The contemporary management of cancers of the sinonasal tract in adults.

Sinonasal malignancies make up <5% of all head and neck neoplasms, with an incidence of 0.5-1.0 per 100,000. The outcome of these rare malignancies has been poor, whereas significant progress has been made in the management of other cancers. The objective of the current review was to describe the incidence, causes, presentation, diagnosis, treatment, and recent developments of malignancies of the sinonasal tract. The diagnoses covered in this review included sinonasal undifferentiated carcinoma, sinonasal adenocarcinoma, sinonasal squamous cell carcinoma, and esthesioneuroblastoma, which are exclusive to the sinonasal tract. In addition, the authors covered malignances that are likely to be encountered in the sinonasal tract-primary mucosal melanoma, NUT (nuclear protein of the testis) carcinoma, and extranodal natural killer cell/T-cell lymphoma. For the purpose of keeping this review as concise and focused as possible, sarcomas and malignancies that can be classified as salivary gland neoplasms were excluded.

Infection-specific phosphorylation of glutamyl-prolyl tRNA synthetase induces antiviral immunity.

The mammalian cytoplasmic multi-tRNA synthetase complex (MSC) is a depot system that regulates non-translational cellular functions. Here we found that the MSC component glutamyl-prolyl-tRNA synthetase (EPRS) switched its function following viral infection and exhibited potent antiviral activity. Infection-specific phosphorylation of EPRS at Ser990 induced its dissociation from the MSC, after which it was guided to the antiviral signaling pathway, where it interacted with PCBP2, a negative regulator of mitochondrial antiviral signaling protein (MAVS) that is critical for antiviral immunity. This interaction blocked PCBP2-mediated ubiquitination of MAVS and ultimately suppressed viral replication. EPRS-haploid (Eprs+/-) mice showed enhanced viremia and inflammation and delayed viral clearance. This stimulus-inducible activation of MAVS by EPRS suggests an unexpected role for the MSC as a regulator of immune responses to viral infection.

Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases.

Resveratrol, a polyphenol in red wine, has been reported as a calorie restriction mimetic with potential antiaging and antidiabetogenic properties. It is widely consumed as a nutritional supplement, but its mechanism of action remains a mystery. Here, we report that the metabolic effects of resveratrol result from competitive inhibition of cAMP-degrading phosphodiesterases, leading to elevated cAMP levels. The resulting activation of Epac1, a cAMP effector protein, increases intracellular Ca(2+) levels and activates the CamKKß-AMPK pathway via phospholipase C and the ryanodine receptor Ca(2+)-release channel. As a consequence, resveratrol increases NAD(+) and the activity of Sirt1. Inhibiting PDE4 with rolipram reproduces all of the metabolic benefits of resveratrol, including prevention of diet-induced obesity and an increase in mitochondrial function, physical stamina, and glucose tolerance in mice. Therefore, administration of PDE4 inhibitors may also protect against and ameliorate the symptoms of metabolic diseases associated with aging.

Specific targeting of cancer vaccines to antigen-presenting cells via an endogenous TLR2/6 ligand derived from cysteinyl-tRNA synthetase 1.

Cancer vaccines have been developed as a promising way to boost cancer immunity. However, their clinical potency is often limited due to the imprecise delivery of tumor antigens. To overcome this problem, we conjugated an endogenous Toll-like receptor (TLR)2/6 ligand, UNE-C1, to human papilloma virus type 16 (HPV-16)-derived peptide antigen, E7, and found that the UNE-C1-conjugated cancer vaccine (UCV) showed significantly enhanced antitumor activity in vivo compared with the noncovalent combination of UNE-C1 and E7. The combination of UCV with PD-1 blockades further augmented its therapeutic efficacy. Specifically, the conjugation of UNE-C1 to E7 enhanced its retention in inguinal draining lymph nodes, the specific delivery to dendritic cells and E7 antigen-specific T cell responses, and antitumor efficacy in vivo compared with the noncovalent combination of the two peptides. These findings suggest the potential of UNE-C1 derived from human cysteinyl-tRNA synthetase 1 as a unique vehicle for the specific delivery of cancer antigens to antigen-presenting cells via TLR2/6 for the improvement of cancer vaccines.

ZNF212 promotes genomic integrity through direct interaction with TRAIP.

TRAIP is a key factor involved in the DNA damage response (DDR), homologous recombination (HR) and DNA interstrand crosslink (ICL) repair. However, the exact functions of TRAIP in these processes in mammalian cells are not fully understood. Here we identify the zinc finger protein 212, ZNF212, as a novel binding partner for TRAIP and find that ZNF212 colocalizes with sites of DNA damage. The recruitment of TRAIP or ZNF212 to sites of DNA damage is mutually interdependent. We show that depletion of ZNF212 causes defects in the DDR and HR-mediated repair in a manner epistatic to TRAIP. In addition, an epistatic analysis of Zfp212, the mouse homolog of human ZNF212, in mouse embryonic stem cells (mESCs), shows that it appears to act upstream of both the Neil3 and Fanconi anemia (FA) pathways of ICLs repair. We find that human ZNF212 interacted directly with NEIL3 and promotes its recruitment to ICL lesions. Collectively, our findings identify ZNF212 as a new factor involved in the DDR, HR-mediated repair and ICL repair though direct interaction with TRAIP.

Antibody-mediated blockade for galectin-3 binding protein in tumor secretome abrogates PDAC metastasis.

The major challenges in pancreatic ductal adenocarcinoma (PDAC) management are local or distant metastasis and limited targeted therapeutics to prevent it. To identify a druggable target in tumor secretome and to explore its therapeutic intervention, we performed a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic analysis of tumors obtained from a patient-derived xenograft model of PDAC. Galectin-3 binding protein (Gal-3BP) is identified as a highly secreted protein, and its overexpression is further validated in multiple PDAC tumors and primary cells. Knockdown and exogenous treatment of Gal-3BP showed that it is required for PDAC cell proliferation, migration, and invasion. Mechanistically, we revealed that Gal-3BP enhances galectin-3-mediated epidermal growth factor receptor signaling, leading to increased cMyc and epithelial-mesenchymal transition. To explore the clinical impact of these findings, two antibody clones were developed, and they profoundly abrogated the metastasis of PDAC cells in vivo. Altogether, our data demonstrate that Gal-3BP is an important therapeutic target in PDAC, and we propose its blockade by antibody as a therapeutic option for suppressing PDAC metastasis.

Protein stability governed by α1-2 helices in Pvr4 is essential for localization and cell death.

Plant nucleotide-binding domain leucine-rich-repeat receptor (NLR) confers disease resistance to various pathogens by recognizing effectors derived from the pathogen. Previous studies have shown that overexpression of the CC domain in several NLRs triggers cell death, implying that the CC domain plays an important role as a signaling module. However, how CC domain transduces immune signals remains largely unknown. A Potyvirus-resistant NLR protein, Pvr4, possesses a CC domain (CCPvr4 ) that induces cell death upon transient overexpression in Nicotiana benthamiana. In this study, loss-of-function mutants were generated by error-prone PCR-based random mutagenesis to understand the molecular mechanisms underlying CCPvr4 -mediated cell death. Cell biology and biochemical studies revealed that M16 and Q52 in the α1 and α2 helices, respectively, are crucial for protein stability, and mutation of these residues disrupts localization to the plasma membrane and oligomerization activity. The increase of the protein stability of these mutants by tagging a green fluorescent protein (GFP) variant led to restoration of cell death-inducing activity and plasma membrane localization. Another mutant, I7E in the very N-terminal region, lost cell death-inducing activity by weakening the interaction with plasma membrane H+ -ATPase compared to CCPvr4 , although the protein remained in the plasma membrane. Moreover, most of the mutated residues are on the outer surface of the funnel shape in the predicted pentameric CCPvr4 , implying that the disordered N-terminal region plays a crucial role in association with PMA as well as targeting to the plasma membrane. This work could provide insights into the molecular mechanisms of cell death induced by NLR immune receptors.

White matter tract density index is associated with disability in multiple sclerosis.

BACKGROUND: The association between common neuroradiological markers of multiple sclerosis (MS) and clinical disability is weak. Given that the disability in patients with MS may depend on the underlying structural connectivity of the brain, our study aimed to examine the association between white matter tracts affected by MS and the patients' disability using a new tract density index (TDI). METHOD: This study included 53 patients diagnosed with MS, examined between 2019 and 2020. Manual lesion segmentation was performed on fluid-attenuated inversion recovery (FLAIR) images, and the density of white matter tracts encompassing the lesion (i.e., TDI) was calculated. Correlation analysis was employed to assess the association between TDI and disability. Additionally, the relationship between disability, TDI, and lesion-derived network metrics was examined by computing a partial correlation network. RESULTS: The TDI significantly correlated with the expanded disability status scale (EDSS) (r = 0.30, p = 0.03). Furthermore, the patient's disability is linked solely through TDI to lesion-derived network metrics -a key metric that 'bridges' the gap between the brain lesion and disability. CONCLUSIONS: In this study, MS lesions encompassing regions with high white matter tract density were associated and linked with severe physical disability. These findings indicate that TDI may be an outcome predictor that may connect radiologic findings to clinical practice.

Glutamyl-prolyl-tRNA synthetase (EPRS1) drives tubulointerstitial nephritis-induced fibrosis by enhancing T cell proliferation and activity.

Toxin- and drug-induced tubulointerstitial nephritis (TIN), characterized by interstitial infiltration of immune cells, frequently necessitates dialysis for patients due to irreversible fibrosis. However, agents modulating interstitial immune cells are lacking. Here, we addressed whether the housekeeping enzyme glutamyl-prolyl-transfer RNA synthetase 1 (EPRS1), responsible for attaching glutamic acid and proline to transfer RNA, modulates immune cell activity during TIN and whether its pharmacological inhibition abrogates fibrotic transformation. The immunological feature following TIN induction by means of an adenine-mixed diet was infiltration of EPRS1high T cells, particularly proliferating T and γδ T cells. The proliferation capacity of both CD4+ and CD8+ T cells, along with interleukin-17 production of γδ T cells, was higher in the kidneys of TIN-induced Eprs1+/+ mice than in the kidneys of TIN-induced Eprs1+/- mice. This discrepancy contributed to the fibrotic amelioration observed in kidneys of Eprs1+/- mice. TIN-induced fibrosis was also reduced in Rag1-/- mice adoptively transferred with Eprs1+/- T cells compared to the Rag1-/- mice transferred with Eprs1+/+ T cells. The use of an EPRS1-targeting small molecule inhibitor (bersiporocin) under clinical trials to evaluate its therapeutic potential against idiopathic pulmonary fibrosis alleviated immunofibrotic aggravation in TIN. EPRS1 expression was also observed in human kidney tissues and blood-derived T cells, and high expression was associated with worse patient outcomes. Thus, EPRS1 may emerge as a therapeutic target in toxin- and drug-induced TIN, modulating the proliferation and activity of infiltrated T cells.

Lysosomal ceramides regulate cathepsin B-mediated processing of saposin C and glucocerebrosidase activity.

Variants in multiple lysosomal enzymes increase Parkinson's disease (PD) risk, including the genes encoding glucocerebrosidase (GCase), acid sphingomyelinase (ASMase) and galactosylceramidase. Each of these enzymes generates ceramide by hydrolysis of sphingolipids in lysosomes, but the role of this common pathway in PD pathogenesis has not yet been explored. Variations in GBA1, the gene encoding GCase, are the most common genetic risk factor for PD. The lysosomal enzyme cathepsin B has recently been implicated as an important genetic modifier of disease penetrance in individuals harboring GBA1 variants, suggesting a mechanistic link between these enzymes. Here, we found that ceramide activates cathepsin B, and identified a novel role for cathepsin B in mediating prosaposin cleavage to form saposin C, the lysosomal coactivator of GCase. Interestingly, this pathway was disrupted in Parkin-linked PD models, and upon treatment with inhibitor of ASMase which resulted in decreased ceramide production. Conversely, increasing ceramide production by inhibiting acid ceramidase activity was sufficient to upregulate cathepsin B- and saposin C-mediated activation of GCase. These results highlight a mechanistic link between ceramide and cathepsin B in regulating GCase activity and suggest that targeting lysosomal ceramide or cathepsin B represents an important therapeutic strategy for activating GCase in PD and related disorders.

Challenges and Recent Analytical Advances in Micro/Nanoplastic Detection.

Despite growing ecological concerns, studies on microplastics and nanoplastics are still in their initial stages owing to technical hurdles in analytical techniques, especially for nanoplastics. We provide an overview of the general attributes of micro/nanoplastics in natural environments and analytical techniques commonly used for their analysis. After demonstrating the analytical challenges associated with the identification of nanoplastics due to their distinctive characteristics, we discuss recent technological advancements for detecting nanoplastics.

HDAC6 preserves BNIP3 expression and mitochondrial integrity by deacetylating p53 at lysine 320.

HDAC6 has been reported as a deacetylase of p53 at multiple lysine residues, associated with the canonical functions of p53, such as apoptosis and tumor suppression. We have previously reported that p53 acetylation at the lysine 320 site accumulates due to the genetic ablation of HDAC6 in mice liver. However, the biological processes affected by K320 acetylation of p53 are yet to be elucidated. In this study, we demonstrate that K320 acetylation of p53 is regulated by HDAC6 deacetylase activity. HDAC6 knockout mouse brains exhibit a significant accumulation of K320 acetylated p53 compared to other tissues. The level of K320 acetylation of p53 inversely correlates with the level of BNIP3, a direct target of p53 and essential for mitophagy. Notably, overexpressing the deacetylation mimic K320R mutant p53 restored BNIP3 expression in HDAC6 knockout MEFs. Furthermore, we observed that neurons are particularly susceptible to the genetic ablation of HDAC6, impacting BNIP3 expression, which inversely correlates with the accumulation of abnormal mitochondria characterized by swollen cristae. Our findings suggest that HDAC6 plays a crucial role in maintaining BNIP3 expression by deacetylating p53 at the K320 site, which is linked to the structural integrity of mitochondria.

Drosophila Activin signaling promotes muscle growth through InR/TORC1-dependent and -independent processes.

The Myostatin/Activin branch of the TGF-ß superfamily acts as a negative regulator of vertebrate skeletal muscle size, in part, through downregulation of insulin/insulin-like growth factor 1 (IGF-1) signaling. Surprisingly, recent studies in Drosophila indicate that motoneuron-derived Activin signaling acts as a positive regulator of muscle size. Here we demonstrate that Drosophila Activin signaling promotes the growth of muscle cells along all three axes: width, thickness and length. Activin signaling positively regulates the insulin receptor (InR)/TORC1 pathway and the level of Myosin heavy chain (Mhc), an essential sarcomeric protein, via increased Pdk1 and Akt1 expression. Enhancing InR/TORC1 signaling in the muscle of Activin pathway mutants restores Mhc levels close to those of the wild type, but only increases muscle width. In contrast, hyperactivation of the Activin pathway in muscles increases overall larval body and muscle fiber length, even when Mhc levels are lowered by suppression of TORC1. Together, these results indicate that the Drosophila Activin pathway regulates larval muscle geometry and body size via promoting InR/TORC1-dependent Mhc production and the differential assembly of sarcomeric components into either pre-existing or new sarcomeric units depending on the balance of InR/TORC1 and Activin signals.

Exploring Doping Mechanisms and Modulating Carrier Concentration in Copper Iodide: Applications in Thermoelectric Materials.

Due to its small hole-effective mass, flexibility, and transparency, copper iodide (CuI) has emerged as a promising p-type alternative to the predominantly used n-type metal oxide semiconductors. However, the lack of effective doping methods hinders the utility of CuI in various applications. Sulfur (S)-doping through liquid iodination is previously reported to significantly enhance electrical conductivity up to 511 S cm-1. In this paper, the underlying doping mechanism with various S-dopants is explored, and suggested a method for controlling electrical conductivity, which is important to various applications, especially thermoelectric (TE) materials. Subsequently, electric and TE properties are systematically controlled by adjusting the carrier concentration from 3.0 × 1019 to 4.5 × 1020 cm-3, and accurately measured thermal conductivity with respect to carrier concentration and film thickness. Sulfur-doped CuI (CuI:S) thin films exhibited a maximum power factor of 5.76 µW cm-1 K-2 at a carrier concentration of 1.3 × 1020 cm-3, and a TE figure of merit (ZT) of 0.25. Furthermore, a transparent and flexible TE power generator is developed, with an impressive output power density of 43 nW cm-2 at a temperature differential of 30 K. Mechanical durability tests validated the potential of CuI:S films in transparent and flexible TE applications.

An Amiable Design of Cobalt Single Atoms as the Active Sites for Oxygen Evolution Reaction in Desalinated Seawater.

Green fuel from water splitting is hardcore for future generations, and the limited source of fresh water (<1%) is a bottleneck. Seawater cannot be used directly as a feedstock in current electrolyzer techniques. Until now single atom catalysts were reported by many synthetic strategies using notorious chemicals and harsh conditions. A cobalt single-atom (CoSA) intruding cobalt oxide ultrasmall nanoparticle (Co3 O4 USNP)-intercalated porous carbon (PC) (CoSA-Co3 O4 @PC) electrocatalyst was synthesized from the waste orange peel as a single feedstock (solvent/template). The extended X-ray absorption fine structure spectroscopy (EXAFS) and theoretical fitting reveal a clear picture of the coordination environment of the CoSA sites (CoSA-Co3 O4 and CoSA-N4 in PC). To impede the direct seawater corrosion and chlorine evolution the seawater has been desalinated (Dseawater) with minimal cost and the obtained PC is used as an adsorbent in this process. CoSA-Co3 O4 @PC shows high oxygen evolution reaction (OER) activity in transitional metal impurity-free (TMIF) 1 M KOH and alkaline Dseawater. CoSA-Co3 O4 @PC exhibits mass activity that is 15 times higher than the commercial RuO2 . Theoretical interpretations suggest that the optimized CoSA sites in Co3 O4 USNPs reduce the energy barrier for alkaline water dissociation and simultaneously trigger an excellent OER followed by an adsorbate evolution mechanism (AEM).

Of sea, rivers and symbiosis: Diversity, systematics, biogeography and evolution of the deeply diverging florideophycean order Hildenbrandiales (Rhodophyta).

The Hildenbrandiales, a typically saxicolous red algal order, is an early diverging florideophycean group with global significance in marine and freshwater ecosystems across diverse temperature zones. To comprehensively elucidate the diversity, phylogeny, biogeography, and evolution of this order, we conducted a thorough re-examination employing molecular data derived from nearly 700 specimens. Employing a species delimitation method, we identified Evolutionary Species Units (ESUs) within the Hildenbrandiales aiming to enhance our understanding of species diversity and generate the first time-calibrated tree and ancestral area reconstruction for this order. Mitochondrial cox1 and chloroplast rbcL markers were used to infer species boundaries, and subsequent phylogenetic reconstructions involved concatenated sequences of cox1, rbcL, and 18S rDNA. Time calibration of the resulting phylogenetic tree used a fossil record from a Triassic purportedly freshwater Hildenbrandia species and three secondary time points from the literature. Our species delimitation analysis revealed an astounding 97 distinct ESUs, quintupling the known diversity within this order. Our time-calibration analysis placed the origin of Hildenbrandiales (crown age) in the Ediacaran period, with freshwater species emerging as a monophyletic group during the later Permian to early Triassic. Phylogenetic reconstructions identified seven major clades, experiencing early diversification during the Silurian to Carboniferous period. Two major evolutionary events-colonization of freshwater habitats and obligate systemic symbiosis with a marine fungus-marked this order, leading to significant morphological alterations without a commensurate increase in species diversification. Despite the remarkable newly discovered diversity, the extant taxon diversity appears relatively constrained when viewed against an evolutionary timeline spanning over 800 million years. This limitation may stem from restricted geographic sampling or the prevalence of asexual reproduction. However, species richness estimation and rarefaction analyses suggest a substantially larger diversity yet to be uncovered-potentially four times greater. These findings drastically reshape our understanding of the deeply diverging florideophycean order Hildenbrandiales species diversity, and contribute valuable insights into this order's evolutionary history and ecological adaptations. Supported by phylogenetic, ecological and morphological evidence, we established the genus Riverina gen. nov. to accommodate freshwater species of Hildenbrandiales, which form a monophyletic clade in our analyses. This marks the first step toward refining the taxonomy of the Hildenbrandiales, an order demanding thorough revisions, notably with the creation of several genera to address the polyphyletic status of Hildenbrandia. However, the limited diagnostic features pose a challenge, necessitating a fresh approach to defining genera. A potential solution lies in embracing a molecular systematic perspective, which can offer precise delineations of taxonomic boundaries.

Metabolomic profiling analysis reveals the benefits of ginseng berry intake on mitochondrial function and glucose metabolism in the liver of obese mice.

INTRODUCTION: Ginseng berry (GB) has previously been demonstrated to improve systemic insulin resistance and regulate hepatic glucose metabolism and steatosis in mice with diet-induced obesity (DIO). OBJECTIVES: In this study, the role of GB in metabolism was assessed using metabolomics analysis on the total liver metabolites of DIO mice. METHODS: Metabolomic profiling was performed using capillary electrophoresis time-of-flight mass spectrometry (CE-TOF/MS) of liver tissue from mice on a 12-wk normal chow diet (NC), high-fat diet (HFD), and HFD supplemented with 0.1% GB (HFD + GB). The detected metabolites, its pathways, and functions were analyzed through partial least square discriminant analysis (PLS-DA), the small molecular pathway database (SMPDB), and MetaboAnalyst 5.0. RESULTS: The liver metabolite profiles of NC, HFD, and GB-fed mice (HFD + GB) were highly compartmentalized. Metabolites involved in major liver functions, such as mitochondrial function, gluconeogenesis/glycolysis, fatty acid metabolism, and primary bile acid biosynthesis, showed differences after GB intake. The metabolites that showed significant correlations with fasting blood glucose (FBG), insulin, and homeostatic model assessment for insulin resistance (HOMA-IR) were highly associated with mitochondrial membrane function, energy homeostasis, and glucose metabolism. Ginseng berry intake increased the levels of metabolites involved in mitochondrial membrane function, decreased the levels of metabolites related to glucose metabolism, and was highly correlated with metabolic phenotypes. CONCLUSION: This study demonstrated that long-term intake of GB changed the metabolite of hepatosteatotic livers in DIO mice, normalizing global liver metabolites involved in mitochondrial function and glucose metabolism and indicating the potential mechanism of GB in ameliorating hyperglycemia in DIO mice.

Elucidation of molecular basis of osteolytic bone lesions in advanced multiple myeloma.

Osteolytic bone lesion is a major cause of lower quality of life and poor prognosis in patients with multiple myeloma (MM), but molecular pathogenesis of the osteolytic process in MM remains elusive. Fms-like tyrosine kinase 3 ligand (FLT3L) was reported to be elevated in bone marrow (BM) and blood of patients with advanced MM who often show osteolysis. Here, we investigated a functional link of FLT3L to osteolytic process in MM. We recruited 86, 306, and 52 patients with MM, acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL), respectively. FLT3L levels of patients with hematologic malignancies were measured in BM-derived plasma and found to be significantly higher in MM than in AML or ALL, which rarely show osteolysis. FLT3L levels were further elevated in MM patients with bone lesion compared with patients without bone lesion. In vitro cell-based assays showed that the administration of FLT3L to HEK293T, HeLa, and U2OS cells led to an increase in the DKK1 transcript level through STAT3 phosphorylation at tyrosine 705. WNT reporter assay showed that FLT3L treatment reduced WNT signaling and nuclear translocation of ß-catenin. These results collectively show that the FLT3L-STAT3-DKK1 pathway inhibits WNT signaling-mediated bone formation in MM, which can cause osteolytic bone lesion. Finally, transcriptomic profiles revealed that FLT3L and DKK1 were predominantly elevated in the hyperdiploidy subtype of MM. Taken together, FLT3L can serve as a promising biomarker for predicting osteolytic bone lesion and also a potential therapeutic target to prohibit the progression of the osteolytic process in MM with hyperdiploidy.

Association of Serum Activin Levels with Allograft Outcomes in Patients with Kidney Transplant: Results from the KNOW-KT.

INTRODUCTION: Serum activin A has been reported to contribute to vascular calcification and kidney fibrosis in chronic kidney disease. We aimed to investigate whether higher serum activin levels were associated with poor allograft outcomes in patients with kidney transplantation (KT). METHODS: A total of 860 KT patients from KNOW-KT (Korean Cohort Study for Outcome in Patients with Kidney Transplantation) were analyzed. We measured serum activin levels pre-KT and 1 year after KT. The primary outcome was the composite of a ≥50% decline in estimated glomerular filtration rate and graft failure. Multivariable cause-specific hazard model was used to analyze association of 1-year activin levels with the primary outcome. The secondary outcome was coronary artery calcification score (CACS) at 5 years after KT. RESULTS: During the median follow-up of 6.7 years, the primary outcome occurred in 109 (12.7%) patients. The serum activin levels at 1 year were significantly lower than those at pre-KT (488.2 ± 247.3 vs. 704.0 ± 349.6). When patients were grouped based on the median activin level at 1 year, the high-activin group had a 1.91-fold higher risk (95% CI, 1.25-2.91) for the primary outcome compared to the low-activin group. A one-standard deviation increase in activin levels as a continuous variable was associated with a 1.36-fold higher risk (95% CI, 1.16-1.60) for the primary outcome. Moreover, high activin levels were significantly associated with 1.56-fold higher CACS (95% CI, 1.12-2.18). CONCLUSION: Post-transplant activin levels were independently associated with allograft functions as well as coronary artery calcification in KT patients.

Global, regional and national epidemiology of alopecia areata: a systematic review and modelling study.

BACKGROUND: Alopecia areata (AA) is a chronic autoimmune disease that leads to a high psychiatric, economic and systemic disease burden. A comprehensive understanding of AA epidemiology is essential for evaluating healthcare source utilization; however, a systematic approach to summarizing epidemiological data on AA is lacking. OBJECTIVES: To investigate systematically the global, regional and national incidence and prevalence of AA. METHODS: A structured search was conducted using the databases MEDLINE, Embase, Cochrane Library, Web of Science, SciELO and Korean Journal Database from their date of inception to 4 October 2023. Studies that reported the prevalence or incidence of AA were included. We used a Bayesian hierarchical linear mixed model to analyse prevalence estimates. The primary outcomes of our study were the global, regional and national prevalence of physician-diagnosed AA for the overall population, for adults and for children. The incidence data were summarized descriptively. RESULTS: In total, 88 studies from 28 countries were included in the analysis. The reported incidence of AA tended to be higher in adults aged 19-50 years, and this trend was consistent with its estimated prevalence. The reported prevalence in overall populations tended to be higher in men vs. women. The estimated lifetime prevalence rate of AA was 0.10% [95% credible interval (CrI) 0.03-0.39] in the general population worldwide, 0.12% (95% CrI 0.02-0.52) in adults and 0.03% (95% CrI 0.01-0.12) in children. The estimated prevalence of AA was highest in the Asian region and lowest in the African region. CONCLUSIONS: In this study, 48% of the Global Burden of Disease regions had insufficient data on the prevalence or incidence of AA. Further studies are needed to provide epidemiological information on middle- and low-income countries. Our study may serve as a crucial reference in terms of healthcare policy decisions.

Alopecia areata (AA) is a chronic autoimmune disease that can have both a psychological and physical impact on patients. An understanding of in whom, when and where the disease occurs ('epidemiology') is important to evaluate how healthcare resources are used in AA. There is a lack of analysis of epidemiological data in AA. This study investigated the global, regional and national incidence (the number of new cases in a specific time period) and prevalence (the rate of new cases occurring in a specific population over a specific period of time) of AA by reviewing multiple databases. Studies that reported the prevalence or incidence of AA were analysed. The primary outcomes were the global, regional and national prevalence of AA diagnosed by a doctor for the overall population, for adults only and for children only. Altogether, 88 studies from 28 countries were included in the review. The incidence of AA tended to be higher in adults aged 19­50 years, and this trend was consistent with its estimated prevalence. The estimated lifetime prevalence rate (i.e. the proportion of individuals that will be affected) of AA was 0.10% in the general population worldwide, 0.12% in adults and 0.03% in children. The estimated prevalence of AA was highest in the Asian region and lowest in the African region. Overall, we found that 48% of regions did not have enough data on the prevalence or incidence of AA. Further studies are needed to provide epidemiological data on AA, especially in middle- and low-income countries. Our results will help with healthcare policy decisions.