfaces, it is found that SVM evaluation indices outperform other algorithms, indicating excellent performance in discriminating working conditions with high accuracy and reliability. The research can realize the identification and regulation of abnormal working conditions of key backfilling equipment mechanism, improve backfilling efficiency, identify the positional parameters of the mechanism, and display the effect of backfilling space tamping, which can provide theoretical guidance for the research, development and application of solid intelligent backfilling and mining technology analyzed by video AI algorithm.

Tendinopathy is a prevalent aging-related disorder characterized by pain, swelling, and impaired function, often resulting from micro-scarring and degeneration caused by overuse or trauma. Current interventions for tendinopathy have limited efficacy, highlighting the need for innovative therapies. Mitochondria play an underappreciated and yet crucial role in tenocytes function, including energy production, redox homeostasis, autophagy, and calcium regulation. Abnormalities in mitochondrial function may lead to cellular senescence. Within this context, this review provides an overview of the physiological functions of mitochondria in tendons and presents current insights into mitochondrial dysfunction in tendinopathy. It also proposes potential therapeutic strategies that focus on targeting mitochondrial health in tenocytes. These strategies include: (1) utilizing reactive oxygen species (ROS) scavengers to mitigate the detrimental effects of aberrant mitochondria, (2) employing mitochondria-protecting agents to reduce the production of dysfunctional mitochondria, and (3) supplementing with exogenous normal mitochondria. In conclusion, mitochondria-targeted therapies hold great promise for restoring mitochondrial function and improving outcomes in patients with tendinopathy.The translational potential of this article: Tendinopathy is challenging to treat effectively due to its poorly understood pathogenesis. This review thoroughly analyzes the role of mitochondria in tenocytes and proposes potential strategies for the mitochondrial treatment of tendinopathy. These findings establish a theoretical basis for future research and the clinical translation of mitochondrial therapy for tendinopathy.

AIM: To observe the changes in corneal subepithelial nerve fibers (CNFs) and Langerhans cells (LCs) in patients with type 2 diabetes using corneal laser confocal microscopy (CLCM). METHODS: A total of 60 patients (64 eyes), including 40 patients with type 2 diabetes (DM group) and 20 subjects without diabetes (control group) were included with CLCM. Neuron J plugin of Image J software were used for quantitative analysis of CNF length (CNFL), CNF density (CNFD), corneal nerve branch fiber density (CNBD), main branch length density, branch length density, corneal nerve fiber tortuosity (NT) score, and LCs density. An independent samples t-test to analyze the variability between the two groups was performed, and Pearson correlation analysis was used to analyze the relationships between CNF and multiple biochemical indicators in the DM group. The predictive power of CNF for type 2 diabetes was assessed using the receiver operating characteristic (ROC) curve. RESULTS: There were significant differences in the CNFL, CNFD, and main branch length density between two groups. The results of Pearson correlation analysis showed a significant negative correlation between CNFD and the duration of diabetes as well as triglyceride levels and total cholesterol, and a significant positive correlation between CNFD and serum albumin. In addition, the NT score showed a positive correlation and urea nitrogen, similar to the positive correlation observed between LC density and glycosylated hemoglobin (HbA1c) levels. CNFD showed the highest area under the curve (AUC of ROC) value, followed by main branch length density and CNFL. The AUC of the ROC curve under the logistic regression model also demonstrated good predictive values. The cut-off values of CNFD, CNFL, and main branch length density for diabetes showed 31.25, 18.85, and 12.56, respectively. CONCLUSION: In patients with type 2 diabetes, there is a notable reduction in both CNFL and CNFD. These measurements can be influenced by various blood biochemical factors. However, the compromised nerve fibers can serve as valuable indicators for predicting the onset of type 2 diabetes and also as biomarkers for detecting diabetic neuropathy and its related complications.

Abstract Rotator cuff tendinopathy is the most common tendinopathy type with the worst prognosis. Conventional treatments often elicit heterogeneous drug responses due to the diversity of tendinopathy. Hence, this study attempted a classification of 126 diseased tendons into three distinct subtypes with opposite pathogenic mechanisms based on transcriptomic and clinical features. The hypoxic atrophic subtype with white appearance (Hw) exhibits downregulated neovascularization pathways. The inflammatory proliferative subtype with white appearance (Iw) shows a moderate upregulation of inflammatory characteristics. The inflammatory proliferative subtype with red appearance (Ir) exhibits the highest levels of upregulated neovascularization and inflammatory pathways, along with severe joint dysfunction. We then established research models, including subtype-specific simulations in animal models and clinical data analysis. These revealed that glucocorticoid, a controversial commonly used drug, was only effective in treating the Ir subtype. Hence, the tendinopathy subtypes elucidated in this study have significant implications for developing precision treatment of tendinopathy.

Abstract Background SHR-1707 is a novel humanized anti-Aβ IgG1 monoclonal antibody that binds to Aβ fibrils and monomers to block the formation of Aβ plaques or to promote the microglial phagocytosis of Aβ. Preclinical studies showed that SHR-1707 reduced brain Aβ deposition in 5xFAD transgenic mice. Herein, we conducted two phase 1 studies to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of a single intravenous dose of SHR-1707 in healthy adult subjects. Methods Two randomized, double-blind, single-ascending-dose, phase 1 studies were conducted in China (Study CHN) and Australia (Study AUS). Study CHN consisted of 2 parts. In Part 1, eligible healthy young adults (18–45 years) were sequentially randomized 8:2 to receive SHR-1707 (five cohorts: 2, 6, 20, 40, and 60 mg/kg) or placebo in each cohort; in Part 2, elderly subjects (55–80 years) were randomized 8:4 to receive SHR-1707 (20 mg/kg) or placebo. A similar design was used in Study AUS, but with only healthy young adults enrolled across three dosing cohorts (2, 20, and 60 mg/kg). Results Sixty-two (part 1/2, n = 50/12; age range, 18–42/55–63 years) and 30 subjects (age range, 18–42 years) received SHR-1707 or placebo in Study CHN and Study AUS, respectively. In Study CHN, all treatment-related adverse events (TRAEs) were mild, with the most common being transient laboratory abnormalities. In Study AUS, TRAEs were mostly mild (1 moderate event each with SHR-1707/placebo); the most common TRAEs with SHR-1707 were dysgeusia and fatigue (8.3% each). In both studies, the exposure of SHR-1707 increased in a slightly greater than dose-proportional manner over the dose range of 2–60 mg/kg in young adults; there was a dose-dependent increase in plasma Aβ42 concentration following SHR-1707 administration compared with the placebo group. The safety and PK and PD profiles of SHR-1707 in the elderly subjects were consistent with the younger counterpart at the same dose level. No ethnic difference in safety, PK and PD of SHR-1707 was observed. Conclusions A single intravenous dose of SHR-1707 at 2–60 mg/kg was safe and well tolerated in healthy young adult and elderly subjects. The PK and PD profiles are supportive for further clinical development. Trial registration NCT04973189 (retrospectively registered on Jul.21, 2021) and NCT04745104 (registered on Feb.6, 2021) on clinicaltrials.gov.

Abstract Label-free, live cell recognition (i.e. instance segmentation) and tracking using computer vision-aided recognition can be a powerful tool that rapidly generates multi-modal readouts of cell populations at single cell resolution. However, this technology remains hindered by the lack of accurate, universal algorithms. This review presents related biological and computer vision concepts to bridge these disciplines, paving the way for broad applications in cell-based diagnostics, drug discovery, and biomanufacturing.

Abstract Tryptophan (Trp) metabolism involves three primary pathways: the kynurenine (Kyn) pathway (KP), the 5-hydroxytryptamine (serotonin, 5-HT) pathway, and the indole pathway. Under normal physiological conditions, Trp metabolism plays crucial roles in regulating inflammation, immunity, and neuronal function. Key rate-limiting enzymes such as indoleamine-2,3-dioxygenase (IDO), Trp-2,3-dioxygenase (TDO), and kynurenine monooxygenase (KMO) drive these metabolic processes. Imbalances in Trp metabolism are linked to various cancers and often correlate with poor prognosis and adverse clinical characteristics. Dysregulated Trp metabolism fosters tumor growth and immune evasion primarily by creating an immunosuppressive tumor microenvironment (TME). Activation of the KP results in the production of immunosuppressive metabolites like Kyn, which modulate immune responses and promote oncogenesis mainly through interaction with the aryl hydrocarbon receptor (AHR). Targeting Trp metabolism therapeutically has shown significant potential, especially with the development of small-molecule inhibitors for IDO1, TDO, and other key enzymes. These inhibitors disrupt the immunosuppressive signals within the TME, potentially restoring effective anti-tumor immune responses. Recently, IDO1 inhibitors have been tested in clinical trials, showing the potential to enhance the effects of existing cancer therapies. However, mixed results in later-stage trials underscore the need for a deeper understanding of Trp metabolism and its complex role in cancer. Recent advancements have also explored combining Trp metabolism inhibitors with other treatments, such as immune checkpoint inhibitors, chemotherapy, and radiotherapy, to enhance therapeutic efficacy and overcome resistance mechanisms. This review summarizes the current understanding of Trp metabolism and signaling in cancer, detailing the oncogenic mechanisms and clinical significance of dysregulated Trp metabolism. Additionally, it provides insights into the challenges in developing Trp-targeted therapies and future research directions aimed at optimizing these therapeutic strategies and improving patient outcomes.

Ophthalmology is a subject that highly depends on imaging examination. Artificial intelligence (AI) technology has great potential in medical imaging analysis, including image diagnosis, classification, grading, guiding treatment and evaluating prognosis. The combination of the two can realize mass screening of grass-roots eye health, making it possible to seek medical treatment in the mode of “first treatment at the grass-roots level, two-way referral, emergency and slow treatment, and linkage between the upper and lower levels”. On the basis of summarizing the AI technology carried out by scholars and their teams all over the world in the field of ophthalmology, quite a lot of studies have confirmed that machine learning can assist in diagnosis, grading, providing optimal treatment plans and evaluating prognosis in corneal and conjunctival diseases, ametropia, lens diseases, glaucoma, iris diseases, etc. This paper systematically shows the application and progress of AI technology in common anterior segment ocular diseases, the current limitations, and prospects for the future.

Abstract Recent advances in imaging suggested that spatial organization of hematopoietic cells in their bone marrow microenvironment (niche) regulates cell expansion, governing progression, and leukemic transformation of hematological clonal disorders. However, our ability to interrogate the niche in pre-malignant conditions has been limited, as standard murine models of these diseases rely largely on transplantation of the mutant clones into conditioned mice where the marrow microenvironment is compromised. Here, we leveraged live-animal microscopy and ultralow dose whole body or focal irradiation to capture single cells and early expansion of benign/pre-malignant clones in the functionally preserved microenvironment. 0.5 Gy whole body irradiation (WBI) allowed steady engraftment of cells beyond 30 weeks compared to non-conditioned controls. In-vivo tracking and functional analyses of the microenvironment showed no change in vessel integrity, cell viability, and HSC-supportive functions of the stromal cells, suggesting minimal inflammation after the radiation insult. The approach enabled in vivo imaging of Tet2 +/− and its healthy counterpart, showing preferential localization within a shared microenvironment while forming discrete micro-niches. Notably, stationary association with the niche only occurred in a subset of cells and would not be identified without live imaging. This strategy may be broadly applied to study clonal disorders in a spatial context.

Abstract The 2-oxoglutarate dehydrogenase complex (OGDHc) orchestrates a critical reaction regulating the TCA cycle. Although the structure of each OGDHc subunit has been solved, the architecture of the intact complex and inter-subunit interactions still remain unknown. Here we report the assembly of native, intact OGDHc from Sus scrofa heart tissue using cryo-electron microscopy (cryo-EM), cryo-electron tomography (cryo-ET), and subtomogram averaging (STA) to discern native structures of the whole complex and each subunit. Our cryo-EM analyses revealed the E2o cubic core structure comprising eight homotrimers at 3.3-Å resolution. More importantly, the numbers, positions and orientations of each OGDHc subunit were determined by cryo-ET and the STA structures of the core were resolved at 7.9-Å with the peripheral subunits reaching nanometer resolution. Although the distribution of the peripheral subunits E1o and E3 vary among complexes, they demonstrate a certain regularity within the position and orientation. Moreover, we analyzed and validated the interactions between each subunit, and determined the flexible binding mode for E1o, E2o and E3, resulting in a proposed model of Sus scrofa OGDHc. Together, our results reveal distinctive factors driving the architecture of the intact, native OGDHc.

Di (2-ethylhexyl) phthalate (DEHP) is widespread in the environment. It can impair sperm function through damaging the sperm development process. However, few studies have focused on the sperm tail that is directly related to sperm motility. In this study, we demonstrate that DEHP impedes the conversion of riboflavin in the mitochondrial sheath in the midsection of the sperm tail, resulting in reduced ATP (adenosine triphosphate) synthesis, thereby inhibiting sperm motility. The results of HPLC-MS/MS showed that DEHP metabolites were transported to the testes and epididium, indicating that MEHP (Mono-2-ethylexyl phthalate) could directly affect the espermatozoa of mature. Sperm motility analysis determined that sperm motility decreased with increasing DEHP concentration. The movement of sperm is mainly dependent on the tail motility, which is largely determined by tail structure and energy supply. Electron microscopy images illustrate that there are no observable changes in the basic kinematic structure of the sperm tail. However, DEHP causes a decrease in complex II activity of mitochondrial respiratory chain by interfering with the synthesis of the cofactor FAD (Flavin adenine dinucleotide), which leads to a decrease in ATP concentration. Therefore, DEHP exposure can reduce sperm motility by decreasing sperm tail energy supply. This study exemplifies the importance of the sperm tail in sperm dysfunction caused by environmental pollutants.

Though the importance and benefits of students’ active role in the feedback process have been widely discussed in the literature, an instrument for measuring students’ self-feedback behavior is still lacking. This paper reports the development and validation of the Self-feedback Behavior Scale (SfBS), which comprises three dimensions (seeking, processing, and using feedback). The SfBS items were constructed in line with the self-feedback behavioral model. One thousand two hundred fifty-two high school students (Grade 10 to Grade 12) in mainland China participated in this survey. The exploratory factor analysis revealed a three-factor model reaffirmed in the confirmatory factor analysis. The multi-group CFA supported the measurement invariance of the SfBS across gender. Using the SfBS can help researchers and teachers better understand students’ self-feedback behavior and optimize benefits derived from the self-feedback process.

The high risks of traumatic cataract treatments promoted the development of the concept of autologous lens regeneration. Biochemical cues can influence the cellular behavior of stem cells, and in this case, biophysical cues may be the important factors in producing rapid activation of cellular behavior. Here we bio-printed mesenchymal stem cells (MSCs) using a commonly used bioink sodium alginate-gelatin blends, and investigated the induction effect of MSC differentiation towards lens epithelial stem cells (LESCs) under a combination of biochemical cues and biophysical cues. It was found that biochemical cues in the porous three-dimensional (3D) matrix constructed using bioink sodium alginate-gelatin blends for bio-printing did not reduce the cell viability of loaded MSCs in the matrix by scanning electron microscope (SEM) observation and cell viability detection. Loaded MSCs in the matrix were consistently upregulated in the expression of proteins and genes involved in phenotypes and development signaling pathways of LESCs, as detected by polymerase chain reaction (PCR) with the support of biochemical cues. These results indicated that biophysical cues could rapidly activate the cellular behavior of MSCs differentiation, and biochemical cues could continuously induce MSCs differentiation towards LESCs.

Summary: The tRNA methyltransferase 1 (TRMT1) enzyme catalyzes the N2,N2-dimethylguanosine (m2,2G) modification in tRNAs. Intriguingly, vertebrates encode an additional tRNA methyltransferase 1-like (TRMT1L) paralog. Here, we use a comprehensive tRNA sequencing approach to decipher targets of human TRMT1 and TRMT1L. We find that TRMT1 methylates all known tRNAs containing guanosine at position 26, while TRMT1L represents the elusive enzyme catalyzing m2,2G at position 27 in tyrosine tRNAs. Surprisingly, TRMT1L is also necessary for maintaining 3-(3-amino-3-carboxypropyl)uridine (acp3U) modifications in a subset of tRNAs through a process that can be uncoupled from methyltransferase activity. We also demonstrate that tyrosine and serine tRNAs are dependent upon m2,2G modifications for their stability and function in translation. Notably, human patient cells with disease-associated TRMT1 variants exhibit reduced levels of tyrosine and serine tRNAs. These findings uncover unexpected roles for TRMT1 paralogs, decipher functions for m2,2G modifications, and pinpoint tRNAs dysregulated in human disorders caused by tRNA modification deficiency.

Abstract Psoriasis is a chronic, immune‐mediated disorder characterized by immune regulation disorders and abnormal keratinocyte proliferation. Deucravacitinib (Deu), a selective oral Tyrosine Kinase 2 (TYK2) inhibitor, shows promise in treating psoriasis but may cause systemic side effects and fail to address persistent localized thickened lesions. Herein, a self‐locking microneedle (MN) patch with a polyvinyl alcohol (PVA) inner ring loaded with Deu is developed, designed to penetrate the transdermal barriers and dissolve rapidly, downregulating the IL‐23/IL‐17 pathway and serve as the first line of defense against the spread of skin‐originated inflammation. Additionally, Calcipotriol (Cal), a vitamin D derivative, is incorporated into a methacrylated hyaluronic acid (HAMA) backing layer and outer ring that mimics occlusive administration, maintaining localized skin surface retention for prolonged anti‐proliferative therapy. The Deu@Cal MN demonstrates satisfactory adhesiveness due to swelling‐mediated mechanical interlocking via the outer ring, ensuring targeted drug release at lesion site. Besides its effectiveness in alleviating both skin inflammation and proliferation, it inhibits the differentiation of Th17 cells in the spleen, suggesting potential to reduce systemic inflammation. These findings offer a new therapeutic approach for treating psoriasis and other autoimmune and inflammatory conditions.

Summary: The hypertrophic mesenteric adipose tissue (htMAT) of Crohn disease (CD) participates in inflammation through the expression of adipokines, but the exact mechanism of this action in the intestine is unknown. Here, we analyzed the expression of secreted frizzled-related protein 5 (SFRP5), an adipokine with cytoprotective effects, in htMAT and its role in CD. The results of this study revealed that the level of SFPR5 increased in the diseased MAT (htMAT) of CD patients and aggregated among intestinal epithelial cells in the diseased intestine and that it could ameliorate intestinal barrier dysfunction in tumor necrosis factor alpha (TNF-α)-stimulated colonic organoids and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced mice at least in part through the inhibition of Wnt5a-mediated apoptosis in epithelial cells. This study elucidates possible mechanisms by which mesenteric adipokines influence the progression of enteritis and provides a new theoretical basis for the treatment of CD via the mesenteric pathway.

Transcription factor 3 (TCF3) is a DNA transcription factor that modulates megakaryocyte development. Although abnormal TCF3 expression has been identified in a range of hematological malignancies, to date, it has not been investigated in myelofibrosis (MF). MF is a Philadelphia-negative myeloproliferative neoplasm (MPN) that can arise de novo or progress from essential thrombocythemia [ET] and polycythemia vera [PV] and where dysfunctional megakaryocytes have a role in driving the fibrotic progression. We aimed to examine whether TCF3 is dysregulated in megakaryocytes in MPN, and specifically in MF. We first assessed TCF3 protein expression in megakaryocytes using an immunohistochemical approach analyses and showed that TCF3 was reduced in MF compared with ET and PV. Further, the TCF3-negative megakaryocytes were primarily located near trabecular bone and had the typical “MF-like” morphology as described by the WHO. Genomic analysis of isolated megakaryocytes showed three mutations, all predicted to result in a loss of function, in patients with MF; none were seen in megakaryocytes isolated from ET or PV marrow samples. We then progressed to transcriptomic sequencing of platelets which showed loss of TCF3 in MF. These proteomic, genomic and transcriptomic analyses appear to indicate that TCF3 is downregulated in megakaryocytes in MF. This infers aberrations in megakaryopoiesis occur in this progressive phase of MPN. Further exploration of this pathway could provide insights into TCF3 and the evolution of fibrosis and potentially lead to new preventative therapeutic targets.

Urbanization and population growth have profoundly impacted the environment of historic and cultural blocks, resulting in a lack of public buildings and spaces for internal adjustment, fostering pronounced homogeneity. This study focuses on completely abandoned areas within historical streets, integrating space syntax analysis with semantic analysis to explore reshaping regional public buildings. Unlike previous studies centered around restoring old objects, the abandoned disconnected areas require a novel regional public architecture design framework through the semantic transformation of archival photographs, historical plans, and local culture. Taking Huishan Ancient Town in Wuxi as a case study, this research comprehends the abandoned disconnection area through a literature review and examination of archival data. By using spatial syntax analysis to combine the overall pedestrian flow space with the depth of ancient historical plans, entrances are set according to the pedestrian flow, preserving unique spatial characteristics and transforming the abandoned land into new public building spaces with distinct regional and contiguous features. Through semantic translation rooted in local culture, classical elements were extracted from intangible cultural heritage and applied to the ancient town’s architectural facades, navigation systems, and structures, thereby mitigating homogenization tendencies in both spatial and cultural elements.

Abstract Background Patients with chronic lung diseases (CLDs), defined as progressive and life-limiting respiratory conditions, experience a heavy symptom burden as the conditions become more advanced, but palliative referral rates are low and late. Prognostic tools can help clinicians identify CLD patients at high risk of deterioration for needs assessments and referral to palliative care. As current prognostic tools may not generalize well across all CLD conditions, we aim to develop and validate a general model to predict one-year mortality in patients presenting with any CLD. Methods A retrospective cohort study of patients with a CLD diagnosis at a public hospital from July 2016 to October 2017 was conducted. The outcome of interest was all-cause mortality within one-year of diagnosis. Potential prognostic factors were identified from reviews of prognostic studies in CLD, and data was extracted from electronic medical records. Missing data was imputed using multiple imputation by chained equations. Logistic regression models were developed using variable selection methods and validated in patients seen from January 2018 to December 2019. Discriminative ability, calibration and clinical usefulness of the model was assessed. Model coefficients and performance were pooled across all imputed datasets and reported. Results Of the 1000 patients, 122 (12.2%) died within one year. Patients had chronic obstructive pulmonary disease or emphysema (55%), bronchiectasis (38%), interstitial lung diseases (12%), or multiple diagnoses (6%). The model selected through forward stepwise variable selection had the highest AUC (0.77 (0.72–0.82)) and consisted of ten prognostic factors. The model AUC for the validation cohort was 0.75 (0.70, 0.81), and the calibration intercept and slope were − 0.14 (-0.54, 0.26) and 0.74 (0.53, 0.95) respectively. Classifying patients with a predicted risk of death exceeding 0.30 as high risk, the model would correctly identify 3 out 10 decedents and 9 of 10 survivors. Conclusions We developed and validated a prognostic model for one-year mortality in patients with CLD using routinely available administrative data. The model will support clinicians in identifying patients across various CLD etiologies who are at risk of deterioration for a basic palliative care assessment to identify unmet needs and trigger an early referral to palliative medicine. Trial registration Not applicable (retrospective study).

Abstract Background Accumulating evidences indicate regional grey matter (GM) morphology alterations in pediatric growth hormone deficiency (GHD); however, large-scale morphological brain networks (MBNs) undergo these patients remains unclear. Objective To investigate the topological organization of individual-level MBNs in pediatric GHD. Methods Sixty-one GHD and 42 typically developing controls (TDs) were enrolled. Inter-regional morphological similarity of GM was taken to construct individual-level MBNs. Between-group differences of topological parameters and network-based statistics analysis were compared. Finally, association relationship between network properties and clinical variables was analyzed. Results Compared to TDs, GHD indicated a disturbance in the normal small-world organization, reflected by increased Lp, γ, λ, σ and decreased Cp, Eglob (all P FDR < 0.017). Regarding nodal properties, GHD exhibited increased nodal profiles at cerebellum 4-5, central executive network-related left inferior frontal gyrus, limbic regions-related right posterior cingulate gyrus, left hippocampus, and bilateral pallidum, thalamus (all P FDR < 0.05). Meanwhile, GHD exhibited decreased nodal profiles at sensorimotor network -related bilateral paracentral lobule, default-mode network-related left superior frontal gyrus, visual network -related right lingual gyrus, auditory network-related right superior temporal gyrus and bilateral amygdala, right cerebellum 3, bilateral cerebellum 10, vermis 1-2, 3, 4-5, 6 (all P FDR < 0.05). Furthermore, serum markers and behavior scores in GHD group were correlated with altered nodal profiles (P ≤ 0.046, uncorrected). Conclusion GHD undergo an extensive reorganization in large-scale individual-level MBNs, probably due to abnormal cortico-striatal-thalamo-cerebellum loops, cortico-limbic-cerebellum, dorsal visual-sensorimotor-striatal, and auditory-cerebellum circuitry. This study highlights the crucial role of abnormal morphological connectivity underlying GHD, which might result in their relatively slower development in motor, cognitive, and linguistic functional within behavior problem performance.

Background: Nestin is an intermediate filament first reported in neuroepithelial stem cells. Nestin expression could be found in a variety of tissues throughout all systems of the body, especially during tissue development and tissue regeneration processes. Aim of Review: This review aimed to summarize and discuss current studies on the distribution, contribution and regulation of nestin+ cells in different systems of the body, to discuss the feasibility of using nestin as a marker of multilineage stem/progenitor cells, and better understand the potential roles of nestin+ cells in tissue development, regeneration and pathological processes. Key Scientific Concepts of Review: This review highlights the potential of nestin as a marker of multilineage stem/progenitor cells, and as a key factor in tissue development and tissue regeneration. The article discussed the current findings, limitations, and potential clinical implications or applications of nestin+ cells. Additionally, it included the relationship of nestin+ cells to other cell populations. We propose potential future research directions to encourage further investigation in the field.

AIM: To explore the effect of silent information regulator factor 2-related enzyme 1 (SIRT1) on modulating apoptosis of human lens epithelial cells (HLECs) and alleviating lens opacification of rats through suppressing endoplasmic reticulum (ER) stress. METHODS: HLECs (SRA01/04) were treated with varying concentrations of tunicamycin (TM) for 24h, and the expression of SIRT1 and C/EBP homologous protein (CHOP) was assessed using real-time quantitative polymerase chain reaction (RT-PCR), Western blotting, and immunofluorescence. Cell morphology and proliferation was evaluated using an inverted microscope and cell counting kit-8 (CCK-8) assay, respectively. In the SRA01/04 cell apoptosis model, which underwent siRNA transfection for SIRT1 knockdown and SRT1720 treatment for its activation, the expression levels of SIRT1, CHOP, glucose regulated protein 78 (GRP78), and activating transcription factor 4 (ATF4) were examined. The potential reversal of SIRT1 knockdown effects by 4-phenyl butyric acid (4-PBA; an ER stress inhibitor) was investigated. In vivo, age-related cataract (ARC) rat models were induced by sodium selenite injection, and the protective role of SIRT1, activated by SRT1720 intraperitoneal injections, was evaluated through morphology observation, hematoxylin and eosin (H&E) staining, Western blotting, and RT-PCR. RESULTS: SIRT1 expression was downregulated in TM-induced SRA01/04 cells. Besides, in SRA01/04 cells, both cell apoptosis and CHOP expression increased with the rising doses of TM. ER stress was stimulated by TM, as evidenced by the increased GRP78 and ATF4 in the SRA01/04 cell apoptosis model. Inhibition of SIRT1 by siRNA knockdown increased ER stress activation, whereas SRT1720 treatment had opposite results. 4-PBA partly reverse the adverse effect of SIRT1 knockdown on apoptosis. In vivo, SRT1720 attenuated the lens opacification and weakened the ER stress activation in ARC rat models. CONCLUSION: SIRT1 plays a protective role against TM-induced apoptosis in HLECs and slows the progression of cataract in rats by inhibiting ER stress. These findings suggest a novel strategy for cataract treatment focused on targeting ER stress, highlighting the therapeutic potential of SIRT1 modulation in ARC development.

Abstract Objective In this study, we compared the analgesic effects of intercostal nerve block (ICNB), ultrasound-guided paravertebral nerve block (PVB), and epidural block (EB) following single-port thoracoscopic lung surgery. Method A total of 120 patients who underwent single-hole thoracoscopic lung surgery were randomly and equally divided into three groups: ICNB group, the PVB group, and the EB group. ICNB was performed under direct thoracoscopic visualization before the conclusion of the surgery in the ICNB group, while PVB and EB were performed after general anesthesia in the PVB and EB groups, respectively. Patient-controlled intravenous analgesia (PCIA) was used following the surgery in all the groups. The following indicators were recorded: Intraoperative sufentanil dosage, anesthesia awakening time, postoperative intubation time, nerve block operation time, postoperative visual analog scale (VAS) pain scores during resting and coughing at regular intervals of 0, 2, 4, 8, 24, and 48 h, the time until first PCIA, number of effective compressions within 24 h postoperatively, number of rescue analgesia interventions, and the side effects. Results In comparison to the ICNB group, the PVB and EB groups had a lower intraoperative sufentanil dosage, significantly shorter anesthesia awakening time, and postoperative intubation time, but longer nerve block operation time, lower VAS scores when resting and coughing within 24 h postoperatively (all p-values less than 0.05). Conversely, there were no statistically significant differences in VAS scores during resting and coughing after 24 h (all p-values greater than 0.05). Time to first PCIA, number of effective compressions and number of rescue analgesia at the 24-hour mark postoperatively were significantly better in the PVB and EB groups than that in the ICNB group (P

Purpose: To evaluate the variation and stability of the posterior cornea surface parameters (posterior cornea curvature [PCC], posterior cornea astigmatism [PCA], and posterior cornea elevation [PCE]) after femtosecond laser-assisted in situ keratomileusis (LASIK) in patients with myopia and myopic astigmatism over a period of 6 months or longer. Methods: This retrospective study comprised 284 right eyes. Patients aged 18 years or older with myopia up to -12.00 D and/or astigmatism up to -6.00 DC and who underwent femtosecond LASIK were recruited. Patients were divided into three subgroups: low myopia (-0.50 to -3.00 D), moderate myopia (>-3.00 to ≤-6.00 D), and high myopia (>-6.00 D), according to their pre-LASIK spherical equivalent (SE). The variables included for analysis were PCC (central 0–3.0 mm, pericentral 3.0–6.0 mm, and peripheral region 6.0–9.0 mm), PCE, PCA, internal anterior chamber depth, intraocular pressure, and central cornea thickness at the pre- and post-LASIK stages. Results: The central PCC remained unchanged across all three myopia subgroups at 1 month when compared to the pre-LASIK stage and remained stable at 6 months. The pericentral regions became flatter across all myopia subgroups at 1 month postsurgery (P < 0.001) and remained unchanged at 6 months. This trend was not seen in the peripheral cornea regions, which remained unchanged at 1 and 6 months post-LASIK when compared to pre-LASIK mean readings. There were minimal changes in post-LASIK posterior cornea astigmatism throughout follow-up. There was no incidence of post-LASIK surgery ectasia in this study population. Conclusion: Post-LASIK, the different cornea subregions behaved differently. Overall, the posterior cornea surface remained stable post-LASIK across all myopia subgroups throughout follow-up.

Global Positioning System (GPS) is a famous technology around the world in identifying the real time precise location of any object with the assistance of satellites. The most common application of GPS is the use of outdoor maps. GPS offers efficient, scalable and cost-effective location services. However, this technology is not reliable when the position is in an indoor environment. The signal is very weak or totally lost due to signal attenuation and multipath effects. Among the indoor positioning technologies, WLAN is the most convenient and cost effective. In recent research, machine learning algorithms have become popular and utilized in wireless indoor positioning to achieve better performance. In this paper, different machine learning algorithms are employed to classify different positions in the real-world environment (e.g., Ixora Apartment - House and Multimedia University Malacca – FIST building). Received Signal Strength Indication (RSSI) is collected at each reference point. This data is then used to train the model with hyperparameter tuning. Based on the experiment result, Random Forest achieved 82% accuracy in Ixora Apartment and 84% accuracy in one of the buildings in Multimedia University Malacca. These results outperformed the other models, i.e., K-Nearest Neighbors (KNN) and Support Vector Machine (SVM).

The short-term associations of ambient temperature exposure with lung function in middle-aged and elderly Chinese remain obscure. The study included 19,128 participants from the Dongfeng-Tongji cohort's first (2013) and second (2018) follow-ups. The lung function for each subject was determined between April and December 2013 and re-assessed in 2018, with three parameters (forced vital capacity [FVC], forced expiratory volume in 1 s [FEV1], and peak expiratory flow [PEF]) selected. The China Meteorological Data Sharing Service Center provided temperature data during the study period. In the two follow-ups, a total of 25,511 records (average age: first, 64.57; second, 65.80) were evaluated, including 10,604 males (41.57%). The inversely J-shaped associations between moving average temperatures (lag01–lag07) and FVC, FEV1, and PEF were observed, and the optimum temperatures at lag04 were 16.5 °C, 18.7 °C, and 16.2 °C, respectively. At lag04, every 1 °C increase in temperature was associated with 14.07 mL, 9.78 mL, and 62.72 mL/s increase in FVC, FEV1, and PEF in the low-temperature zone (

Abstract Background Interprofessional collaborative care such as a split-shared care model involving family physicians and community pharmacists can reduce the economic burden of diabetes management. This study aimed to evaluate the economic outcome of a split-shared care model between family physicians and community pharmacists within a pharmacy chain in managing people with uncontrolled type 2 diabetes and polypharmacy. Method This was a multi-center, parallel arm, open label, randomized controlled trial comparing the direct and indirect economic outcomes of people who received collaborative care involving community pharmacists (intervention) versus those who received usual care without community pharmacist involvement (control). People with uncontrolled type 2 diabetes, defined as HbA1c > 7.0% and taking ≥ 5 chronic medications were included while people with missing baseline economic data (such as consultation costs, medication costs) were excluded. Direct medical costs were extracted from the institution’s financial database while indirect costs were calculated from self-reported gross income and productivity loss, using Work Productivity Activity Impairment Global Health questionnaire. Separate generalized linear models with log link function and gamma distribution were used to analyze changes in direct and indirect medical costs. Results A total of 175 patients (intervention = 70, control = 105) completed the trial and were included for analysis. The mean age of the participants was 66.9 (9.2) years, with majority being male and Chinese. The direct medical costs were significantly lower in the intervention than the control group over 6 months (intervention: -US$70.51, control: -US$47.66, p

Abstract Quantum loop and dimer models are prototypical correlated systems with local constraints, which are not only intimately connected to lattice gauge theories and topological orders but are also widely applicable to the broad research areas of quantum materials and quantum simulation. Employing our sweeping cluster quantum Monte Carlo algorithm, we reveal the complete phase diagram of the triangular-lattice fully packed quantum loop model. Apart from the known lattice nematic (LN) solid and the even $${{\mathbb{Z}}}_{2}$$ Z 2 quantum spin liquid (QSL) phases, we discover a hidden vison plaquette (VP) phase, which had been overlooked and misinterpreted as a QSL for more than a decade. Moreover, the VP-to-QSL continuous transition belongs to the (2 + 1)D cubic* universality class, which offers a lattice realization of the (fractionalized) cubic fixed point that had long been considered as irrelevant towards the O(3) symmetry until corrected recently by conformal bootstrap calculations. Our results are therefore of relevance to recent developments in both experiments and theory, and facilitate further investigations of hidden phases and transitions.

Introduction: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare haematologic disease characterised by intravascular haemolysis, thrombophilia and bone marrow failure. There is a lack of established clinical guidance on the screening, diagnosis and management of PNH in Singapore. A relatively low level of awareness among healthcare professionals regarding PNH manifestations further contributes to diagnostic delays. Additionally, limited access to complement inhibitors, like eculizumab, may delay treatment and impact patient outcomes. Method: Nine haematologists from different institutions in Singapore convened to formulate evidence-based consensus recommendations for optimising the diagnosis and management of patients with PNH and improving access to novel treatments. The experts reviewed the existing literature and international guidelines published from January 2010 to July 2023, focusing on 7 clinical questions spanning PNH screening, diagnostic criteria, investigations, treatment and monitoring of subclinical and classic disease, PNH with underlying bone marrow disorders, and PNH in pregnancy. A total of 181 papers were reviewed to formulate the statements. All experts voted on the statements via 2 rounds of Delphi and convened for an expert panel discussion to finetune the recommendations. Results: Sixteen statements have been formulated for optimising the screening, diagnosis and management of PNH. Upon confirmation of PNH diagnosis, individuals with active haemolysis and/or thrombosis should be considered for anti-complement therapy, with eculizumab being the only approved drug in Singapore. Conclusion: The current recommendations aim to guide the clinicians in optimising the screening, diagnosis and management of PNH in Singapore.