To screen the potential epigenetic biomarkers associated with endometriosis (EMS) and traditional Chinese medicine (TCM) syndrome EMS types.  A cohort of 99 participants comprising 42 EMS patients with cold coagulation blood stasis (CCBS) syndrome, 35 EMS patients with Qi stagnation blood stasis (QSBS) syndrome, and 22 women of childbearing age without EMS were recruited. Reduced representation bisulfite sequencing (RRBS) was used to establish the differential DNA methylation profiles in human peripheral blood samples obtained from four non-EMS and four EMS patients with CCBS or QSBS syndrome, respectively. Differentially expressed genes (DEGs) were verified in 18 non-EMS, 38 CCBS-EMS, and 31 QSBS-EMS using pyrosequencing.  Methylation sites of 123942, 127229, and 115961 were found in peripheral blood DNA of non-EMS, CCBS-EMS, and QSBS-EMS patients, respectively. GO and KEGG analyses showed that the pathological process of EMS may be closely related to the nervous system development, cell junctions, GABA-gated chloride ion channel activity, nicotine addiction, Hippo signaling pathway, mRNA surveillance pathway, and Wnt signaling pathway. The methylation level at CpG site within HDAC6 gene in QSBS-EMS patients was significantly different from that in control women.  The changes in DNA methylation in peripheral blood samples may be associated with EMS and TCM syndrome EMS types. The methylation level of HDAC6 gene may be used to distinguish QSBS-EMS patients from women without EMS. Endometriosis (EMS) is a common chronic gynecological disease occurring in women of reproductive age , 2. It iThe treatment approaches for EMS in Western medicine are mainly surgery and drugs; however, the recurrence rate is high with these two measures . The effPrevious studies have shown that epigenetic pathways play important roles in the pathology of EMS –16 and tThis study aimed to establish the differential profiles of DNA methylation in peripheral blood of patients with CCBS-type and QSBS-type EMS and to screen for potential biomarkers that may be useful to diagnose EMS and determine TCM syndrome. This will provide a reference for early clinical diagnosis of EMS and the development of personalized TCM treatment approaches, providing new methods to study the pathological mechanism of EMS.With approval from the Ethics Committee of Yueyang Integrated Traditional Chinese and Western Medicine Hospital Affiliated to Shanghai University of Traditional Chinese Medicine  and from the patients using the informed patient consent, 42 CCBS-type and 35 QSBS-type EMS patients who visited the gynecology department of the hospital from September 2018 to June 2020 were selected. These 77 participants were diagnosed with EMS and were aged 20–45 years. With the approval of the Medical Ethics Committee of Shanghai Institute of Family Planning Science No. PJ2018-0818, 22 healthy, nonpregnant women of childbearing age were selected as controls. Patients' diagnoses were according to the 2019 guidelines for the diagnosis and treatment of endometriosis with integrated traditional Chinese and Western medicine .https://www.bioinformatics.babraham.ac.uk/projects/fastqc/available from) [Total genomic DNA was extracted from blood samples using the EasyPure® Genomic DNA Kit according to the manufacturer's instructions. Genome-wide DNA methylation profiles from four non-EMS, four CCBS-EMS, and four QSBS-EMS were examined using RRBS. Briefly, library construction was completed using the TruSeq® DNA LT Sample Prep Kit v2 (Illumina). Extracted DNA of 500 ng was digested using MspI. DNA fragments were processed by 3' and repair, A' tailing, and followed by ligation with barcoded methylated TruSeq LT adapters (Illumina). After bisulfite disposal using the Qiagen EpiTect kit, PCR amplification was performed. Multiplexed samples were pooled into a DNA library, and 100 bp paired-end sequencing was performed on HiSeq-2500 (Illumina). Quality control analysis of sequencing reads was conducted using FastQC software 7 (le from) .https://www.geneontology.org/), and the analysis of pathway enrichment in EMS was performed in accordance with the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database. Search Tool for the Retrieval of Interacting Genes (STRING) was applied to analyze protein-protein interactions among genomes with a confidence coefficient threshold of >0.7. PPI network was visualized using Cytoscape software  and molecular complex detection (MCODE). MCODE score was >4. Functional enrichment analysis of the genomes from single modules was conducted using DAVID when P values were <0.05 (https://david.abcc.ncifcrf.gov/home.jsp) [Gene Ontology (GO) analysis was conducted using Gene Ontology Consortium (ome.jsp) .P value <0.05 and |log2FC|>0.8, FC, fold change) DMRs were tested using pyrosequencing assay. Extracted DNA methylation was assessed using the Qiagen EpiTect Bisulfite kit . PCR amplification  for 40 cycles was performed. Pyrosequencing was performed using PyroMark Q96/48 ID (Qiagen), and the final datasets were calculated using PyroQ CpG software (Biotage) according to the manufacturer's protocols [Sizeable, significant (rotocols .x ± s). One-way ANOVA was used for comparison among multiple groups and nonparametric tests were used for data that did not conform to normal distribution and/or homogeneity of variance. P value was bilateral, and P < 0.05 was considered significant.SPSS software (version 23.0) was used to analyze the data. Measured data were expressed as means ± standard deviation (P < 0.05)  .Using RRBS genome-wide methylation high-throughput sequencing technology, compared to women without EMS, we identified 123942, 127229, and 115961 differentially methylated loci in the peripheral blood DNA of women with EMS, CCBS-EMS, and QSBS-EMS, respectively. There were also 122545 differentially methylated loci between CCBS-EMS and QSBS-EMS patients .GO functional analysis showed that DEGs were useful in nervous system development, cell junctions, and GABA-gated chloride ion channel activity . KEGG enAfter comparing the differentially methylated genes with GO and KEGG analyses results for non-EMS, CCBS-EMS, and QSBS-EMS groups, we verified and compared the DNA methylation levels of three different sites on the CGI of GPR50 gene in peripheral blood of non-EMS, QSBS-EMS, and EMS-CCBS groups. The results showed no significant difference .We also verified and compared the DNA methylation levels of four different sites on CGI of HDAC6 gene in peripheral blood of non-EMS, QSBS-EMS, and CCBS-EMS groups. The results revealed a significant difference in site 2 between QSBS-EMS and non-EMS groups, indicating that methylation was lower in the QSBS group than in the non-EMS group. No significant differences were found among the other sites .In this study, we comprehensively analyzed the differences in the levels of peripheral blood DNA methylation between non-EMS, CCBS-EMS, and QSBS-EMS groups. Using RRBS genome-wide methylation sequencing, compared to the non-EMS group, we screened 123942, 127229, and 115961 differential loci in the peripheral blood DNA of EMS, CCBS-EMS, and QSBS-EMS patients, respectively, of which about 24% were distributed in CGI or LTR regions. There were also 122545 differentially methylated loci between CCBS-EMS and QSBS-EMS, and 25% of these loci were distributed in CGI or LTR region. These results suggest that there may be many differentially expressed genes among these groups.GO enrichment analysis identified the functions of the differentially expressed genes, which may be related to connections between cells, especially neurons, and cell metabolic functions. KEGG analysis suggested that methylation differences may cause primary immune deficiency and O-glycan biosynthesis. The common pathways in CCBS-EMS and QSBS-EMS included melanin production and dorsal ventral axis formation pathways, and the different pathways included fatty acid synthesis, pancreatic secretory activity, and hedgehog signaling pathways.β1 (CTNN β1) regulate the growth of EMS lesions and indicate the boundary of lesions, which are the typical stimulants of the Wnt/β-catenin signaling pathway [β-catenin target genes in EMS [Yes-associated protein (YAP) is a central downstream effector of the Hippo signaling pathway, which is involved in cell proliferation, differentiation, and apoptosis. The expression of YAP is upregulated in the ectopic and eutopic endometria of EMS patients . The dec pathway . Studiess in EMS , and fors in EMS .Differentially methylated genes in peripheral blood of EMS patients are likely to be related to nerve function and the activities of Hippo and Wnt signaling pathways, indicating that these changes may be related to the pathological mechanism of EMS. In particular, the pathology of CCBS-EMS and EMS may be closely related to immune and nervous systems functions. We speculate that the complex interactions between the immune system, nerves, blood vessels, local inflammation, sensory nerve hypersensitivity, and hyperalgesia are important contributors of dysmenorrhea in CCBS-EMS and EMS. The main underlying cause of CCBS syndrome in TCM is improper diet and lifestyle, such as exposure to cold and rain, excessive eating, or excessive consumption of raw and cold substances, causing injury to the internal organ due to cold. Cold stagnation can easily block Qi, blood, and body fluids. Blood stasis can occur in the uterus and Chong-Ren can be obstructed. Cold dominates pain and cold exposure hurts the body, which most likely damages Yang Qi of the body. If Qi and blood channels lose their warmth, their functions will be hindered, causing blood to coagulate and stagnate, and this is usually painful. Pain due to cold generally has two characteristics: one is that the patient has obvious signs of cold exposure and the other is that the degree of pain is reduced in warm temperature and aggravated by cold. Among the six evils, cold has the closest relationship with pain. Our experimental results may provide evidence supporting the TCM theory.After verification, we found that there was a significant difference in the methylation level of site 2 within HDAC6 gene between the QSBS-EMS group and non-EMS group. The HDAC gene family encodes histone deacetylases whose main function is to regulate chromosome structure modification and gene expression. HDAC6 is a member of class II HDAC family and a major cytoplasmic enzyme. It can participate in a variety of biological processes by regulating lysine acetylation and related cellular pathways, and it plays important roles in regulating gene expression, cell cycle processes, autophagy, and apoptosis. Abnormal expression of HDAC6 contributes to the pathological mechanisms of a variety of malignant tumors , 30.β-catenin signaling, thereby inhibiting cell proliferation and migration [Studies have shown that tamoxifen-resistant T47D (T47D-TAR) cells are sensitive to HDAC6 inhibition by its effect on the Hippo pathway and inhibiting HDAC6 by suppressing YAP expression is considered a potential new strategy for treating tamoxifen-resistant breast cancer. Abnormal upregulation of HDAC6 expression can also decrease igration . In addiigration . Notablyigration , 34. Othigration , and HDAigration , 37.EMS-QSBS is mainly caused by depression, anger, and anxiety in TCM. TCM believes that the liver plays an important role in regulating emotions. Abnormal mood leads to the stagnation of liver Qi and liver failure to maintain normal Qi flow. Abnormal blood circulation often occurs when Qi is not flowing smoothly and its stagnation causes blood stasis, dysmenorrhea, late menstruation, and accumulation of ruffian mass. We speculate that QSBS-EMS patients have a more common and stronger tendency of having depression and/or anxiety than patients with other syndrome types. Therefore, we further believe that abnormal HDAC6 gene expression caused by an abnormal HDAC6 methylation level may be one of the pathological causes of immune system disorders and emotional depression in QSBS-EMS patients. In the GO and KEGG analyses, QSBS-EMS type was not found to correlate with immune function. We think it is necessary to increase the sample size and the number of EMS patients with other TCM syndrome types in future research to further explore the occurrence and the mechanism underlying the development of EMS in association with other TCM syndrome types.This study has two limitations. First, the mechanisms relating signal pathways to pathological processes in different types of EMS were not experimentally confirmed. Second, the sample size was relatively small. Larger sample sizes are needed for further experimental validation of DEGs and their expression.This study systematically elucidated the unique observed changes in peripheral blood DNA methylation levels in CCBS-EMS and QSBS-EMS patients and confirmed the existence of many differences in peripheral blood DNA methylation levels between CCBS-EMS and QSBS-EMS patients.This study also found that the pathological mechanism of CCBS and QSBS-type EMS may be related to disorders in the nervous system development and immune system function, but there may be differences in pathological characteristics including metabolic function and emotional influence, and HDAC6 may be a potential molecular marker of QSBS-type EMS.


Agrobacterium-mediated transformation of established wheat cell suspension cultures. This system was used for the evaluation of a CRISPR/Cas9 construct designed to target the ABA 8′-hydroxylase 1 gene. The efficiency of editing was verified by cost-effective means of Sanger sequencing and bioinformatic analysis. We discuss advantages and potential future developments of this method in contrast to other in vitro approaches.Despite intensive optimization efforts, developing an efficient sequence-specific CRISPR/Cas-mediated genome editing method remains a challenge, especially in polyploid cereal species such as wheat. Validating the efficacy of nuclease constructs prior to using them in planta is, thus, a major step of every editing experiment. Several construct evaluation strategies were proposed, with PEG-mediated plasmid transfection of seedling-derived protoplasts becoming the most popular. However, the usefulness of this approach is affected by associated construct copy number bias and chromatin relaxation, both influencing the outcome. Therefore, to achieve a reliable evaluation of CRISPR/Cas9 constructs, we proposed a system based on an  Triticum aestivum L.) with CRISPR/Cas9 are still very limited due to various factors, namely the efficiency of T-DNA integration, the in vitro regeneration capacity of a given genotype and the high number of single nucleotide polymorphisms (SNPs) interfering with sgRNA annealing . The 5% cut-off was used as a limit of detection for TIDE analysis. Non-transgenic suspension-derived genomic DNA was used as a control template in all experiments.The TRIzol-based method  was usedous work , whereasous work  with TID


Viruses on 30 November 2021. The authors developed a double-antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA) for porcine deltacoronavirus (PDCoV) detection using a monoclonal antibody against the PDCoV N protein and an anti-PDCoV rabbit polyclonal antibody. They used kappa analysis to determine the consistency between the DAS-ELISA and reverse transcriptase real-time PCR (RT-qPCR). The kappa value obtained was 0.827, indicating an almost perfect agreement between the two methods.We were interested in reading an article published by Wang et al.  in VirusAlthough this article has provided valuable information, some substantial points that may cause misinterpretation of the results need to be clarified. Kappa analysis includes Cohen’s and Fleiss’ kappa analyses. Generally, Cohen’s and Fleiss’ kappa analyses are used to analyze intra- and inter-rater agreements, respectively . Cohen’sThe value of The authors compared the two detection methods using two types of clinical samples, namely, 205 fecal and 59 intestinal samples. Unlike the authors, we calculated the agreement between the RT-qPCR and DAS-ELISA by using the two types of samples with SPSS 18 statistical package  software. The kappa values in the fecal and intestinal samples were 0.807 and 0.645, respectively. Furthermore, a simple sum of the data was performed, and the kappa value obtained was 0.781 . The thrConsidering the applicability of Cohen’s kappa analysis, we suggest that the kappa values should be calculated in the presence of two or more types of samples. In our opinion, any agreed conclusions must be supported by methodological and statistical methods. We emphasize the importance of rigor and using the correct statistical approach in any scientific publication. Otherwise, misinterpretation cannot be avoided.


Patients receiving thoracic aortic repair suffer from long-term impairment in daily functioning and quality of life following intervention due to a combination of their life-threatening condition (i.e. aortic aneurysm or dissection), undergoing major surgery, as well as long-term exercise restrictions thereafter. Despite the known risks of exercise, it is vital that patients regain physical activity in order to recover their daily functioning and quality of life. Cardiac rehabilitation could be a safe and effective treatment to support patients to become physically active by providing exercise training, comprehensive rehabilitation services, and safety recommendations. Despite new insights in recent literature and clinical practice, international guidelines do not recommend cardiac rehabilitation due to limited evidence. We aim to fill this knowledge gap by performing a systematic review and meta-analysis on the effectiveness of cardiac rehabilitation in patients following thoracic aortic repair.This protocol has been developed following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). MEDLINE, Embase, and CINAHL will be searched for eligible observational and interventional studies from inception up to April 2022. Screening (title/abstract and full text), data extraction, risk of bias assessment, and therapeutic validity rating will be conducted by two independent reviewers. A random-effects model will be used to meta-analyse performance-based outcomes, patient-reported outcomes, clinician-reported outcomes, and researcher-reported outcomes. Subsequently, meta-bias and confidence in evidence will be analysed by two independent reviewers.To exercise or not to exercise in patients following thoracic aortic repair has been a topic of discussion for years. The intended systematic review and meta-analysis will provide comprehensive evidence on the effectiveness of phase III outpatient exercise-based cardiac rehabilitation in patients following thoracic aortic repair. Findings from this review may inform future guidelines for the management of patients with thoracic aortic disease.PROSPERO CRD42022301204.The online version contains supplementary material available at 10.1186/s13643-023-02180-x. Thoracic aortic aneurysm or dissection, also known as thoracic aortic disease, is a life-threatening condition . The incCardiac rehabilitation could be a promising strategy to improve outcomes such as daily functioning and quality of life following thoracic aortic repair. It consists of several core components, including exercise training, lifestyle coaching, medication monitoring to support cardio-vascular risk reduction, healthy behaviour, psychosocial well-being, and an active lifestyle in patients with heart disease . The effInternational guidelines are restraint on cardiac rehabilitation recommendations for patients following thoracic aortic repair. The 2010 ACCF/AHA guideline  and 2014Recent studies indicate that there is an urgent need for cardiac rehabilitation in patients following thoracic aortic repair , 19–21. Our study protocol follows the Preferred Items for Systematic Reviews and Meta-Analysis – protocol (PRISMA-P) statement  and has A comprehensive electronic search will be conducted in MEDLINE (Ovid), Embase (Ovid), and CINAHL  Plus (EBSCO) from inception up to April 2022. Additional studies will be identified from (1) reviewing the reference lists of eligible full-text studies through a hand search (backward citation searching) and (2) screening studies that cited the eligible full-text studies according to Web of Science (forward citation searching). Conference proceedings, bibliographies of systematic reviews and trial registers will not be searched. No language or other limitations will be used.Observational studies (i.e. cohort studies and registries) and interventional studies  will be searched for outcomes after cardiac rehabilitation. The search fields ‘Title’, ‘Abstract’, and ‘Medical Subject Headings (MeSH)/Thesaurus’ will be applied to ensure the best possible study retrieval. Detailed search strategies will be developed for each electronic database searched with input from a medical librarian  . After rversus dissection), and medical history (i.e. connective tissue disease such as Marfan or Loeys-Dietz). Details of the intervention will be extracted about the rehabilitation program . Extracted data will include information on study author(s), year of publication, journal, study design, inclusion criteria, exclusion criteria, number of participants, outcome measures, and follow-up. Details regarding participants in each study will include sex, age, cardiovascular risk factors , pharmaceutical treatment (i.e. beta blockers), diagnosis received . Depending on the data reported in the studies, we will collect the raw data, the aggregated outcomes or both. In studies reporting aggregated data, the estimates (i.e. means and medians) will be extracted along with their variation . Details of the outcomes will be extracted about performance-based, patient-reported, clinician-reported, and researcher-reported outcomes Table .The Risk of Bias In Non-randomised Studies of Interventions (ROBINS-I) tool will be used to assess the risk of bias of non-randomised interventional studies . StudiesTherapeutic validity will be scored with the International Consensus on Therapeutic Exercise and Training (i-CONTENT) tool and considers the following seven items: patient selection, dosage of exercise program, type of exercise program, qualified supervisor, type and timing of outcome assessment, safety of exercise program, and adherence to exercise program (online supplementary file https://automeris.io/WebPlotDigitizer) if not reported in text.We will try to contact the original investigators to request missing data. If estimates and variation  were reported differently between studies (i.e. median and range), the formula of Hozo et al.  will be I2 statistics are used to assess the heterogeneity, with I2 statistics ≤ 25% representing low heterogeneity and ≥ 75% (p < 0.10) representing high heterogeneity [versus other) or diagnosis (patients with connective tissue disease versus other) [If possible, a meta-analysis will be conducted using Review Manager . Extractogeneity . A subgrs other) . No sensFor the assessment of meta-bias, outcome reporting bias will be assessed by comparing outcomes listed in the study protocol or methods section with the actually reported outcomes . PublicaThe overall confidence in the body of evidence will be determined with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach . Two revA paradigm shift is perceptible in the recent scientific literature. Healthcare professionals are willing to provide cardiac rehabilitation in patients following thoracic aortic repair. However, they do not know what the benefits are, which safety recommendations apply, and whether the risk of adverse events outweighs the benefits . To our There are limitations to this study protocol. First, we excluded studies using endovascular procedures. We acknowledge that thoracic endovascular aortic repair is a promising, safe, and effective procedure to treat descending thoracic aortic aneurysms showing similar perioperative and long-term results compared to open thoracic aortic repair . HoweverAdditional file 1. Concept search strings.Additional file 2. i-CONTENT tool.


Objective: to measure the HPV vaccination rate and knowledge about HPV and its vaccine among foreign-born college students; additionally, to measure the effect of acculturation and HBM constructs on the HPV vaccination behavior among foreign-born college students. Methods: a cross-sectional design with a non-probability sample of foreign-born college students was collected via a web-based self-administered survey that measured the HPV vaccination rate, assessed knowledge about HPV and its vaccine, and evaluated the effect of acculturation and HBM constructs on HPV vaccination behavior among foreign-born college students. Results: Foreign-born college students had moderate knowledge about HPV and the HPV vaccine, and about 63% were HPV-vaccinated. Perceived susceptibility, perceived barriers, and cues to action were significantly associated with the HPV vaccination behavior, while knowledge levels about HPV and the HPV vaccine and acculturation levels were not significantly associated with the HPV vaccination behavior of foreign-born college students. Conclusions: The current study shows a moderate vaccination rate and moderate knowledge about HPV and its vaccine among foreign-born college students. Additionally, vaccination campaigns need to increase awareness about the susceptibility to acquiring HPV and minimize the barriers to receiving the vaccine to increase the HPV vaccination rate among foreign-born college students. Human papillomavirus (HPV) is the most prevalent sexually transmitted disease (STD), with over 43 million people already carrying HPV and 14 million contracting it yearly in the United States . The HPVIn 2018, over 1.7 million foreign-born students attended colleges and universities in the U.S., representing 9% of the U.S. college student population . RegardiForeign-born college students come from countries with different languages, beliefs, values, and backgrounds, and they must choose how much of their cultural identity to preserve and how much to adapt to the host culture when interacting with their new environment . AccultuAcculturation significantly impacts how foreign-born adults seek health information . HoweverThe Health Belief Model (HBM), a cognitive theory, was developed by psychologists to explain why many individuals failed to participate in a program that prevented and detected disease . The HBMThe HBM is one of the most extensively used conceptual frameworks in health behavior research, used to explain changes in health-related behaviors as well as to guide intervention design ,16. NumeWhile limited studies measured the HPV vaccination rate and knowledge levels about HPV and the HPV vaccine among foreign-born college students in the U.S., this study aimed to measure the HPV vaccination rate and knowledge about HPV and the HPV vaccine among foreign-born college students in the U.S. Additionally, while limited studies measured the effect of acculturation levels of foreign-born college students on HPV vaccination behavior, and no prior research measured the impact of six HBM constructs on the HPV vaccination behavior among foreign-born college students in the U.S., this study aimed to estimate the effect of acculturation levels and the six HBM constructs on the HPV vaccination behavior of foreign-born college students in the U.S.A quantitative cross-sectional survey with a non-probability sample of college students at Nova Southeastern University (NSU) was collected via a self-administered web-based survey. REDCap (Research Electronic Data Capture) is a secure online system for developing and administering web-based surveys. In April 2022, an email with a study invitation and survey link was sent to all NSU students. Students were eligible to participate in the study based on these inclusion criteria: (1) 18 years old and older, (2) proficient in English, and (3) able to provide informed consent. To increase the response rate, the first 400 student participants received a USD 15 gift card as compensation for their participation after completing the survey. A total of 2843 college students filled up the online survey. Only foreign-born college students were included in the analysis of this study (n = 376).The study survey consisted of a series of validated instruments, including a sociodemographic, HPV vaccination status, knowledge about HPV and the HPV vaccine, HBM constructs, and acculturation instruments. Ten student volunteers pre-tested these instruments to ensure the adequacy of the survey instruments.The HPV vaccination behavior was measured by using one item whereby students who received at least one dose of the HPV vaccine were coded as (HPV-vaccinated = 1), and those who did not receive any dose of the HPV vaccine were coded as (non-HPV-vaccinated = 0).Students were asked a series of questions regarding HPV and the HPV vaccine  adapted from different studies  vaccination is recommended only for women and girls” “HPV can infect the oral cavity, respiratory tract, and eyes” and “A person usually has symptoms when infected with HPV”) ,22,23. RThe HBM instrument contained six constructs of HBM  adapted from the literature ,25,26. TAcculturation was measured using a modified version of the East Asian Acculturation Measure (EAAM). EAAM was developed by Berry (2001), contained 29 items, and used a 7-point Likert scale to measure four acculturation modes: Assimilation, Integration, Separation, and Marginalization [t-test was computed to test the mean difference in HPV knowledge scores, perceived susceptibility, perceived severity, perceived benefits, perceived barriers, self-efficacy, and cues to action constructs across different HPV vaccination statutes and acculturation levels. Finally, multivariate logistic regression analysis was conducted to determine the unique effect of independent variables  on the outcome variable (HPV vaccination status of foreign-born college students). All data analyses were performed using IBM® Statistical Package for the Social Sciences (SPSS), version 28.0.Descriptive analysis was used to summarize and describe the data. The Chi-square test was calculated to test the difference in HPV vaccination rate and acculturation levels across different sociodemographic characteristics of foreign-born college students. Additionally, the independent samples A total of 376 foreign-born college students were included in this study. About 67% of them were females. The mean age was 25.4 years old, and about 65% were young adult students (18 to 26 years old). About 33% of foreign-born college students identified themselves as international students. Additionally, 42%, 22%, and 20% of foreign-born college students were Hispanic/Latino, White, and Asian, respectively. Further, 58% of foreign-born college students had been living in the U.S for ten years or less. A majority were in a health professional major (69%). Additionally, about 7% were HPV-positive and 5% had a family history of cervical cancer .p-value < 0.001). Additionally, about 72% and 46% of young adult students (18 to 26 years old) and middle-aged adults (26 years old and older) of foreign-born college students were HPV-vaccinated, respectively . Further, 72%, 69%, and 63% of Hispanic/Latino, Black, and White foreign-born college students were HPV-vaccinated, respectively . About 71% of foreign-born college students with more than ten years of living in the U.S. were HPV-vaccinated, while about 57% of foreign-born college students with ten years or less of living in the U.S. were HPV-vaccinated . About 54% of international foreign-born college students were HPV-vaccinated, while about 68% of non-international foreign-born college students were HPV-vaccinated   .p-value < 0.001). On the other hand, about 50% of low acculturated foreign-born college students were females and 63% were international students . Additionally, about 51% of foreign-born college students with high acculturation had ten years or less of living in the U.S. In comparison, about 85% of foreign-born college students with low acculturation had ten years or less of living in the U.S. .According to their acculturation score, 80% of foreign-born college students had a high acculturation level. A Chi-square test was performed to identify any significant difference in the sociodemographic characteristics between the two acculturation levels. About 72% of high acculturated foreign-born college students were female and 25% were international students   .Foreign-born college students had moderate knowledge about HPV and the HPV vaccine . Eighty-three percent of foreign-born college students did not know that no screening is used to test males for HPV infection. Additionally, about 61%, 60%, and 57% of foreign-born college students did not know that HPV infection can cause penile cancer, anal cancer, and oropharyngeal cancer, respectively. Additionally, about 79% of them did not realize that a condom does not prevent HPV infection .t-test was conducted to test the mean difference in HPV knowledge levels among foreign-born college students across different HPV vaccination statuses and acculturation levels. Foreign-born college students who received at least one dose of the HPV vaccine had higher knowledge levels about HPV and the HPV vaccine than those who did not receive the HPV vaccine . Additionally, foreign-born college students with a high acculturation level had higher knowledge levels about HPV and the HPV vaccine than those with a low acculturation level  (An independent sample < 0.001) .Foreign-born college students perceived the high severity of HPV and HPV-related diseases (M = 4.07), high self-efficacy to receive the HPV vaccine (M = 4.02), and high benefits of receiving the HPV vaccine (M = 3.99). In addition, they perceived high to moderate susceptibility to acquiring HPV (M = 3.12). Additionally, Foreign-born college students perceived low to moderate cues to receive the HPV vaccine (M = 2.86) and barriers to receiving the HPV vaccine (M = 2.30).t-test was conducted to test the mean difference of the six HBM constructs levels among foreign-born college students across different HPV vaccination statuses and acculturation levels. Foreign-born college students who received at least one dose of the HPV vaccine perceived a high susceptibility to acquiring HPV, perceived a high severity of HPV-related diseases, perceived more benefits of receiving the HPV vaccine, perceived fewer barriers to receiving the HPV vaccine, perceived more cues to receive the HPV vaccine, and perceived more self-efficacy to receive the HPV vaccine compared with those who did not receive the HPV vaccine .An independent sample p-value < 0.05)  .2 = 108.6, p-value < 0.001) and explained roughly 34% of the variation in HPV vaccination behavior of foreign-born college students (Nagelkerke R2 = 0.343). Three constructs of HBM  were significantly associated with the HPV vaccination status of foreign-born college students. Perceived susceptibility and cues to action were significantly associated with increased HPV vaccination behavior . The perceived barrier to receiving the HPV vaccine was significantly associated with decreased HPV vaccination behavior . However, knowledge levels about HPV and the HPV vaccine and acculturation levels were not significantly associated with the HPV vaccination uptake of foreign-born college students  on the HPV vaccination behavior of foreign-born college students. The model was significant . These results are consistent with other studies, whereas college students have moderate knowledge about HPV and the HPV vaccine . Most foPerceived susceptibility, perceived barriers, and cues to action constructs of HBM were significant predictors of HPV vaccination behavior among foreign-born college students. Foreign-born college students who perceived high susceptibility to acquiring HPV or HPV-related diseases were more likely to be HPV-vaccinated. This finding is consistent with other studies ,42. As aContrary to expectations, acculturation levels were not significantly associated with the HPV vaccination behavior of foreign-born college students, which is consistent with previous studies. Acculturation level did not affect Latina parents’ decision to vaccinate their children against HPV, and it did not affect the HPV vaccine completion among Latina adolescents ,43,44. HThe outcomes of this study have significant implications for researchers and healthcare providers. This study indicates that the HPV vaccination rate among foreign-born college students remains lower than the target of 2020 healthy people of 80%. Additionally, the findings of this study highlight a low to moderate knowledge level about HPV and the HPV vaccine among them. The study’s results help identify foreign-born college student categories with lower HPV vaccination rates. Additionally, this study’s results may help develop interventions to encourage foreign-born college students to receive the HPV vaccine. Educating foreign-born college students on the risks and vulnerabilities associated with HPV infection, providing a recommendation for receiving the HPV vaccine, and removing obstacles to receiving the vaccine can enhance their attitudes toward HPV vaccination. Therefore, healthcare professionals and student health centers can provide recommendations and education to encourage more college students to receive the HPV vaccine. Additionally, community pharmacists play a crucial role in boosting the HPV vaccination as they provide immunization services. Community pharmacists help educate foreign-born students about the importance of receiving the HPV vaccine and give recommendations for receiving the vaccine . This stSeveral limitations need to be acknowledged. First, the only language in which the study’s questionnaires were given out was English. Therefore, only foreign-born college students who were proficient in English were able to respond. Second, the convenience sampling method used in this study restricted the generalizability of the results to other populations. Third, foreign-born college students in this study were recruited from one university, which also restricted the generalizability of the results. Fourth, conclusions regarding causality were limited because of the use of a cross-sectional design in this study. Fifth, using a self-report survey in this study may include recall bias, which might overstate or understate the strength of the suggested correlations. Sixth, the lack of standardization for the health belief model instrument for the HPV vaccination behavior is another limitation of this study. Seventh, this study measured HPV and the HPV vaccine knowledge levels without evaluating the awareness of HPV and the HPV vaccine, which might overstate or understate their knowledge levels about HPV and the HPV vaccine. Lastly, this study compared foreign-born college students who received at least one dose of the HPV vaccine and those who did not without estimating the rate of foreign-born college students who received all doses of the HPV vaccine.This study was one of few studies that aimed to assess the HPV vaccination rate and knowledge of HPV and the HPV vaccine among foreign-born college students in the U.S. Additionally, it examined the effect of acculturation levels and six HBM constructs on the HPV vaccination behavior of foreign-born college students. This study indicates the percentage of HPV vaccination among foreign-born college students is still below the 80% target for healthy people in 2020. About three-fifths of foreign-born college students received at least one dose of the HPV vaccine, and they had a moderate knowledge level about HPV and the HPV vaccine. In addition, foreign-born college students with low acculturation had very low HPV vaccination rates and very low knowledge levels about HPV and the HPV vaccine compared with those with high acculturation. Perceived susceptibility, perceived barriers, and cues to the action of HBM constructs were significantly associated with HPV vaccination behavior among foreign-born college students. However, acculturation was not significantly associated with HPV vaccination behavior. Therefore, increasing awareness about the vulnerability of acquiring the HPV, recommending the HPV vaccine, and eliminating barriers associated with receiving the vaccine can improve the HPV vaccination rate among foreign-born college students. The results of this study offer relevant findings about HPV vaccination behavior and predictor factors of receiving the HPV vaccine among foreign-born college students in the U.S. Additionally, these findings may help in developing an intervention to enhance the vaccination behavior among this minor group of college students.


Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), continues to pose a major public health problem and is the leading cause of mortality in people infected with human immunodeficiency virus (HIV). HIV infection greatly increases the risk of developing TB even before CD4+ T-cell counts decrease. Co-infection provides reciprocal advantages to both pathogens and leads to acceleration of both diseases. In HIV-coinfected persons, the diagnosis and treatment of tuberculosis are particularly challenging. Intensifying integration of HIV and tuberculosis control programmes has an impact on reducing diagnostic delays, increasing early case detection, providing prompt treatment onset, and ultimately reducing transmission. In this Review, we describe our current understanding of how these two pathogens interact with each other, new sensitive rapid assays for TB, several new prevention methods, new drugs and regimens. Human immunodeficiency virus (HIV) can increase the risk of active TB up to 26 times, which leads to atypical clinical manifestations of the latter, further complicates diagnosis and treatment, and ultimately affects its prognosis. This article mainly expounds on the pathogenesis, diagnosis, treatment, and prevention of HIV-TB co-infection.Tuberculosis (TB) is the second leading cause of death from infectious diseases after coronavirus disease 2019 (COVID-19). In 2020, there were an estimated 9.9 million new cases of TB and ≈1.5 million deaths from TB worldwide.Mycobacterium tuberculosis (MTB) enters the airway in the form of aerosols. Macrophages absorb it in the alveoli and then form granulomas after the recruitment of innate immune cells and antigen-specific lymphocytes. After the body’s immune response, TB survives in granulomas in the form of latent infection. Macrophage necrosis may be a critical stage, which not only promotes the extracellular growth of MTB but also leads to damage to the lung matrix, formation of cavities, and expulsion of large numbers of bacteria from the respiratory tract, thus promoting transmission. Nevertheless, we believe that phagocytosis of MTB by macrophages can limit its growth. The impact of HIV infection on the spread of TB is controversial. Generally, TB complicated with HIV results in lower sputum bacterial load, fewer pulmonary cavities, and lower infectivity of TB. However, for the population, HIV increases the incidence rate of active TB after exposure to MTB and may lead to the further spread of drug-resistant TB. Some researchers believe that HIV significantly affects the immune environment and may affect the selective differentiation of MTB. For example, HIV has an impact on the directional selection of the three codon sites: celAb2, katG, cyp138. Moreover, MTB could increase replication, promote activated transcription and affect diversity for HIV. The coordination and cooperation of HIV and MTB promotes each survival and development, which finally constitutes a fatal threat to patients.By inhibiting macrophage apoptosis, consuming CD4 + T lymphocytes affecting the functional structure of granulomas and other complex immune responses, HIV makes it difficult for the body to effectively limit the growth and dissemination of MTB, and increases significantly the risk of active pulmonary TB and its extrapulmonary transmission. It is a broadly immune-mediated dysregulated inflammatory response caused by activating inflammatory corpuscles. The clinical manifestations mainly include further deterioration of confirmed TB  or conversion from latent pulmonary TB to active pulmonary TB (exposure type). The immune pathogenesis of TB-IRIS is complex and has not yet been fully elucidated. Studies have shown that both innate and adaptive immunity are involved in the occurrence of TB-IRIS, in which innate immunity plays a key role. The risk factors for TB-IRIS include when starting antiretroviral therapy, the count of CD4 + T cells is low, especially its count is < 50/mm3; the interval between initiation of anti-TB therapy and antiretroviral therapy is short; extrapulmonary or disseminated TB; HIV viral load is high. Currently, the diagnosis of TB-IRIS is mainly based on clinical manifestations and imaging. French scholars have found that T-cell activation markers may help predict and diagnose TB-IRIS. Anti-inflammatory therapy with corticosteroids is required when paradoxical TB-IRIS is refractory to treatment. In a clinical trial using steroids to prevent TB-IRIS, prednisone (40 mg/day for 2 weeks + 20 mg/day for 2 weeks) reduced the incidence of TB-IRIS from 47% in the placebo group to 33% in the prednisone group.TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) occurs in ≈15% of HIV-infected individuals after initiation of antiretroviral therapy. Currently, the proportion of TB among HIV-infected individuals may be greatly underestimated. Rapid diagnostic methods for TB based on nonrespiratory specimens have been proposed to improve the diagnostic efficiency of TB in HIV-infected people.Patients with HIV-TB co-infection have low immunity and a lower bacterial load in the sputum; therefore, their clinical and imaging manifestations are more atypical. The detection rates of conventional methods for TB, such as sputum smear, sputum culture, tuberculin skin test, and interferon (IFN)-γ release test, are also low. Autopsy research in South Africa showed that up to 45.8% of HIV-infected patients fail to diagnose TB before death.The interferon-gamma release assay for MTB can detect IFN-γ released by specific effector T lymphocytes, which is stimulated by specific TB antigens. It is of great significance for screening latent TB infection in HIV-infected patients. A multicentre prospective study of 1510 people with HIV (PLWH) in the United States was conducted to evaluate the diagnostic characteristics of the TB skin test (TST), QuantiFERON Gold In-Tube (QFT), and T.SPOT-TB (TSPOT). This study found that TSPOT had a significantly higher positive predictive value (90.0%) than the TST (45.4%) or QFT (50.7%) and was more applicable to US-born PLWH at low risk for TB exposure and with high CD4 + counts. It is a nonspecific marker of the acute phase of the systemic inflammatory response, which can be measured using finger-prick blood collection. Lipoarabinomannan (LAM), the lipopolysaccharide component of the cell wall of MTB, is a low-cost and point-of-care assay that can be performed in untreated urine within 25 minutes. A new generation of lateral flow lipoarabinomannan (LF-LAM) has optimized the sensitivity of LAM detection in urine. In 2019, the WHO explicitly recommended using LF-LAM in hospitalized HIV-positive patients regardless of their CD4 + T-cell count. TB-LAM positivity is also an independent risk factor for mortality in people with HIV/TB double infection.,14 It has been incorporated into the latest guidelines of countries such as Malawi and South Africa as a screening test.Rapid, sensitive, and low-cost screening tests for TB are even more important in areas with a high burden of HIV and TB. Among PLWH, C-reactive protein (CRP) was the first inexpensive, immediate, and effective screening test for TB (sensitivity ≥ 90% and specificity ≥ 70%) that met World Health Organization (WHO) requirements. The algorithm can exclude TB through symptom screening, but it is difficult to apply to resource-constrained areas with a high incidence of TB because of its high cost. Yoon et al proposed a novel ICF algorithm based on CRP combined with TB-LAM of urine, Xpert of sputum, or sputum culture. The algorithm could increase the speed for diagnosis of TB in PLWH and reduce costs without reducing the rate of case discovery. The accuracy of the Xpert test after TB screening based on CRP is similar, but the amount of Xpert analysis required for each TB case is less than half (9–4). The addition of TB-LAM did not significantly improve diagnostic efficiency compared to the current ICF algorithm. Still, it provided a same-day diagnosis for 26% of advanced patients with HIV complicated with TB. The addition of sputum culture to TB-LAM and Xpert significantly increased the yield of ICF and identified 78% of all TB cases.The case finding (ICF) algorithm recommended by the WHO for PLWH consists of symptom-based screening followed by confirmatory testing using Xpert MTB/rifampicin (RIF) for all individuals who screen positive. In addition, the Xpert MTB/XDR assay showed high diagnostic accuracy. The sensitivity of the Xpert MTB/XDR detection of resistance was 94% for isoniazid, 94% for fluoroquinolones, 54% for ethionamide, 73% for amikacin, 86%for kanamycin, and 61% for capreomycin. The specificity was 98% to 100% for all drugs.The next step in TB screening is to develop accurate, rapid, and comprehensive diagnostic tools. Xpert Ultra, the next generation of Xpert MTB/RIF kits, is more sensitive than standard kits. In a multicentre study on the clinical diagnostic accuracy of Xpert Ultra and conventional Xpert, the sensitivities of Xpert Ultra and Xpert were 63% and 46%, respectively, for participants with smear-negative and culture-positive sputum. In HIV-positive participants with culture-positive sputum, Xpert Ultra also had better sensitivities than Xpert , and both performed similarly in detecting RIF resistance.High-throughput NAAT platforms can accommodate dozens of samples simultaneously and are mainly used in reference laboratories. Some platforms are polyvalent; they can detect different pathogens simultaneously or sequentially on one platform. The integration of TB and HIV testing services is currently being achieved by developing pipelines and polyvalent platforms. Abbott’s m2000 automated platform is a polyvalent platform designed to detect HIV and TB, perform RIF/isoniazid testing for MTB, and screen for first-line drug resistance. Some studies have compared the bottom real-time MTB of the m2000 automation platform with the Xpert MTB/RIF. Among HIV-infected people, both the Abottom Real-Time MTB and the Xpert MTB/RIF have a sensitivity of > 70% and a specificity of > 90%. WHO is building and improving a sequencing database for TB to standardize genotypes, phenotypic tests for drug sensitivity testing, and other components. Comprehensive, rapid, and straightforward DNA sequencing is routinely used to guide the management of TB patients.The DNA sequencing method of MTB can provide comprehensive genetic information about strains, such as drug susceptibility and drug resistance, and facilitate the selection of the most effective treatment options. Still, it is difficult to apply clinically because of insufficient understanding and technical reasons.Globally, nearly 1 million HIV-infected patients are estimated to have active TB yearly. Although the anti-TB drugs for this group of patients are essentially the same as those for HIV-negative patients, there are still many problems to be solved in the combined use of anti-TB therapy and antiretroviral therapy, including the optimal timing of antiretroviral therapy, the interaction between drugs, and drug tolerance. With the continuous update of randomized controlled trials, the count of CD4 + T cells initiating ART has increased from an initial 350/mm3 to 500/mm3.,22 Most international guidelines recommend starting antiretroviral therapy immediately after the diagnosis of HIV infection. That is, a strategy of rapid antiretroviral therapy  should be implemented regardless of the CD4 + T-cell count.,25 Also, studies have shown that combination therapy with ART and anti-TB drugs is generally well tolerated. Early ART initiation allows for rapid immune recovery and reduces the risk of other opportunistic infections and all-cause mortality for people with HIV-TB co-infection. Despite the increased risk of paradoxical TB-IRIS, it is recommended that patients with CD4 + T-cell count < 50/mm3 and without consideration of tuberculous meningitis initiate antiretroviral therapy within 2 weeks of starting TB therapy. For patients with CD4 + T cell count ≥ 50/mm3, it is recommended to start antiretroviral therapy within 2 to 8 weeks of anti-TB therapy. In South Africa, waiting for TB test results is the main reason for ART treatment delays. Therefore, the SLATE II study allows LAM-negative patients with mild TB symptoms to start ART immediately without waiting for TB test results. The results suggest that early antiretroviral therapy benefits patients with TB symptoms and that rapid ART therapy are not a problem in patients diagnosed with TB after treatment.Traditionally, given the high cost, poor compliance, and drug side effects of long-term antiretroviral therapy, many clinicians have recommended delaying the initiation of antiretroviral therapy(ART). Blanc et al recruited HIV-infected individuals with CD4 + T-cell counts < 100 cells/mm3 who did not receive ART treatment in areas with a high prevalence of TB and HIV, such as Côte d’Ivoire. The patients were divided into 2 groups. The first group completed Xpert MTB/RIF, LAM, chest X-ray, and other TB screening and received an anti-TB treatment called scientifically guided treatment. The other group started empiric anti-TB treatment immediately. They found that empiric anti-TB treatment was not superior to scientifically guided treatment but had a higher probability of grade 3 or 4 adverse events.In primary care settings, the identification and diagnosis of TB can be slow; thus, ART initiation is delayed. It is common in primary healthcare settings to initiate empiric TB treatment without bacteriological confirmation. Ten percent of these patients develop resistance mutations to fluoroquinolones and second-line injectable drugs due to improper treatment, which leads to extensively drug-resistant TB (XDR-TB). DR-TB treatment is more complex, has a higher failure rate, and is more expensive than susceptible TB. The global treatment success rate for MDR/rifampicin-resistant TB in 2020 is 59%. HIV-positive patients have up to 2 to 4 times the risk of death when treated for multidrug-resistant TB. ART and high-quality anti-TB treatment can reduce mortality in HIV patients with MDR-TB. Improved drug regimens for drug-resistant TB are critical for controlling the acquisition and transmission of drug-resistant TB in HIV-endemic settings.Multidrug-resistant tuberculosis (MDR-TB) arises from the mutational selection of Mtb during first-line anti-TB treatment, which leads to resistance to rifampicin and isoniazid. The 26-week safety and efficacy of the new regimen BPaL  were evaluated in patients who had failed second-line therapy for XDR-TB or MDR-TB. The study included 109 patients, of whom 56 (51%) were HIV-positive. The study showed that 98/109 (90%) patients had good results 6 months after treatment, but the toxic side effects of linezolid were also obvious. Peripheral neuropathy and myelosuppression occurred in 81% and 48% of the patients, respectively. Following the NIX-TB trial, the ZeNix regimen completed questions regarding the dose and safety of linezolid in the BPaL regimen. This study found that by reducing the dose and duration of linezolid, toxicity could be reduced without compromising efficacy. Although the BPaL regimen has shown a high success rate in treating patients with XDR-TB in South Africa, its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation.–37 More controlled studies are still needed to prove whether BPaL is safer and more effective than other anti-TB regimens. Ongoing clinical trials, such as endTB and TB PRACTECAL, are expected to provide high-quality and direct evidence for short-duration and all-oral drug-resistant regimens.,39The NIX-TB trial is a single-arm, open-label study conducted in South Africa. Compared with tenofovir, tenofovir alafenamide has a lower risk of side effects such as osteoporosis and nephrotoxicity and does not require dose adjustment when co-administered with rifampicin.Interactions between antiretroviral and anti-TB drugs, especially those involving rifamycin, require attention. Raltegravir, an integrase strand transfer inhibitor, is widely recommended as a first-line maintenance antiretroviral therapy (ART) and efavirenz to be co-administered with rifampicin in the treatment of HIV patients with TB. However, there still remains controversy over whether it is necessary to adjust the dosage of raltegravir when combined with rifampicin. The guidelines recommend that patients taking both raltegravir and rifampicin use a double dose of raltegravir. However, Grinsztejn et al showed that in HIV patients receiving rifampicin for TB, a dose of 400 mg twice daily of raltegravir was as effective and better tolerated as the currently recommended dose of 800 mg twice daily. Delamanid is also a novel antibacterial drug used to treat patients who are resistant to first-line anti-TB drugs, and both it and Bedaquiline can prolong the QTc interval. Given the possible increased QTc-related cardiac risk, the WHO recommends not using Bedaquiline and Delamanid simultaneously. The ACTG A5343 trial compared the effects of Bedaquiline, Delamanid, and the combination of the 2 on the QTc interval in patients with MDR-TB or rifampicin-resistant TB. The combination of Bedaquiline and Delamanid had a culture conversion rate of 95% at the 8th week, showing a high early culture conversion rate, and there were no grade 3 or 4 adverse QTc prolongation events. This study provides evidence for the concomitant use of Bedaquiline and Delamanid in patients with MDR-TB or rifampicin-resistant TB (including HIV-infected patients).Bedaquiline is a new and effective diarylquinoline(class) drug for the treatment of drug-resistant TB. Bedaquiline-containing regimens are associated with reduced mortality, quicker time to sputum culture conversion, and higher MXDR-TB treatment success, including in HIV patients. Bedaquiline is metabolized by cytochrome p450 3A (CYP3A). When co-administered, efavirenz-induced CYP3A production resulted in a decrease in bedaquiline concentration. Therefore, WHO recommends that consideration be given to changing the antiretroviral regimen from efavirenz to nevirapine when using bedaquiline. For patients with HIV-TB co-infection, it is necessary to pay attention to drug interactions and monitor adverse drug reactions. If necessary, monitoring blood drug concentrations can be used to guide treatment.The incidence of adverse effects of anti-TB drugs, especially drug-induced liver injury, is higher in HIV-infected patients.Host-directed therapy (HDT) for TB involves various immunological, biological, and pharmacological interventions. The aim is to alter the host response to M. TB infection, which can be broadly divided into boosting the immune response to improve bacterial clearance and combating hyper inflammation to prevent tissue damage. Attention must be paid to issues related to HIV and TB co-infection. A randomized controlled trial showed that among HIV-infected adults starting ART, vitamin supplementation had no effect on mortality risk and incidence of TB but may reduce the incidence of TB with positive sputum smear and high bacterial load. Further research is needed on vitamin D3 in patients with HIV/TB co-infection before implementing a treatment regimen supplemented with vitamin D3. Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a unique and critical role in controlling MTB infection. Exogenous supplementation with GM-CSF can activate HIV-infected macrophages to kill MTB and improve its bactericidal effect. Myeloid-derived suppressor cells (MDSCs) impair the proliferation, function, and trafficking of CD4 + T lymphocytes and CD8 + T lymphocytes and alter the host protective responses of people with HIV/TB co-infection. The therapeutic effects of drugs that inhibit MDSCs, such as tyrosine kinase inhibitors, all-trans retinoic acid, and PDL1, can be further studied in patients with HIV-TB co-infection.Vitamin D is a fat-soluble vitamin with immune regulation function, which can fight against intracellular virulent MTB through the activation of macrophages. At the same time, it can inhibit the replication of HIV-1 in macrophages. However, in clinical research, vitamin D appears to be ineffective for treating TB in HIV-infected adults. HIV could block the ability of macrophages cytokine: Vitamin D3, IL-1β, IFN-γ and TNF-α both alone and in combination to response to MTB infection, which may explain this outcomes. were the first to report the bactericidal effects of macrophage-targeted selenium nanoparticles (Se NPs) against MTB. A novel nanomaterial was proposed to assist anti-TB treatment; that is, it preferentially enters macrophages through Ison@Man–Se NPs, accumulates in lysosomes, and releases isoniazid to achieve synergistic antibacterial and bactericidal effects. This approach has broad innate immune regulatory functions and a rather low cytotoxicity and is expected to be one of the more effective treatments for drug-resistant TB.New treatments are also expected to achieve good results in HIV-infected patients. Pi et al The recommended regimens for treating HIV complicated with latent TB include the administration of rifapentine and isoniazid once a week for 12 weeks, rifampicin daily for 4 months, or isoniazid and rifampicin daily for 3 months. Recommended alternatives are daily treatment with isoniazid for 6 or 9 months or daily treatment with rifapentine and isoniazid for 1 month. Among them, daily oral rifapentine and isoniazid for 1 month were equivalent to isoniazid alone for 9 months, and the 1-month group had better compliance and fewer adverse effects. The study by Dooley et al showed that a dolutegravir-based regimen could be safely used with a weekly regimen of rifapentine and isoniazid for 12 weeks.The addition of TB preventive therapy (TPT) to antiretroviral therapy has been shown to reduce TB incidence by 30% and mortality by 35% to 50%. suggested that the immediate initiation of IPT during pregnancy may be riskier than postpartum IPT. A randomized noninferiority study showed that IPT during pregnancy increased the risk of adverse pregnancy outcomes and recommended that healthy pregnant women who had received ART start IPT at 12 weeks postpartum.In addition, WHO recommends the use of isoniazid prophylactic therapy for TB (IPT) and antiretroviral therapy during pregnancy. However, because pregnant women are often excluded from IPT trials, there are relatively little data on their safety and efficacy. Gupta et alIn recent years, research and innovation achievements in the diagnosis, treatment, and prevention of TB worldwide have changed with each passing day. Nonetheless, TB remains one of the deadliest infectious diseases facing humanity. Under the novel coronavirus pandemic background, the number of TB cases detected and reported in 2020 has dropped sharply. The continuous global TB mortality rate decline in recent years has been interrupted. Interruption of diagnosis and treatment has seriously affected the prognosis of patients with TB. HIV infection results in higher incidence of drug-resistant tuberculosis, poor treatment effects, and increased mortality that makes a grim situation of tuberculosis control in the world. In short, we should take actions to increase investment in research, expand the coverage of ART and TPT, and delve into the genetics, immunology, and other contents of HIV-TB for developing new intervention measures against TB, such as new vaccines and immunotherapies, finally eradicate the two infectious diseases.QY, JH, JS, and LZ participated in design, methodology and manuscript edit. XP and XY participated in literature search, data collection, and manuscript editing.Conceptualization: Lurong Zhou,Qiaoli Yang.Methodology: Qiaoli Yang,Jinjin Han,Jingjing Shen.Project administration: Lurong Zhou, Qiaoli Yang.Supervision: Lurong Zhou, Qiaoli Yang,Xinsen Peng.Validation: Lurong Zhou, Xuejing Yin.Writing – Original Draft: Qiaoli Yang,Jinjin Han.Writing – Review & Editing:Qiaoli Yang,Jinjin Han,Jingjing Shen,Xinsen Peng,Lurong Zhou,Xuejing Yin.


To quantitatively summarize the specific changes in brain structure and function in migraine patients.A literature screening of migraine was conducted from inception to Sept 1, 2022, in PubMed, Web of Science, Cochrane Library, and Medline databases using the keyword combination of “migraine and MRI.” Activation likelihood estimation (ALE) was performed to assess the differentiation of functional connectivity (FC), regional homogeneity (ReHo), and gray matter volume (GMV) of migraine patients.Eleven voxel-based morphometry (VBM) studies and 25 resting-state fMRI (rs-fMRI) studies (16 FC and 9 ReHo studies) were included in this study. ALE analysis revealed the ReHo increase in the brainstem and left thalamus, with no decreased area. Neither increased nor decreased regions were detected in FC and GMV of migraine patients.The left thalamus and brainstem were the significantly activated regions of migraine. It is a meaningful insights into the pathophysiology of migraine. The consistent alterated brain areas of morphometrical and functional in migraine patients were far from reached based on current studies. Migraine is a complex neurological dysfunction characterized by recurrent attacks and pulsating headaches susceptible to physical or environmental factors. Broad clinical symptoms, such as nausea, vomiting, photophobia, and phonophobia etc., have been complained by suffers, with a headache duration ranging from 4 to 72 h . The estHowever, the underlying neuroimaging alterations in migraine patients have previously been studied using functional and structural MRI techniques, with inconsistent conclusions –5. Some If there are regions that both function and structure altered in migraine patients. Based on ReHo, amplitude low-frequency fluctuation (ALFF) and positron emission tomography (PET), meta-analysis demonstrated decreased activity in the angular gyrus, visual cortex, and cerebellum, while increased in the caudate, thalamus, pons, and prefrontal cortex . On the Therefore, we conduct the current neuroimaging meta-analysis on brain structure and function changes in migraine patients, with the hope of drawing a solid conclusion.https://www.crd.york.ac.uk/PROSPERO/), with the registration number CRD42021257300.This study was registered on the PROSPERO  . The subStudies that meet the following criteria were eligible for inclusion in this meta-analysis: 1) migraine patients diagnosed according to the International Classification of Headache Disorders (ICHD) ( migraineExclusion criteria were as follows: (1) no HC group, (2) study was neither VBM nor FC and ReHo, (3) studies on the region of interest (ROI)-ROI, seed-ROI or independent component analysis (ICA), (4) intervention studies , (5) seed-points or peak effect coordinates could not be retrieved, or (6) other types of migraine  and studies for comorbidities . We alsohttp://www.sdmproject.com/) (http://www.brainmap.org/)  according to the data extraction protocol. Any vagueness or disagreements were discussed with a third author (CYL), and a consensus was reached. The data information was sequentially collected, such as author, published year, sample size, characteristics of participants , classification of migraine, and technical details . The peak coordinates of included studies were edited as available files according to the guidelines of AES-SDM 5.15 (ct.com/)  or ALE 3ap.org/) . Talairahttp://www.ohri.ca/programs/clinical_epidemiology/oxford.htm). The detailed items and scores of included studies are listed in There is no consensus on the quality evaluation of neuroimaging studies up to now. We performed a customized checklist to assess the quality of included studies based on the assessment items of the Newcastle Ottawa Quality Assessment Scale (p < 0.05) to carry out multiple comparisons, using an initial cluster threshold of uncorrected p < 0.001, and permutation tests were 5,000  for a given study in comparison with a random distribution of foci. It treated reported significant foci as spatial probability distributions centered on given coordinates rather than as single points. ALE assesses the cumulative probabilities of each voxel based on reported foci. ALE map was acquired after calculating the union probabilities of each voxel. The true convergence of foci and random clustering was tested by permutation tests. Based on the sample size and random effect model, the likelihood of consensus among different experiments is attained. Each focus is modeled as the center of a Gaussian probability distribution. Then, the modeled activation (MA) map for each study is generated. We employed the recommendation setting of cluster-level family-wise error (FWE) , individually. There were no significant differences in age and ratio of gender between migraine and HC, when the data were independently assessed. The preprocessing of fMRI images in all studies was performed by several steps, such as slice timing, realigning, normalizing, regressing nuisance covariates, filtering, and smoothing.Thirty-nine MRI studies were included in this analysis, covering 11 VBM , 16 FC , and 9 R3) and brainstem  were increased, no decreased found. The changes of FC were not found  that reported by the Zhao's study  were notAccording to the diagnosis classification of migraine, we performed subgroup meta-analysis of migraine patients and migraine without aura to establish the consistency of findings. No clusters were above the threshold.To our knowledge, this is the first study adopting functional and structural fMRI metrics to verify brain alterations  in migraine patients. The solid conclusion is that the ReHo values of left thalamus and brainstem were consistently increased. While GMV and FC were not illustrated alterations in migraine in terms of current evidence.Migraine is associated with various central nervous system disorders . Profounvia the trigeminovascular pathway starting from trigeminal ganglion neurons  were not included in our meta-analysis, which inevitably leads to publication bias. And the coordinates-based meta-analysis also has inherently biased, as it employs pooled stereotactic coordinates that are statistically significantly different, rather than raw data. Thirdly, this meta-analysis was limited to seed-based to whole-brain fMRI studies of FC, the studies using independent component analysis (ICA) and positron emission tomography (PET) approach not included.Functional and structural changes were evaluated simultaneously.Robust results were attributed to the rigorous processing analyses.More studies are needed to verify the changes in GMV.Z-HC, Y-LC, J-TS, Y-TL, and CZ devoted to this study equally as the co-first authors. Z-HC wrote the original draft. Y-MZ, Z-YL, Y-XS, and M-HN were constrictive for data abstraction and software analysis for this study. BH and L-FY monitored the analysis procedure. WW supervised the overall procedure. All authors revised and approved the final manuscript.This work was supported by the Hovering Program of Fourth Military Medical University (axjhww to WW), and the Talent Foundation of Tangdu Hospital (2018BJ003 to WW).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Spinal pain has been previously linked with cardiovascular disease risk factors in children. This study investigated the prospective associations between cardiovascular disease risk factors and non-traumatic spinal pain occurrences in children, and examined the moderating role of sex and health-related physical activity in these relationships.We used prospective data from the Childhood Health, Activity, and Motor Performance School Study Denmark (CHAMPS Study-DK). The exposure variables were a clustered cardiovascular risk score and homeostasis assessment model-estimated insulin resistance (HOMA-IR) score collected in 2008 and 2010. The spinal pain outcome comprised the number of weeks of non-traumatic spinal pain from 2008–2010 and 2010–2012. Potential confounders included age, sex, and time spent in moderate-to-vigorous intensity physical activity. We constructed age-adjusted mixed negative binominal regression models to investigate the prospective associations of cardiovascular disease risk factors and non-traumatic spinal pain, while considering the potential moderating roles of sex and physical activity in these relationships.low HOMA-IR scores and boys with low clustered cardiovascular disease risk scores, who engaged in higher levels of moderate-to-vigorous physical activity, reported more weeks of spinal pain, compared to girls with high HOMA-IR scores (p = 0.001) and boys with high clustered cardiovascular disease risk scores (p = 0.024). whereas boys with higher clustered cardiovascular disease risk who had less time in moderate-to-vigorous physical activity reported more weeks of spinal pain than boys with low clustered cardiovascular disease risk score (p = 0.024).Girls with Our results show that cardiovascular disease risk factors are related to future occurrences of non-traumatic spinal pain. However, these relationships appear complex and dependent on the nature of the interactions with sex and physical activity. Spinal pain is a significant public health problem. Even during adolescence, low back pain is ranked as one of the top ten causes of years lived with disability , and adoCardiovascular disease is often one part of multimorbidity, and is the leading source of worldwide mortality . We are Clustering of cardiovascular disease risk factors begins in childhood and continues into adulthood –19. TherThis study aimed to 1) investigate the prospective associations between cardiovascular disease risk factors and non-traumatic spinal pain occurrences in children, and 2) examine the moderating roles of sex and health-related physical activity in these relationships. Non-traumatic pain is reported pain not arising from a traumatic aetiology . We hypothesized that children with greater cardiovascular disease risk factors would be at increased risk of developing spinal pain and that sex and health-related physical activity would moderate this relationship.In this prospective cohort study, we used data from the participants of the Childhood Health, Activity, and Motor Performance School Study Demark (CHAMPS study-DK) . All stuThe current study analyses were conducted in two phases (including the same participants in both phases) to account for the two exposure periods and subsequent spinal pain measurements. Phase one included cardiovascular disease risk factors sampled in October 2008 and spinal pain data collected weekly during November 2008 to November 2010. Phase two included cardiovascular disease risk factors sampled in October 2010 and spinal pain data collected weekly during November 2010 to November 2012.Ethics approval was obtained from the Regional Scientific Committee of Southern Denmark for the CHAMPS study-DK (ID S20080047) and the study was registered with the Danish Data protection Agency, as stipulated by Danish law J.nr 2008-41-2240. Written informed consent was obtained from parents. Every child and parent also gave verbal consent prior to enrolment. Ethics approval for the current analyses was provided by Murdoch University Human Research Ethics Committee . Data was obtained after applying for accessing through the CHAMPS Study Steering Committee. All data were fully anonymised before we accessed them for this current analyses.Fasting blood samples were obtained between 8.00 to 10.30 AM, stored on ice, and transported to the laboratory within four hours, where they were pipetted, centrifuged, and stored at -80 degrees Celsius . BiochemSystolic blood pressure was measured with an automated blood pressure monitor [Welch Allyn®  vital signs monitor 300 series with FlexiPort™]. Blood pressure was taken seated after the participants had rested for five minutes and were recorded at 1-minute intervals until three stable measurements or five total measurements were obtained. The mean of the final three measurements was used for analysis .The primary exposure variable was a clustered cardiovascular risk score, which has been reported as a better assessment of cardiovascular health in children compared to a single risk factor . The cluSpinal pain was defined as any pain in the neck, mid-back, and/or low back during the past week. Spinal pain data were collected through weekly text messages over approximately four years. When pain was reported, the parents were contacted by telephone the following day. If pain persisted at that time, the child was examined by a clinician . ICD codIn the current analyses, we excluded all occurrences of diagnosed spinal pain arising from a traumatic aetiology . Therefore, the spinal pain outcome comprised the total number of weeks of non-traumatic spinal pain  occurring in each of the two study phases. To be included in the analysis, participants needed to have at least 60% valid reporting of spinal pain data during the respective two-year phase. For example, to be included in phase one, participants needed at least 60% valid reporting of spinal pain data in phase one, irrespective of reporting in phase two.Potential moderators and confounders included age, sex, and time spent in moderate-to-vigorous intensity physical activity . Demographic information was collected through a questionnaire at baseline. Physical activity was measured at baseline of each study period using Actigraph GTX3 accelerometers , 30. ParDemographic data were summarised with descriptive statistics. We log-transformed exposure variables with non-normal distributions.In the first analysis (phase one), we used the baseline cardiovascular disease risk factors sampled in September–October 2008 as predictors for the number of weeks with non-traumatic spinal pain from November 2008 to November 2010. In the second analysis (phase two), we used the cardiovascular disease risk factors sampled in September–October 2010 as predictors for the number of weeks with non-traumatic spinal pain from November 2010 to November 2012.To examine the prospective associations between childhood cardiovascular disease risk factors and spinal pain occurrences in each study phase (aim one), we constructed separate, mixed negative binominal regression models. Negative binomial models are well suited for zero-inflated count data  . To accoTo investigate for additional moderating by health-related physical activity in the relationship between cardiovascular disease risk factors and spinal pain (aim two), we repeated the same modelling procedure and included a three-way interaction between the cardiovascular risk factor (HOMA-IR and clustered cardiovascular disease risk factors), sex, and time in moderate-to-vigorous physical activity. We examined the nature of these interactions by stratifying model results on sex, estimating the predicted margins, and plotting these results graphically.P values less than 0.05 were considered statistically significant.Data were analysed using and Stata/SE version 15 software . Overall, 1630 participants participated in the study. In the first study phase, the study sample consisted of 1104 children  with a mean (SD) age of 8.4 (1.4) years and the second phase included 1291 children  with a mean (SD) age of 10.4 (1.4) years .p = 0.0002) but not boys, and more children reported four or more weeks with pain , and between clustered cardiovascular disease risk and sex (p = 0.006). We found that girls with moderate log HOMA-IR (tertile two) were less likely to experience non-traumatic spinal pain compared to girls with low log HOMA-IR (tertile one)   .p = 0.002) but not between clustered cardiovascular risk and sex (p = 0.465). We found girls with high log HOMA-IR (tertile three) were less likely to experience non-traumatic spinal pain than girls with low log HOMA-IR (tertile one) . There were no other associations between the cardiovascular disease risk factors and spinal pain  between log-HOMA-IR, moderate-to-vigorous physical activity, and sex. Overall, girls with low HOMA-IR scores, who engaged in higher levels of moderate-to-vigorous physical activity, reported more weeks of spinal pain. Boys with lower clustered cardiovascular disease risk and more time in moderate-to-vigorous physical activity, reported more weeks with spinal pain. Further, boys with higher clustered cardiovascular risk, who had less time in moderate -to-vigorous physical activity also reported more weeks of spinal pain  (p = 0.033)  log HOMA-IR risk scores and more moderate-to-vigorous physical activity had a higher likelihood of non-traumatic spinal pain than girls with moderate (tertile two) and high (tertile three) log HOMA-IR scores (two-way interaction o 0.009) . Boys wi= 0.033) .p = 0.024) (p = 0.024)  . Further= 0.024) .low cardiovascular risk profile (low clustered cardiovascular risk score and low HOMA-IR or) indicated a risk for spinal pain for both girls and boys who had higher levels of moderate-to-vigorous physical activity. For those with a higher cardiovascular risk profile, boys, but not girls, would report spinal pain also with less moderate or vigorous physical activity. However, these findings were observed only when the children were older. Throughout the literature there has been an increased reported incidence and prevalence of back pain with female sex and advancing age towards adolescence and young adulthood [Boys and girls seem to react somewhat differently to moderate or vigorous physical activities depending on their cardiovascular risk profile, as a dulthood , 16, potA previous study reported that girls with spinal pain had greater clustered cardiovascular risk compared to girls without spinal pain, independent of health-related physical activity . HoweverStrengths of the current study include its longitudinal design and large, representative cohort of children. We used uniquely robust measurements of spinal pain, cardiovascular disease risk factors, and physical activity. Spinal pain data were intensively collected with weekly text messaging, which likely reduces recall bias and resulted in high levels of participant engagement, with the average weekly response rate of 96.5% . AlthougHowever, there are limitations to our study. Our study was exploratory and hypothesis generating. These results require confirmation before considering clinical or policy-related implications. In order to identify a causal relationship, at a minimum, the risk factor should be established before the onset of the disorder  . As thisGirls with low insulin resistance and boys with low clustered cardiovascular risk scores at baseline and who spent high amounts of time doing moderate-to-vigorous physical activity reported more weeks with spinal pain during the two year follow up. Boys with higher clustered cardiovascular risk with low time in moderate-to-vigorous physical activity also reported more weeks with spinal pain. Thus, there appears to be a relationship between insulin resistance, clustered cardiovascular risk factors and future spinal pain in children aged approximately 10 to 12 years of age and this relationship may be moderated by sex and health-related physical activity.