STEEP mediates STING ER exit and activation of signaling.

STING is essential for control of infections and for tumor immunosurveillance, but it can also drive pathological inflammation. STING resides on the endoplasmic reticulum (ER) and traffics following stimulation to the ERGIC/Golgi, where signaling occurs. Although STING ER exit is the rate-limiting step in STING signaling, the mechanism that drives this process is not understood. Here we identify STEEP as a positive regulator of STING signaling. STEEP was associated with STING and promoted trafficking from the ER. This was mediated through stimulation of phosphatidylinositol-3-phosphate (PtdIns(3)P) production and ER membrane curvature formation, thus inducing COPII-mediated ER-to-Golgi trafficking of STING. Depletion of STEEP impaired STING-driven gene expression in response to virus infection in brain tissue and in cells from patients with STING-associated diseases. Interestingly, STING gain-of-function mutants from patients interacted strongly with STEEP, leading to increased ER PtdIns(3)P levels and membrane curvature. Thus, STEEP enables STING signaling by promoting ER exit.

Author Correction: STEEP mediates STING ER exit and activation of signaling.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Single-nucleus transcriptome inventory of giant panda reveals cellular basis for fitness optimization under low metabolism.

BACKGROUND: Energy homeostasis is essential for the adaptation of animals to their environment and some wild animals keep low metabolism adaptive to their low-nutrient dietary supply. Giant panda is such a typical low-metabolic mammal exhibiting species specialization of extremely low daily energy expenditure. It has low levels of basal metabolic rate, thyroid hormone, and physical activities, whereas the cellular bases of its low metabolic adaptation remain rarely explored. RESULTS: In this study, we generate a single-nucleus transcriptome atlas of 21 organs/tissues from a female giant panda. We focused on the central metabolic organ (liver) and dissected cellular metabolic status by cross-species comparison. Adaptive expression mode (i.e., AMPK related) was prominently displayed in the hepatocyte of giant panda. In the highest energy-consuming organ, the heart, we found a possibly optimized utilization of fatty acid. Detailed cell subtype annotation of endothelial cells showed the uterine-specific deficiency of blood vascular subclasses, indicating a potential adaptation for a low reproductive energy expenditure. CONCLUSIONS: Our findings shed light on the possible cellular basis and transcriptomic regulatory clues for the low metabolism in giant pandas and helped to understand physiological adaptation response to nutrient stress.

Genome-wide annotation of protein-coding genes in pig.

BACKGROUND: There is a need for functional genome-wide annotation of the protein-coding genes to get a deeper understanding of mammalian biology. Here, a new annotation strategy is introduced based on dimensionality reduction and density-based clustering of whole-body co-expression patterns. This strategy has been used to explore the gene expression landscape in pig, and we present a whole-body map of all protein-coding genes in all major pig tissues and organs. RESULTS: An open-access pig expression map ( www.rnaatlas.org ) is presented based on the expression of 350 samples across 98 well-defined pig tissues divided into 44 tissue groups. A new UMAP-based classification scheme is introduced, in which all protein-coding genes are stratified into tissue expression clusters based on body-wide expression profiles. The distribution and tissue specificity of all 22,342 protein-coding pig genes are presented. CONCLUSIONS: Here, we present a new genome-wide annotation strategy based on dimensionality reduction and density-based clustering. A genome-wide resource of the transcriptome map across all major tissues and organs in pig is presented, and the data is available as an open-access resource ( www.rnaatlas.org ), including a comparison to the expression of human orthologs.

IgG1 Is the Optimal Subtype for Treating Atherosclerosis by Inducing M2 Macrophage Differentiation, and Is Independent of the FcγRIIA Gene Polymorphism.

In recent years, it has been established that atherosclerosis is an autoimmune disease. However, little is currently known about the role of FcγRIIA in atherosclerosis. Herein, we sought to investigate the relationship between FcγRIIA genotypes and the effectiveness of different IgG subclasses in treating atherosclerosis. We constructed and produced different subtypes of IgG and Fc-engineered antibodies. In vitro, we observed the effect of different subtypes of IgG and Fc-engineered antibodies on the differentiation of CD14+ monocytes from patients or healthy individuals. In vivo, Apoe-/- mice were fed a high-fat diet (HFD) for 20 weeks and administered injections of different CVI-IgG subclasses or Fc-engineered antibodies. Flow cytometry was used to assess the polarization of monocytes and macrophages. Although CVI-IgG4 reduced the release of MCP-1 compared to the other subtypes, IgG4 did not yield an anti-inflammatory effect by induction of human monocyte and macrophage differentiation in vitro. Furthermore, genetic polymorphisms of FcγRIIA were not associated with different CVI-IgG subclasses during the treatment of atherosclerosis. In vivo, CVI-IgG1 decreased Ly6Chigh monocyte differentiation and promoted M2 macrophage polarization. We also found that the secretion of IL-10 was upregulated in the CVI-IgG1-treated group, whereas V11 and GAALIE exerted no significant effect. These findings highlight that IgG1 is the optimal subtype for treating atherosclerosis, and CVI-IgG1 can induce monocyte/macrophage polarization. Overall, these results have important implications for the development of therapeutic antibodies.

Isolation and identification of angiotensin-converting enzyme inhibitory peptides from Tartary buckwheat albumin.

BACKGROUND: Tartary buckwheat protein peptides have been shown to be able to inhibit angiotensin-converting enzyme (ACE), but the exact protein type has been less studied for ACE activity inhibition, and only a few types of ACE inhibitory peptides have been reported. In this study, we purified and identified ACE inhibitory peptides from albumin hydrolysate (AH). RESULTS: Albumin, globulin, prolamin and glutelin were extracted from Tartary buckwheat, and their ACE active peptides were obtained by a pepsin-trypsin sequential hydrolysis process. All four hydrolysates exhibited ACE inhibitory activity, and AH displayed the strongest ACE inhibition activity and the highest peptide yield (82.28%). At 0.2 mg mL-1 , the inhibition rate of AH was 79.89%, followed by globulin hydrolysate at 71.84%, while prolamin hydrolysate and glutelin hydrolysate showed lower inhibition rates. The peptides with the highest inhibition rate were then isolated from AH using gel filtration chromatography and reversed-phase high-performance liquid chromatography, and identified using nanoscale high-performance liquid chromatography-tandem mass spectrometry. After isolation and purification, 42 ACE inhibitory peptides were identified in the fraction with the highest inhibition rate, 14 of which were completely novel discoveries in this study. These 14 peptides showed potent ACE inhibitory effects through computer analysis. CONCLUSION: Tartary buckwheat albumin can be used as a good source of ACE inhibitory peptides and can be further developed and utilized as edible supplements or drugs. © 2023 Society of Chemical Industry.

Haplotyping by CRISPR-mediated DNA circularization (CRISPR-hapC) broadens allele-specific gene editing.

Allele-specific protospacer adjacent motif (asPAM)-positioning SNPs and CRISPRs are valuable resources for gene therapy of dominant disorders. However, one technical hurdle is to identify the haplotype comprising the disease-causing allele and the distal asPAM SNPs. Here, we describe a novel CRISPR-based method (CRISPR-hapC) for haplotyping. Based on the generation (with a pair of CRISPRs) of extrachromosomal circular DNA in cells, the CRISPR-hapC can map haplotypes from a few hundred bases to over 200 Mb. To streamline and demonstrate the applicability of the CRISPR-hapC and asPAM CRISPR for allele-specific gene editing, we reanalyzed the 1000 human pan-genome and generated a high frequency asPAM SNP and CRISPR database (www.crispratlas.com/knockout) for four CRISPR systems (SaCas9, SpCas9, xCas9 and Cas12a). Using the huntingtin (HTT) CAG expansion and transthyretin (TTR) exon 2 mutation as examples, we showed that the asPAM CRISPRs can specifically discriminate active and dead PAMs for all 23 loci tested. Combination of the CRISPR-hapC and asPAM CRISPRs further demonstrated the capability for achieving highly accurate and haplotype-specific deletion of the HTT CAG expansion allele and TTR exon 2 mutation in human cells. Taken together, our study provides a new approach and an important resource for genome research and allele-specific (haplotype-specific) gene therapy.

Systematical analysis reveals a strong cancer relevance of CREB1-regulated genes.

The transcription factor cyclic-AMP response element-binding protein 1 (CREB1) responds to cAMP level and controls the expression of target genes, which regulates nutrition partitioning. The promoters of CREB1-targeted genes responsive to cAMP have been extensively investigated and characterized with the presence of both cAMP response element and TATA box. Compelling evidence demonstrates that CREB1 also plays an essential role in promoting tumor development. However, only very few genes required for cell survival, proliferation and migration are known to be constitutively regulated by CREB1 in tumors. Their promoters mostly do not harbor any cAMP response element. Thus, it is very likely that CREB1 regulates the expressions of distinct sets of target genes in normal tissues and tumors. The whole gene network constitutively regulated by CREB1 in tumors has remained unrevealed. Here, we employ a systematical and integrative approach to decipher this gene network in the context of both tissue cultured cancer cells and patient samples. We combine transcriptomic, Rank-Rank Hypergeometric Overlap, and Chipseq analysis, to define and characterize CREB1-regulated genes in a multidimensional fashion. A strong cancer relevance of those top-ranked targets, which meet the most stringent criteria, is eventually verified by overall survival analysis of cancer patients. These findings strongly suggest the importance of genes constitutively regulated by CREB1 for their implicative involvement in promoting tumorigenesis.

CRISPR-C: circularization of genes and chromosome by CRISPR in human cells.

Extrachromosomal circular DNA (eccDNA) and ring chromosomes are genetic alterations found in humans with genetic disorders. However, there is a lack of genetic engineering tools to recapitulate and study the biogenesis of eccDNAs. Here, we created a dual-fluorescence biosensor cassette, which upon the delivery of pairs of CRISPR/Cas9 guide RNAs, CRISPR-C, allows us to study the biogenesis of a specific fluorophore expressing eccDNA in human cells. We show that CRISPR-C can generate functional eccDNA, using the novel eccDNA biosensor system. We further reveal that CRISPR-C also can generate eccDNAs from intergenic and genic loci in human embryonic kidney 293T cells and human mammary fibroblasts. EccDNAs mainly forms by end-joining mediated DNA-repair and we show that CRISPR-C is able to generate endogenous eccDNAs in sizes from a few hundred base pairs and ranging up to 207 kb. Even a 47.4 megabase-sized ring chromosome 18 can be created by CRISPR-C. Our study creates a new territory for CRISPR gene editing and highlights CRISPR-C as a useful tool for studying the cellular impact, persistence and function of eccDNAs.

[Effect of Biofeedback Combined with Task-oriented Training on Hand Function, Gesell Scale Score and Balance Ability in Children with Spastic Cerebral Palsy].

OBJECTIVE: To analyze the effects of biofeedback combined with task-oriented training on hand function, Gesell's infant development scale score (Gesell) and balance ability in children with spastic cerebral palsy (SCP). METHODS: 66 children with SCP admitted to our hospital from January 2016 to June 2018 were randomly divided into the control group and the observation group. The control group ( n=33) received conventional rehabilitation treatment, and the observation group ( n=33) received biofeedback combined with task-oriented training based on the treatment of control group. After 6-month treatment, Modified Ashworth scale (MAS) score, Berg balance scale (BBS) score, standing and walking function score in gross motor function scale (GMFM), assisting hand assessment scales (AHA) score, Gesell scale score and satisfaction of the children's parents were compared between the two groups. RESULTS: The MAS score after treatment was lower than that before treatment in both two groups ( P<0.05), and the BBS score after treatment was higher than that before treatment in both two groups ( P<0.05). After treatment, the MAS score in the observation group was lower than the control group, and the BBS score in the observation group was higher than the control group ( P<0.05). The scores of standing and walking function after treatment were higher than that before treatment in both two groups ( P<0.05). After treatment, the scores of standing and walking function in the observation group were higher than the control group ( P<0.05). The AHA score and Gesell developmental quotient (DQ) score after treatment were higher than that before treatment in both two groups ( P<0.05). After the treatment, the AHA score and Gesell DQ score in the observation group were higher than the control group ( P<0.05). The satisfaction rate of rehabilitation treatment in the observation group was higher than the control group (90.91% vs. 60.61%, P<0.05). CONCLUSION: Biofeedback combined with task-oriented training can improve balance ability, spasm relieve, hand function, development level, standing and walking function in the children with spastic cerebral palsy and increase the treatment satisfaction degree of children's guardians.

Single-cell RNA-seq reveals distinct dynamic behavior of sex chromosomes during early human embryogenesis.

Several animal and human studies have demonstrated that sex affects kinetics and metabolism during early embryo development. However, the mechanism governing these differences at the molecular level before the expression of the sex-determining gene SRY is unknown. We performed a systematic profiling of gene expression comparing male and female embryos using available single-cell RNA-sequencing data of 1607 individual cells from 99 human preimplantation embryos, covering development stages from 4-cell to late blastocyst. We observed consistent chromosome-wide transcription of autosomes, whereas expression from sex chromosomes exhibits significant differences after embryonic genome activation (EGA). Activation of the Y chromosome is initiated by expression of two genes, RPS4Y1 and DDX3Y, whereas the X chromosome is widely activated, with both copies in females being activated after EGA. In contrast to the stable activation of the Y chromosome, expression of X-linked genes in females declines at the late blastocyst stage, especially in trophectoderm cells, revealing a rapid process of dosage compensation. This dynamic behavior results in a dosage imbalance between male and female embryos, which influences genes involved in cell cycle, protein translation and metabolism. Our results reveal the dynamics of sex chromosomes expression and silencing during early embryogenesis. Studying sex differences during human embryogenesis, as well as understanding the process of X chromosome inactivation and their effects on the sex bias development of in vitro fertilized embryos, will expand the capabilities of assisted reproductive technology and possibly improve the treatment of infertility and enhance reproductive health.

Two-year topographic and densitometric outcomes of accelerated (45 mW/cm2) transepithelial corneal cross-linking for keratoconus: a case-control study.

BACKGROUND: Conventional corneal cross-linking is effective for retarding the progression of keratoconus. However the long-term efficacy and safety of accelerated (45 mW/cm2) transepithelial corneal cross-linking (ATE-CXL) on progressive keratoconus (KC) treatment is not fully understood. The purpose of this study is to evaluate the 2-year changes in corneal topographic parameters and densitometry values after ATE-CXL for KC. METHODS: Twenty-five progressive eyes of 25 KC patients (KC group) and 25 eyes of 25 myopes without KC (control group) were enrolled. Corneal topography and densitometry values were evaluated pre-operatively and at 6, 12 and 24 months post-operatively in the KC group. RESULTS: The mean values of flat keratometry (K1), steep keratometry (K2), mean keratometry (Km), corneal astigmatism (CA), maximum keratometry (Kmax), central corneal thickness (CCT), thinnest corneal thickness (TCT), anterior corneal elevation (ACE) and posterior corneal elevation (PCE) all remained unchanged over time (all P values > 0.05). The densitometry values of the anterior, central, posterior and total layers over the annular diameters 0 mm to 2 mm (Φ0-2 mm) and Φ2-6 mm all decreased significantly (all P values < 0.05). At post-operative month 24, except for the densitometry value of the posterior layer (Φ0-2 mm), which was significantly lower than that of the control group (post hoc P = 0.010), all densitometry values obtained from the remaining locations of the KC eyes were equal to those of the control group (All post hoc P values > 0.05). Subgroups with Km ≥ 50.30D or ACE ≥35.3 µm progressed significantly when compared with those with Km < 50.30D (F = 8.167, P = 0.004) or ACE< 35.3 µm (F = 5.207, P = 0.022). CONCLUSIONS: K1, K2, Km, CA, Kmax, CCT, TCT, ACE, and PCE values may remain stable but severer KC patients tend to have poorer long-term outcomes. The densitometry values of the full corneal thickness (total layer over Φ0-2 mm and Φ2-6 mm) may decrease to normal levels at 2 years after ATE-CXL for KC.

Sequencing, annotation, and characterization of the influenza ferret infectome.

Ferrets have become an indispensable tool in the understanding of influenza virus virulence and pathogenesis. Furthermore, ferrets are the preferred preclinical model for influenza vaccine and therapeutic testing. Here we characterized the influenza infectome during the different stages of the infectious process in ferrets with and without prior specific immunity to influenza. RNA from lung tissue and lymph nodes from infected and naïve animals was subjected to next-generation sequencing, followed by de novo data assembly and annotation of the resulting sequences; this process generated a library comprising 13,202 ferret mRNAs. Gene expression profiles during pandemic H1N1 (pdmH1N1) influenza virus infection were analyzed by digital gene expression and solid support microarrays. As expected during primary infection, innate immune responses were triggered in the lung tissue; meanwhile, in the lymphoid tissue, genes encoding antigen presentation and maturation of effector cells of adaptive immunity increased dramatically. After 5 days postinfection, the innate immune gene expression was replaced by the adaptive immune response, which correlates with viral clearance. Reinfection with homologous pandemic influenza virus resulted in a diminished innate immune response, early adaptive immune gene regulation, and a reduction in clinical severity. The fully annotated ferret infectome will be a critical aid to the understanding of the molecular events that regulate disease severity and host-influenza virus interactions among seasonal, pandemic, and highly pathogenic avian influenzas.

Incidence rate and implications of splenic ischemia during sleeve gastrectomy and its related procedure.

Splenic ischemia (SI) is a common finding during sleeve gastrectomy (SG) procedures; however, reports are still lacking. In this study, we retrospectively analyzed our SG patients to understand better the incidence rate and implications of SI. Patients' data from the beginning of the year 2021 until December 2022 that underwent bariatric surgery at our university hospital were retrospectively analyzed. Patient surgery video was reviewed by all the authors to investigate the incidence of SI. Thereafter, the corresponding patient age, height, weight, BMI, and their postoperative day 1 (POD1) temperature and blood routine test results (patients were routinely discharged at POD2) were collected and analyzed. 204 patients were included in this study. The mean age and preoperative BMI were 31.7 ±â€…7.4 years old and 38.8 ±â€…5.6 kg/m2, respectively. SI was observed in 18 cases (8.8%). 30-day readmission rate was seen in 3 patients (1.5%, all without SI during the primary surgery). There was no statistical difference with regard to the POD1 temperature and blood test results between the patients with and without SI. The incidence of SI during sleeve gastrectomy-related procedures is a common finding in our study. We did not observe significant differences postoperatively between the patients with and without SI before discharge. Further study is needed to understand the mechanism for the incidence of SI during SG.

Living alone increases the risk of developing type 2 diabetes mellitus: A systematic review and meta-analysis based on longitudinal studies.

BACKGROUND: Living alone is a prevalent psychological issue that has been found to have significant implications for lifestyle and health status. While considerable research has been conducted to explore the relationship between living alone and the risk of developing type 2 diabetes mellitus (T2DM), the majority of studies have been cross-sectional, leaving direct correlations elusive. Therefore, this study aims to analyze data from longitudinal studies to determine whether living alone increases the risk of T2DM. METHODS: A comprehensive search was conducted in the PubMed, Cochrane, and Embase databases to identify studies examining the association between living alone and T2DM risk. The search encompassed studies published until September 2023. Pooled analysis utilized the random-effects model with inverse variance and included adjusted hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs). RESULTS: The meta-analysis comprised a total of 8 studies, which consisted of 5 prospective cohort studies and 3 retrospective cohort studies. The total population under consideration included 11,686,677 individuals without T2DM, of whom 54.3% were female. Among this population, 396,368 individuals developed T2DM. To account for heterogeneity, a random-effects model was employed. Overall, the pooled data demonstrated a significant association between living alone and an increased risk of T2DM when compared to living with others (HR 1.24, 95% CI 1.06-1.46). Subgroup analysis revealed that this risk was not statistically significant for either males (HR 1.28, 95% CI 0.93-1.76) or females (HR 1.06, 95% CI 0.84-1.33), nor in prospective cohort studies (HR 1.26, 95% CI 0.91-1.74) or retrospective cohort studies (HR 1.26, 95% CI 0.91-1.74). CONCLUSION: Individuals living alone faced a significantly higher risk of developing diabetes compared to those who did not live alone. However, no significant difference in this risk was observed between genders and study types. Further high-quality studies are necessary in the future to elucidate this causal association.

Recurrent hematuria involving urinary system with Klippel-Trenaunay syndrome: A case report.

RATIONALE: Klippel-Trenaunay syndrome (KTS) is a rare congenital venous malformation, it had been found to be caused by mutations of the phosphatidylinositol 4, 5-diphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene. Currently KTS is defined as a triad of skin wine pigmented spots, varicose veins and malformations of the lower extremities, and hypertrophy of bone and soft tissue, involving urinary system up to 6% to 30%. When the urinary system is involved, KTS is often presented as painless massive gross hematuria. PATIENT CONCERNS: This article describes a woman who was hospitalized with painless massive gross hematuria. Physical examination revealed significant hypertrophy of the right lower limb with varicose veins, port-wine stains in the skin, and right perineal hemangiomatous changes with swelling. The patient was admitted to hospital 4 times for repeated hematuria and infection. DIAGNOSES: By physical examination, CT urography, ureteroscopy and cystoscopy, the patient was diagnosed to have Klippel-Trenaunay syndrome, involving the urinary system. INTERVENTIONS: The patient hematuria improved after multiple indwelling D-J tubes and anti-inflammatory treatment. OUTCOMES: The final symptoms of hematuria improved significantly, follow-up so far has not recurred. LESSONS: This case presents the possibility of painless gross hematuria with KTS. Most of patients can be improved by conservative treatment. Cystoscopic laser therapy is the preferred treatment for poor bleeding control. Cystectomy and nephrectomy should be considered when life-threatening.

Spatial Heterogeneity of Nontuberculous Mycobacterial Pulmonary Disease in Shanghai: Insights from a Ten-Year Population-Based Study.

OBJECTIVE: To investigate the spatial heterogeneity of nontuberculous mycobacterial pulmonary disease (NTM-PD) in Shanghai. METHODS: A population-based retrospective study was conducted using presumptive pulmonary tuberculosis surveillance data of Shanghai between 2010 and 2019. The study described the spatial distribution of NTM-PD notification rates, employing hierarchical Bayesian mapping for high-risk areas and the Getis-Ord Gi* statistic to identify hot spots and explore associated factors. RESULTS: Of 1652 NTM-PD cases, the most common species was Mycobacterium kansasii complex (MKC) (41.9%), followed by Mycobacterium avium complex (MAC) (27.1%) and Mycobacterium abscessus complex (MABC) (16.2%). MKC-PD patients were generally younger males with a higher incidence of pulmonary cavities, while MAC-PD patients were more often farmers or had a history of tuberculosis treatment. MKC-PD hot spots were primarily located in the areas alongside the Huangpu River, while MAC-PD hot spots were mainly in the western agricultural areas. Patients with MKC-PD and MAC-PD exhibited a higher risk of spatial clustering compared to those with MABC-PD. CONCLUSIONS: Different types of NTM-PD exhibit distinct patterns of spatial clustering and are associated with various factors. These findings underscore the importance of environmental and host factors in the epidemic of NTM-PD.

Intake of compound probiotics accelerates the construction of immune function and gut microbiome in Holstein calves.

Acquired immunity is an important way to construct the intestinal immune barrier in mammals, which is almost dependent on suckling. To develop a new strategy for accelerating the construction of gut microbiome, newborn Holstein calves were continuously fed with 40 mL of compound probiotics (containing Lactobacillus plantarum T-14, Enterococcus faecium T-11, Saccharomyces cerevisiae T-209, and Bacillus licheniformis T-231) per day for 60 days. Through diarrhea rate monitoring, immune index testing, antioxidant capacity detection, and metagenome sequencing, the changes in diarrhea incidence, average daily gain, immune index, and gut microbiome of newborn calves within 60 days were investigated. Results indicated that feeding the compound probiotics reduced the average diarrhea rate of calves by 42.90%, increased the average daily gain by 43.40%, raised the antioxidant indexes of catalase, superoxide dismutase, total antioxidant capacity, and Glutathione peroxidase by 22.81%, 6.49%, 8.33%, and 13.67%, respectively, and increased the immune indexes of IgA, IgG, and IgM by 10.44%, 4.85%, and 6.12%, respectively. Moreover, metagenome sequencing data showed that feeding the compound probiotics increased the abundance of beneficial strains (e.g., Lactococcus lactis and Bacillus massionigeriensis) and decreased the abundance of some harmful strains (e.g., Escherichia sp. MOD1-EC5189 and Mycobacterium brisbane) in the gut microbiome of calves, thus contributing to accelerating the construction of healthy gut microbiome in newborn Holstein calves. IMPORTANCE: The unstable gut microbiome and incomplete intestinal function of newborn calves are important factors for the high incidence of early diarrhea. This study presents an effective strategy to improve the overall immunity and gut microbiome in calves and provides new insights into the application of compound probiotics in mammals.

Corrigendum: Assessing heterogeneity of patient and health system delay among TB in a population with internal migrants in China.

[This corrects the article DOI: 10.3389/fpubh.2024.1354515.].

Assessing heterogeneity of patient and health system delay among TB in a population with internal migrants in China.

Backgrounds: The diagnostic delay of tuberculosis (TB) contributes to further transmission and impedes the implementation of the End TB Strategy. Therefore, we aimed to describe the characteristics of patient delay, health system delay, and total delay among TB patients in Shanghai, identify areas at high risk for delay, and explore the potential factors of long delay at individual and spatial levels. Method: The study included TB patients among migrants and residents in Shanghai between January 2010 and December 2018. Patient and health system delays exceeding 14 days and total delays exceeding 28 days were defined as long delays. Time trends of long delays were evaluated by Joinpoint regression. Multivariable logistic regression analysis was employed to analyze influencing factors of long delays. Spatial analysis of delays was conducted using ArcGIS, and the hierarchical Bayesian spatial model was utilized to explore associated spatial factors. Results: Overall, 61,050 TB patients were notified during the study period. Median patient, health system, and total delays were 12 days (IQR: 3-26), 9 days (IQR: 4-18), and 27 days (IQR: 15-43), respectively. Migrants, females, older adults, symptomatic visits to TB-designated facilities, and pathogen-positive were associated with longer patient delays, while pathogen-negative, active case findings and symptomatic visits to non-TB-designated facilities were associated with long health system delays (LHD). Spatial analysis revealed Chongming Island was a hotspot for patient delay, while western areas of Shanghai, with a high proportion of internal migrants and industrial parks, were at high risk for LHD. The application of rapid molecular diagnostic methods was associated with reduced health system delays. Conclusion: Despite a relatively shorter diagnostic delay of TB than in the other regions in China, there was vital social-demographic and spatial heterogeneity in the occurrence of long delays in Shanghai. While the active case finding and rapid molecular diagnosis reduced the delay, novel targeted interventions are still required to address the challenges of TB diagnosis among both migrants and residents in this urban setting.