N > 1,000, p < .000001) in (1) anxiety; (2) depression; (3) smoking cessation; (4) stress; and (5) quality of life. Perhaps the appropriate conclusions would be that existing syntheses of data testing smartphone intervention suggests that these interventions are promising, but additional work is needed to separate what types of interventions and mechanisms are more promising. Evidence syntheses will be useful as the field matures, but such syntheses should focus on smartphone treatments that are created equal  or use standards for evidence that promote rigorous evaluation while allowing identification of resources that can help those in need.The current manuscript is a commentary on “Mobile phone–based interventions for mental health: A systematic meta-review of 14 meta-analyses of randomized controlled trials”. Although embedded within a nuanced discussion, one of the primary conclusions readers have taken from the meta-analysis was “we failed to find convincing evidence in support of any mobile phone–based intervention on any outcome”, which seems to contradict the entirety of the evidence presented when taken out of context of the methods applied. In evaluating whether the area produced “convincing evidence of efficacy,” the authors used a standard that appeared destined to fail. Specifically, the authors required “no evidence of publication bias”, which is a standard that would be unlikely to be found in any area of psychology or medicine. Second, the authors required low to moderate heterogeneity in effect sizes when comparing interventions with fundamentally different and entirely dissimilar target mechanisms. However absent these 2 untenable criteria, the authors actually found highly suggestive evidence of efficacy ( PLOS Digital Health, “Mobile phone–based interventions for mental health: A systematic meta-review of 14 meta-analysis of randomized controlled trials” [A recent publication in  trials” ,3. WhileN) > 1,000Total # of subjects (p < .000001no evidence of publication bias2 < 50%)low to moderate heterogeneity in the effect sizes  to establish “convincing evidence of efficacy”, this requires all studies to have an approximately similar level of efficacy when the app’s purpose, target mechanisms, and, thus, the study design are very different.First, the authors set the assumption that all apps are created equal. Specifically, by requiring low to moderate heterogeneity in effect size , anxiety, depression, smoking cessation, stress, quality of life, findings consistent with recommendations from the Banbury Forum [Given these 2 problems, we offer a different interpretation of their findings. In the absence of these 2 very high bars, and if one inspects their density and forest plots, practically every study shows evidence of effectiveness in the following domains evidence of efficacy (ry Forum . The appSo what do we learn from this study and where does the field need to go next? First, the evidence is promising for a number of common mental and behavioral health concerns. Second, not all apps are created equal; these tools have different features, goals, and linkages in a continuum of care model, it would be best to stop lumping them together, but rather make better distinctions between them. Third, we need more evidence, but we also need to set reasonable standards to ensure ineffective resources are designated as such, but not to set them too high, as this will prevent people from accessing potentially useful services.


Among 19 comparisons, 3% were rated as high in quality of evidence, 9% moderate, 54% low, and 34% very low. Non-pharmacological interventions with moderate quality, hospital-based cognitive rehabilitation and cognitive didactic therapy, likely produced minimal to no changes in the return-to-work rate. Anti-epileptic drugs and neuroprotective agents resulted in a minimal difference to the frequency of late seizure episodes in post-traumatic epilepsy. Conclusions: No prominent advances in treatment options were reported in any of the CSRs. The high rate of low and very low quality of evidence makes it difficult to ascertain the effectiveness of several recommended non-pharmacological interventions.Background: The World Health Organization has identified an unmet global need for rehabilitation interventions concerning 20 non-communicable diseases, traumatic brain injury included. This overview compiles and synthesizes the quality and quantity of available evidence on the effectiveness of rehabilitation interventions for traumatic brain injury from Cochrane systematic reviews (CSRs). The results will be used to develop the Package of Interventions for Rehabilitation. Methods: All CSRs on TBI tagged in the Cochrane Rehabilitation database published between August 2009 and September 2021 were included. Evidence mapping was implemented to extract study characteristics and evidence from the CSRs. Results: Six CSRs (42 studies;  The World Health Organization (WHO) has described an unmet global need for the delivery of rehabilitation interventions in health systems, which is amplified in low- and middle- income countries with limited availability of resources ,2,3. TheTBI is defined as ‘any alteration in brain function or other evidence of brain pathology caused by an external force’  and it iResearch has identified falls and road injuries as the two main causes of TBI worldwide ,10, althA major step to the development of the PIR encompasses the “Best Evidence for Rehabilitation” be4rehab) approach, which is applied to this work. Be4rehab supports the gathering of best evidence on the effectiveness and quality of pharmacological and non-pharmacological rehabilitation interventions for individuals with TBI and the delivery of this overview of Cochrane systematic reviews (CSRs) [rehab appSupplemented by evidence mapping to aid in the synthesis of available evidence, this work aims at identifying the broad quality and the quantity of evidence, published in CSRs, on the effectiveness of rehabilitation interventions in person with TBI.https://doi.org/0.17605/OSF.IO/M5XVG) and was reported following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA 2020 statement) [The WHO PIR adheres to methods designed from the collaborative efforts of the WHO Rehabilitation Programme and Cochrane Rehabilitation, and the directives from the WHO Guidelines Review Committee . We usedatement) .https://rehabilitation.cochrane.org/evidence, accessed on 1 September 2019). We initially searched all CSRs related to TBI published between August 2009 and August 2019 and reported the results to the WHO. We subsequently searched the Cochrane Library to August 2021 to preserve the timeliness of evidence. Eligible CSRs included those assessing interventions for persons with TBI provided or prescribed by rehabilitation professionals [According to the methodology developed by the Cochrane Rehabilitation , CSRs reWe included only tagged CSRs that examined rehabilitation interventions on individuals with TBI, of any age and gender. CSRs focused on persons with acquired brain injury or non-traumatic brain injury were excluded to ensure that the evidence synthesis is strictly applicable to persons who sustained a TBI.The methodological quality of each CSR was appraised by two assessors using the 16-item A Measurement Tool to Assess Systematic Reviews (AMSTAR) 2 tool. In this updated version, the 16 items are scored on a binary yes or no scale. AMSTAR-2 does not generate an ‘overall score’; a high score may disguise weaknesses in 7 critical items . The assThe authors referred to the Table of Findings presented in each of the included CSRs; these contain the following data: type of outcome, outcome measure(s), number of primary studies, sample sizes, type of population, intervention, comparator(s), and effect . Data were collected and entered into an Excel datasheet.In addition, the quality of evidence for each outcome was extracted using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) rating system. For CSRs that did not include GRADE ratings, two members of the Cochrane Rehabilitation team independently appraised the quality of evidence for the primary outcomes only using the GRADE approach . Any disQuality of evidence and effect data were transferred into evidence maps developed in Excel. The evidence map integrates the outcome and rehabilitation intervention values for each comparison. The magnitude of the effect  and the quality of evidence  were presented laterally and color-coded for each outcome in order to generate a visual aid to facilitate the understanding of the overall judgement of the evidence.Evidence mapping was employed as a complementary method to collating and appraising evidence from the CSRs, and subsequently used to summarize the results for the overview. The instrument collated outcomes and rehabilitation interventions and resulted in a comprehensive overview of the quality of evidence and effects. Because we did not consider other outcomes and interventions in addition to the those examined in the included CSRs, evidence mapping was not used to identify evidence gaps.The authors identified six tagged CSRs related to TBI: one published in 2013 , two in Three CSRs included only participants who sustained a TBI and excluded people with acquired brain injury and non-traumatic injury. Two CSRs included studies with a mixed population only when disaggregated data were reported to ensure that evidence was relevant to TBI. Finally, one CSR reported including studies where the etiology of the TBI is uncertain. The characteristics of the included systematic reviews are reported in Comprehensively, this mapping review encompasses 42 primary studies, 3983 participants, and 19 comparisons that examined the effectiveness and safety of either non-pharmacological or pharmacological interventions for individuals with TBI. Among non-pharmacological comparisons, four interventions (six outcomes) were categorized as very low quality of evidence, and eight interventions (16 outcomes) were deemed as low quality of evidence. Among the pharmacological comparisons, we found that four interventions (six outcomes) were rated very low and three interventions (three outcomes) were rated low in quality. The AMSTAR 2 assessment tool identified high methodological quality in the six CSRs; even when sources of funding were not reported. Results of the AMSTAR 2 assessment are displayed in The evidence map findings were divided into two categories: (1) non-pharmacological interventions and (2) pharmacological interventions. n = 120) [n = 366) [Hospital-based versus home-based cognitive rehabilitation likely has little to no effect on the return-to-work rate for moderate-to-severe TBI  . Similarn = 366) .n = 67) [Exercise using large muscle groups may have little to no effect on the cardiorespiratory fitness compared to usual care in severe and unspecified TBI severity levels  .n = 12) [n = 68) [n = 123) [Cognitive rehabilitation may have little or no effect compared to no treatment on community integration in severe TBI  , while i[n = 68) , and comn = 123)  in mild-n = 150) [n = 50) [n = 122) [Electro-acupuncture as an adjunct treatment to rehabilitation training may have a positive effect on sensorimotor impairment (Fugl-Meyer Assessment) at 1 and 3 months, and on disability (Modified Barthel index) at 1 month, but not at 3 months, when the effects favored rehabilitation training alone  . When ad[n = 50) . Added tn = 122) .n = 50) [n = 41) [n = 146) [n = 48) [n = 25) [In mild-to-moderate TBI, the true effect of cognitive rehabilitation remains uncertain on return-to-work when compared to no treatment  ; on acti[n = 41) ; on deprn = 146)  and supp[n = 48) . There i[n = 25) .n = 498) [Neuroprotective agents had little to no effect versus placebo on late seizures 6 months after the start of treatment in moderate-to-severe TBI in participants aged 14 and older  .n = 378) [Phenytoin likely resulted in no changes in late seizures 6 to 24 months after the start of the treatment relative to other antiepileptic drugs in moderate-to-severe TBI  .n = 499) [n=987) [n = 431) [There may be minimal effect on the frequency of early seizures (7 days) for neuroprotective agents compared to placebo,  . Antiepi [n=987) . Neuroprn = 431) .n = 11) and examined the effects on spasticity (6 h), and adverse events [A review comparing baclofen 50 µg versus saline placebo included one study (e events . The finn = 47) [A review evaluated the efficacy of botulinum toxin A × 1 dose (500/1000 U) or botulinum toxin A × 1 dose of 200 U + serial casting versus placebo on spasticity (4–12 weeks post treatment), and adverse events  . No statEvaluating 1029 participants and six studies, one CSR examined the difference in effects on late seizure occurrence (3 to 24 months after the start of the treatment) comparing between antiepileptic medications and placebo . No signIn a total sample of 67 participants and one study, the reviewers found a significant difference in depression level between the repetitive transcranial magnetic stimulation and repetitive transcranial magnetic stimulation plus antidepressant groups (TBI severity unspecified) . While tThis overview summarizes evidence on the effects of non-pharmacological and pharmacological interventions for any level of TBI severity, and reports the challenges identified in TBI research that are critical for further developing the integration and augmentation of rehabilitation services.Amongst the options for non-pharmacological interventions, hospital-based cognitive rehabilitation and cognitive didactic therapy likely produce minimal or no changes in the return-to-work rate (moderate certainty evidence). These findings agree with published reports in the literature on neurocognitive status and the return-to-work rates, ref. ,30,31 whThe low-certainty of evidence found in acupuncture, splint therapy, and exercise of large muscle groups prevented us from ascertaining the role of these interventions on Glasgow Coma Scale scores, spasticity, and cardiorespiratory fitness, respectively. With respect to acupuncture, the lack of information on the etiology of the TBI from three of the four RCTs prevented us from determining whether the results are equally applicable to acquired brain injury, traumatic brain injury, and non-traumatic brain injury cases. Likewise, there is insufficient quality of evidence to support the roles of cognitive therapeutic approaches as monotherapy in improving community integration, depression, and activities of daily living (very low certainty evidence).Amongst the pharmacological interventions used to reduce the number and frequency of late-seizure episodes , neuroprotective agents produced little to no difference on the frequency of late-seizures  and minimal differences on early seizures . The anti-convulsant drug, phenytoin, for example, appeared to have little effect on the number and frequency of late seizures  and little to no effect on early-seizure events . This finding aligns with current guidelines that support the use of phenytoin to treat early seizures or active seizures, but not late seizures .Our evidence mapping shows that other antiepileptic drugs do not reduce the number and frequency of late seizure events. The literature primarily focuses on early seizures, and data on late seizures after TBI are limited. Discussions of study results typically note that no evidence supports the use of neuroprotective agents and antiepileptic drugs for late seizures, mainly due to the differences observed in studies on pathogenesis of early seizures in post-traumatic epilepsy ,35. ThisFor the remaining two pharmacological interventions (botulinum toxin A × 1 dose (500/1000 U) or botulinum toxin A × 1 dose of 200 U + serial casting; intrathecal baclofen 50 μg), uncertainty of their effects on spasticity and adverse events remain, as the quality of evidence for these two therapies has been assessed as very low .The absence and/or low quality of evidence for pharmacological interventions to reduce early- and late-seizure frequency, and improve spasticity, may be associated in part with the following situations: (1) research challenges exacerbated by the narrow window for effective intervention; (2) the inability of candidate medications to cross the blood–brain barrier; and (3) possible delays and ethical issues encountered when patients are unable to provide consent . These dThe low to very- low quality evidence found is in accordance with past reviews that focused on clinical practice guidelines for TBI ,40, whicFor non-pharmacological trials, the primary issues concerned the number of studies and the small sample sizes (cumulative <500 participants), which affected the estimated effect sizes, heterogeneity among the respondents, and the imprecision of the results . Similar to pharmacological trials, some studies showed a lack of clarity regarding random sequence generation, blinding, and allocation concealment.Overall, our evidence map shows that no prominent advances were reported in any of the CSRs, confirming the concerns expressed a decade ago by Maas et al. , who obsThe landscape displayed by this evidence map places strong emphasis on the need to prioritize and augment rehabilitation research efforts for patients with TBI. Hence, we reiterate four priorities for bolstering the quality of evidence associated with rehabilitation outcomes: (1) revisit the recruitment and consent process and preserve ethical standards; (2) increase efforts and funding to support trials that examine functioning ; (3) consider multi-site recruitment options to increase participant diversity and sample sizes; (4) clearly identify the etiology of brain injury or offer disaggregate data in studies with mixed brain injury populations; and (5) promote the transparent reporting of adverse events, if applicable.Evidence maps represent a novel approach that can be employed to detect broader issues, lead to research synthesis, and guide researchers in formulating both future research and studies with a narrower focus ,43. EvidA limitation that requires some discussion pertains to the search strategy. This overview exclusively analyzed systematic reviews published in the Cochrane library, which may have limited the inclusion of other high-quality systematic reviews on TBI. Nevertheless, Cochrane suggests this approach to preserve consistency in the results of the overview since the included works follow the same methodological standard .We acknowledge that the evidence map developed for TBI is unable to address specific questions or nuances regarding the effectiveness of rehabilitation interventions in individuals with TBI.Despite its limitations, the evidence map we have constructed disseminates evidence from existing literature findings on TBI, draws attention to the current challenges faced by researchers, and can provide an effective tool in guiding future research efforts and policymaking.This work clarifies the need to expand research efforts in the context of TBI and clinical rehabilitation research to augment clinical applicability. In general, patients receiving rehabilitation services display a broad range of deficits and needs, which is particularly apparent among patients with TBI. Currently, the efficacy and safety of non-pharmacological and pharmacological interventions that are able to meet the needs of individuals with TBI remain uncertain, jeopardizing the clinical applicability of potentially effective interventions. To address the challenges experienced in clinical rehabilitation research, increasing the number of clinical and non-clinical trials performed that reflect sound methodology remains a priority.


Non-alcoholic fatty liver disease (NAFLD), an emerging global health problem affecting 25–30% of the total population, refers to excessive lipid accumulation in the liver accompanied by insulin resistance (IR) without significant alcohol intake. The increasing prevalence of NAFLD will lead to an increasing number of cirrhosis patients, as well as hepatocellular carcinoma (HCC) requiring liver transplantation, while the current treatments for NAFLD and its advanced diseases are suboptimal. Accordingly, it is necessary to find signaling pathways and targets related to the pathogenesis of NAFLD for the development of novel drugs. A large number of studies and reviews have described the critical roles of bile acids (BAs) and their receptors in the pathogenesis of NAFLD. The gut microbiota (GM), whose composition varies between healthy and NAFLD patients, promotes the transformation of more than 50 secondary bile acids and is involved in the pathophysiology of NAFLD through the GM-BAs axis. Correspondingly, BAs inhibit the overgrowth of GM and maintain a healthy gut through their antibacterial effects. Here we review the biosynthesis, enterohepatic circulation, and major receptors of BAs, as well as the relationship of GM, BAs, and the pathogenesis of NAFLD in different disease progression. This article also reviews several therapeutic approaches for the management and prevention of NAFLD targeting the GM-BAs axis. Non-alcoholic fatty liver disease (NAFLD), an emerging global health problem affecting 25–30% of the total population, refers to excessive lipid accumulation in the liver accompanied by insulin resistance (IR) without significant alcohol intake . NAFLD, Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria at the phylum level , considered as a special organ involved in the pathophysiology of NAFLD, is being intensively studied using various high-throughput techniques . GM in Num level . Furtheres level . GM can es level . The roles level .Primary bile acids (BAs) are synthesized from cholesterol firstly in the liver and account for about half of the organic constituent of bile. Once primary BAs enter the gastrointestinal tract, over 50 secondary BAs are formed . In otheIn this review, we review the bio-synthesis, transport, and major receptors of BAs, the interactions between BAs and the GM, and elucidate the function of BAs as signaling molecules in the gut-liver axis, focusing on their roles in the pathogenesis of each stage of the NAFLD progression. Several management and preventive approaches for NAFLD targeting the GM-BAs axis have been proposed .via bacterial biotransformations, including deconjugation, dehydroxylation, oxidation, desulfation, dehydrogenation, and epimerization  and chenodeoxycholic acid (CDCA)  across the canalicular  membrane and stored in the cholecyst  , 2020. Sd (CDCA) . The altd (CDCA) . Feedbacd (CDCA) . Most prd (CDCA) . Then coholecyst . Cholecyholecyst . After rholecyst . These Bholecyst . In otheholecyst . The mecholecyst , and exeholecyst . Small aholecyst . A fractholecyst .Bile acids were under study over the past several decades and were well-recognized to function as endogenous signaling molecules to regulate metabolic processes, such as liver function and cholesterol metabolism by diverse receptors . Specifivia negative feedback inhibition (Farnesoid X receptor is activated by different BAs (CDCA > DCA > LCA≫CA) and in turn firmly regulates the synthesis and transport of BAs hibition . The binhibition . It is chibition . Thus, Fhibition . In termhibition . Therefohibition . As for hibition . CAR conhibition .via ERK1/2 and AKT signaling pathways, which are crucial in the regulation of glucose and lipid metabolism in the liver , and these free BAs are able to trigger BA signaling receptors . Many bateroides .Clostridium scindens   . The actdary BAs . Furtherdary BAs . The difdary BAs . A recennococcus .In addition to the known transformations of BAs by GM , anabolic reactions suggest that the microbiome conjugates CA by unique amino acids, thereby creating newly identified BAs  . AlthougNon-alcoholic fatty liver disease is defined as steatosis, which influences >5% of hepatic cells and is accompanied by IR with a lack of excessive alcohol intake . SteatosStreptococcus and Lactobacillus, Anaerobacter, and Escherichia, and decreased abundances of Ruminococcaceae and Faecalibacterium prausnitzii were observed in NAFLD patients  . For exadiseases . FMT, a diseases . Thus, sdiseases .The composition of the BA pool shows great plasticity because of the modification by GM, thus affecting digestion, nuclear receptor binding, bile fluid toxicity, and solubility, which displays considerable differences between normal individuals and patients with liver diseases . Due to Bile acids have been revealed as signaling molecules, most likely to induce NAFLD through FXR and TGR5 . A recenvia the TGR5-cAMP-PKA axis, thereby improving insulin and glucose tolerance   . ContrarF ≥ 2) . TaurodeF ≥ 2) .via whole-genome shotgun sequencing of DNA extracted from stool samples and revealed that the abundance of Firmicutes was higher in moderate NAFLD while Proteobacteria was higher in advanced fibrosis (Bacteroides and Ruminococcus was increased in fibrosis patients, whereas Prevotella abundance was decreased (Ruminococcus bromii, F. prausnitzii, Roseburia intestinalis, and Megamonas (F. prausnitzii, one of the butyrate-producing bacteria, has the ability of immunomodulation and is highly sensitive to a slight increase in bile salts concentrations (F. prausnitzii and Megamonas (Compositions of GM in fibrosis patients were determined in a prospective study fibrosis . Anotherecreased . In seveegamonas . For exatrations . Moreoveegamonas . Steriliegamonas .Ruminococcaceae and Blautia are known to produce 7α-dehydroxylase, leading to higher DCA levels in the stool of patients with cirrhosis (Bacteroides/Firmicutes and elevation of Gram-negative bacteria are pathogenic (Bacteroidetes and Firmicutes but higher abundances of Proteobacteria and Fusobacteria (Enterobacteriaceae as well as strains from oral microbiota, such as Veillonella and Streptococcus were enriched in patients with cirrhosis, consistent with the spread of bacteria from the mouth to the gut (Lachnospiraceae, Ruminococcaceae, Clostridialies XIV, and F. prausnitzii and a higher abundance of Bacteroidaceae (Megasphaera, Dialister, Atopobium, Prevotella, and Gallibacterium (Decreased conversion of primary to secondary BAs in feces is more common in patients with cirrhosis, which is associated with the abundance of certain GMs . In a reirrhosis . Changesthogenic . Comparebacteria . Moreove the gut . The GM oidaceae . The micacterium .Bifidobacterium and Blautia, and higher levels of Enterococcus, Ruminococcus, Bacteroides, Phascolarctobacterium, and Oscillospira (Lactobacilli was found to be associated with BAs levels in serum samples and liver injury in NASH-HCC patients (Hepatocellular carcinoma is one of the top three causes of cancer mortality worldwide . TLR4 acllospira . In a repatients .Clostridium scindens colonization was found to mediate BA conversion and reduce hepatic NKT cells by suppressing CXCL16 expression in hepatic sinusoidal endothelial cells to affect the growth of HCC (Changes in BAs may cause metabolic disorders, hepatic lesions, resistance to apoptosis, and high proliferation, which contribute to tumorigenesis . A preclh of HCC . Rifaximh of HCC .Growing evidence suggests that BAs and GM play critical roles in the pathogenesis of NAFLD. BAs are endogenous molecules and therapeutic targets in liver diseases, effectively maintain cholesterol and lipid homeostasis in the gut, regulate metabolic signaling through multiple receptors, and act as the intermedium of complex molecular crosstalk between humans and their gut microbiota . GM inteYN and ML edited the manuscript. YX, QW, XYG, and YL searched the references. TXZ, CX, and TZ prepared the figures and table. X-JG and MZ were responsible for the supervision of the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Detection and quantification limits range from 9.3 to 60.5 and from 31.1 to 202.3 µg L−1, respectively. The validated method was applied to the analysis of four ale beers and one lager craft beer. Ethylamine, spermidine, spermine, and tyramine were detected in all analyzed samples while methylamine and phenylethylamine were not detected. Overall, pale ale beers had a significantly higher total content of BAs than those found in wheat pale and dark samples. A general least square regression model showed a good correlation between the total content of BAs and the brewing process, especially for Plato degree, mashing, and fermentation temperatures. Knowledge about the type of ingredients and manufacturing processes that contribute to higher concentrations of these compounds is crucial to ensuring consumer safety.The evaluation of the biogenic amines (BAs) profile of different types of craft beers is herein presented. A previously developed and validated analytical method based on ion-pair chromatography coupled with potentiometric detection was used to determine the presence of 10 BAs. Good analytical features were obtained for all amines regarding linearity (R Beer brewing has been practised for thousands of years by many cultures and continues to be a popular and financially significant practice . The breIn general, beer has been considered a safe beverage from a microbiological point of view due to its low pH, oxygen, and nutrient contents as well as the presence of ethanol, hop bitter compounds, and a suitable content of carbon dioxide ,7. HowevBAs are low-molecular-weight nitrogenous compounds with biological activity. Further insight into chemical structure classes them as aliphatic , aromatic (phenylethylamine and tyramine), and heterocyclic (histamine and tryptamine) amines. While some BAs are essential for many physiological functions, others are considered metabolic by-products found in many fermented foods and beverages such as fish, aged meat, cheese, chocolate, vegetables, wine, and beer . Their pThe presence of BAs in beers has become of concern to producers, consumers, and international authorities for reasons of food quality and safety ,16. HoweSeveral analytical methods for the determination of BAs have been reported by several authors ,19. AmonThe aim of this work is the determination of aliphatic, aromatic, and heterocyclic BAs in different craft beers commercialized in Portugal using a previously validated method. In addition, a statistical approach was implemented to evaluate the influence of the brewing process on the content of BAs. Overall, this work intended to highlight the competitiveness of potentiometric detection in HPLC for implementation in food quality control laboratories.BA standards were obtained, all as hydrochloride salts, from Sigma-Aldrich , which included cadaverine , ethylamine , histamine , methylamine , phenylethylamine , putrescine , spermine , spermidine , tryptamine , and tyramine .4OH, ref. 320145) acquired from Sigma-Aldrich  and methanol  from VWR . Ultra-pure water with conductivity < 0.055 µS cm−1 was used .The solid-phase extraction (SPE) of BAs was performed using ammonium hydroxide solution  from Fluka , and acetonitrile , of HPLC gradient grade, from VWR .The mobile phase was prepared using butane-1-sulfonic acid sodium salt  from Sigma-Aldrich , glacial acetic acid , Araldite M (ref. 10951), cucurbit [3COOH solution at 10 mmol L−1 was prepared weekly in ultra-pure water. The eluent A was prepared by dissolving the SBS powder in the previous solution to a final concentration of 5.0 mmol L−1. The eluent B was prepared by diluting the CH3COOH in ultra-pure water to a concentration of 1.0 mmol L−1 and then mixing with ACN in the proportion of 90:10 (v/v), respectively. Mixed cellulose ester membranes, hydrophilic, 0.22 µm (ref. GSWP04700) from Millipore  were used to filter the eluents. Stock solutions of BAs were prepared in the CH3COOH solution for a concentration of 10.0 mmol L−1 and stored in the fridge at 4 °C. Working standard mixtures of BA were prepared by dilution in solvent A before injection.CHFive individual craft beers of German origin were purchased from the local market in Portugal , includi4OH solution . Finally, each extract was dried under a nitrogen stream, reconstituted in 1.0 mL of the solvent A of the mobile phase, and further injected three times into the chromatographic system (n = 9).The sample preparation procedure is reported elsewhere . BrieflyThe HPLC-potentiometry (HPLC-POT) analysis was performed on a Waters 600 Solvent Delivery Pump  equipped with a Rheodyne 7725i six-port external sample injector  where a sample loop of 100 µL was connected.−1 SBS in 10.0 mmol L−1 CH3COOH, pH = 2.5) and solvent B . The gradient elution program started with 0% of solvent B for 5 min. Then, solvent B linearly increased to 100% within 5.0 min and remained constant until 17.0 min. Finally, the initial conditions were re-established within 0.5 min and held for 7.0 min to ensure column equilibration. The flow rate was 1.2 mL min−1 and the column was kept at a controlled room temperature (±2 °C).A reversed-phase Luna Omega Polar C18 column  was used as the stationary phase. The elution was performed in gradient mode using solvent A , ionic The analytical validation of the proposed method followed the Eurachem  and Inte−1 using seven calibration solutions. The potentiometric signal (E) in mV  was firstly plotted as a function of the logarithmic of BAs concentration and fitted by the Nikolsky–Eisenman equation. Afterwards, it was converted in a transformed response tR = 10E⁄S − 1, which was plotted against BA concentration [2) were calculated from the intra-assay calibration curves. The LOD and LOQ were determined by the analysis of standard solutions with decreasing amounts of the analytes until a signal-to-noise ratio of three and ten was reached, respectively. The precision of the potentiometric detector was evaluated by repeatability and intermediate precision using standard solutions of BAs at three concentration levels , analyzed in triplicate. The precision of the whole procedure was similarly evaluated by analyzing replicates of craft beer samples on the same day and three independent days. The obtained results were expressed as relative standard deviation (%RSD). The accuracy was determined by the analysis of spiked beer samples at three fortification levels , which were submitted to the whole analytical procedure. The results were expressed as recovery values accordingly to the following Equation (1):Found is the concentration of BA measured in the extracts obtained from the spiked beer samples, BAInitial is the intrinsic concentration of BAs measured in the beer samples, and BASpiked is the amount of BAs added to the beer samples.The linearity was assessed in the range of 1.0–100.0 µmol Lntration . The coeThe differences between average concentrations founded on the tested craft beer samples were evaluated by the one-way ANOVA test (at 5% significance level) using the Phyton programming language .A model to evaluate the influence of the brewing process on the content of BAs in craft beers was developed by a general least square regression (GLSR) using R programming language . The GLSR was comprised of three independent  and one dependent  variable.−1 whereas for methylamine, ethylamine, phenylethylamine, and tryptamine in the range between 1.0–30.0 µmol L−1, with coefficients of determination (R2) ranging from 0.9873 to 0.9973, respectively  and intermediate precision (inter-day) obtained after the triplicate injection of standard mixtures of 10 BAs at different concentrations. The results were expressed as relative standard deviation %RSD, . The int−1) and subjected to the whole analytical procedure. The recovery values ranged from 85.3 ± 4.4 to 107.6 ± 4.0%, 86.7 ± 5.7 to 108.9 ± 6.2%, and 83.2 ± 1.9 to 107.7 ± 5.3% for 1.0, 3.0, and 10.0 µmol L−1, respectively, with %RSD values lower than 9.2%. These obtained values are in agreement with the European requirements because they fall within the ranges of −20% to +10% for the applied target concentrations [The accuracy of the whole procedure was evaluated by the analysis of a representative craft beer sample  spiked with three concentration levels  and three replicates of the same sample on three independent days (inter-day precision). The %RSD of BA concentration ranged from 0.1 to 7.8% and 1.8 to 9.7% for the intra-day and inter-day precision, respectively . NotablyFive craft beer samples, namely ale  and lager (red) types were analyzed. The individual and total levels of BAs are summarized in p < 0.05) for the total content of BAs (−1) [To better understand BAs variability among samples, a statistical study correlating the BAs content with the type of craft beer was made using a one-way Anova test. Comparing the five samples, significant differences were observed   while inBAs (−1) . Putresc−1 [−1 [Overall, the total content of BAs found in this study is slightly lower than those reported in the literature for craft beer samples commercialized in the central Europe region, with average values of 11.9 mg L−1  and 23.7−1 [−1 . More da−1 [−1 .−1 [−1 [−1 [−1 [−1 [Regarding aliphatic amines, the presence of the polyamines spermine and spermidine in all samples might be attributed to the barley malt ,37 while−1 ; 2.097 t−1 [−1 ; or 3.60 [−1 [−1 ), suppor [−1 [−1 . On the  [−1 [−1  and 0.69 [−1 [−1 ). It is  [−1 [−1 .−1 [−1 [−1 [−1 [−1 [Regarding heterocyclic amines, a similar content of histamine was found in four samples, whose levels are in agreement with those reported for craft beers (0.33 mg L−1  or 0.017−1 [−1 ). Howeve [−1 [−1  or 3.8 t [−1 [−1 . Despite [−1 [−1 . Tryptam [−1 [−1 . This am [−1 [−1 ,43 or de [−1 [−1 . The dif [−1 [−1 .−1 [−1 [−1 [−1 [For aromatic amines, tyramine was found at levels in line with, or lower than, those reported by other authors . This a [−1 [−1 ,41.To evaluate the influence of the brewing process on the content of BAs, a statistical model was developed using several variables: malt and yeast types, the Plato degree, and mashing and fermentation temperatures. However, the low number of observations obtained from the experimental work only allowed the inclusion of up to three variables for the estimation of the parameters because when minimizing the sum of the squared residuals, more observations than variables are required. In this context, several subsets of the variables were tested and the mashing temperature, fermentation temperature, and Plato degree were those selected for further analysis because a lower Akaike information criterion (AIC) value was obtained.As the nine observations per beer category were obtained from the same bottle of beer, despite it being divided into three different aliquots (measured three times each), the errors of these observations were surely dependent when fitting the model. For this reason, a general least square regression (GLSR) was used to model not only the correlations amongst the errors but also the heteroscedasticity observed in the data, which is required for more accurate predictions.1 is the mashing temperature between 66–68 and 76–78 °C, D2 is the mashing temperature between 66–69 and 76 °C, D3 is the fermentation temperature between 8 and 12 °C, and X1 is the Plato degree.The proposed GLSR model included thus two categorical variables (“fermentation temperature” and “mashing temperature”) that were converted to dummy variables  and one quantitative variable (“Plato degree”) that ranged approximately between 10 and 16. Interactions between the independent variables and the total content of BAs were observed, as demonstrated by Equation (2):p-value of <0.0001 for the estimated model coefficients (beta coefficients), which highlight the statistically significant effect of the independent variables on the total content of BAs (2 > 0.99) and similarity between the observed and predicted values from the model  but maintained the mashing temperature, the total content of BAs in the craft beers will be higher by 19.37 mg L−1, despite the decrease of 4.81 mg L−1 by a unit of Plato degree on average. In contrast, if the fermentation temperature is maintained at 18–22 °C but the mashing temperature changed to 66–69 and 76 °C, the total content of BAs will be lower by 5.09 mg L−1 and 4.81 mg L−1 by a unit of Plato degree, on average. Overall, the predictive ability of the proposed model gives crucial information about the content of BAs based on the processing conditions and final beer type.From Equation (2), the total content of BAs can be easily determined by attending to the brewing conditions. For instance, craft beers with a mashing temperature of 56–68 and 76–78 °C and a fermentation temperature of 18–22 °C  have a decrease in the total content of BAs by 4.81 mg LThe implementation of an HPLC-POT method for routine analysis of BAs in craft beers proved to be simple, effective, and affordable. The major advantage relies on the fast determination of BAs without chemical derivatization and using water-based eluents, under a concept of green chemical analysis.−1 for wheat pale ale and pale ale types, respectively. Ethylamine, spermidine, spermine, and tyramine were detected in all analyzed samples, followed by putrescine, histamine, and tryptamine, which were detected in more than 50% of the samples. Histamine and tyramine, considered the most toxic and food safety-relevant BAs, were found in low levels , which did not entail any risk to the health of consumers.Overall, the total content of amines in the five craft beers was low, ranging from 3.83 to 9.60 mg LA GLSR model demonstrated a good correlation between the total content of BAs and the brewing process, especially for Plato degree, mashing, and fermentation temperatures. As microbreweries continue to reinvent the landscape of beer by using different ingredients and techniques, the predictive ability of the proposed model is an important landmark to assess the effect of new recipes on the profile of biogenic amines.


Not all evidence is equal. Evidence-based public health and medicine emanate from the principle that there is a hierarchy of evidence, with systematic reviews and meta-analyses (SRMAs) being at the top, as the highest level of evidence. Despite this, it is common in literature to find SRMAs with methodological issues that can distort the results and can thus have serious public health or clinical implications. During the Coronavirus Disease 2019 (COVID-19) pandemic, the importance of evidence and the way in which evidence was produced was stress tested and revealed a wide array of methodological biases that might have led to misleading conclusions and recommendations. We provide a critical examination of methodological biases in selected SRMAs on COVID-19, which have been widely used to guide or justify some pharmaceutical and nonpharmaceutical interventions with high public health and clinical significance, such as mask wearing, asymptomatic transmission, and ivermectin. Through these selected examples, we highlight the need to address biases related to the methodological quality and relevance of study designs and effect size computations and considerations for critical appraisal of available data in the evidence synthesis process for better quality evidence. Such considerations help researchers and decision makers avoid misleading conclusions, while encouraging the provision of the best policy recommendations for individual and public health. Evidence-based public health and medicine researchers have continuously exposed the fact that while many evidence synthesis efforts for widely used healthcare interventions show potential benefits, there is little high-quality evidence supporting their effectiveness and safety . In the Information on asymptomatic transmission has high public health relevance as it dictates population-level measures, epidemiological practice, and routine outpatient care. In 2020, an SRMA of observational data showed the secondary attack rate was lower in contacts of people with asymptomatic infection than those with symptomatic infection , suggesting that there is asymptomatic transmission, but at a lower rate compared to symptomatic transmission . The artIn their analysis, the authors included five studies that conducted detailed contact investigations with sufficient data to estimate a secondary attack rate according to the symptom status of index cases. When examining the included studies, the authors appeared to have misclassified the preprint study by Chaw et al. , as repoMetaprop command in STATA 16.1 [Similarly, in the study by Park et al. , describATA 16.1 ) after tAdditionally, adding results on asymptomatic transmission by Chaw et al., provided after peer review, generated similar conclusions . In another meta-analysis, Freeman-Tukey double-arcsine variance-stabilizing transformation was applied to address the issue arising from zero events, showing overall 1% (95% CI 0–2%) asymptomatic transmission . However2 = 84%) [Facemasks are suggested to create a barrier against a high percentage of the viral particles released from a wearer’s mouth and nose , and hig2 = 84%) . In thisThere are several concerns regarding the analysis presented in this work. The first (major) concern was the inclusion in the meta-analysis of heterogeneous study designs, including an ecological study , one croSecondly, the authors appear to have missed other relevant studies, including two prospective cohort studies ,33. A prIvermectin, a horse dewormer and antiparasitic medication, has been widely promoted across the world for the treatment of COVID-19. After an in vitro experiment , a debatn = 22) or ivermectin 12 mg and doxycycline daily for 5 days (n = 23) against a placebo (n = 23) [p = 0.02), but ivermectin plus doxycycline did not show a comparable reduction (11.5 days). A preprint of a prospective controlled (nonrandomized) trial compared two to three doses of the drug in combination with 5 to 10 days of doxycycline (n = 70) with standard care (n = 70) [p < 0.0001), but during the writing of this commentary, these results were not yet peer-reviewed or published.A relatively small RCT compared an ivermectin dose of 12 mg/daily for 5 days ((n = 23) . Ivermec(n = 70) . Ivermecn = 173, 15% mortality) compared to those receiving standard of care . After further adjustment, differences in mortality between the groups remained statistically significant . These findings, however, require randomized controlled trials for confirmation.A retrospective study of 280 patients hospitalized with confirmed COVID-19, reviewed the impact of ivermectin use in COVID-19 in four Florida hospitals . The morCochrane Reviews are not effective according to methodologically high-quality evidence [While meta-analyses on ivermectin and COVID-19 have shown a potential beneficial role of ivermectin, there are several serious methodological concerns observed in these meta-analyses, such as the inclusion of small and flawed RCTs  and posiMethodologically sound meta-analyses are important to not only improve our knowledge on a specific topic and understand gaps, but also to provide methodological rigor for scientific guidance for policy and decision-making. While pandemic situations require high-speed work in a context of tremendous professional pressure, it is important to preserve methodological rigor and ethical standards to ensure public health and clinical practice are informed by the best available evidence. Examples of methodological issues in meta-analyses related to COVID-19 are an indicator of common and repeated flaws in meta-analyses in general, generating misleading conclusions with serious health, economic, and social implications. While our work was not systematic, but rather focused on highly cited and influential meta-analysis in COVID-19, our paper highlights the importance of investigating systematically the extent to which meta-analyses published during the COVID-19 pandemic carry methodological issues that led to distorted conclusions. For high-quality and rigorous evidence synthesis, it is imperative for researchers to have a clear understanding of study methodological quality and designs, confounding and different types of biases, statistical models, and expertise of relevant meta-analytic methods for the specific topic under investigation . What is


A single sensor is prone to decline recognition accuracy in the face of a complex environment, while the existing multi-sensor evidence theory fusion methods do not comprehensively consider the impact of evidence conflict and fuzziness. In this paper, a new evidence weight combination and probability allocation method is proposed, which calculated the degree of evidence fuzziness through the maximum entropy principle, and also considered the impact of evidence conflict on fusing results. The two impact factors were combined to calculate the trusted discount and reallocate the probability function. Finally, Dempster’s combination rule was used to fuse every piece of evidence. On this basis, experiments were first conducted to prove that the existing weight combination methods produce results contrary to common sense when handling high-conflicting and high-clarity evidence, and then comparative experiments were conducted to prove the effectiveness of the proposed evidence weight combination and probability allocation method. Moreover, it was verified, on the PAMAP2 data set, that the proposed method can obtain higher fusing accuracy and more reliable fusing results in all kinds of behavior recognition. Compared with the traditional methods and the existing improved methods, the weight allocation method proposed in this paper dynamically adjusts the weight of fuzziness and conflict in the fusing process and improves the fusing accuracy by about 3.3% and 1.7% respectively which solved the limitations of the existing weight combination methods. In recent years, human behavior recognition has received more attention because monitoring a person’s state provides valuable information for safety and health. The methods based on a visual sensor and an inertial sensor are the main research methods of human behavior recognition, but the methods based on vision have some disadvantages. The video data may be occluded, and further video recording will cause privacy problems in many cases, due to the illumination conditions, clothing types and background colors. Additionally, many sensors need infrastructure support, such as installing cameras in the monitoring area. Compared with other human behavior data acquisition equipment, accelerometers, gyroscopes, heart rate sensors, and other sensors with small sizes, and high-detection accuracy have been widely used in human behavior recognition.However, the sensor itself is vulnerable to the environment, equipment aging, and interference of other impact factors in the signal acquisition process, resulting in abnormal data and uncertainty, a single sensor can no longer meet the demand for identification reliability. The multi-sensor data fusion technology proposed in the 1980s still has wide application prospects in this field. Up to now, some classical multi-sensor data fusion algorithms have been developed, mainly divided into four types: estimation theory, statistical inference, information theory, and artificial intelligence. The common data fusion algorithms include weighted average, Kalman filter, Bayesian estimation, evidence theory, neural network, and so on. In the face of the uncertainty generated by sensor abnormal data, evidence theory and Bayesian estimation are usually used. D-S evidence theory  can flexAlthough D-S evidence theory can be applied in many fields, it may produce results contrary to common sense when handling highly uncertain evidence. Uncertain evidence consists of conflicting evidence and fuzzy evidence. Aiming at the impact of these two pieces of evidence on fusion, researchers have proposed many improvement methods to improve fusing accuracy. There are two ways to alleviate the above shortcomings in the combination rules of evidence theory. The first is to modify Dempster’s combination rule. Scholars who applied this method believed that the shortcomings of the original D-S evidence combination rule lead to the failure of handling conflicting evidence and the results of going against common sense. Therefore, Yager  defined It can be seen from the above analysis that researchers have conducted in-depth research on the measurement methods of evidence conflict and evidence fuzziness, and made a lot of achievements, which have laid a solid foundation for the application of evidence theory. Yet most researchers tended to only consider conflict or fuzziness. Although some researchers have given comprehensive consideration to the two impact factors, they usually believed that fuzziness and conflict have the same impact on the fusing results.Gou, L  proposedJing, M  assignedWang, J  analyzedHowever, in some real cases, the above simple weight allocation combination will eventually lead to a large deviation between the fusion result and the real result. As shown in Experiment 1 in On the basis of measuring the clarity and conflict degree of evidence correctly, a new weight combination method is proposed to combine the two influence factors, which makes the weight distribution of fuzziness and conflict more reasonable. The combined weight is used to calculate the discount coefficient, and the basic probability distribution is redistributed to reduce the influence of evidence conflict and fuzzy on the fusion result. Finally, the proposed method is applied to human behavior recognition, and the results show that the proposed method can effectively resolve the influence of conflicting evidence and fuzzy evidence on fusion results.The rest of the paper is as follows: The evidence theory is established by the famous scholar Shafer based on Dempster’s combination rule, so it is also called D-S evidence theory. Compared with other data fusion algorithms, D-S evidence theory has higher efficiency in solving uncertainty problems. It is mainly viewed and analyzed by transforming propositions into mathematical sets. Since a set can contain multiple elements, different from probability theory, which only considers a single element, it is because of the fuzziness of evidence theory that it can better express the uncertainty of propositions. In fact, it is more like a simulation of the human brain’s integrated processing of events under the influence of multiple environmental factors. The first problem is to observe and collect information, namely evidence. Then the information from all aspects is integrated to make judgments, and the final results of the problem are obtained, that is, evidence combination. The most important ones are to determine the range of answers (recognition framework), the probability corresponding to evidence set assignment (base trust assignment function), and the combination of evidence probability data (Dempster’s combination rule).Definition 1. Recognition framework: If all elements in a complete set Θ are mutually exclusive, and the number of elements is enumerable and finite, the set can be called a recognition framework, denoted as [noted as ,2:(1)Θ={Definition 2. Base trust assignment function: The base trust assignment function m on the recognition framework Θ is a mapping from the set, and satisfies [set2Θ→0, , and satDefinition 3. Dempster’s combination rule: Assuming that the base trust assignment function corresponding to two pieces of evidence isandin the recognition framework Θ, Dempster’s combination rule is [where is the conflict coefficient, which is defined as follows:The essence of the maximum entropy principle is that when we need to predict the probability distribution of a random event, we should not make any subjective assumption about the unknown situation under the premise of partial knowledge. In this case, the probability allocation is the most uniform and the risk of prediction is the least. At this time, the information entropy of the probability allocation is the maximum. The advantage of meeting the maximum entropy distribution is that the result can cover the currently known feasibility without making any subjective guess. Such a model is the smoothest and the risk of prediction is the least. When faced with uncertainty, we should keep all the possibilities open instead of making arbitrary assumptions. Jing, M  improvedWhen measuring evidence conflict, the most commonly used method is to measure conflict by the distance between pieces of evidence. Jousselme distance  is an efAssuming that there are two pieces of evidence  follows .(6)JBPAAfter obtaining the distance between evidences, the similarity of evidence body In addition, the conflict can be measured from a geometric perspective. In mathematics, the cosine of an angle can measure the difference between the directions of two vectors. Similarly, in D-S evidence theory, this concept can also be used to measure the similarity between evidence vectors.Assuming that evidence  follows :(9)SimijRen  combinedThis paper mainly studies the combination method of conflict and fuzzy measures, so the widely used Jousselme distance is chosen to measure conflict.Information entropy is a classical method to measure the uncertainty of evidence. Shannon entropy has a good performance in measuring the uncertainty of evidence. Shannon entropy can be used to calculate the amount of information contained in the evidence body, and then calculate the uncertainty of evidence. Höhle  first deOn this basis, Deng  proposedDue to the strong ability to measure the uncertainty of BPA, Deng entropy has attracted the attention of many researchers ,23 and hOther scholars measured the fuzziness of evidence from the perspective of probability distribution . AccordiAssuming that we will transform the probability distribution fined as ,32:(12)WThe Wasserstein distance between the evidence  follows ,32.(13)By calculating the Wasserstein distance between the BPA and uniform distribution, the clarity of evidence can be obtained, which is defined as:In this section, common examples are used to illustrate the counterintuitive problems of the existing weight combination methods in handling high-conflict and high-clarity evidence data fusion of the combination rules of D-S evidence theory.Supposing a recognition framework is given as ΘOn the basis of existing research, considering the measurement of evidence conflict (Equation (8)) and fuzziness (Equation (4)) comprehensively, the existing methods are used to directly multiply the weight coefficients of conflict and fuzziness or assign the same weight (arithmetic average) to conflict and fuzziness. The fusing results under the Dempster combination rule are shown in According to the fusing results in Based on the effective measurement of evidence conflict and evidence fuzziness, this Section analyzed the influence of weight combination rules on fusing results and proposed a new adaptive weight allocation method, which effectively solved the limitations of existing methods. On this basis, a multi-sensor data fusion model was established, as shown in Firstly, the distance between each sensor and the corresponding grade interval was calculated to generate BPA. Then, the degree of evidence fuzziness was calculated according to the method in Wang . At the As can be seen from the examples in On the basis of obtaining the weight of evidence (trust degree), BPA is modified by the trust discount formula, denoted as The PAMAP2  contains 18 different physical activity data  performed by nine subjects wearing three inertial measurement devices and heart rate monitors. This data set can be used for activity recognition and intensity estimation, as well as developed and applied to data processing, segmentation, feature extraction, and classification algorithms. In order to justify the research method, we selected five actions  from the PAMAP2 data set and used the proposed method for behavioral classification.The main focus of this study is on the measurement of conflict and fuzziness as well as weight allocation. Therefore, the feature extraction process of the original data is simplified. To classify these 18 actions, we are required to deal with the original data and choose appropriate methods for feature extraction. In order to reduce the test period and complexity, only five actions  were selected in the PAMAP2 data set for classification.The multi-sensor data fusion model proposed in A set of sensor data with high conflict and clarity in walking was selected for the experiment, and the data collected by each sensor was Step 1: Calculate the Euclidean distance between each sensor data and the corresponding behavioral feature level, and then normalize it as BPA. As shown in Step 2: Calculate Jouselme distance between pieces of evidence according to Equations (6) and (7), and then calculate the similarity of evidence bodies (Equation (8)). Step 3: Calculate the Wasserstein distance between each piece of evidence and uniform distribution (5) according to formula (14), and the evidence clarity can be obtained after normalization. Step 4: Calculate the weight of the evidence. The evidence similarity and clarity calculated in steps 2 and 3 are taken into the weight combination formula (15) proposed in Step 5: Reallocate BPA. Put the weight calculated in Step 4 into Equation (16) to reallocate BPA.Step 6: Combing the rules (3) and (4) according to D-S evidence theory, the modified BPA is fused to obtain the fusing results of multi-sensor (evidence) data, and then compare with other methods, as shown in It can be seen from the experimental results, both the traditional method of D-S evidence theory (blue) and the proposed method (gray) can obtain the correct classification results. Wang, J’s  method  and calculates the accuracy of behavior recognition to verify the applicability of the method proposed in this paper and make a comparison with other methods. The results are shown in The results in In order to better evaluate the proposed multi-classification model, we choose the Kappa coefficient, which is commonly used in multi-classification problems, to evaluate our model. The Kappa coefficient is calculated as follows:By calculation, the kappa coefficient of the multi-classification model proposed in this paper is 0.8357.It can be seen from the experimental results that the conflict and fuzziness of evidence have different degrees of influence on fusion accuracy. The proposed method distributes the weight of conflict and fuzziness more reasonably and improves the fusion accuracy, which can be seen from the following three points.(1) Conflict and Fuzzy represent the measurement of conflict and fuzziness of evidence respectively. Compared with the traditional method (D-S), these two methods calculate the degree of conflict and fuzziness of evidence, respectively, and reallocate BPA, which improves the fusing accuracy by about 1.3%. Wang, J  used the(2) Comparing the results of (3) The results of the model evaluation show that the multi-sensor data fusion model proposed in this paper has good balance, and has reached a high level for the classification of different behaviors, which can be effectively applied to human behavior recognition.The proposed weight allocation method dynamically adjusts the weight coefficients of conflict and fuzziness in the fusion process, and the fusion accuracy is improved by 3.1% and 1.6%, respectively, compared with the traditional method and the existing method. Moreover, high fusion accuracy and balance can be obtained under different sensor numbers. The problem of evidence conflict and fuzziness in the process of multi-sensor data fusion is solved effectively.D-S evidence theory has been widely used in various fields since it was proposed, especially in dealing with decision problems under multi-sensor conditions. The method proposed in this paper aims to present a fusion method for embedded devices to solve the problems of data conflict and fuzziness in existing multi-sensor data fusion.Based on the existing research, this paper selects a suitable method to measure the degree of conflict and fuzziness of evidence. A new weight combination scheme is proposed which can dynamically adjust the proportion of conflict and fuzziness in the fusion process. The experimental results show that the proposed method reduces the adverse effects of evidence conflict and is fuzzy on the results of data fusion, and the fusion accuracy of the model is improved by 3.1% and 1.6%, respectively, compared with the traditional method and the existing method. It has certain advantages in the accuracy of behavior classification problems.The method proposed in this paper is not only suitable for human behavior recognition but also suitable for other systems which need to consider multiple factors. The focus of this study is data fusion, thus simplifying data preprocessing and feature extraction. Considering the complexity and uncertainty of classification problems, we will try more appropriate feature extraction methods in future work to further improve the fusion accuracy. In addition, this study also focuses on the fusion of single-mode data. In the future, we will try to fuse cross-modal data to obtain more reliable recognition results.


Awareness, knowledge, beliefs, and behavioral intentions of physical activity (PA) guidelines may be important mediating factors for promoting PA. However, these pathways of the psychological process to PA behavior have not been examined. These pathways may differ depending on health literacy levels. This study investigated the pathways to PA, from guideline awareness to behavior, and further examined whether they differed by health literacy.A cross-sectional study was conducted with 7,000 Japanese participants aged 20–69 years. The participants were registered with an Internet survey company. Participants’ awareness, knowledge, beliefs, and behavioral intentions regarding the PA guidelines of Japan, the volume of moderate-to-vigorous intensity PA, activity level, and health literacy were examined through a questionnaire. The PA pathways, from guideline awareness to behavior, were examined by structural equation modeling (SEM), with PA behavior as the dependent variable. Multi-group SEM was conducted to examine the moderating effect of health literacy on PA pathways. Health literacy scores were dichotomized into high and low groups in multi-group modeling by the median split.SEM revealed that PA guideline awareness directly affects PA behavior and has certain indirect effects through the mediation of knowledge, beliefs, and behavioral intentions. Furthermore, the multi-group SEM showed that the proportion of indirect effects  was higher than direct effects  in the high-health literacy group. In contrast, the proportion of direct effects  was higher than indirect effects  in the low-health literacy group.PA guideline awareness is both directly and indirectly associated with PA behavior, mediated by psychological pathways of knowledge, beliefs, and behavioral intentions, and influenced by health literacy. These results suggest that health literacy should be considered when implementing PA guideline-based interventions.The online version contains supplementary material available at 10.1186/s12889-023-15012-3. Physical activity (PA) is an important factor to maintain and improve health in adults, including reductions in all-cause and cardiovascular mortality, development of type 2 diabetes and certain cancers, and improvements in mental health –6. HowevThese guidelines not only provide detailed information for professionals but also contain “summary sheets” that explain the guidelines for ease of understanding of the public. In Japan, “Active Guide” has been developed as a “summary sheet” for the public in 2013 . The purSeveral factors have been suggested to promote PA, including awareness and knowledge, beliefs about, and behavioral intentions regarding PA guidelines , 11. ForIn addition, these pathways may be influenced by health literacy. As such, the effectiveness or issues of the guidelines as a tool for behavior change may also be impacted by health literacy.There are various concepts and definitions of health literacy. In the health promotion domain, there are three classifications: functional health literacy, interactional health literacy, and critical health literacy . ReadingTherefore, the research questions for this cross-sectional study are as follows: (1) whether the PA guideline awareness was associated with PA behavior, mediated by the psychological pathways of knowledge, beliefs, and behavioral intentions; and (2) whether these psychological pathways were influenced by health literacy.In this cross-sectional study, an online survey was conducted between October and November 2020. The target population included registered users of a social survey company (approximately 1.07 million users as of October 2020) between the ages of 20 and 69 years. The users registered with this company are an open-access panel recruited in various ways that does not rely on a specific platform. Among these users, 7,000 responses were requested to be collected. The sample size was determined to be as large as possible based on available funding resources. The registered participants, stratified by age group , sex (men/women), and education , were randomly selected so that the study population would match the population distribution in Japan. The survey company sent an e-mail to 23,188 registered users with the details of the study and a link to the response web page. The survey was closed when the number of respondents reached the target number in each stratum and when the total number of respondents reached 7,000.This study was conducted after obtaining approval from the ethical review committees of Arakawa campus, Tokyo Metropolitan University (No. 20039), and Graduate School of Human Development and Environment, Kobe University (No. 455). All methods were carried out in accordance with the Japanese ethical guidelines for medical and biological research involving human subjects and the ethical standards of the Declaration of Helsinki. Consent for this study was obtained by presenting an explanatory statement at the beginning and requesting that only those who fully understood and consented to the statement would access the survey site. This survey has multiple research objectives and two papers have already been published using this survey , 23. TheBased on previous studies, we chose participant characteristics associated with guideline awareness and knowledge, PA behavior, and health literacy –24. ClasAwareness of the Japanese PA guidelines was surveyed using the unprompted and prompted recalls. The unprompted recall method does not present clues, such as options or pictures, and the participant is asked to respond freely based on their memory . For thiNext, we assessed knowledge of the PA guidelines. While awareness of the guidelines assessed whether participants had seen or recognized the guidelines, knowledge investigated whether they understood the recommended quantities, which are an essential component of the guidelines. Knowledge of the PA guidelines was based on numerical responses with open-text fields to the following three items: (1) recommended PA amount for individuals aged 18–64 years, (2) recommended amount of physical activity for individuals aged 65 years or older, and (3) PA amount that should currently be increased. For each item, 60 min/day, 40 min/day, and 10 min/day were considered correct answers. Among respondents aged 18–64 years, those who correctly answered both items (1) and (3) were classified as “adequate,” and those who incorrectly answered item (1) and/or (3) were classified as “inadequate.” Similarly, among respondents aged 65 years and older, those who correctly answered both items (2) and (3) were classified as “adequate”, and those who incorrectly answered item (2) and/or (3) were classified as “inadequate.”Eight items, which were developed based on the information in the Active Guide, were used to assess beliefs about PA guidelines . The beliefs included items related to PA and health promotion and the development of PA habits  “Do you intend to move your body for 60 min (18–64 years)/ 40 min (65 years and older) per day?” and (2) “Do you intend to move your body 10 min more than you do currently?” The options for both items were on a five-point scale from 1  to 5 (very strongly). The average of the scores of the two items was calculated and used to score behavioral intention.PA was assessed using two questionnaires used in the Japan Public Health Center-based prospective Study (JPHC Study)  and in sFor health literacy, we used the Japanese version of the Communicative and Critical Health Literacy (CCHL) . The CCHTo minimize the influence of each survey item on the others, the following order was used for the survey: awareness of the Active Guide , awareness of the Active Guide , knowledge of the Active Guide, awareness of “Plus-ten” , awareness of the Active Guide , behavioral intentions, and beliefs. Each question was displayed on a separate web screen. Additionally, it was not possible to return to the previous question.The present study conducted the structural equation modeling to examine the PA pathways from the guideline awareness to behavior. The dependent variable was PA behavior. PA behavior was treated as a latent variable, defined by two observed variables: volume of MVPA (METs-hours per day) measured by the JPHC Study’s questionnaire , 33 and In the initial model, the present study examined the statistical significances of the following 10 standardized path coefficients based on the logic model: path from awareness to knowledge, belief, behavioral intention, and behavior; path from knowledge to belief, behavioral intention, and behavior; path from belief to behavioral intention and behavior, and path from behavioral intention to behavior , variances of five main variables , and path coefficients among main variables. For each parameter, a significant change in Chi-squared in the constrained model indicated that the corresponding parameter was different between the low- and high-health literacy groups. An insignificant change in Chi-squared in the constrained model indicated that equality constraint of the corresponding parameter between the two groups was reasonable. Thus, if the changes in Chi-squared were significant for the coefficients of the paths from awareness to knowledge, beliefs, intention, or PA behavior, the present study confirmed the moderating effects of health literacy on these psychological pathways, which addresses the second research goal. In the third step, the final model was constructed. The present study added the equality constraints identified in the second step on the unconstrained model. Using the bias-corrected bootstrap method , standardized direct, indirect, and total effects and 95% confidence intervals of awareness and knowledge of, beliefs about, and behavioral intention regarding PA behavior were estimated for the low- and high-health literacy groups.p < 0.05. Due to the nature of the web-based questionnaire survey, the database did not have missing values. The present study used AMOS v.25.0  to perform the structural equation modeling.Statistical significance was set at Table Figure The fit indices of the unconstrained model were CFI = 0.975, TLI = 0.969, RMSEA = 0.052, and AIC = 1550.8. The comparisons of fit indices between the unconstrained model and the models with equality constraints are shown in Table Figure Direct, indirect, and total effects of PA guideline awareness on PA behavior in the final model among both groups are shown in Table The present study revealed that the awareness of PA guidelines is directly and indirectly associated with PA behavior through the mediation of knowledge, beliefs, and behavioral intentions. Furthermore, health literacy was related to the degree of association between direct and indirect pathways.It is essential to examine the psychological pathway in Cavil & Bauman's logic model to explore strategies to promote behavior from the awareness of PA guidelines . Many prThe Active Guide, summary sheet of Japanese physical activity guidelines, contains a lot of information to encourage PA behavior change, which may also be an important factor in these associations. In particular, the Active Guide is designed for ease of understanding through the use of illustrations to convey necessary information in a concise three-fold pamphlet format. As such, the appealing message of “Plus Ten” could be fully conveyed, and information that encourages environmental awareness could be included , 9. ThisAnother important finding of this study is that the direct and indirect effects of the PA guideline awareness on PA behavior depend on health literacy. The high-health literacy group had a 0.63 times smaller proportion of the direct effect of awareness on PA behavior than that of the indirect effects. In contrast, the proportion of direct effect was 3.14 times larger in the low-health literacy group than in the high-health literacy group. Therefore, the high-health literacy group is more likely to translate PA guideline awareness into PA behavior indirectly and gradually via the psychological pathways of knowledge, beliefs, and behavioral intentions. In contrast, the low-health literacy group is more likely to translate PA guideline awareness into PA behavior directly without those pathways. Furthermore, our previous study  also shoIn the future, creating a strategy to increase awareness of the Active Guide is required in Japan. Milton et al. emphasized the need to conduct a stakeholder analysis and consider key audiences, communication aims, and approaches as examples of measures to maximize the effectiveness of PA guidelines . Howeverr = 0.45). Fourth, since this study is based on a logic model, we assumed that those with behavioral intentions would show more association with PA. Therefore, we did not assume here that participants were already physically active and did not have that intention. Fifth, the health literacy scale used in this study does not measure functional health literacy. Therefore, this study assumes that the participants have some degree of health literacy and that they do not have many problems with functional health literacy. Furthermore, the scale used in this study was divided into two groups based on median values since there is no cutoff point as of yet. However, this method is population-dependent, and results may differ between studies. Finally, we could not use accelerometers to objectively measure the amount of PA. To enhance the validity of these findings, a longitudinal study of the PA pathways from guideline awareness, with a reliable measurement of beliefs and objective PA measures, is warranted.The strength of this study is its novel comprehensive assessment of awareness, knowledge, beliefs, and behavioral intentions regarding PA guidelines. The study also revealed the influence of health literacy on pathways to PA behavior. In addition, stratified random sampling was conducted among the registrants of a social survey company to match the distribution of sex, age, and educational background of the Japanese population. As such, this survey was conducted on a large scale with 7,000 participants. However, since stratified sampling was not conducted for current marital status, household income level, current working status, and PA level, their representativeness is not known. Furthermore, there are several limitations. First, this is a cross-sectional study; therefore, causality could not be established. Second, since this is an online survey of registrants of a social research firm, the possibility of sampling bias cannot be ruled out. Third, standardized assessment instruments for awareness, knowledge, beliefs and behavioral intentions in PA guidelines have yet to be established. Therefore, the probability of valid and reliable assessment instruments is needed in the future. In this study, the test–retest reliability of the beliefs section of the Active Guide is low  had a poor model fit, the 8-item, one-factor model, with 2 items excluded, improved the goodness-of-fit index. Therefore, model 2 was adopted.Additional file 2. Model fit indices of models with equality constraints of additional parameters between low- and high- health literacy groups. The comparisons of fit indices between the unconstrained model and the models with equality constraints are shown in Table 3 for the main path coefficients among awareness, knowledge, belief, behavioral intention, and PA behavior and in Additional file 2 for other additional parameters.Additional file 3. STROBE Statement—checklist of items that should be included in reports of observational studies. Since this is an observational study, we have reported the article in accordance with the STROBE Statement.


The Plain Language Summary published with above EGM report should correctly read as:There is scattered evidence on the effectiveness of social and behaviour change communication interventions for HIV prevention among adolescent girls and young women.Interest in socio‐behavioural interventions to support demand and uptake of HIV services is on the rise. Therefore, the evidence of their effectiveness needs to be systematically mapped to enable informed decision‐making by sponsors, researchers, policymakers and public health experts.This evidence and gap map (EGM) presents a consolidated evidence base of existing social and behaviour change communication interventions, and the end‐user behaviours they target, in low‐ and middle‐income countries. It looks at a range of strategies including mass media, community‐based interventions, interpersonal interventions, and ICT and digital media‐based interventions, and identifies gaps in programming.


This study aimed to clarify the relationship between the joint and ligament structures of the subtalar joint and degeneration of the subtalar articular facet. We examined 50 feet from 25 Japanese cadavers. The number of articular facets, joint congruence, and intersecting angles were measured for the joint structure of the subtalar joint, and the footprint areas of the ligament attachments of the cervical ligament, interosseous talocalcaneal ligament (ITCL), and anterior capsular ligament were measured for the ligament structure. Additionally, subtalar joint facets were classified into Degeneration (+) and (−) groups according to degeneration of the talus and calcaneus. No significant relationship was identified between the joint structure of the subtalar joint and degeneration of the subtalar articular facet. In contrast, footprint area of the ITCL was significantly higher in the Degeneration (+) group than in the Degeneration (−) group for the subtalar joint facet. These results suggest that the joint structure of the subtalar joint may not affect degeneration of the subtalar articular facet. Degeneration of the subtalar articular facet may be related to the size of the ITCL. Recently, subtalar joint instability was reported to occur in 10–80% of patients with chronic lateral ankle instability . ReasonsPrevious studies suggested that nerves, articular facets and ligaments, and muscles are involved in foot stability . The anaThe relationships between joint structure of the subtalar joint facet  and degeneration of the subtalar articular facet were long investigated. In addition, the presence of degeneration of the subtalar articular facet was considered to indicate that the joint is unstable . PreviouThe ligaments involved in the braking of the subtalar joint include the calcaneofibular ligament ,13, cervThe present study aimed to clarify relationships between joint and ligament structures of the subtalar joint and degeneration of the subtalar articular facet. We hypothesized that the joint structure of the subtalar joint facet is independent of the presence or absence of degeneration of the subtalar articular facet and that ligaments are larger in feet with degeneration of the subtalar articular facet.This investigation examined 50 feet from 25 Japanese fixed cadavers  donated to Nippon Dental University School of Life Dentistry at Niigata. All cadavers were fixed in 10% formalin that was then replaced with alcohol. Inclusion criteria were no history of surgery on the foot or ankle joint. This investigation was conducted with the approval of the Ethics Committee at our institution . This study complied with the Declaration of Helsinki and was conducted after informed consent was obtained from all donor families.The dissection procedure consisted of amputation of the donor foot 10 cm above the ankle joint, followed by dissection of the skin, subcutaneous tissue, inferior extensor retinaculum, and lower leg muscle and tendons from the isolated foot specimen. In addition, to transect the talus at the subtalar joint, ligaments were cut in the following order: calcaneofibular ligament, lateral talocalcaneal ligament, CL, dorsal talonavicular ligament, ACaL, posterior talocalcaneal ligament, deltoid ligament, and ITCL. To disarticulate the calcaneus at the transverse tarsal joint, ligaments were cut in the following order: bifurcated ligament, dorsal calcaneocuboid ligament, plantar calcaneonavicular ligament, short plantar ligament, long plantar ligament, and plantar calcaneocuboid ligament.Based on previous studies ,19,20,21The footprint area of the ligament attachment was used to evaluate ligament structure. Footprint areas were analyzed for CL, ITCL, and ACaL. These ligaments were carefully exposed from the disarticulated talus and calcaneus, and each ligament was detached from each bone. The detached areas were then colored with a pen to identify the footprint area for each ligament attachment. A three-dimensional (3D) scanner   was used to create 3D models of the talus and calcaneus. The 3D model data were transferred to Geomagic Freeform 2021 design software (3D SYSTEMS), and curves were drawn on the boundaries of the footprint area using a pen-type device . Afterward, footprint areas on the talar and calcaneal sides were calculated using Rhinoceros7 3D software (McNeel) . FootpriDegeneration of the subtalar articular facet of the talus and calcaneus AF, MF, and PF was evaluated with a gross anatomical method based on the classification of Hirose et al. . This meThe reliabilities of intersecting angle and footprint area measurements were examined for 10 feet from 5 Japanese fixed cadavers  with no history of ankle or ankle joint surgery. Intersecting angles were measured as described above, and re-measurements were taken on the same day as the first measurement. The footprint area was measured by the method described above, and re-measurements were taken the next day or later.Statistical analyses were performed using IBM SPSS Statistics Version 28.0 . The intraclass correlation coefficient (ICC) was used to examine the reliability, and intra-examiner reliability  was calculated for each intersecting angle and footprint area.t-test was used for the footprint area of the ACaL, and a two-sample t-test was used for the total footprint area of the CL, ITCL, and ACaL in comparisons of the Degeneration (+) and Degeneration (−) groups of the subtalar joint facet. Intersecting angle and footprint areas of CL and ITCL were compared between the Degeneration (+) and Degeneration (−) groups of the subtalar joint facet using the Mann–Whitney U test. The significance level was set at 5%.Relationships between number of articular facets of the talus, joint congruence, and degeneration of the subtalar articular facet were examined using Fisher’s exact test. The relationship between the number of articular facets of the calcaneus and degeneration of the subtalar articular facet was examined using the Chi-square test. After performing the Shapiro–Wilk test and Levene’s test on the intersecting angle and footprint area, Welch’s t-test, two-sample t-test, and Mann–Whitney U test, effect size was calculated using the fourfold point correlation coefficient (φ) [Based on each the Fisher’s exact test, chi-square test, Welch’s ient (φ) , Cohen’sient (φ) , and ranient (φ)  and cateient (φ) .ICC  values for measurement of the intersecting angle and footprint area were 0.989 and 0.975, respectively. According to the criteria of Landis et al. , an ICC 2 for CL, 48.4 ± 24.3 mm2 for ITCL, and 48.3 ± 25.1 mm2 for ACaL. Total footprint area of the CL, ITCL, and ACaL was 208.9 ± 68.8 mm2  . No significant group differences between Degeneration (+) and Degeneration (−) groups were seen in footprint areas of the CL , ACaL , or total footprint area for the CL, ITCL, and ACaL   and Degeneration (−) groups  . In term= 0.026) .This study examined the relationship between joint and ligament structures of the subtalar joint and degeneration of the subtalar articular facet in Japanese fixed cadavers. To the best of our knowledge, this represents the first study to examine the relationship between joint and ligament structure of the subtalar joint and degeneration of the subtalar articular facet. Two main findings were obtained from this study. First, no significant relationship was apparent between joint structure of the subtalar joint  and degeneration of the subtalar articular facet. Second, in terms of the ligamentous structure of the subtalar joint, footprint area of the ITCL was significantly higher in the Degeneration (+) group than in the Degeneration (−) group.The present study did not find any relationship between joint structure of the subtalar joint  and degeneration of the subtalar articular facet. These results are similar to those described by Kleipool et al. , who exaIn the present study, among the ligamentous structures of the subtalar joint, only the footprint area of the ITCL showed significantly higher values in the Degeneration (+) group compared to the Degeneration (−) group for the subtalar joint facet. Previous studies suggested that the CL, ITCL, and ACaL in the subtalar joint are each important for stability of the subtalar joint ,15,16. ISeveral limitations to this study need to be kept in mind. The first is that the lifestyles, medical history, and history of sprains for donors remained unknown. In previous studies, osteoarthritis was reported to show many risk factors . ThickenIn this study, no significant relationship was identified between joint structure and the presence of degeneration of the subtalar articular facet. In terms of ligament structure, only footprint area of the ITCL was significantly higher in the Degeneration (+) group than in the Degeneration (−) group of the subtalar joint facet. The present results suggest that the joint structure of the subtalar joint may not affect degeneration of the subtalar articular facet. In the ligament structure of the subtalar joint, the footprint area of the ITCL was significantly larger in the group with degeneration of the subtalar joint facet, suggesting that degeneration of the subtalar joint facet may be related to the size of the ITCL. Further studies using biomechanical methods are needed to clarify the relationship between subtalar joint motion and variations in subtalar articular facet morphology, as well as the detailed functions of the ligaments of the subtalar joints.