A primary focus of HIV‐1 vaccine development is the activation of B cell receptors for naïve or precursor broadly neutralizing antibodies (bnAbs), followed by expansion and maturation of bnAb B cell lineage intermediates leading to highly affinity‐matured bnAbs. HIV‐1 envelope (Env) encodes epitopes for bnAbs of different specificities. Design of immunogens to induce bnAb precursors of different specificities and mature them into bnAb status is a goal for HIV‐1 vaccine development. We review vaccine strategies for bnAb lineages development and highlight the immunological barriers that these strategies must overcome to generate bnAbs.We provide perspectives based on published research articles and reviews.The recent Antibody Mediated Protection (AMP) trial that tested the protective efficacy of one HIV‐1 Env bnAb specificity demonstrated that relatively high levels of long‐lasting serum titers of multiple specificities of bnAbs will be required for protection from HIV‐1 transmission. Current vaccine efforts for induction of bnAb lineages are focused on immunogens designed to expand naïve HIV‐1 bnAb precursor B cells following the recent success of vaccine‐induction of bnAb precursor B cells in macaques and humans. BnAb precursor B cells serve as templates for priming‐immunogen design. However, design of boosting immunogens for bnAb maturation requires knowledge of the optimal immunogen design and immunological environment for bnAb B cell lineage affinity maturation. BnAb lineages acquire rare genetic changes as mutations during B cell maturation. Moreover, the immunological environment that supports bnAb development during HIV‐1 infection is perturbed with an altered B cell repertoire and dysfunctional immunoregulatory controls, suggesting that in normal settings, bnAb development will be disfavoured. Thus, strategies for vaccine induction of bnAbs must circumvent immunological barriers for bnAb development that normally constrain bnAb B cell affinity maturation.A fully protective HIV‐1 vaccine needs to induce durable high titers of bnAbs that can be generated by a sequential set of Env immunogens for expansion and maturation of bnAb B cell lineages in a permitted immunological environment. Moreover, multiple specificities of bnAbs will be required to be sufficiently broad to prevent the escape of HIV‐1 strains during transmission. However, bnAbs have features of autoreactive antibodies, thus making them disfavoured for production by host immunity — as discussed in detail in previous reviews , 3. AddiVaccine‐induced neutralizing antibodies have been effective against many viruses , and serPrevious human HIV‐1 vaccine efficacy trials that studied first‐generation HIV‐1 Env vaccines did not generate bnAbs and showed either modest success , 23 or nDuring bnAb lineage maturation, bnAbs acquire genetic mutations at sites that are rarely targeted for somatic hypermutation, resulting in a low probability of their occurrence in germinal centres (GCs) during affinity maturation — these mutations were described as improbable mutations that impact antibody structure and affinity for antigen to improve antibody function , 34. ImpHere, we review strategies for vaccine induction of HIV‐1 Env bnAbs, which include multiple different approaches by different researchers. These strategies were informed by preclinical studies in mice and rhesus macaques, and some are currently being tested in humans. Moreover, we highlight immunological barriers that an effective HIV‐1 Env bnAb‐inducing vaccine must overcome.2We referenced 131 research articles and reviews that were published between 2001 and 2021 in peer‐reviewed journals, and a press‐release in 2021. These references were accessed from PubMed between 10 May 2021 and 6 September 2021 when this review was written and revised. We referenced the initial research articles that report seminal discoveries or concepts discussed in this review. For well‐established concepts that are commonly discussed in the field of HIV‐1 vaccine development and perspectives, we reference review articles.3Many HIV‐1 sexually transmitted infections are caused by a limited number of transmitted/founder (TF) viruses . Antibod3.1The AMP trials conducted by the HVTN and HIV Prevention Trials Networks (HPTN) studied at‐risk cisgender men and transgender persons in the Americas and Europe (HVTN 703/HPTN 081) and at‐risk women in sub‐Saharan Africa (HVTN 703/HPTN 081). Participants were randomized to receive infusion of the VRC01 bnAb every 8 weeks at doses of either 10 or 30 mg/kg, or placebo, over 20 months . Overall3.2Retrospective studies in people living with HIV‐1 who generate bnAbs have identified immunologic perturbations associated with bnAb induction , 46, 47.Animal models are key for testing immunogen strategies to elicit bnAbs. Knock‐in (KI) mouse models that express bnAb UCA VH and VL genes produce B cells bearing bnAb UCA BCRs serve as important tools to determine experimentally whether HIV‐1 Env priming or boosting immunogens can either expand bnAb precursors or as boosting immunogens select for affinity matured bnAb intermediate or mature antibodies , 50, 51.BnAb lineage induction by activation and expansion of bnAb precursor B cells, followed by bnAb lineage maturation are key concepts for vaccine induction of bnAbs. We review strategies for bnAb lineage induction and maturation, including vaccine immunogens that are widely being studied for bnAb lineage induction and maturation. We also review vaccine delivery platforms, including more recently attractive platforms for HIV‐1 vaccines. For example, lipid nanoparticles are widely employed in vaccine efforts against multiple infectious diseases, including SARS‐CoV‐2 , 55, 56,3.2.1To successfully target bnAb precursor B cells, a better understanding of the human naïve B cell repertoire that is capable of Env recognition and maturation into bnAbs is essential . The cha9‐V3) that expanded FDG B cells in macaques and as a bait isolated candidate FDG precursor B cells from HIV‐1 naïve individuals. Man9‐V3 Star polymer composed of a 30‐mer array of Man9‐V3 glycopeptide , 6627, 6D = 550 nM) is being studied in HVTN115 (NCT03220724) to determine if repetitive boosting with low affinity gp120 in GLA‐SE adjuvant can induce CH103 precursor B cells. For comparison, HVTN300 (NCT04915768) will study repetitive boosting of GLA‐SE adjuvanted, stabilized CH505 TF SOSIP trimers that have a higher binding affinity to CH103 UCA (KD = 171 nM) than the CH505 TF gp120. HVTN115 (NCT03220724) is also studying sequential CH505 gp120s to test the hypothesis that CH505 TF gp120 can prime CH103 precursor B cells and sequential immunizations with natural variants of CH505 TF will mature these B cells towards breadth, in a manner that recapitulates viral Env and CH103 antibody co‐evolution in an individual living with HIV‐1 [HVTN115 (NCT03220724), HVTN300 (NCT04915768) and HVTN133 (NCT03934541) studied bnAb‐lineage vaccine design [th HIV‐1 . For immth HIV‐1 , 95.Gp41 MPER liposome was studied in HVTN133 (NCT03934541) as a promising immunogen for eliciting MPER bnAb precursor B cells given that a first‐generation gp41 MPER peptide‐liposome‐containing vaccine regimen expanded 2F5‐like B cell precursors and intermediate antibodies in 2F5 bnAb precursor KI mice and rhesus macaques . In HVTNAdditionally, eOD‐GT8 60mer was tested in healthy volunteers IAVI G001) as a VRC01 germline‐targeting immunogen and expanded B cells with characteristics of VRC01 bnAb precursors (Table  as a VRC4A successful bnAb‐inducing vaccine strategy will facilitate an interplay between host immunity and HIV‐1 Env immunogens to mature bnAb B cells Figure . There aBFH, KW, and KOS have patents submitted on select immunogens and concepts described in this review.WBW and BFH drafted the outline and wrote the review. KW and KOS edited the review.


ObjectiveEvaluate nutrition literacy in uninsured subjects with diabetes mellitus (DM) who presented to free diabetes management classes. Design This single-site, cross-sectional observational study recruited thirty subjects from a free clinic for uninsured patients to attend diabetes mellitus, self-management classes. Before starting the classes, DM care-related data were collected, and subjects were administered the Nutrition Literacy Assessment Instrument (NLit). The assessment covers six subscales in nutrition and categorizes results into three possible categories: the likelihood of poor nutrition literacy (NLit Score ≤ 44), the possibility of poor nutrition literacy (NLit Score- 45-57), and the likelihood of good nutrition literacy (NLit score ≥ 58). Results Median glycated haemoglobin (HbA1c) was 7.45% for study participants. The mean NLit score was 38.1 (SD ± 9.4), correlating with a likelihood of poor nutrition literacy. All participants had either likelihood or the possibility of poor nutrition literacy based on the NLit Assessment. There were no participants who scored in the range of likelihood of good nutrition literacy. Subjects who scored in the range of likelihood of poor nutrition literacy had a significantly higher mean HbA1c (8.6 %) than those who scored in the possibility of poor nutrition literacy .ConclusionsPoor nutrition literacy is associated with worse glycemic control among uninsured subjects with diabetes mellitus. As of 2018, the Center for Disease Control and Prevention reported 34.2 million Americans with DM and 88 million with pre-diabetes. One out of ten Americans has diabetes, and one-third are at a high risk of developing diabetes. Furthermore, diabetes management issues have a direct impact on the health and socioeconomic wellbeing of our society. In 2017, the US's estimated total diabetes direct and indirect cost was $327 billion . TargetiHealth literacy is a measure of a person's ability to obtain, read, understand, and use health information to make appropriate health decisions and to follow treatment recommendations . PreviouAn essential component of health literacy is nutrition literacy, defined as how individuals can obtain, process, and understand nutrition information ,15. It aThis single-site, cross-sectional observational pilot study describes the baseline characteristics, diabetes care-related data, and nutritional literacy of uninsured patients attending a monthly diabetes education class at a free clinic in Tampa, Florida, between October 2018 to March 2019. Uninsured men and women aged 18 years or older who had a diagnosis of DM were invited to participate in the study. Exclusion criteria included: insured subjects, pediatric subjects, and pregnant women. This free diabetes self-management class was publicly advertised as a University-funded resource that awarded voluntary participation with free supplies that included glucometers, test strips, and lancets. Subjects with diabetes, evaluated and managed at the free clinic, were encouraged and referred to attend this class. This study was approved by the University of South Florida Institutional Review Board with an expedited review (protocol #Pro00023920). Each patient was provided written informed consent to have recorded de-identified data collected via surveys utilizing portable electronic devices.We gathered self-reported diabetes-care related data and the NLit Assessment answers. The NLit Assessment Instrument is a 64-item survey that has been validated and demonstrated to be reliable at measuring nutrition literacy  . The assData were collected and managed using REDCap electronic data capture tools hosted at the University of South Florida. REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies, providing our study with an intuitive interface for a validated data entry. All further data analyses were performed using SAS 9.4 . Differences in continuous outcomes between groups were tested using Welch's t-test for two groups and Welch's one-way analysis of variance (ANOVA) for three or more groups. A two-tailed value of p<0.05 was selected to indicate statistical significance .Patient characteristicsThis free clinic population has reported chronic disease incidence and socioeconomic factors in prior studies ,18. FromNutrition LiteracyThe mean score in the NLit was 38.1 (SD±9.4), which corresponds with a likelihood of poor nutrition literacy. The maximum score was 56, which corresponds with the possibility of poor nutrition literacy. There were no patients who scored in the range of likelihood of good nutrition literacy Table . Gender,Patients scored the lowest in the domain of food numeracy and labels (Mean score: 4.2 SD ± 2.2) and scored the highest in food groups (mean score 11.7 SD± 3.6), compared to all other sections , but this association did not reach statistical significance. However, patients who scored in the range of likelihood of poor nutrition literacy had a significantly higher mean HbA1c  than those who scored in the possibility of poor nutrition literacy (6.9%) . Poor nutrition literacy could be a barrier to diabetes control. Assessment of nutrition literacy before the start of medical nutrition therapy and after could be helpful in understanding and guiding patients to modify their diet and achieve treatment goals optimally.Furthermore, this difference in HbA1c, which we would expect to be even more if comparing patients in the likelihood of poor nutrition literacy to those in the range of good nutrition literacy, could potentially have a significant clinical impact on health outcomes and healthcare expenditure. It is essential to highlight that currently available medications for the treatment of diabetes decrease HbA1c approximately by 0.5-1.5%, and based on our results, medical nutrition therapy could be of a higher impact than medications . The NLit assessment tested six nutrition domains. Subjects scored the worst in the Food numeracy and Labels. Data regarding health literacy, food label interpretation, and food numeracy is controversial. Some studies have shown that patients with limited health literacy have greater difficulty interpreting food labels and are less likely to refer to food labels -27. HoweThere are several limitations to this study. Some diabetes-related data was self-reported due to a lack of medical records access. Monthly resources and advertising limited our class size. None of our subjects scored in the likelihood of good nutrition literacy category, and we could not assess if there were a significant difference in HbA1c in this subgroup. Longitudinal studies and post-intervention analyses were not possible due to a lack of consistent monthly follow-up. Future studies with a larger sample size may be beneficial to elucidate further understanding of nutrition literacy and how this can improve diabetes outcomes in groups with socioeconomic disparities.To our knowledge, this is the first study utilizing the Nutrition Literacy (NLit) assessment to evaluate nutrition literacy in uninsured subjects with diabetes mellitus. This study demonstrated that poor nutrition literacy is associated with worse glycemic control among uninsured patients with diabetes mellitus based on the Nutrition Literacy Assessment. We suggest a possible role in assessing nutrition literacy in patients with diabetes to identify deficiencies that could be improved upon with adequate medical, nutritional therapy. Furthermore, empowering patients with diabetes and providing broader access to nutritional education to improve nutrition literacy could represent a high yield intervention that can improve health outcomes and reduce the cost associated with the disease. More research is needed to understand better how nutritional literacy optimizes or modulates glycemic control among uninsured and insured patients to address health outcomes and disparities.


Myasthenia gravis (MG) is an autoimmune antibody-mediated disorder caused by dysfunction at the neuromuscular junction spreads. The main clinical features of this disease are fluctuating fatigue, and weakness of the skeletal muscles of the eyes and limbs. At present, the tonifying the spleen and replenishing the kidney method in traditional Chinese medicine has been widely used for MG. The present study was conducted to evaluate the efficacy and safety of the tonifying the spleen and replenishing the kidney method in traditional Chinese medicine for MG.The following 10 databases were searched from inception to March 2021: PubMed, Cochrane Library, EMBASE, Web of Science, Springer, China National Knowledge Infrastructure (CNKI), Wan fang, VIP Chinese Science and Technique Journals Database, the Chinese Bio Medical Database (CBM), and Baidu Scholar. The language was limited to the Chinese and English language. Merely randomized controlled trials (RCTs) were included. The Cochrane Collaboration risk-of-bias tool was used for the methodological quality assessment and risk of bias. The meta-analysis was assessed using the Cochrane RevMan 5.3 software.In the present study, a meta-analysis was conducted, and RCTs that met the eligibility criteria were included. Furthermore, the different outcome indicators of different methods were objectively compared. The main outcome indicators included the effective rate, quantitative myasthenia gravis (QMG) scores, adverse events, and quality of life (QOL). The secondary outcome indicators included AchRAb, serum-related immune cells (such as CD3+CD4+cells and CD4+/CD8+cells), the traditional Chinese medicine syndrome score scale (TCMSSS), the serum interleukin-6 level, the level of IFN-γ and its mRNA, and the clinical score that contains the clinical absolute score (CAS) and clinical relative score (CRS).This study would provide credible evidence to determine whether the tonifying the spleen and replenishing the kidney method in traditional Chinese medicine is an effective treatment method for MG.INPLASY202110097 The clinical manifestations of MG are blepharoptosis, diplopia, dysphagia, limbs weakness, breathing difficulties, and so on. These above symptoms are characterized by undulatory for the whole day. The diagnosis of the disease is based on the clinical symptoms, pharmacological examination, and nerve electrophysiology detection. At present, the main treatment for MG is drugs , plasma exchange, and surgery. Although these treatments have been effective in alleviating the symptoms of MG, the disease cannot be cured. Traditional Chinese medicine (TCM) and its related medical systems have been developed in China, and in some other parts of Asia, for thousands of years, in order to ensure the health of the people in these areas. A large number of studies have proven that the TCM decoction is a simple and effective approach to treat MG.Myasthenia gravis (MG) is autoimmune chronic disorder, in which skeletal muscle weakness and fatigability account for the impairment of neuromuscular junctions (NMJ) transmission. Its global prevalence is 150 to 250 per million population, and its incidence rate has been increasing. The treatment performed by Professor Qian Renyi for MG by tonifying the spleen and replenishing the kidney was effective, and this may be correlated to the decrease in the level of IFN-γ, IL-4, CD4+/CD8+, and other indicators. Therefore, the treatment of tonifying the kidney and replenishing the spleen has been used as the complementary medical treatment for MG. However, there has been no systematic evaluation of the safety and efficacy of tonifying the kidney and replenishing the spleen in the treatment of MG. Thus, a systematic review was conducted on the tonifying the kidney and replenishing the spleen method for MG, with focus on clinical evidence, according to the included randomized-controlled clinical trials (RCTs).MG is described as “drooping eyelids” or “ flaccidity syndrome” in TCM literature. According to the TCM theory, the deficiency of the spleen qi leads to the weakness of the limbs. The deficiency of the kidney aggravates the deficiency of spleen, thereby worsening the symptoms of MG. Deng Tie-tao, who is an expert in TCM, considered that the main pathogenesis of MG was deficiency of the spleen and kidney, and that the treatment principle was to tonify the spleen and replenish the kidney.22.1 and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) were used to report and guide the systematic review and meta-analysis protocol. Since there is no direct human involvement, there was no need for ethical approval.The present study was registered in INPLASY, with registration number: INPLASY202110097. The Cochrane Collaboration Handbook for Systematic Reviews of Interventions2.2Merely RCTs that reported the efficacy and (or) safety of tonifying the spleen and replenishing the kidney method in TCM and Western medicine were included. These articles were published in the English and Chinese language. Animal mechanism studies, case reports, self-pre- and post-control, or non-RCTs were excluded.2.3Patients with MG  were included. The included patients were approximately 18 years old. There was no restriction in sex, ethnicity, race, and disease stage. Furthermore, patients with severe cardiovascular diseases, mental illnesses, and similar disease were excluded.2.4In the experiment group, the types of tonifying the spleen and replenishing the kidney methods of TCM for oral administration  combined with Western medicine were used for the treatment of MG.In the control group, one or more Western medicine  or placebo control were used, or no therapy was performed. There were no limitations on the intervention approach.2.5The primary outcomes are listed below:a.Effective rate;b.The quantitative myasthenia gravis (QMG) score;c.Adverse events;d.Quality of life.The secondary outcomes were, as follows:a.The concentration of acetylcholine receptor antibody (AchRAb) in serum;b.The change in related immune cells in the serum traditional Chinese medicine syndrome score scale (TCMSSS);c.The serum interleukin-6 level;d.The level of IFN-γ and its mRNA;e.The clinical score calculated based on The Chinese Expert Consensus on The Diagnosis and Treatment of Myasthenia Gravis .2.6A systematic literature search of articles published up to February 28, 2021 was conducted with the assistance of an experienced librarian in the following electronic databases: PubMed, Cochrane Library, EMBASE, Web of Science, Springer, China National Knowledge Infrastructure (CNKI), Wan-fang database, VIP Chinese Science and Technique Journals Database, the Chinese Bio Medical Database (CBM), and Baidu Scholar. All RCTs that used the tonifying the spleen and replenishing the kidney method in TCM, in combination with Western medicine, for the treatment of MG were collected. Merely the English and Chinese language was applied for the present study. Unpublished studies were not be sought Essential information: first author, year of publication, and country;(2)Study design: setting, inclusion and exclusion criteria, randomization method, blinding, sample size, and drop outs;(3)Participants: sex, age, and disease duration;(4)Methodological characteristics: title study design, MG severity, and diagnostic criteria;(5)Details of intervention: type of intervention, the names of the traditional Chinese prescriptions for treatment, duration of treatment, and follow-up time;(6)Outcome measures.2.7.2For missing or insufficient data, the authors were contacted to request for adequate data by email or telephone. If the missing data could not be obtained, the trails with missing data were detached from the data synthesis. Furthermore, a sensitivity analysis was performed to determine the impact of the missing data.2.8The methodological quality of each included study was assessed by 2 reviewers using the Cochrane Collaboration's risk of bias tool. Attention was given on the following terms: generation of random sequence, allocation concealment, blinding of participants and personnel, incomplete outcome data, duration of follow-up, selective reporting, and other bias. These terms were be categorized into 3 levels: low risk, unclear risk, or high risk. Any disagreements between the reviewers were settled by discussion, or seeking advice from a third reviewer.2.9P < .05. The SMD with 95% confidence interval (CI) was used to evaluate the continuous outcomes, and the RR with 95% CI was used to evaluate the dichotomous data. The fixed effects model (I2 < 50%) was used to estimate the RR and MD. The random effects model (I2 > 50%) was considered for the indication of substantial statistical heterogeneity, and used for the synthesis of the data, and the subgroup analysis or sensitivity analysis. Funnel plots were drawn for obvious publication bias.If a meta-analysis was possible, the data synthesis was presented using the RevMan V.5.3 statistical software. The statistically data were meaningful when 2.10The sensitivity analysis was conducted to evaluate the robustness and reliability of the pooled results. If adequate data were available for analysis, a sensitivity analysis for the primary outcomes was conducted to test the strength of the review conclusions, which included the quality of the methods and studies, and the impact of the sample size and missing data.2.11If >10 studies were included, the funnel plot would be used to determine the publication bias. Egger test and Begg test were used to quantitatively assess the publication bias using the Stata V.16.0 software. The results were estimated based on the Cochrane Handbook for Systematic Reviews of Interventions.2.12The strength of evidence was evaluated based on the Grading of Recommendations assessment, Development, and Evaluation system. The evidence was classified into 4 levels: high, moderate, low, or very low.2.13Two review authors, who have been trained in systematic review techniques, independently searched and assessed the titles and abstracts of the potential studies identified through the search strategy for eligibility. If the eligibility of a study was inexplicit from the title and abstract, the whole article was browsed. Studies that did not meet the inclusion criteria for the present review were excluded, and the reasons for the exclusion of these articles were recorded. If there was any disagreement, this was resolved through the consensus of all authors. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) study flowchart was used to record the screening process Fig. .3 have been used to suppress immune system disorders and control the symptoms. In particular, new molecules with selective action in targeting compounds of the immunological system have been identified. However, it remains difficult to cure MG, and some adverse reactions continue to appear. Hence, more researchers on TCM for MG have been published in recent years. In particular, the tonifying the spleen and replenishing the kidney method in TCM for MG has been applied for patients with spleen and kidney deficiency. According to the TCM theory, the spleen is responsible for the transportation and transformation of Qi and blood, and the distribution of water and grain. The deficiency of the spleen qi prevents the transportation and distribution of water and grain, which are subtle to the muscles and veins of the limbs, and the loss of water and grain subtle support leads to weakness of the limbs. The kidney is the place of yuan Yin and yuan Yang. The function of the spleen to transport water and grain depends on the warmness of the yuan-yang in the kidney, and the essence of the kidney depends on the filling and nourishing of the water and grain from the spleen. Therefore, the treatment of tonifying the spleen and replenishing the kidney has been used as a complementary medical treatment for MG. However, no systematic reviews and meta-analyses on the tonifying the spleen and replenishing the kidney method for MG have been published, to date. The evaluation of the effectiveness and safety of the tonifying the spleen and replenishing the kidney method in TCM for MG would offer better evidence for clinical treatment.MG is a chronic disease that seriously affects the quality of patients with MG. Western medicines, such as acetylcholine preparation, hormone, immunosuppressants, and intravenous immunoglobulinConceptualization: Xueping Yang, Min He.Data curation: Lu Li, Yuxuan Peng.Formal analysis: Lu Li, Yuxuan Peng.Funding acquisition: Weiyin Chen.Investigation: Qing Ye, Yuting Pan.Methodology: Bibo Lu, Jiachun Lu.Project administration: Bibo Lu, Jiachun Lu.Resources: Xueping Yang, Min He.Software: Yuxuan Peng, Qing Ye, Yuting Pan.Supervision: Qing Ye, Yuting Pan.Validation: Weiyin Chen.Visualization: Xueping Yang, Min He.Writing – original draft: Yuxuan Peng, Bibo Lu, Jiachun Lu.Writing – review & editing: Qing Ye, Yuting Pan.


Bile acids (BAs) are produced from cholesterol in the liver and are termed primary BAs. Primary BAs are conjugated with glycine and taurine in the liver and then released into the intestine via the gallbladder. After the deconjugation of glycine or taurine by the gut microbiome, primary BAs are converted into secondary BAs by the gut microbiome through modifications such as dehydroxylation, oxidation, and epimerization. Most BAs in the intestine are reabsorbed and transported to the liver, where both primary and secondary BAs are conjugated with glycine or taurine and rereleased into the intestine. Thus, unconjugated primary Bas, as well as conjugated and unconjugated secondary BAs, have been modified by the gut microbiome. Some of the BAs reabsorbed from the intestine spill into the systemic circulation, where they bind to a variety of nuclear and cell-surface receptors in tissues, whereas some of the BAs are not reabsorbed and bind to receptors in the terminal ileum. BAs play crucial roles in the physiological regulation of various tissues. Furthermore, various factors, such as diet, age, and antibiotics influence BA composition. Here, we review recent findings regarding the physiological roles of BAs modified by the gut microbiome in the metabolic, immune, and nervous systems. Bile acids (BAs) are amphipathic steroid acids produced from cholesterol in the liver, and de novo synthesized bile acids in the liver are termed primary BAs. Primary BAs are conjugated with glycine and taurine in the liver and are then stored in the gallbladder. BAs are released from the gallbladder into the small intestine via food intake to facilitate the digestion and absorption of lipids and lipophilic vitamins by forming micelles in the small intestine. While most of the BAs are absorbed in the intestine, there is a significant deconjugation of conjugated BAs prior to reabsorption in the terminal ileum. BAs that are not absorbed in the intestine are converted to secondary BAs by the gut microbiome and these secondary BAs are then absorbed into the colon via passive diffusion ,2. AfterAs BAs are amphipathic, they can affect cell-surface and intracellular membranes, including those of mitochondria and the endoplasmic reticulum (ER). Recent studies suggest that BAs are also hormones or signaling molecules because they can bind to several nuclear and cell-surface receptors, including farnesoid X receptor (FXR) and Takeda G protein receptor 5 (TGR5)—also known as G protein-coupled bile acid receptor 1 (GPBAR1) ,4. By acBAs are principally produced in the liver via the classical or alternative pathways ,9. Over Lactobacillus spp. [Bifidobacterium spp. [Enterococcus spp. [Clostridium spp. [Bacteroides spp. [Clostridium spp. [bai) operon. BaiB ligates CoA to the unconjugated BA. BaiA oxidizes the 3α-hydroxyl group. BaiCD catalyzes the formation of the C4=C5 bond. BaiF hydrolyzes CoA. BaiE catalyzes the 7α-dehydration, which is a rate-limiting step. BaiH catalyzes the removal of the C6=C7 bond and BaiCD catalyzes the removal of the C4=C5 bond. BaiA converts the 3-oxo-intermediate to a secondary BA [Eggerthella lenta strains also possess 7α-HSDH and produce 7-Oxo-DCA from CA [Clostridium spp. [Eggerthella lenta also has 3α- and one 3β-HSDH for converting DCA to isoDCA. Since IsoDCA is less toxic to bacteria than DCA, the conversion of DCA to isoDCA leads to the growth of bacteria in the gut [Clostridium bolteae strains significantly activates FXR [BAs are deconjugated, dehydroxylated, dehydrogenated, and epimerized by the gut microbiome . Conjugalus spp. ,16, Bificus spp. , Clostriium spp. ,19, and des spp. ,21. Mostdes spp. . After gium spp. . The 7α-ndary BA . Furtherndary BA ,25. HDSHndary BA . Additio from CA . 7-Oxo-Dium spp. ,28. Egge the gut . Additio the gut . Furtherates FXR .+-dependent and Na+-independent transporters. Na+-taurocholate co-transporting polypeptide (NTCP) transports BAs into the hepatocytes in a Na+-dependent manner [+-independent manner [Approximately 95% of BAs are reabsorbed from the gut, and the remainder is excreted in the feces . Reabsort manner ,42,43. Ot manner . OATP1B1t manner . The reat manner . Thus, bSpecific diet components influence BA composition. High- and low-fat diets are associated with a decrease in the synthesis of primary BAs . In feceThe plasma concentrations of most BAs decrease with age in men but not in women. A decrease in CDCA, GCDCA, TCDCA, and GUDCA is significantly related to age in men. The concentrations of DCA, GCA, UDCA, GDCA, and TDCA decrease with age in both men and women. Additionally, the concentration of DCA, GCA, and UDCA is significantly different between sexes . FurtherAntibiotic treatment changes the gut microbiota by reducing specific species and modifying the bile acid composition ,58. VancFXR and TGR5 are the most widely studied BA receptors . BAs alsThe main BA receptors are FXR and TGR5. BA binding to FXR and TGR5 regulates BA, glucose, and lipid levels. CDCA and DCA have a high affinity for FXR ,65,66,67glucagon-like peptide 1 (GLP-1) receptor [FXR regulates the expression of various genes by binding to specific DNA sequences in the genome, either as a monomer or as a heterodimer with the retinoid X receptor (RXR). These specific DNA sequences are an inverted repeat of AGGTCA separated by one nucleotide (IR1), IR0, an everted repeat of AGGTCA separated by two or eight nucleotides (ER2 or 8), and a direct repeat of AGGTCA separated by one, four, or five nucleotides  ,70,71,72receptor ,74,75. Ireceptor  and histreceptor . It has receptor . This sureceptor .s. Activated TGR5 leads to the activation of adenylyl cyclase, an increase in cyclic AMP (cAMP) concentration, and the activation of protein kinase A (PKA) and exchange proteins directly activated by cAMP (EPAC) [TGR5 is a member of the G-protein-coupled receptor (GPCR) superfamily and couples to GαP (EPAC) . LCA, DCP (EPAC) ,81,82. AP (EPAC) .FXR inhibits BA synthesis by inducing small heterodimer partner (SHP), a nuclear receptor that lacks a ligand-binding domain . SHP intGlucose and insulin upregulate and downregulate FXR expression, respectively, and FXR is associated with glucose metabolism ,113. The2+ from the ER and extracellular sources via voltage-dependent Ca2+ channels [TGR5 activation increases the intestinal level of GLP-1 ,126,127.channels ,129. Addchannels ,130  are absorbed and incorporated into chylomicrons in the intestine. Chylomicrons are then converted to very low-density lipoprotein (VLDL) in the liver. VLDL transports lipids from the liver to the systemic circulation. VLDL is then converted to HDL and returned to the liver . In the The liver in FXR-knockout mice exhibits an elevated expression of pro-inflammatory genes, such as interleukin-1 (IL-1), IL-6, interferon-γ (IFN-γ), inducible nitric oxide synthase, and cyclooxygenase-2. FXR activation inhibits the expression of these genes by inhibiting the activity of nuclear factor-κB (NF-κB), and also has an anti-inflammatory function . MoreoveMacrophages express both FXR and TGR5. Macrophages from FXR-knockout mice exhibit enhanced release of pro-inflammatory cytokines . CDCA anDendritic cells are antigen-presenting cells that play an essential role in the adaptive immune system and express TGR5. DCA suppresses lipopolysaccharide (LPS)-induced expression of pro-inflammatory genes, including IL-1, IL-6, and TNFα in dendritic cells. Furthermore, TGR5-knockout mice exhibit a recovery of LPS-induced expression of pro-inflammatory genes. These inhibitory effects of TGR5 are mediated by the repression of NF-κB via TGR5–cAMP–PKA signaling .Odoribacteraceae strains can produce isoalloLCA via 5α-reductase and 3β-HSDH. Moreover, isoalloLCA shows selective antibacterial activity against gram-positive multidrug-resistant pathogens [Recent studies have shown that 3-oxoLCA and isoalloLCA regulate T cell differentiation. IsoalloLCA triggers oxidative phosphorylation in mitochondria, leading to the production of reactive oxygen species (ROS). ROS from the mitochondria, not from the cytoplasm, induces forkhead box P3 (FOXP3). FOXP3 is a transcription factor and a master regulator of the development of regulatory T cells (Tregs), which release immunosuppressive factors. This 3-oxoLCA acts as an inverse agonist of retinoid-related orphan receptor γt (RORγt), leading to the inhibition of the development of T helper 17 (Th17) cells, which release pro-inflammatory factors. Both 3-oxoLCA and isoalloLCA are not produced in germ-free mice ,157. It athogens .A) receptor activation inhibits neurotransmission [A receptors [A receptor activation in neurons in the tuberomammillary nucleus of the hypothalamus [Both conjugated and unconjugated BAs can be detected in human and rodent brains ,158,159.smission ,172. CA,eceptors . UDCA inthalamus . G/T DCAthalamus ,176,177.thalamus . Additiothalamus .MRGPRX4, also known as sensory neuron-specific G-Protein coupled receptor 5/6, is involved in cholestatic itch ,180,181.BAs are synthesized in the liver as primary BAs, and a variety of secondary BAs are synthesized in the intestine through the involvement of various microorganisms. These BAs bind to multiple nuclear and cell-surface receptors. Therefore, BAs have been recognized as signaling molecules. Each BA has a different affinity for the receptor to which it can bind. The abundance ratio of primary and secondary BAs may affect short- and long-term health. Thus, factors such as food, aging, and antibiotics affect the gut microbiome and may change the BA composition and affect health. Currently, probiotics, prebiotics, synbiotics, and postbiotics are considered substances that maintain health by preventing metabolic diseases by controlling the composition of the gut microbiome . A recen


In the process of intelligent system operation fault diagnosis and decision making, the multi-source, heterogeneous, complex, and fuzzy characteristics of information make the conflict, uncertainty, and validity problems appear in the process of information fusion, which has not been solved. In this study, we analyze the credibility and variation of conflict among evidence from the perspective of conflict credibility weight and propose an improved model of multi-source information fusion based on Dempster-Shafer theory (DST). From the perspectives of the weighting strategy and Euclidean distance strategy, we process the basic probability assignment (BPA) of evidence and assign the credible weight of conflict between evidence to achieve the extraction of credible conflicts and the adoption of credible conflicts in the process of evidence fusion. The improved algorithm weakens the problem of uncertainty and ambiguity caused by conflicts in the information fusion process, and reduces the impact of information complexity on analysis results. And it carries a practical application out with the fault diagnosis of wind turbine system to analyze the operation status of wind turbines in a wind farm to verify the effectiveness of the proposed algorithm. The result shows that under the conditions of improved distance metric evidence discrepancy and credible conflict quantification, the algorithm better shows the conflict and correlation among the evidence. It improves the accuracy of system operation reliability analysis, improves the utilization rate of wind energy resources, and has practical implication value. Information fusion technology has solved many troubles –7 in theIn the information explosion era, information presents a massive, multi-source, heterogeneous, multi-dimensional, complex, and fuzzy feature. It has developed rapidly emerging information technology. The development of intelligence has significantly increased the complexity of the various levels of the system, which makes the system faces reliable operation challenges , 21. UndWith extended the prior research, the Dempster-Shafer theory (DST) fusion algorithm has achieved better performance in comprehensive system state analysis and decision making. However, it has a strong subjective dependence  on basicIn terms of fusion frameworks, researchers have proposed different framework models, which improved the algorithm effectiveness. Brommer et al.  proposedTo deal with the diversity, uncertainty, and conflict of information, researchers have proposed ideas of feature correlation, difference, different conflict values, and non-similarity measures. They improved and integrated algorithms –31 from Wu et al.  proposedUnder the Dempster-Shafer framework, Tang et al.  proposedFrom the researchers’ exploration, the information fusion algorithm based on Dempster-Shafer has always been a hot focus of research, which has a broad theoretical and practical value. In the current development process, the widespread application of intelligent systems increases the demand for system operation and maintenance. However, the existing algorithms –42 stillSome studies –46 suggeThe multi-source information fusion problem in this paper refers to integrating multiple sources of information. Multiple sources are information originates from different means of monitoring the same part of the same thing. Therefore, in our proposed fusion framework, the multi-source information fusion problem  is summaNi, <Ni>, and D represent data, features, and decisions respectively.Where, Ni contains an enormous amount of information, and the information is represented in the knowledge form, and the data feature set <Ni> is constructed by mining the information of potential features’ data from the perspective of knowledge management. The knowledge is fused with algorithms to improve the recognition framework, and the accuracy and reliability of algorithms in the fusion process are improved to provide the foundation for management decisions. The relationship between data, features, and decisions is shown in The type, state, format, and scenario of data lead to its multi-source heterogeneity and complexity in the information management. Data set Vi is different perspectives, then there is some correspondence between the whole process from the mapping of perspective space to data space and then to data feature space, as shown in Eq /2, where n>1. Each group of evidence that forms a series of similarities with other evidence and the number of similarity data between evidence i and other evidence is (n-1).Then, it gets a set of similarity sequences of length i and other evidence can be expressed by Eq /2, where, n > 1. It aggregates the differences between one evidence and the other to get n sets of variation data.The total number of data on the variation among the evidence is i and all others that affects the conclusion.Then, Eq  can expri and others is the difference of evidence i, which can be expressed by Eq ∈, ∑Cre(mi) = 1.Where, When the credibility weight of evidence to focal element support is high, it shows that the supports of other evidence is to a high degree. The credible weight corresponds to the confidence function in the identification framework, and the product of the credible weight and the confidence function is the reliability of that subsystem. Then the reliability transfer function of the entire system is the product of the subsystem reliability.The BPA calculation session introduces evidence similarity, evidence difference, and evidence trustworthiness weights to improve the BPA calculation process of the original algorithm. To fully retain the trustworthy conflicts, this part improves the fusion session of the algorithm based on the improved BPA calculation session.The conflict involvement in fusion directly affects the BPA of the event. Therefore, we construct an improved probability assignment model in terms of the credible weight assignment of conflict information, which uses the product of the credibility of evidence to focal element support and the original probability assignment function. Then, it shows the BPA function of evidence under the new probability assignment model calculated through the BPA calculation session in Eq .By introducing credible conflict, the sum of the fusion results of the relevance of evidence and the fusion results of the credible conflicting evidence makes up a new fusion function. The improved probability assignment function is a fusion calculation of the BPA of the non-conflicting information and the credible conflicting information in the conflict under the new support condition. It means that the improved BPA function is the fusion calculation of the basic probability assignment of the non-conflicting information under the new support condition and the credible conflicting information in the conflict. Thus, the improved probability assignment function is the sum of the BPA function of evidence to a focal element and the support of other evidence to that focal element under the conflict condition, which contains the credible conflict extraction treatment under the new weight for the changed evidence. It shows the new probability distribution function in Eq .s≠j, i、j、s≤n. j in support of focal element Ai.Where, Normalizing the improved probability assignment to keep the probabilities are in the same mapping environment. Reassigning the weights of conflict and the sum of all evidence probabilities is 1. Under the new conditions, we classify the features of credible conflicts into the category of trustworthy features; the evidence is independent of each other, and the remaining conflicts that are not considered are discardable.Therefore, the evidence under the new BPA is re-fused, and it shows the fusion rule in Eq .A≠∅, indicates that the conflicting factors in the original evidence are involved in the fusion by credible weights.Where, Wind power generation technology is mature in renewable energy generation. China has abundant wind energy resources, especially on the southeast coast, Liaotung Peninsula, and northeast. Compared with fossil fuels, the use of clean energy such as wind power can have an effect on reducing carbon dioxide emissions and mitigating global climate change trends. According to a study , nearly According to the preliminary analysis, we find that wind speed is one of the key parameters of wind turbine operation; some data showed consistency in the variation pattern; parameters such as pressure and temperature are more sensitive to environmental changes; changes in voltage and current are associated with other parameters, and the overall fluctuations of different wind turbine operations have some similarity. Therefore, we organize and analyze data with a tendency, and select a representative wind turbine in the wind farm to study the parameters such as generator speed, gearbox low-speed bearing temperature, gearbox oil pressure, gearbox inlet oil temperature, and grid current in a certain period. And it does not describe the screening process here. When the wind speed is in the steady-state range, the wind turbine speed in the normal operation state of the system is also in the steady-state range. So we analyze the relative change trends of generator speed, gearbox low-speed bearing temperature, gearbox oil pressure, gearbox inlet oil temperature, and grid current during the operation of the wind turbine at a certain time with the wind turbine speed as the base reference parameter. And we find that there is a correlation between the change patterns of some data; the variation trend of different data is different, and the inconsistency of variation shows that there is a conflict between the evidence. Therefore, according to the difference in the changing pattern of data features, we judge whether there is a credible part of the evidence conflict, dig deeply into the consistency information and conflict information in the data, extract credible fault features, analyze the system operation status, and diagnose the system fault.E1, E2, E3, E4, and E5, respectively. According to the characterization of distinct features, we excerpt valid and representative data periods from the data set, select the basic feature parameters of the evidence in the operation state, and map them into the  interval to eliminate the influence of data heterogeneity on feature fusion, as shown in Let the relative change trends of parameters such as generator speed, gearbox low-speed bearing temperature, gearbox oil pressure, gearbox inlet oil temperature, and grid current are the evidence E1 and E2 is higher than that of E3, E4, and E5; from the cliff factor, the fluctuation of the evidence is roughly a continuous flat change, showing that the data situation is more stable, and it can select the above parameters for the next analysis of the wind turbine.In We divide the mapping of the evidence to system fault support into four types: normal state, implicit fault, explicit fault, and warning. According to the actual occurrence of faults, we identify the points with a more stable change trend in the evidence, define the distribution of the evidence characteristics in the fault characterization, and determine the interval of the fault characterization, as shown in F0, which means that it excludes the status data at the moment of normal wind turbine start-up. While processing element 0 in the fault state by adding 1 and classifying it into the warning state F3. The fault interval varies for different systems under different climatic conditions and needs to be determined dynamically based on historical state data.Since 0 in the mapping interval  contains the cases of the continuous shutdown without starting and shutdown due to fault, we remove element 0 from the normal state Organize the data of wind turbine operation, and analyze the fluctuation of data characteristics under different state conditions in the historical data. According to the distribution of the points of the evidence fluctuation interval in different states, such as normal state, hidden fault, explicit fault, and warning, we select a certain moment region with certain credibility and representativeness and calculate the dynamic BPA of each evidence. Depending on the selected interval of the system, it dynamically changes the basic probability distribution. The basic probabilities of selected regions in this paper are calculated and derived, as shown in E1, E4, and E5 considering the system to have a higher probability of explicit failure, Evidence E2 considering the system to have a higher probability of hidden failure, and Evidence E3 considering the system to have a higher probability of normal state. Exhibit E5 considers that the system also has a higher risk of implicit failure under the high probability of explicit failure.From Based on the typical DST, we fuses the above evidence and it shows the fusion results in E1, E4, and E5 consider the system to have a higher probability of explicit failure, it significantly weakens the support of evidence E3 for the system to be in a normal state and the support of evidence E2 and E5 for the occurrence of implicit failure to some extent. If evidence E2 considers the system to be in a warning state with a lower probability, it weakens the support of evidence E1 for the system to be in a warning state. The trends of the same features strengthen each other and the trends of distinct features weaken each other.From Calculate the similarity of the above evidence using a fusion model improved by the weighting method. Then we can get:From this, calculate the weight of evidence, as 0.1980, 0.2003, 0.1937, 0.2047, and 0.2033, respectively.After reassigning the weights, calculate the new BPA values for each piece of evidence: The fusion results under the new probability are shown in Analyze the above evidence using the algorithm under the improved distance strategy of this paper. Calculate the variance of distinct evidence for event support.The normalized variance is:Calculate the conflicting credible weights of the evidence, and the credible weights of evidence for event support are 0.1983, 0.1983, 0.1846, 0.2107, and 0.2081, respectively, as shown in Based on the reassigned weights, calculate the new basic probability function values of the evidence, as shown in E2 decreases, and the explicit failure rate increases; the probability of the normal state of evidence E3 decreases and the probability of explicit failure increases; the probability of the normal state of evidence E5 increases, and the changes of evidence E1 and E4 are smaller. Re-fused them, and it shows the new fusion results in From This paper introduces the improved weighting strategy and distance strategy to quantify the correlation and conflict between evidence features in the research process. Compares the fusion results of the original, and improved algorithms, with the actual situation, as shown in From The analysis of the fusion results, as shown in E1 and E2 before and after the algorithm improved are small, show that the conflicting nature between the two pieces of evidence is small and the conflict participation in the fusion has little impact on the results, as shown in The changes in the fusion of evidence E3 and E4, there is a significant change in the judgment that the system is in the F0 state and F2 state. The improved algorithm discards part of the worthless conflicting information in the evidence and absorbs part of the conflicting information in the two states of F0 and F2, leading to a large deviation before and after the improvement, as shown in In the fusion with evidence E5, the probability that the system is in each state shows irregular fluctuations, but overall, the probability that the system is in F3 state has been decreasing, as shown in When fused with E2 and E3 and E1, E4 and E5 if the evidence E2 and E3 have fully support for the hidden fault and normal states, respectively.The stability analysis of the changing trend of the fusion results, as shown in In this paper, we propose an improved model of multi-source information fusion under the weighting strategy and distance strategy and check the validity by a case of wind turbine system fault diagnosis in northeastern China. The research results show that the improved algorithm approach under distance strategy has a better adaptability and fits to conflicting information, and quantifies the discrepancy of evidence to event support, credibility, and credible conflict weights considering the fit to reality. The involvement of credible conflicts in the fusion diagnosis solves some uncertainties caused by the loss of credible conflicts and weakens the interference of untrustworthy conflicts on the results.The proposed algorithm in this paper improves the accuracy of the calculation model, reduces the relevance and uncertainty in the process of using information features, and interprets the practical application significance of the evidence factors after readjusting the basic probability of the evidence. It also improves the scientific and rational system management, enables managers to have a better understand to the system operation status in time. Effectively reducing the system operation and maintenance costs and losses caused by the faults as well as improves the energy utilization efficiency and it has certain advantages in accuracy and timeliness of fault diagnosis.The method is not only applicable to the wind farm calculations but also to the operational reliability analysis of other energy utilization systems that require comprehensive consideration of multiple factors. Considering the resource utilization efficiency in China, and the complexity and uncertainty of the system operational environment, in the future, we will study the complex system operation reliability in information technology developmentto improve the overall accuracy of the model and realize efficient management of system operation.S1 Data(XLSX)Click here for additional data file.


Cardiac magnetic resonance (CMR) imaging is a key test in the diagnosis of cardiac amyloidosis (CA). Extracardiac involvement is common in light chain (AL) amyloidosis and MRI findings may assist in its diagnosis. We sought to investigate the utility of splenic CMR parameters for the diagnosis of CA.Thirty-four patients with AL amyloidosis and 32 patients with severe left ventricular hypertrophy in the setting of aortic stenosis (LVH-AS) who completed 3T cardiac MRI at the time of their diagnosis of AL or LVH-AS were assessed with T1, T2 (modified Look-Locker inversion recovery), extracellular volume (ECV) mapping, and late gadolinium enhancement (LGE) imaging of the heart and spleen.p < 0.001), and significantly lower short tau inversion recovery ratio  both with very good diagnostic performance to diagnose AL. We identified 16 AL patients with spleen involvement and 16 without. Spleen ECV and “normalized” spleen ratio, defined as the ratio of spleen LGE to muscle values exhibited strong correlation and had excellent diagnostic performance to discriminate those with spleen involvement.Age, left ventricular mass index, wall thickness, ejection fraction, and splenic dimensions did not differ significantly between groups. All AL patients had cardiac involvement. T1 and T2 spleen mapping did not differ significantly between groups but AL patients had higher median ECV in the spleen than in LVH-AS (AL 46.9%, LVH-AS: 31%, Our findings show that spleen CMR parameters can identify spleen involvement in AL patients and differentiate them from those without AL amyloidosis. Cardiac magnetic resonance (CMR) provides imaging biomarkers to diagnose patients with amyloidosis.CMR non-invasive imaging features and parameters can identify spleen involvement in AL patients.Extracellular volume (ECV) may demonstrate splenic involvement in AL Amyloidosis.Splenic LGE may provide an alternative and/or additional parameter to ECV.Systemic amyloidosis represents a complex and heterogeneous group of diseases, defined by the deposition of abnormal proteins, in different tissues and organs, with main consequence organs failure. Classification of amyloidosis is based on the amyloid protein type, and up to date 36 different have been identified . The depTherefore, there is an up growing demand for appropriate imaging techniques able to identify involved organs, including spleen. MRI parameters such as diffuse low signal intensity of spleen on T2 weighted images and the increased spleen extracellular volume suggest splenic involvement , 7. The This is a retrospective, single-center analysis approved by the Institutional Review Board that included 34 consecutive patients with cardiac AL amyloidosis. All patients were treated at Department of Clinical Therapeutics, at Alexandra General Hospital of National Kapodistrian University of Athens between September 2020 through November 2021. This is a national high-volume reference center of amyloidosis. The diagnosis of cardiac amyloidosis was based on a combination of typical features on echocardiography, 99 m technetium phyrophosphate scintigraphy, cardiac magnetic resonance imaging and histologically proven systemic AL amyloidosis according to current international recommendation . PatientAll participants underwent a CMR examination at Research Unit of Radiology of 2nd Department of Radiology of National and Kapodistrian University of Athens, using a 3.0T MRI Philips (Achieva TX) manufactured scanner equipped with a 16-channel XL-Torso2 anterior and posterior receiver coils. The imaging protocol included cine imaging using a retrospectively ECG gated balanced turbo field echo (bTFE) to assess left ventricular (LV) and right ventricular (RV) function, mass and dimensions ; a ECG triggered black blood T2 short tau inversion recovery (STIR) to assess myocardium edema ; a three slices ECG triggered mutli echo turbo spin echo combined with black blood pre-pulse to create T2 map images ; a ECG triggered phase sensitive inversion (PSIR)  5 and 10 min after the gadolinium injection to assess the myocardium viability; a 2D retrospectively ECG gated phase contrast sequence to quantify the flow of aorta and pulmonary vessel . Three slices native and late gadolinium enhanced (LGE) T1 maps were also acquired using modified Look-Locker Inversion recovery (MOLLI) sequence to estimate structural lesions and calculate ECV map considering the hematocrit levels .CMR analysis was performed by an experienced to CMR imaging radiologist and one MRI physicist blinded to participants’ clinical history using the commercially available software . Left ventricular endo- and epicardial borders were manually outlined in the short-axis slices at the end-diastolic and end-systolic phases. Left ventricular features and function, including LV wall thickness, wall mass, ejection fraction, end-systolic volume, end-diastolic volume and stroke volume, were computed based on short-axis slices. Native and post contrast T1 myocardial relaxation images were firstly manually segmented drawing endocardial and epicardial contours and then were co-registered to eliminate motion-related artifacts, using CVI42 software. Subsequently, the automatically derived global T1, extracellular volume (ECV) and R2 maps were visually checked for the presence of artifacts. Regions of interest were drawn in artifact free spleen area on the short-axis T1, T2 and ECV maps. Regions of interest were also drawn by two experienced raters in spleen and adjacent muscles (preferable Serratus anterior muscle) on short-axis PSIR (phase sensitive inversion recovery) images at 5- and 10-min post contrast enhancement, avoiding vessels, lesions, and artifacts , body surface area (1.9 m2 for both groups) and gender  did not differ significantly between groups. Systolic blood pressure but not diastolic blood pressure was significantly higher among LVH-AS patients than AL .We studied 66 patients (34 with AL amyloidosis with cardiac involvement and 32 with LVH-AS) who underwent CMR at the time of diagnosis of amyloidosis or LVH-AS. Age . However, we found significantly higher ECV in the spleen of AL patients than in LVH-AS , and significantly lower short tau inversion recovery (STIR) ratio in AL . Spleen ECV had very good diagnostic performance to discriminate between AL and LVH-AS with area under the curve AUC = 0.82, 95% Confidence Intervals 0.72–0.92 . Spleen ECV had excellent diagnostic performance to discriminate spleen involvement with AUC = 0.97, 95% Confidence Intervals 0.91–1 . A cut-off point of 46.9% had sensitivity and specificity of 94%. The normalized spleen LGE ratio at 5 min was significantly lower among those with spleen involvement compared with patients exhibiting no spleen involvement . A cut-off point of 0.01 had sensitivity and specificity of 94% to diagnose spleen involvement.Among AL amyloidosis patients, we identified 16 patients with spleen involvement and 16 patients without involvement. No patient with LVH-AS had abnormal spleen findings. Spleen ECV was significantly higher in the spleen involvement group . Normalized spleen LGE ratio at 10 min had excellent diagnostic performance to discriminate spleen involvement with AUC 0.98, 95% Confidence Intervals 0.95–1, and no significant difference compared with the AUC of spleen ECV (p = 0.37). A cut-off point of 0.35 had sensitivity of 88% and specificity of 100% to diagnose spleen involvement.Similarly, the normalized spleen LGE ratio at 10 min was significantly lower among those with spleen involvement compared with patients exhibiting no spleen involvement . Also, we found significant correlation between ECV and LGE spleen ratio at 10 min in AL patients . We found no differences in myocardial native T1 and ECV between those with and without spleen involvement . The inter-rater agreement was substantial for all metrics .There was a significant negative correlation between spleen ECV and LGE spleen ratio at 5 min in AL patients  imaging of the spleen and measurement of several parameters including T1, T2 mapping and ECV was feasible in all AL and LVH-AS patients, (2) no differences in T1 and T2 mapping were identified between groups, 3) ECV and STIR ratio of the spleen was significantly higher in AL patients with very good diagnostic performance to discriminate between AL and LVH-AS  CMR parameters for diagnostic and prognostic purposes is warranted.


The infographic about red flags that should raise suspicion of physical child abuse (


Despite consistent international guidelines for osteoarthritis (OA) management, evidence-based treatments are underutilised. OA management programmes (OAMPs) are being implemented internationally to address this evidence-practice gap. An OAMP is defined as a ‘model of evidence-based, non-surgical OA care that has been implemented in a real-world setting’. Our objective is to identify, synthesise and appraise qualitative research identifying anticipated or experienced micro , meso  or macro (context/system) level barriers or facilitators to the implementation of primary or community care-based OAMPs.Five electronic databases will be searched for papers published between 2010 and 2021. Qualitative or mixed-methods studies that include qualitative data on the anticipated or experienced barriers or facilitators to the implementation of primary or community care-based OAMPs, from the perspective of service users or service providers, will be included. The review will be reported using the PRISMA and ENTREQ guidelines. A data extraction form will be used to provide details of the included studies. Data will be analysed and identified barriers and facilitators will be mapped onto an appropriate implementation framework, such as the Theoretical Domains Framework. The appropriate JBI critical appraisal tools will be used to assess methodological quality, whilethe GRADE‐CERQual approach will be used to assess confidence in the findings.Translation of evidence-based guidelines into practice is challenging and reliant on the quality of implementation. By comparing and contrasting anticipated and experienced barriers, this review will determine the extent of congruence between the two, and provide valuable insights into the views and experiences of key stakeholders involved in the implementation of OAMPs. The mapping of identified barriers and facilitators to behaviour change theory will enhance the applicability and construct validity of our findings and will offer significant utility for future development and implementation of OAMPs.Registration: This protocol was registered with PROSPERO (CRD42021255698) on 15/07/21. OA is associated with an extremely high individual, economic and societal burden, frequently affecting multiple joint sites and accompanied by comorbid physical and mental health conditions, increased mortality, and decreased participation and quality of life. The World Health Organisation (WHO) estimates that by the year 2050, 130 million people worldwide will have OA and 40 million will be severely disabled by OA, representing a growing global public health concern. Public health interventions are required to address the existing overuse of inappropriate and low-value care and provide equitable access to cost-effective, evidence-based management . Although numerous international clinical practice guidelines have been published endorsing exercise, education and weight management as first-line core treatments, delivery and uptake of these treatments remains suboptimal and not consistently aligned with patient preferences.Osteoarthritis (OA) is the most common joint disease worldwide and is one of the fastest growing causes of years lived with disability. In response to growing international development of OAMPs, the Osteoarthritis Research Society International (OARSI) OAMP Joint Effort Initiative (JEI) has been established. This is a collaboration of international researchers progressing the standardisation and harmonisation of the development and delivery of OAMPs. The OAMP JEI define an OAMP as a ‘model of evidence-based, non-surgical OA care that has been implemented in a real-world setting and includes the following four components: personalised OA care; delivered as a package of care with longitudinal reassessment and progression; comprising two or more elements of the core, guideline-recommended first line interventions ; with optional adjunct treatments as required ”. OAMPs focussing on education and exercise for patients with knee, hip and hand OA have shown positive effects on patient outcomes including pain, physical function, health-related quality of life and self-efficacy in developed countries. Reduced sick leave and analgesia use, decreased willingness for surgery and delayed knee or hip replacement surgery have also been reported.Efforts to optimise evidence-based non-surgical treatments have led to the development and implementation of primary care-based OA management programmes (OAMPs) internationally. Successful translation of evidence into clinical practice can be challenging and requires a comprehensive and targeted micro-, meso- and macro-level approach adapted to the specific setting and relevant stakeholders. An understanding of anticipated or experienced barriers and facilitators to implementation is vital to realise the full value of OAMPs. Furthermore, evidence on the factors that facilitate this process could improve recruitment to, and uptake of, future OAMPs. Barrier themes identified in a previous systematic review exploring clinicians’ perceived barriers and enablers to management of OA in primary care included: clinician beliefs, knowledge gaps, communication, behaviour change skills, dissonant patient expectations and co-morbidities which increase complexity of care, while no enabler themes were identified. A recent systematic review also identified factors influencing implementation of evidence-based guidelines in primary care settings including: research and ‘real-world’ disconnects, views of patients and primary care clinicians and engagement of whole primary care practice settings in the implementation process. However, the anticipated and experienced barriers have yet to be combined and subsequently compared and contrasted. Hence, this review will explore whether, for example, clinicians’ concerns or fears are corroborated by experienced barriers. Furthermore, unlike earlier reviews, this review will be theory-informed, barriers and facilitators will be reviewed through a micro-meso-macro level lens and will be linked to evidence-based behaviour change theory. Our a priori framework, the Theoretical Domains Framework (TDF), is a comprehensive evidence-based implementation framework developed for systematically identifying and assessing barriers to change interventions. By mapping the data to the TDF, this review will add to the current literature and will inform future intervention design and allow for tailored implementation solutions.However, the potential benefits of primary care-based OAMPs may be constrained by barriers to their effective and sustained implementation. These may occur at the micro , meso  or macro (context and system) levelsThis review aims to identify, synthesise and appraise the qualitative evidence on barriers and facilitators to the implementation of primary or community care-based OAMPs. To describe the anticipated or experienced micro-, meso- or macro-level barriers or facilitators to the implementation of primary or community care-based OAMPs from the perspectives of patients, carers, healthcare professionals and other relevant stakeholders across these levels.To compare and contrast anticipated and experienced facilitators.To map the identified barriers and facilitators to the TDF domains. and the Enhancing Transparency in Reporting the Synthesis of Qualitative Research (ENTREQ) guidelines will be used to guide the conduct of this review. The review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO), ID: CRD42021255698, on 15/07/21.The Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) guidelines. TheOAMP JEI discussion group established by OARSI will be contacted to identify other relevant research. This platform has been deemed suitable given its international reach.To identify eligible studies, we will search electronic databases including Ovid MEDLINE, EMBASE, CINAHLvia EBSCOhost, PsychINFO, and Web of Science from 2010 onwards to present to align with publication dates of recent guidelines. A combination of Mesh terms and keywords will be developed in conjunction with a medical librarian. The search strategy will include terms related to ‘osteoarthritis’, ‘implementation’, ‘management programme’, ‘primary and community care’ and ‘qualitative design’ with Boolean operator “and”. An academic librarian will be consulted regarding the appropriate Medical Subject Heading (MeSH) terms used for each electronic database. This will be initially tested in Ovid MEDLINE and adapted for all other databases. The search strategy will be restricted to English language articles published from 2010 onwards. A sample search strategy for Ovid MEDLINE is available (see extended data)Articles retrieved will be exported to Endnote X9  with duplicate entries removed. Titles and abstracts will be screened independently by two review authors (JC and AF or ES), according to the inclusion criteria. Any disagreements will be resolved through a third arbitrator (HPF). The same process will be employed for potentially eligible full-text publications. Finally, we will search for additional studies using the reference lists of identified articles. This will involve forward and backward citation checking of all identified systematic reviews and all articles eligible for inclusion will be conducted.  will be used to identify eligibility criteria for study inclusion [The SPIDER  frameworkclusion ., and will be determined by the original research articles. Primary care clinicians may include general practitioners (GPs), nurses, physiotherapists, occupational therapists, dieticians, podiatrists etc. Community care service providers may include health workers, lay and professional, formal and informal, paid and unpaid, involved in the implementation of an OAMP, for example personal trainers, gym instructors, strength and conditioning coaches, community leaders etc. Other relevant stakeholders may include individuals involved at an organisational or system level such as health service managers, policy makers, funders/insurers or service commissioners. The population of interest will include individuals involved in the implementation of an OAMP, namely service users  and service providers  as described in an included study. For individuals with OA, diagnosis may be based on radiographic criteria, clinical features or combination criteria. It should comprise the following four components: ‘personalised OA care; provided as a package of care with longitudinal reassessment and progression; comprising two or more components of the core, non-surgical, non-pharmacological interventions  and optional evidence-based adjunctive treatments as required ’. The setting for initiation and delivery of the OAMP must be in primary or community care, but can include pathways for referring patients to secondary care. OAMPs delivered in secondary care or other specialist ambulatory settings will be excluded. We will adopt the World Health Organisation (WHO) definitions of primary and community care. The OAMP may be implemented at a small-scale  or large-scale level .The phenomenon of interest includes anticipated or experienced barriers or facilitators to implementing community or primary care-based OAMPs. At least one service user or provider-related barrier or facilitator theme must be described in a primary study to be included in this review. Experiences of OA not related to an OAMP will not be eligible for inclusion, but the explicit use of the term ‘OAMP’ is not required for inclusion. For the purpose of this review, an OAMP will be defined as per the OARSI OAMP JEI as a ‘model of evidence-based, non-surgical OA care that has been implemented in a real-world setting’All identified full-text original research that provide qualitative data on anticipated or experienced barriers or facilitators to the implementation of primary or community care-based OAMPs will be included. We will consider primary studies using focus groups or one-to-one, in-depth or semi-structured interviews, explicitly reporting one or more barrier or facilitator. Surveys that provide qualitative data or studies of mixed methods design, where qualitative data can be extracted separately, will be included. Excluded study designs include stand-alone quantitative research, individual case reports (<10 participants), systematic or narrative reviews, conference proceedings and opinion/narrative/discussion and editorial articles.Included studies must be published from 2010 onwards to align with publication dates of recent guidelines. In the case of abstracts or protocols being retrieved, attempts will be made to access full-texts by contacting the authors.Two review authors (JC and HPF or ES) will extract descriptive study characteristics independently using a structured data extraction form. Detailed data and contextual information  will be extracted.. This will be conducted by two independent review authors (JC and AB) with a third review author (FD) available should any disagreements arise.Methodological quality assessment of included studies will be performed using the appropriate Joanna Briggs Institute Critical Appraisal tool for qualitative and quantitative research. Extracted data labelled ‘results’ from included studies will be imported into NVIVO version 12 . A two-stage analytical approach will be employed incorporating 1) an inductive line-by-line coding of the extracted results to identify emergent themes, followed by 2) a deductive exercise to map identified codes to an a priori framework. During analysis we will adopt a micro-meso-macro level lens to ensure individual, organisational and broader factors are considered. Following extensive familiarisation with the data, two independent review authors (JC and HPF) will code the data. A third review author (LS) will inductively code a sample of transcripts to explore shared meanings and interpretations. The consistency of coding will be explored to facilitate the coding framework development. Codes with similar meanings will be grouped together to form broader themes, whilst checking for confirmatory or challenging evidence. At this stage, a final coding will be agreed through consensus discussion of codes and themes among a study panel of approximately six individuals (including review authors and members of a patient advisory panel). The coding framework will then be systematically applied to the whole dataset. Findings will be synthesised using a framework synthesis, which is a review method that combines inductive and deductive approaches to synthesise empirical findings from qualitative research studies. It allows researchers to capture the potentially broad range of potential determinants of implementation, which are relevant to behaviour change. The refined version of the TDF consists of 14 domains and 84 constructs relating to behaviour change theory. Identified barrier and facilitator themes will be mapped according to the TDF: (1) knowledge, (2) skills, (3) social influences, (4) memory, attention and decision processes, (5) behavioural regulation, (6) professional/social role and identity, (7) beliefs about capabilities, (8) belief about consequences, (9) optimism, (10) intentions, (11) goals, (12) emotion, (13) environmental context and resources and (14) reinforcement. A coding manual with theoretical and working definitions and component constructs of each of the 14 domains will be used to operationalise the TDF and facilitate coding consistency. The framework will be adapted to accommodate any themes that cannot be mapped to a TDF domain. This mapping exercise will initially be carried out by two review authors (JC and FD), and then verified through detailed discussion with two other review authors (ZP and LS). This process will involve the examination of each data extract (exemplifying each theme), and exploring how these extracts fit (or did not fit) within the parameters of each theoretical domain. All codes will then be reviewed and themes will be discussed within the study panel to ensure consistency and ‘fit’ to the framework. A preliminary synthesis will be achieved using tabulation of studies, organising the studies into groups e.g. relating to anticipated and experienced barriers, and exploring relationships between studies and between groups e.g. comparing and contrasting anticipated and experienced barriers and identify areas of dissonance/concordance. A final coding framework will be agreed through consensus discussion of the themes and interpretations between the study panel. This method, commonly used in health research and TDF analyses, allows for exploration of unanticipated factors associated with implementation. The GRADE CERQual approach will be used to summarise confidence in the evidence, where each review finding will be assessed under four components: (1) methodological limitations, (2) coherence, (3) adequacy of data, and (4) relevance. This will be carried out independently by two review authors (JC and LS). A third review author will resolve any disagreements (FD). Following this process, an overall assessment of confidence in each finding will be made, and categorised as High, Moderate, Low or Very Low confidence.Following this, the second stage of analysis will involve using a framework. Our a priori framework, the TDF, provides a robust theoretical basis for implementation studies, as it is one of the few frameworks linked to a comprehensive method for intervention designOn completion of the analysis, this review will be submitted for publication in a high-ranking international peer-reviewed journal. It will be shared with the Implementation subgroup of OARSI’s Joint Effort Initiative and the JEI website resources for OARSI.At the time of publication of this protocol, database searches have been completed and study selection is underway. Completion of the review is expected by March 2022., particularly in the context of increasing life expectancy and obesity. Despite this, OA remains under-diagnosed and under-treated, when compared to non-musculoskeletal chronic diseases. There is an urgent need to address the shortcomings in the management of OA, given that OA commonly co-exists with other conditions such as hypertension, cardiovascular disease and diabetes, and worsens the morbidity and mortality associated with these chronic diseases. While the majority of research on musculoskeletal disorders to date has been conducted in high-income settings, limited data suggest that the prevalence of arthritis may be equivalent or higher in lower-middle-income countries. The development of OAMPs internationally remains in its infancy, and they have been for the most part implemented at a relatively small-scale and typically in high income nations. Therefore, a comprehensive understanding of the barriers and facilitators to implementation of OAMPs represents an important area of implementation research and informing scalability of OAMPs. By mapping the barriers and facilitators to the TDF, this review will provide a theoretical pathway to inform intervention and guide service designers and implementers in identifying and overcoming likely micro-, meso- or macro-level barriers to sustainable service delivery. This theory-based approach will enhance adoption of future OAMPs into community and primary care settings and narrow the evidence-practice gap by informing future research in developing targeted efficacious management programmes and implementation strategies in high, middle and low-income countries.Musculoskeletal health conditions such as OA impart a substantial individual, socioeconomic and societal burden worldwideThe findings of this qualitative synthesis will provide valuable information on the anticipated or experienced barriers or facilitators to the implementation of primary or community care-based OAMPs. By mapping the identified barriers and facilitators to behaviour change theory, this review will help to reduce the evidence-practice gap in future development and implementation of OAMPs.No underlying data are associated with this article.https://doi.org/10.17605/OSF.IO/YGTCN. Open Science Framework: Barriers and facilitators to the implementation of osteoarthritis management programmes in primary or community care settings; a qualitative framework synthesis protocol.This project contains the following extended data:-Additional file 1 Ovid MEDLINE Preliminary Search Strategy.pdf for ‘Barriers and facilitators to the implementation of osteoarthritis management programmes in primary or community care settings; a qualitative framework synthesis protocol’.https://doi.org/10.17605/OSF.IO/YGTCN.Open Science Framework: PRISMA-P checklistCreative Commons Attribution 4.0 International license (CC-BY 4.0).Data are available under the terms of the This is the protocol for a systematic review of barriers and facilitators to the implementation of osteoarthritis management programs in primary or community care settings as reported in qualitative studies. It is a rather straightforward protocol. My most important comment concerns the relevance of this review. Two systematic reviews on the same topic haven been published. The authors’ state two reasons for doing another review. First, the authors aim to map the identified barriers and facilitators to behavior change theory and at the micro-, meso- or macro-level. They expect this to enhance the applicability and construct validity of their findings. This is all done a posteriori (post hoc). I am not so sure that a post hoc categorization of barriers/facilitators adds much to what we know or to the applicability of the findings. I am not against it, but I just do not think that at this stage this is very helpful. The findings in previous systematic reviews can be mapped to behavior change theory and at the micro-, meso- or macro-level. Second, they aim to compare anticipated and experienced barriers, and they expect this to provide valuable insights. I am not sure that anticipated and experienced barriers are different: I would expect that anticipated barriers are based on actual experiences. So, I am not against this review, but I think that our efforts should now focus on theory- and evidence-driven efforts to improve implementation of osteoarthritis management programs. I doubt that the review will add much to what we already know.An osteoarthritis management program is defined as a ‘model of evidence-based, non-surgical OA care ….’. What is the meaning of ‘evidence-based’ ? Does this concern evidence for the effectiveness of the entire program, or for the components of the program? How much evidence is needed to include a program/study, or conversely: how little evidence results in exclusion of the program/study?A definition of micro-, meso- and macro-level is needed. I have only two comment on the methods.Is the study design appropriate for the research question?YesIs the rationale for, and objectives of, the study clearly described?PartlyAre sufficient details of the methods provided to allow replication by others?YesAre the datasets clearly presented in a useable and accessible format?Not applicableReviewer Expertise:Rehabilitation, osteoarthritisI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. It is not clear if the authors will include community-based OA programs that are implemented virtually or online? Please clarify with study inclusion criteria.Would authors consider mapping the results of real and anticipated barriers and enablers to the Behaviour Change Wheel intervention functions to illustrate concrete examples of evidence-based behaviour change strategies to target these found barriers and enablers? This would provide potential solutions to these key problems. Thank you for the opportunity to review this study protocol on barriers and facilitators to implementation of osteoarthritis management. This is a well written protocol describing an novel systematic review that will use a theory driven approach to improve the implementation of future OA community programs. I only have a few suggestions:Is the study design appropriate for the research question?YesIs the rationale for, and objectives of, the study clearly described?YesAre sufficient details of the methods provided to allow replication by others?YesAre the datasets clearly presented in a useable and accessible format?YesReviewer Expertise:Implementation science with focus on knee injury prevention and knee osteoarthritis managementI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Overview:  This is a study protocol describing a systematic review and qualitative framework synthesis protocol for barriers and facilitators implementation of OA management programmes. This is a very important study to do. We know so much about the effects of OA management programs, but they are still not used in the “real world”.Comments:1. Title:  The title is good and clear.2. Abstract:  The abstract is clear, but will the review include all OA management programs  or only knee and hip? Please describe that both in the abstract and background.3. Keywords:  Maybe you should add osteoarthritis and hip, knee depending on what you will evaluate?4. Introduction and aim: .Better Management of Patients with Osteoarthritis: Development and Nationwide Implementation of an Evidence-Based Supported Osteoarthritis Self Management Programme Carina A. Thorstensson, Göran Garellick, Hans Rystedt & Leif E. Dahlberg (my article).The Better Management of Patients with Osteoarthritis Program: Outcomes after evidence-based education and exercise delivered nationwide in Sweden. Therese Jönsson, Frida Eek, Andrea Dell’Isola, Leif E. Dahlberg, Eva Ekvall Hansson Otherwise, I think the background is good and clear. In the background you describe OA management programs internationally, I think you should add BOA with more than 150 000 patients included all over Sweden (a huge and successful implementation project):5. Materials and methods:  The method is good and clear.6. Discussion:  The discussion is good, clear, and relevant for the study.7. Conclusion: The conclusion is good and clear.Is the study design appropriate for the research question?YesIs the rationale for, and objectives of, the study clearly described?YesAre sufficient details of the methods provided to allow replication by others?YesAre the datasets clearly presented in a useable and accessible format?YesReviewer Expertise:Osteoarthritis, physical therapy, first-line treatment for osteoarthritisI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.


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