Robust probabilistic modeling for single-cell multimodal mosaic integration and imputation via scVAEIT.

Recent advances in single-cell technologies enable joint profiling of multiple omics. These profiles can reveal the complex interplay of different regulatory layers in single cells; still, new challenges arise when integrating datasets with some features shared across experiments and others exclusive to a single source; combining information across these sources is called mosaic integration. The difficulties lie in imputing missing molecular layers to build a self-consistent atlas, finding a common latent space, and transferring learning to new data sources robustly. Existing mosaic integration approaches based on matrix factorization cannot efficiently adapt to nonlinear embeddings for the latent cell space and are not designed for accurate imputation of missing molecular layers. By contrast, we propose a probabilistic variational autoencoder model, scVAEIT, to integrate and impute multimodal datasets with mosaic measurements. A key advance is the use of a missing mask for learning the conditional distribution of unobserved modalities and features, which makes scVAEIT flexible to combine different panels of measurements from multimodal datasets accurately and in an end-to-end manner. Imputing the masked features serves as a supervised learning procedure while preventing overfitting by regularization. Focusing on gene expression, protein abundance, and chromatin accessibility, we validate that scVAEIT robustly imputes the missing modalities and features of cells biologically different from the training data. scVAEIT also adjusts for batch effects while maintaining the biological variation, which provides better latent representations for the integrated datasets. We demonstrate that scVAEIT significantly improves integration and imputation across unseen cell types, different technologies, and different tissues.

Structure of human NADK2 reveals atypical assembly and regulation of NAD kinases from animal mitochondria.

All kingdoms of life produce essential nicotinamide dinucleotide NADP(H) using NAD kinases (NADKs). A panel of published NADK structures from bacteria, eukaryotic cytosol, and yeast mitochondria revealed similar tetrameric enzymes. Here, we present the 2.8-Å structure of the human mitochondrial kinase NADK2 with a bound substrate, which is an exception to this uniformity, diverging both structurally and biochemically from NADKs. We show that NADK2 harbors a unique tetramer disruptor/dimerization element, which is conserved in mitochondrial kinases of animals (EMKA) and absent from other NADKs. EMKA stabilizes the NADK2 dimer but prevents further NADK2 oligomerization by blocking the tetramerization interface. This structural change bears functional consequences and alters the activation mechanism of the enzyme. Whereas tetrameric NADKs undergo cooperative activation via oligomerization, NADK2 is a constitutively active noncooperative dimer. Thus, our data point to a unique regulation of NADP(H) synthesis in animal mitochondria achieved via structural adaptation of the NADK2 kinase.

Virus-Inspired Glucose and Polydopamine (GPDA)-Coating as an Effective Strategy for the Construction of Brain Delivery Platforms.

The ability of drugs to cross the blood-brain barrier (BBB) is crucial for treating central nervous system (CNS) disorders. Inspired by natural viruses, here we report a glucose and polydopamine (GPDA) coating method for the construction of delivery platforms for efficient BBB crossing. Such platforms are composed of nanoparticles (NPs) as the inner core and surface functionalized with glucose-poly(ethylene glycol) (Glu-PEG) and polydopamine (PDA) coating. Glu-PEG provides selective targeting of the NPs to brain capillary endothelial cells (BCECs), while PDA enhances the transcytosis of the NPs. This strategy is applicable to gold NPs (AuNPs), silica, and polymeric NPs, which achieves as high as 1.87% of the injected dose/g of brain in healthy brain tissues. In addition, the GPDA coating manages to deliver NPs into the tumor tissue in the orthotopic glioblastoma model. Our study may provide a universal strategy for the construction of delivery platforms for efficient BBB crossing and brain drug delivery.

Interference-induced generation of a chirp-free short isolated attosecond pulse in the water window region with multicolor laser fields.

Compensating for the intrinsic attosecond chirp (atto-chirp) of wideband high-order harmonics in the water window region is a significant challenge, in order to obtain isolated attosecond pulses (IAPs) with a width of tens of attoseconds (as). Here, we propose to realize the generation of IAP with duration as short as 20 as, central energy of 365 eV, and bandwidth exceeding 150 eV from chirp-free high harmonics generated by a four-color driving laser, without the necessity for atto-chirp compensation with natural materials. Unlike any other gating methods that an IAP arises from only one electron ionization event, we take advantage of the interference between harmonic radiation produced by multiple ionizing events. We further demonstrate that such chirp-free short IAP survives after taking account of macroscopic propagation effects. Given that the synthesized multicolor laser field can also effectively increase the harmonic flux, this work provides a practical way for experiments to generate the broad bandwidth chirp-free IAPs in the water window region.

Natural Product Baohuoside I Impairs the Stability and Membrane Location of MRP2 Reciprocally Regulated by SUMOylation and Ubiquitination in Hepatocytes.

Epimedii Folium (EF) is a botanical dietary supplement to benefit immunity. Baohuoside I (BI), a prenylated flavonoid derived from EF, has exhibited the cholestatic risk before. Here, the mechanism of BI on the stability and membrane localization of liver MRP2, a bile acid exporter in the canalicular membrane of hepatocytes, was investigated. The fluorescent substrate of MRP2, CMFDA was accumulated in sandwich-cultured primary mouse hepatocytes (SCH) under BI stimulation, followed by reduced membrane MRP2 expression. BI triggered MRP2 endocytosis associated with oxidative stress via inhibition of the NRF2 signaling pathway. Meanwhile, BI promoted the degradation of MRP2 by reducing its SUMOylation and enhancing its ubiquitination level. Co-IP and fluorescence colocalization experiments all proved that MRP2 was a substrate protein for SUMOylation for SUMO proteins. CHX assays showed that SUMO1 prolonged the half-life of MRP2 and further increased its membrane expression, which could be reversed by UBC9 knockdown. Correspondingly, MRP2 accumulated in the cytoplasm by GP78 knockdown or under MG132 treatment. Additionally, the SUMOylation sites of MRP2 were predicted by the algorithm, and a conversion of lysines to arginines at positions 940 and 953 of human MRP2 caused its decreased stability and membrane location. K940 was further identified as the essential ubiquitination site for MRP2 by an in vitro ubiquitination assay. Moreover, the decreased ubiquitination of MRP2 enhanced the SUMOylation MRP2 and vice versa, and the crosstalk of these two modifiers could be disrupted by BI. Collectively, our findings indicated the process of MRP2 turnover from the membrane to cytoplasm at the post-translational level and further elucidated the novel toxicological mechanism of BI.

High Risk of Non-Melanoma Skin Cancer in Actinic Keratosis Patients with Skin of Color: A Nationwide Register-Based Cohort Study.

INTRODUCTION: Actinic keratoses (AK) are rough, scaly patches from UV exposure, increasing the risk of non-melanoma skin cancer (NMSC). This study examines AK incidence in Korea and its role as a risk factor for NMSC. METHODS: A retrospective nationwide register-based cohort study analyzed 2,917 AK patients and 14,585 controls from 2002 to 2019. Patients diagnosed with AK were followed until NMSC occurrence, death, emigration, or December 2019. RESULTS: AK incidence reached 44.8 per 100,000 person-years in 2019. The adjusted hazard ratio for NMSC in AK patients was 8.91 (95% confidence interval, 5.72-13.90). Higher NMSC risk was observed in female AK patients, those under 60 years, and those with lower income levels. The 16-year cumulative incidence of NMSC was 4.19% in AK patients versus 0.44% in controls. CONCLUSION: AK significantly increases the risk of NMSC in Koreans, highlighting the need for tailored surveillance and treatment strategies.

Effects of fecal microbial transplantation on police performance and transportation stress in Kunming police dogs.

Fecal microbiota transplantation (FMT) has been shown to improve gut dysbiosis in dogs; however, it has not completely been understood in police dogs. This study aimed to investigate the effects of FMT on performance and gut microflora in Kunming police dogs. Twenty Wolf Cyan dogs were randomly assigned to receive physiological saline or fecal suspension at low, medium, or high doses through oral gavage for 14 days. Growth performance, police performance, serum biochemical profiling, and gut microflora were determined 2-week post-FMT. Dogs after FMT treatment were also subjected to an hour road transportation and then were evaluated for serum stress indicators. Overall, FMT enhanced the growth performance and alleviated diarrhea rate in Kunming dogs with the greatest effects occurring in the low dose FMT (KML) group. The improvement of FMT on police performance was also determined. These above alterations were accompanied by changed serum biochemical parameters as indicated by elevated total protein and albumin and reduced total cholesterol and glycerol. Furthermore, the serum stress indicators after road transportation in dog post-FMT significantly decreased. Increased bacterial diversity and modified bacterial composition were found in the feces of dogs receiving FMT. The fecal samples from FMT dogs were characterized by higher abundances of the genera Lactobacillus, Prevotella, and Fusobacterium and lower concentrations of Cetobacterium, Allobaculum, Bifidobacterium, and Streptococcus. The present study supports a potential benefit of FMT on police performance in Kunming dogs. KEY POINTS: • FMT improves the growth performance and reduces diarrhea rates in Kunming police dogs. • FMT alleviates the serum stress profiles after road transportation in Kunming police dogs. • FMT modifies the gut microbiota composition of Kunming police dogs.

Fear of cancer recurrence in adolescent patients with malignant bone tumors: a cross-section survey.

BACKGROUND: Adolescent malignant-bone tumor patients' fear of cancer recurrence is a significant psychological issue, and exploring the influencing factors associated with fear of cancer recurrence in this population is important for developing effective interventions. This study is to investigate the current status and factors influencing fear of cancer recurrence (FCR) related to malignant bone-tumors in adolescent patients, providing evidence for future targeted mental health support and interventions. DESIGN: A cross-sectional survey. METHODS: In total, 269 adolescent malignant-bone tumor cases were treated at two hospitals in Zhejiang Province, China from January 2023 to December 2023. Patients completed a General Information Questionnaire, Fear of Progression Questionnaire-Short Form (FoP-Q-SF), Family Hardiness Index (FHI), and a Simple Coping Style Questionnaire (SCSQ). Univariate and multivariable logistic regressions analysis were used to assess fear of cancer recurrence. RESULTS: A total of 122 (45.4%) patients experienced FCR (FoP-Q-SF ≥ 34). Logistic regression analysis analyses showed that per capita-monthly family income, tumor stage, communication between the treating physician and the patient, patient's family relationships, family hardiness a positive coping score, and a negative coping score were the main factors influencing FCR in these patients (P < 0.05). CONCLUSIONS: FCR in malignant-bone tumor adolescent patients is profound. Healthcare professionals should develop targeted interventional strategies based on the identified factors, which affect these patients; helping patients increase family hardiness, helping patients to positively adapt, and avoid negative coping styles.

Introns encode dsRNAs undetected by RIG-I/MDA5/interferons and sensed via RNase L.

Double-stranded RNA (dsRNA), a hallmark viral material that activates antiviral interferon (IFN) responses, can appear in human cells also in the absence of viruses. We identify phosphorothioate DNAs (PS DNAs) as triggers of such endogenous dsRNA (endo-dsRNA). PS DNAs inhibit decay of nuclear RNAs and induce endo-dsRNA via accumulation of high levels of intronic and intergenic inverted retroelements (IIIR). IIIRs activate endo-dsRNA responses distinct from antiviral defense programs. IIIRs do not turn on transcriptional RIG-I/MDA5/IFN signaling, but they trigger the dsRNA-sensing pathways of OAS3/RNase L and PKR. Thus, nuclear RNA decay and nuclear-cytosolic RNA sorting actively protect from these innate immune responses to self. Our data suggest that the OAS3/RNase L and PKR arms of innate immunity diverge from antiviral IFN responses and monitor nuclear RNA decay by sensing cytosolic escape of IIIRs. OAS3 provides a receptor for IIIRs, whereas RNase L cleaves IIIR-carrying introns and intergenic RNAs.

Orchestrated Cytosolic Delivery of Antigen and Adjuvant by Manganese Ion-Coordinated Nanovaccine for Enhanced Cancer Immunotherapy.

Cancer vaccines have received tremendous attention in cancer immunotherapy due to their capability to induce a tumor-specific immune response. However, their effectiveness is compromised by the insufficient spatiotemporal delivery of antigens and adjuvants in the subcellular level to induce a robust CD8+ T cell response. Herein, a cancer nanovaccine G5-pBA/OVA@Mn is prepared through multiple interactions of manganese ions (Mn2+), benzoic acid (BA)-modified fifth generation polyamidoamine (G5-PAMAM) dendrimer, and the model protein antigen ovalbumin (OVA). In the nanovaccine, Mn2+ not only exerts a structural function to assist OVA loading as well as its endosomal escape, but works as an adjuvant of stimulator of interferon genes (STING) pathway. These collaboratively facilitate the orchestrated codelivery of OVA antigen and Mn2+ into cell cytoplasm. Vaccination with G5-pBA/OVA@Mn not only shows a prophylactic effect, but also significantly inhibits growth against B16-OVA tumors, indicating its great potential for cancer immunotherapy.

Automatic block-wise genotype-phenotype association detection based on hidden Markov model.

BACKGROUND: For detecting genotype-phenotype association from case-control single nucleotide polymorphism (SNP) data, one class of methods relies on testing each genomic variant site individually. However, this approach ignores the tendency for associated variant sites to be spatially clustered instead of uniformly distributed along the genome. Therefore, a more recent class of methods looks for blocks of influential variant sites. Unfortunately, existing such methods either assume prior knowledge of the blocks, or rely on ad hoc moving windows. A principled method is needed to automatically detect genomic variant blocks which are associated with the phenotype. RESULTS: In this paper, we introduce an automatic block-wise Genome-Wide Association Study (GWAS) method based on Hidden Markov model. Using case-control SNP data as input, our method detects the number of blocks associated with the phenotype and the locations of the blocks. Correspondingly, the minor allele of each variate site will be classified as having negative influence, no influence or positive influence on the phenotype. We evaluated our method using both datasets simulated from our model and datasets from a block model different from ours, and compared the performance with other methods. These included both simple methods based on the Fisher's exact test, applied site-by-site, as well as more complex methods built into the recent Zoom-Focus Algorithm. Across all simulations, our method consistently outperformed the comparisons. CONCLUSIONS: With its demonstrated better performance, we expect our algorithm for detecting influential variant sites may help find more accurate signals across a wide range of case-control GWAS.

Whole exome sequencing with a focus on cardiac disease-associated genes in families of sudden unexplained deaths in Yunnan, southwest of China.

OBJECTIVES: To explore the causes of sudden unexpected death (SUD) and to search for high-risk people, whole exome sequencing (WES) was performed in families with SUDs.  METHODS: Whole exome sequencing of 25 people from 14 SUD families were screened based on cardiac disease-associated gene variants, and their echocardiograms and electrocardiograms (ECG) were also examined. The protein function of mutated genes was predicted by SIFT, PolyPhen2 and Mutation Assessor. RESULTS: In the group of 25 people from 14 SUD families, 49 single nucleotide variants (SNVs) of cardiac disease-associated genes were found and verified by Sanger sequencing. 29 SNVs of 14 cardiac disorder-related genes were predicted as pathogens by software. Among them, 7 SNVs carried by two or more members were found in 5 families, including SCN5A (c.3577C > T), IRX4 (c.230A > G), LDB3 (c.2104 T > G), MYH6 (c.3G > A), MYH6 (c.3928 T > C), TTN (c.80987C > T) and TTN (c.8069C > T). 25 ECGs were collected. In summary, 4 people had J-point elevation, 2 people had long QT syndrome (LQTS), 4 people had prolonged QT interval, 3 people had T-wave changes, 3 people had sinus tachycardia, 4 people had sinus bradycardia, 4 people had left side of QRS electrical axis, and 3 people had P wave broadening. Echocardiographic results showed that 1 person had atrial septal defect, 1 person had tricuspid regurgitation, and 2 people had left ventricular diastolic dysfunction. CONCLUSIONS: Of the 14 heart disease-associated genes in 14 SUDs families, there are 7 possible pathological SNVS may be associated with SUDs. Our results indicate that people with ECG abnormalities, such as prolonged QT interval, ST segment changes, T-wave change and carrying the above 7 SNVs, should be the focus of prevention of sudden death.

Integrative Analysis of the Role of TP53 in Human Pan-Cancer.

Tumor protein P53 (TP53) is an important tumor suppressor gene in humans. Under normal circumstances, TP53 can help repair mutated genes, or promote the death of cells with severe gene mutations (specifically, TP53 prevents cells from arrest in the G1/S phase when deoxyribonucleic acid (DNA) is damaged and promotes apoptosis if not repaired), and prevents normal cells from becoming malignant cells. TP53 mutations affect its tumor suppressor function, leading to the development of malignant tumors. In this study, using a public database, we explored the pan-cancer expression of TP53, its impact on patient survival and prognosis, the types of gene mutations, its correlation with immunity, and its regulation of other transcription factors and micro RNA (miRNA). The docking sites of therapeutic drugs and key amino acid sites of action provide a basis for future targeted therapies. TP53 has important biological functions in the human body. This study provides a theoretical basis for clinical TP53 gene therapy.

Mitochondrial damage in a Takotsubo syndrome-like mouse model mediated by activation of ß-adrenoceptor-Hippo signaling pathway.

Takotsubo syndrome (TTS) is characterized by short-term contractile dysfunction with its mechanism undefined. We showed that activation of cardiac Hippo pathway mediates mitochondrial dysfunction and that stimulation of ß-adrenoceptors (ßAR) activates Hippo pathway. Here, we investigated the role of ßAR-Hippo signaling in mediating mitochondrial dysfunction in isoproterenol (Iso)-induced TTS-like mouse model. Elderly postmenopausal female mice were administered with Iso (1.25 mg/kg/h for 23 h). Cardiac function was determined by serially echocardiography. At days 1 and 7 post-Iso exposure, mitochondrial ultrastructure and function were examined by electron microscopy and various assays. Alterations in cardiac Hippo pathway and effects of genetic inactivation of Hippo kinase (Mst1) on mitochondrial damage and dysfunction in the acute phase of TTS were investigated. Isoproterenol exposure induced acute increase in biomarkers of cardiac damage and ventricular contractile dysfunction and dilation. At day 1 post-Iso, we observed extensive abnormalities in mitochondrial ultrastructure, downregulation of mitochondrial marker proteins, and mitochondrial dysfunction evidenced by lower ATP content, increased lipid droplets, higher contents of lactate, and augmented reactive oxygen species (ROS). All changes were reversed by day 7. ßAR stimulation led to activation of cardiac Hippo pathway with enhanced expression of Hippo kinase Mst1 and inhibitory YAP phosphorylation, as well as reduced nuclear YAP-TEAD1 interaction. In mice with cardiac expression of inactive mutant Mst1 gene, acute mitochondrial damage and dysfunction were mitigated. Stimulation of cardiac ßAR activates Hippo pathway that mediates mitochondrial dysfunction with energy insufficiency and enhanced ROS, promoting acute but short-term ventricular dysfunction.NEW & NOTEWORTHY Takotsubo syndrome (TTS) is featured by activation of sympatho-ß-adrenoceptor (ßAR) system leading to acute loss of ventricular contractile performance. However, the molecular mechanism remains undefined. We demonstrated, in an isoproterenol-induced murine TTS-like model, extensive mitochondrial damage, metabolic dysfunction, and downregulated mitochondrial marker proteins, changes temporarily associated with cardiac dysfunction. Mechanistically, stimulation of ßAR activated Hippo signaling pathway and genetic inactivation of Mst1 kinase ameliorated mitochondrial damage and metabolic dysfunction at the acute phase of TTS.

Evaluation of Coenzyme Q10 (CoQ10) Deficiency and Therapy in Mouse Models of Cardiomyopathy.

ABSTRACT: Mitochondrial dysfunction plays a key role in the development of heart failure, but targeted therapeutic interventions remain elusive. Previous studies have shown coenzyme Q10 (CoQ10) insufficiency in patients with heart disease with undefined mechanism and modest effectiveness of CoQ10 supplement therapy. Using 2 transgenic mouse models of cardiomyopathy owing to cardiac overexpression of Mst1 (Mst1-TG) or ß 2 -adrenoceptor (ß 2 AR-TG), we studied changes in cardiac CoQ10 content and alterations in CoQ10 biosynthesis genes. We also studied in Mst1-TG mice effects of CoQ10, delivered by oral or injection regimens, on both cardiac CoQ10 content and cardiomyopathy phenotypes. High performance liquid chromatography and RNA sequencing revealed in both models significant reduction in cardiac content of CoQ10 and downregulation of most genes encoding CoQ10 biosynthesis enzymes. Mst1-TG mice with 70% reduction in cardiac CoQ10 were treated with CoQ10 either by oral gavage or i.p. injection for 4-8 weeks. Oral regimens failed in increasing cardiac CoQ10 content, whereas injection regimen effectively restored the cardiac CoQ10 level in a time-dependent manner. However, CoQ10 restoration in Mst1-TG mice did not correct mitochondrial dysfunction measured by energy metabolism, downregulated expression of marker proteins, and oxidative stress nor to preserve cardiac contractile function. In conclusion, mouse models of cardiomyopathy exhibited myocardial CoQ10 deficiency likely due to suppressed endogenous synthesis of CoQ10. In contrast to ineffectiveness of oral administration, CoQ10 administration by injection regimen in cardiomyopathy mice restored cardiac CoQ10 content, which, however, failed in achieving detectable efficacy at molecular and global functional levels.

Constructing Type-II and S-Scheme Heterojunctions of Cu2O@Cu4(SO4)(OH)6·H2O Polyhedra by In Situ Etching Cu2O with Different Exposed Facets for Enhanced Photocatalytic Sterilization and Degradation Performance.

The construction of type-II or S-scheme heterojunctions can effectively accelerate the directional migration of charge carriers and inhibit the recombination of electron-hole pairs to improve the catalytic performance of the composite catalyst; therefore, the construction and formation mechanism of a heterojunction are worth further investigation. Herein, Cu2O@Cu4(SO4)(OH)6·H2O core-shell polyhedral heterojunctions were fabricated via in situ etching Cu2O with octahedral, cuboctahedral, and cubic shapes by sodium thiosulfate (Na2S2O3). Cu2O@Cu4(SO4)(OH)6·H2O polyhedral heterojunctions demonstrated obviously enhanced sterilization and degradation performance than the corresponding single Cu2O polyhedra and Cu4(SO4)(OH)6·H2O. When Cu2O with a different morphology contacts with Cu4(SO4)(OH)6·H2O, a built-in electric field is established at the interface due to the difference in Fermi level (Ef); meanwhile, the direction of band bending and the band alignment are determined. These lead to the different migration pathways of electrons and holes, and thereby, a type-II or S-scheme heterojunction is constructed. The results showed that octahedral o-Cu2O@Cu4(SO4)(OH)6·H2O is an S-scheme heterojunction; however, cuboctahedral co-Cu2O@Cu4(SO4)(OH)6·H2O and cubic c-Cu2O@Cu4(SO4)(OH)6·H2O are type-II heterojunctions. By means of X-ray photoelectron spectroscopy (XPS), ultraviolet photoelectron spectroscopy (UPS), diffuse reflectance spectra (DRS), and Mott-Schottky analyses, the band alignments, Fermi levels, and band offsets (ΔECB, ΔEVB) of Cu2O@Cu4(SO4)(OH)6·H2O polyhedral heterojunctions were estimated; the results indicated that the catalytic ability of the composite catalyst is determined by the type of heterojunction and the sizes of band offsets. Cubic c-Cu2O@Cu4(SO4)(OH)6·H2O has the strongest driving force (namely, biggest band offsets) to accelerate charge migration and effectively separate charge carriers, so it exhibits the strongest catalytic bactericidal and degrading abilities.

Baohuoside I inhibits FXR signaling pathway to interfere with bile acid homeostasis via targeting ER α degradation.

Epimedii folium (EF) is an effective herbal medicine in osteoporosis treatment, but the clinical utilization of EF has been limited due to potential hepatotoxicity. The previous studies identified that baohuoside I (BI), the main active component of EF, was relevant to EF-induced liver injury. However, the mechanisms of BI causing direct injury to hepatocytes remain unclear. Here, we reveal that BI inhibits FXR-mediated signaling pathway via targeting estrogen receptor α (ER α), leading to the accumulation of bile acids (BAs). Targeted bile acid analyses show BI alters the BA composition and distribution, resulting in impaired BA homeostasis. Mechanistically, BI induces FXR-dependent hepatotoxicity at transcriptional level. Additionally, ER α is predicted to bind to the FXR promoter region based on transcription factor binding sites databases and we further demonstrate that ER α positively regulates FXR promoter activity and affects the expression of target genes involved in BA metabolism. Importantly, we discover that ER α and its mediated FXR transcription regulation might be involved in BI-induced liver injury via ligand-dependent ER α degradation. Collectively, our findings indicate that FXR is a newly discovered target gene of ER α mediated BI-induced liver injury, and suggest BI may be responsible for EF-induced liver injury.

Smoking-related cancer death among men and women in an ageing society (China 2020-2040): a population-based modelling study.

BACKGROUND: China is experiencing a postpeak smoking epidemic with accelerating population ageing. Understanding the impacts of these factors on the future cancer burden has widespread implications. METHODS: We developed predictive models to estimate smoking-related cancer deaths among men and women aged ≥35 years in China during 2020-2040. Data sources for model parameters included the United Nations World Population Prospects, China Death Surveillance Database, national adult tobacco surveys and the largest national survey of smoking and all causes of death to date. The main assumptions included stable sex-specific and age-specific cancer mortality rates and carcinogenic risks of smoking over time. RESULTS: In a base-case scenario of continuing trends in current smoking prevalence (men: 57.4%-50.5%; women: 2.6%-2.1% during 2002-2018), the smoking-related cancer mortality rate with population ageing during 2020-2040 would rise by 44.0% (from 337.2/100 000 to 485.6/100 000) among men and 52.8% (from 157.3/100 000 to 240.4/100 000) among women; over 20 years, there would be 8.6 million excess deaths (0.5 million more considering former smoking), and a total of 117.3 million smoking-attributable years of life lost (110.3 million (94.0%) in men; 54.1 million (46.1%) in working-age (35-64 years) adults). An inflection point may occur in 2030 if smoking prevalence were reduced to 20% (Healthy China 2030 goal), and 1.4 million deaths would be averted relative to the base-case scenario if the trend were maintained through 2040. CONCLUSIONS: Coordinated efforts are urgently needed to curtail a rising tide of cancer deaths in China, with intensified tobacco control being key.

A novel treatment for Riehl's melanosis targeting both dermal melanin and vessels.

BACKGROUND/PURPOSE: Riehl's melanosis is a difficult-to-treat condition characterized by persisting dermal hyperpigmentation. This study aimed to evaluate the efficacy of a histology-specific targeted therapy for Riehl's melanosis. METHODS: Skin biopsy samples of Riehl's melanosis were assessed to identify histology-specific targets for treatment. Subsequently, the efficacy of a combination involving a fractional picosecond laser and a pulsed dye laser (PDL) targeting the dermal melanin and vessels, respectively, was evaluated. Clinical improvement was assessed using the dermal pigmentation area and severity index (DPASI). The treatment outcomes were compared to those of a control, in this case a single laser treatment solely targeting pigmentation. RESULTS: Histological and immunohistochemical analyses identified dermal melanin pigment and dilated vessels as treatment targets for Riehl's melanosis. The combined treatment of the fractional picosecond laser and PDL showed a significant reduction of the DPASI scores, which was significantly better than the control group. Patients who underwent the combined laser treatment indicated high levels of satisfaction with no adverse events except of transient erythema and oedema. CONCLUSION: The combined treatment of a fractional picosecond laser and a PDL was more effective for Riehl's melanosis compared to single laser treatment. The treatment targets both dermal pigmentation and dilated vessels, offering promising results for those working to manage Riehl's melanosis.

Development and validation of a nomogram for postoperative sleep disturbance in adults: a prospective survey of 640 patients undergoing spinal surgery.

BACKGROUND: Postoperative sleep disturbance (PSD) is a prevalent clinical complication that may arise due to various factors. The purpose of this investigation is to identify the risk factors for PSD in spinal surgery and establish a risk prediction nomogram. METHODS: The clinical records of individuals who underwent spinal surgery from January 2020 to January 2021 were gathered prospectively. The least absolute shrinkage and selection operator (LASSO) regression, along with multivariate logistic regression analysis, was employed to establish independent risk factors. A nomogram prediction model was devised based on these factors. The nomogram's effectiveness was evaluated and verified via the receiver operating characteristic (ROC) curve, calibration plot, and decision curve analysis (DCA). RESULTS: A total of 640 patients who underwent spinal surgery were analyzed in this investigation, among which 393 patients experienced PSD with an incidence rate of 61.4%. After conducting LASSO regression and logistic regression analyses using R software on the variables in training set, 8 independent risk factors associated to PSD were identified, including female, preoperative sleep disorder, high preoperative anxiety score, high intraoperative bleeding volume, high postoperative pain score, dissatisfaction with ward sleep environment, non-use of dexmedetomidine and non-use of erector spinae plane block (ESPB). The nomogram and online dynamic nomogram were constructed after incorporating these variables. In the training and validation sets, the area under the curve (AUC) in the receiver operating characteristic (ROC) curves were 0.806 (0.768-0.844) and 0.755 (0.667-0.844), respectively. The calibration plots indicated that the mean absolute error (MAE) values in both sets were respectively 1.2% and 1.7%. The decision curve analysis demonstrated the model had a substantial net benefit within the range of threshold probabilities between 20% and 90%. CONCLUSIONS: The nomogram model proposed in this study included eight frequently observed clinical factors and exhibited favorable accuracy and calibration. TRIAL REGISTRATION: The study was retrospectively registered with the Chinese Clinical Trial Registry (ChiCTR2200061257, 18/06/2022).