To develop the first value assessment index system for off-label use of antineoplastic agents in China.via a questionnaire or doing interview among a multidisciplinary panel of experts by collecting their feedback to inform the next round, exchanging their individual knowledge, experience, and opinions anonymously, and resolving uncertainties.A modified two-round Delphi method was employed to establish consensus within a ﬁeld to reach agreement P-values of Kendall’s W test were all < 0.001 for each round. At the end of two rounds, W-value for concordance was 0.395 . The final value assessment index system comprised of eight domains, 21 subdomains, and 56 indicators. The weight and combination weight of each domain were 0.4211 for therapeutic value, 0.1678 for source and type of evidence, 0.0961 for public feedback/comments, 0.0894 for novelty in drug discovery, 0.0689 for grading of evidence recommendation, 0.0578 for consistency of evidence results, 0.0561 for disease burden, and 0.0428 for ratio of composition/integration.Expert’s positive coefficient was 94.74% in the first round and 100.00% in the second round. In the first round, expert’s authority coefficient for a majority of 61 indicators was ≥ 0.80  and coefﬁcient of variation for all the 61 indicators was ≥ 22% . In two rounds, the mean expert’s authority coefficient raised to 0.85 (ranging from 0.75 to 0.90), and coefﬁcient of variation for all indicators was < 20% . The Use of Delphi method to develop the proposed value assessment index system was found scientific and credible. This value assessment index system is highly appropriate for off-label use of antineoplastic agents in China. The growing global cancer burden has accelerated the innovation in treatment, including the influx of new drugs. Nevertheless, skyrocketing healthcare costs, especially for antineoplastic agents combined with modest survival gains, raise questions that new anticancer drugs are not necessarily cost-effective .Oxford English Dictionary  , EuropeaOff-label use for antineoplastic agents, sometimes the only option for patients with advanced cancer in real-world settings, is an inevitable challenge and remains to be solved urgently in clinical practice. However, at present, lack of general specification and technical criteria for evaluation is tangible. Similar with “new drugs” or “new treatment” compared with a standard therapeutic regimen, it is feasible to use a value assessment framework to comprehensively evaluate off-label use for antineoplastic agents, so as to solve the technical bottleneck for evaluation of off-label use of antineoplastic agents.Although there are compendiums of indicators for value assessment, there are currently no validated indicators to guide implementation and value evaluation of off-label use of antineoplastic agents. The aim of the present study was to explore establishment of the first value assessment index system for off-label use of antineoplastic agents in China using the modified Delphi method, which encompassed an iterative process and has been widely applied in diverse areas of healthcare system.via a questionnaire or doing interview among a multidisciplinary panel of experts by collecting their feedback to inform the next round, exchanging their individual knowledge, experience and opinions anonymously, and resolving uncertainties  working in hospitals and were employed in clinical pharmacy, pharmaceutical affairs, oncology, evidence-based medicine, clinical epidemiology and statistics, or pharmacoeconomics. Demographic characteristics of participants, including gender, profession, the highest level of education, etc. were also collected and shown in A multidisciplinary panel enrolled 19 participants for consultation from geographically diverse areas, including North, South, and West of China who met experts’ defined criteria. Eighteen experts agreed to participate in the first and second rounds. All the experts had at least nine or more years of experience . Experts were predominantly (ajC) was 94.74% in the first round and 100.00% in the second round.In general, expert positive coefficient (rC) for majority of 61 indicators was ≥ 0.80 , and coefﬁcient of variation (CV) for all the 61 indicators was ≥ 22% . After two rounds, rC for the majority of indicators was higher than that of the first round. The average rC raised to 0.85 (ranging from 0.75 to 0.90), and CV for all the indicators was < 20% , indicating that consensus has been achieved.In the first round, expert’s authority coefficient , which was statistically significant at the level of α=0.05, indicating that the consensus could be reached among the experts .Although our framework was developed in the Chinese context, we believe that it can be implemented in other countries for assessing adherence to best decision-making, practice, and management in off-label use of antineoplastic agents.Our study has several strengths. Firstly, the eight domains in the framework, which were strongly endorsed by the experts, disease burden, and novelty in drug discovery, covered different types of cancer burden about the state, society, and individual, and also reflected the orientation of drug research and development policy in China. Source and type of evidence, grading of evidence recommendation, and consistency of evidence-based results highly condensed the methodological support of evidence-based medicine for the present study, and emphasized the importance of evidence and patients’ decision-making. These key domains were not proposed in other value assessment frameworks, and they therefore can be used in global scale.Secondly, we invited 18 well-known experts in related fields who concentrated on clinical pharmacy, pharmaceutical affairs, oncology, evidence-based medicine, clinical epidemiology and statistics, and pharmacoeconomics, 16 of which had doctor’s or master’s degrees. The number of experts should be appropriately selected for a Delphi-based study . Expert’Thirdly, a reasonable weight setting is crucial for establishing an index system. In the present study, therapeutic value plays a leading role in value assessment index system, demonstrating that multiple forms of evidence should be taken into account for value assessment, including but not limited to patient-reported outcomes, results from randomized controlled trials(RCTs), and real-world evidence as appropriate. The weight coefficient of the first-level indicators was in the following order: therapeutic value (0.4211), source and type of evidence (0.1678), public feedback/comments (0.0961), novelty in drug discovery (0.0894), grading of evidence recommendation (0.0689), consistency of evidence-based results (0.0578), disease burden (0.0561), and ratio of composition/integration (0.0428). Obviously, the top three weights were therapeutic value, source and type of evidence, and public feedback/comments, which highly condensed the methodological support of evidence-based medicine for the current study and emphasized the importance of evidence and patients’ decision-making .Fourthly, open questions were raised during each round to gain more in-depth insight into the indicator, promoting more well-defined indicators, as well as ensuing guidance for satisfactory practice, so that the index system could be more appropriate for the purpose of value assessment.However, the present study has also a number of limitations. Firstly, we did not include potential experts from some provinces or regions across China . Secondly, we did not include payers of healthcare for consultation, which are important stakeholders in the value assessment of pharmacotherapy. Thirdly, the present study did not provide a face-to-face meeting for experts to discuss disagreement. Fourthly, Delphi consensus has its own limited validity. Fifthly, there were a great number of indicators, and it is therefore necessary to remove those indicators with low operability in the future according to empirical research on different types of cancer and drugs.Future research should aim at setting an international consensus on a value assessment index system for off-label use of antineoplastic agents using Delphi method as a contribution to robust evidence for governments’ evidence-based decision-making, providing further insights into value and its relevance with drug prices to promote value-oriented medicine.We conducted a Delphi-based method and process to develop and validate the first value assessment index system for off-label use of antineoplastic agents in China. The ﬁnal 56 indicators need to be further tested, veriﬁed, and revised in clinical practice.i) disease burden, ii) therapeutic value, iii) novelty in drug discovery, iv) source and type of evidence, v) grading of evidence recommendation, vi) consistency of evidence-based results, vii) ratio of composition/integration, and viii) public feedback/comments , exported into Excel 2016 spreadsheets, and all statistical analyses were carried out by SPSS 25.0 software . Both descriptive statistics and quantitative analyses were undertaken. Each round of the Delphi survey was analyzed separately. A two-tailed CV were calculated for each indicator and round. CV ≤ 25% indicated less variability of the experts’ opinions.The mean scores and ajC) and expert’s authority coefficient (rC), involving two factors (the judgment criteria for the indicators (aC) and the experts’ familiarity with the indicators (sC)), were correlated together as follows: rC=(aC+sC)/2. P-values of Kendall’s W test and W-values were determined to evaluate the expert’s positive degree, expert’s authority degree, and degree of coordination of experts’ opinions (CV ≤ 25% were recommended for Delphi studies and set as the consensus level (Expert’s positivity coefficient (opinions . Mean scus level , and resThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.QJ: study design, drafting out and revising the manuscript critically for important intellectual content. WZ: study design, analysis and method directing. JY: participated in its design, revising the manuscript. HL: analysis and interpretation of data. MM: analysis and interpretation of data. YL: conceiving of the study, revising the manuscript finally.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.


To generate comparative evidence in a timely fashion for drugs without restricting or delaying access, value-based pricing and reimbursement could be conditioned on a prospective, post-approval evidence generation plan. Drug regulatory policies aim to balance evidence generation with patient access. Overly onerous demands for evidence lead to longer development times and higher costs. Approving drugs too early may lead to uninformed use due to unestablished or uncertain benefits and risks, potentially harming patients and adding to increased and unjustified health care spending .After a drug is approved, a key issue for patients, prescribers, and payers is how much clinical benefit on patient-relevant outcomes can be expected compared to available alternatives. However, formal regulatory requirements by the FDA or EMA do not include active control comparisons based on patient-relevant clinical endpoints, resulting in a limited number of regulatory dossiers containing such data . Furthervia expedited pathways such as accelerated approval in the United States or conditional approval in Europe. Both regulatory systems require under such circumstances additional evidence generation post-approval for these drugs, but studies have revealed that these post-approval trials often have similar characteristics to pre-approval trials, and are too frequently delayed or difficult to get finished , a term that encompasses clinical and economic value assessments of new drugs informed by the evidence and medical experts. Independent organizations in the United States such as the Institute for Clinical and Economic Review (ICER) systematically assess comparative benefits on patient-relevant endpoints of certain drugs. ICER explicitly highlights remaining uncertainties related to the available evidence beyond the benefit-risk balance. In Europe, formal HTA processes exist in most countries, leading to dossiers about comparative benefit and economic value of medicines similar to those of ICER. However, ICER has no mandate to enforce evidence generation and in Europe additional evidence generation for HTA purposes is organized nationally with only little international coordination.Besides outlining the remaining uncertainties and the types of trials needed to resolve them, HTA processes can also provide suggestions for reasonable drug prices based on the drug’s effects and the uncertainties around these effects. Linking the value that a product delivers to its price may incentivize the development of transformative drugs. Value-based pricing mechanisms have contributed to lower drug prices in Europe as compared to the United States . HoweverClearly, there are institutes such as HTA organizations that have the capacity to outline the most relevant uncertainties to patients, clinicians, and payers that should be resolved post-approval. But who can enforce this type of evidence generation?To increase post-approval evidence generation, regulators could be given more authority to work with HTA bodies to determine an agenda for post-approval comparative trials related to newly-approved drugs. In a comprehensive review of regulatory and HTA dossiers, we found that regulators and HTA bodies were usually able to agree on appropriate endpoints and comparators in pre-approval scientific advice procedures, and that manufacturers often followed this combined advice for clinical trials . Such joHowever, studies have pointed to regulators’ inability to consistently enforce post-approval trial obligations, because it is politically and socially challenging to withdraw marketing authorization purely because evidence generation is delayed. In a previous study, seven guiding principles were put forward to guide the generation of evidence post-approval. One of the principles states that it is necessary to create the right incentives for generating comparative evidence post-approval . One wayThe viability of such an approach depends on the willingness of the involved stakeholders. In the US, private insurers already negotiate drug prices and they have stressed the relevance of value assessments for coverage and pricing decisions . HoweverClinical evidence at drug approval is often not sufficient to ensure informed clinical and reimbursement decision making. One solution to incentivize companies to generate such comparative evidence in a timely fashion without restricting or delaying access could be to condition value-based pricing and reimbursement on a prospective, post-approval evidence generation plan. Whether such schemes will deliver on their promise depends on the quality of early dialogue between stakeholders, predictability of the outcomes, and on stakeholders’ ability to establish a fair balance between sufficient prospects of returns on trial investments for manufacturers and reasonable value for money for payers.HGML declares that he is a member of the Lygature Leadership Team.All authors contributed to the article and approved the submitted version.HL declares that he is a member of the Lygature Leadership Team. AK’s work is supported by Arnold Ventures, as well as the Harvard-MIT Center for Regulatory Science. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the agencies or organizations with which the authors are affiliated.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.


An apparent short isoform of dystrophin and associated glycoproteins were identified in spleen by mass spectrometry but appear not be affected in muscular dystrophy. In contrast, the mdx-4cv spleen showed significant proteome-wide changes in other protein species that are involved in metabolism, signaling, and cellular architecture. Since the spleen plays a key role in the immune response, these proteomic alterations may reflect pathophysiological cross talk between the lymphoid system and dystrophic muscles, which are affected by both fiber degeneration and inflammation.Duchenne muscular dystrophy is primarily characterized by progressive muscle wasting due to deficiency in the membrane cytoskeletal protein dystrophin but is also associated with body-wide cellular disturbances in a variety of non-muscle tissues. In this study, we have focused on the comparative proteomic analysis of the spleen and established considerable changes in this crucial secondary lymphoid organ from the genetic   •Biochemical and proteomic analyses have identified dystrophin isoform Dp71 in spleen•mdx-4cv model of dystrophinopathyNormal Dp71 levels were found in the spleen of the •mdx-4cv spleenThe enzymes TGM2 and MMP-9 are drastically increased in •mdx-4cv spleenApolipoproteins ApoE and ApoB are greatly reduced in  Disease; Pathophysiology; Proteomics DMD gene  was generated by chemical mutagenesis with N-ethyl-N-nitrosourea  and consists of high-confidence peptides that were filtered based on Xcorr values. Importantly, a wide range of spleen-associated proteins were confirmed to be present in the examined tissue extracts.Prior to carrying out a comprehensive proteome-wide comparison between wild-type and Of note, the proteomic survey of mouse spleen included the identification of major types of splenic receptors, enzymes, and lymphoid proteins, such as cell surface antigens. The spleen marker named CD5 antigen-like protein, which was previously shown to be one of the most highly expressed splenic proteins , was cleThe screening of the experimentally accessible mouse spleen proteome revealed the coverage of major protein constituents belonging to the family of “classical plasma proteins” , as listmdx-4cv spleen extracts identified 10.93% change in protein constituents. Of these components, 93 protein species were identified by a coverage of their amino acid sequence by at least 2 peptides and a minimum fold change of 1.5. A reduced expression was found to occur in 55 proteins, and 38 proteins were shown to be increased in their abundance, as listed in mdx-4cv spleen. The most decreased and the most increased spleen-associated proteins were identified as apolipoprotein B-100 (E9Q414) and protein-glutamine gamma-glutamyl-transferase TGM2 (P21981), respectively, in mdx-4cv preparations. The heatmap of the comparative mass spectrometric survey is provided in mdx-4cv spleen.The comparative mass spectrometric survey of wild-type versus mdx-4cv spleen, as well as potentially altered protein-protein interaction patterns of changed spleen-associated proteins. Both considerable decreases and increases were observed for metabolic interconversion enzymes, such as hydrolases, ligases, lyases, oxidoreductases, and transferases. Striking increases included protein modifiers such as proteases, protein modulators such as protease inhibitors, and transfer carriers. In relation to altered protein interactions, especially striking is the apolipoprotein hub with ApoE and ApoB of reduced protein species. Immunofluorescence microscopy clearly confirmed the drastic reduction of ApoE in the mdx-4cv spleen  and matrix metalloproteinase MMP9. The protein band pattern of gel electrophoretically separated spleen samples did not show major differences between wild-type and arations A. Howevehenotype D and 7G.mdx-type mouse models of dystrophinopathy have been widely used in muscular dystrophy research , the complement system (complement C3), metabolite transportation , digestion (amylase), and factors involved in the acute response and inflammation . Spleen-associated proteins with a drastic reduction in the mdx-4cv mouse model were previously shown to be also reduced in mdx-4cv serum .For further information, requests should be directed to the Lead Contact: Kay Ohlendieck (This study did not generate new unique reagents.https://osf.io/f85ve/. This link also features a multi-consensus file of the proteomic cataloging of mouse spleen with the help of an Orbitrap Fusion Tribrid mass spectrometer.The proteomic datasets from the mass spectrometric analysis of 14 separate spleen sample runs have been deposited to the Open Science Framework repository as OSF entry “f85ve” under the following link: All methods can be found in the accompanying


Bile acids (BAs) are facial amphiphiles synthesized in the body of all vertebrates. They undergo the enterohepatic circulation: they are produced in the liver, stored in the gallbladder, released in the intestine, taken into the bloodstream and lastly re-absorbed in the liver. During this pathway, BAs are modified in their molecular structure by the action of enzymes and bacteria. Such transformations allow them to acquire the chemical–physical properties needed for fulling several activities including metabolic regulation, antimicrobial functions and solubilization of lipids in digestion. The versatility of BAs in the physiological functions has inspired their use in many bio-applications, making them important tools for active molecule delivery, metabolic disease treatments and emulsification processes in food and drug industries. Moreover, moving over the borders of the biological field, BAs have been largely investigated as building blocks for the construction of supramolecular aggregates having peculiar structural, mechanical, chemical and optical properties. The review starts with a biological analysis of the BAs functions before progressively switching to a general overview of BAs in pharmacology and medicine applications. Lastly the focus moves to the BAs use in material science. Bile acids (BAs) constitute an important class of biological molecules produced in the metabolism of all vertebrates. In mammals, they exhibit the so called C24 structure: 24 carbon atoms form a steroid nucleus  and a five-carbon side chain with a carboxyl group at the C-24 position.cis configuration, inducing an overall bent shape. Such a structural feature delineates a concave and convex side of the steroidal backbone where OH groups in α orientation (up to three) and two methyl groups in β orientation, respectively, point out. Therefore, two opposite faces with hydrophilic and hydrophobic properties can be distinguished.  acids—3 and 2 OH groups, respectively—are first synthesized by the hepatocyte and thus named primary BAs. Subsequently CA and CDCA are conjugated to glycine or taurine, giving rise to glycocholic (GCA), taurocholic (TCA) acids and glycochenodeoxycholic (GCDCA), taurochenodeoxycholic (TCDCA) acids, respectively. Further metabolization leads to the secondary BAs, deoxycholic (DCA) and lithocholic (LCA) acids, that present two and one OH groups, respectively c,d. The Generally speaking, five major physiological roles can be distinguished in BA activity: (1) regulation of cholesterol homeostasis; (2) deterrence for the formation of gallstones and kidney stones; (3) emulsification of dietary lipids and absorption of fat-soluble vitamins; (4) antimicrobial activity; (5) regulation function.These functions will be described in the next paragraphs, following the BA physiological pathway—from biosynthesis to elimination/recirculation.BAs are produced in the liver and stored in the gallbladder. Subsequently they are secreted through the biliary tract in the intestine, absorbed in the intestinal epithelium to pass into the portal circulation and return to the liver. The overall process is named enterohepatic circulation . A smallBAs are produced in their primary forms (CA and CDCA) in the liver, adopting cholesterol as starting substrate and the activity of 16 enzymes. Such enzymes catalyze 17 different reactions. In humans, the synthesis takes place in multiple intracellular compartments such as the cytosol, endoplasmic reticulum, mitochondria and peroxisomes.A living organism can exploit two different synthetic routes for the BA synthesis .The route, that is quantitively more important for adult humans, is known as “classic or neutral path” and provides for more than 90% of the BA needs. Such a synthetic pathway starts with the hydroxylation of the sterol ring on C7 mediated by the cholesterol 7α-hydroxylase (CYP7A1). Subsequently the intermediate is immediately modified on the lateral chain by the sterol 27-hydroxylase (CYP27) for the CDCA synthesis or, in the case of the CA synthesis, is further hydroxylated on C-12 by the 12α-hydroxylase (CY8B1) before the CYP27 catalyzed step. In this pathway, the CYP7A1 activity is the kinetic key that determines the overall rate of the metabolic pathway. On the other hand, the CY8B1 activity, modulating the hydrophilicity composition of the steroid nucleus, controls the CA and CDCA production ratio.The second biosynthetic route, named “acidic path”, leads to the production of CDCA in humans and it is dominant in human neonates. In this pathway the chemical modifications of the cholesterol substrate involve first the lateral chain where a hydroxyl group is introduced on C27 by the CYP27 activity. Subsequently the modification of the sterol part is performed by the oxysterol 7α-hydroxylase (CYP7B1). A minority fraction of C25- and C24-hydroxycholesterols generated by the corresponding hydroxylases can also enter the acidic pathway to form BAs. Although most of the hydroxycholesterols are produced in the liver, hydroxycholesterols generated in extra hepatic tissues, such as lungs and brain, may be transported to the liver and be also involved in this BAs biosynthetic route. After their synthesis, CA and CDCA are conjugated to taurine and glycine by the activity of two enzymes, bile acid-CoA synthase and bile acid-CoAamino acid N-acyltransferase. The conjugation makes the produced BA more hydrophilic and more acidic on the side chain: the pKa decreases from ~5.0 to ~3.9 and <2 for glycine and taurine conjugates, respectively. The amount of synthesized BA is regulated by control mechanisms that operate at transcriptional level, where the transcription factors are nuclear receptors. An exceeding amount of BA triggers a negative feedback mechanism, starting with the BAs binding to the hepatic farnesoid X receptor (FXR) and ending with the inhibition of the genes expressing the CYP7A1 and CYP8B1 enzymes involved in the biosynthesis of BA ,11. The BA production utilizes a consistent amount of the cholesterol pool (about 500 mg per day), thus turning out to be one of the main mechanisms for cholesterol regulation in the human body.  ConsisteA further important role of BAs towards cholesterol concerns the solubilization activity in the bile. Cholesterol is majorly eliminated through the secretion in bile. Bile is a solution produced in the liver that is composed by 95% of water. Free cholesterol is insoluble in aqueous solutions. However, in bile due to the presence of BAs (about 0.7%) and lipids like lecithin, cholesterol is easily solubilized through the formation of mixed micelles. Such a process avoids the cholesterol supersaturation and in turn the formation of gallstones. The interaction between cholesterol and BAs has been analyzed both from a chemical and medical point of view. In the first case, several studies analyzed the structure, stability and parameter formation of BAs–cholesterol-based micelles and crystals ,35,36. IAfter the synthesis, conjugated BAs are transferred into bile, passing through the hepatocyte’s membrane to the canaliculi via the bile salt export pump. The bile in the canaliculi converge in a series of ducts that eventually terminate into the common hepatic duct. Via the hepatic duct, the bile reaches the gallbladder, where it is stored or is delivered directly to the intestinal lumen .2+ ions. In the distal small intestine, bacteria break the conjugation with the aminoacidic of a fraction of conjugated BAs. Deconjugation is completed in the colon where further modifications as dihydroxylation and epimerization occur to give rise to secondary BAs, i.e., DCA, LCA and UDCA. Recently, anaerobic in vitro reconstitution experiments showed that six enzymes are sufficient for the conversion of cholic acid into DCA ,4645,46]The fundamental understanding of these mechanisms is supported by a large collection of literature that by means of microscopic, spectroscopic and rheological techniques, (i) analyzed the displacement mechanism of BAs with respect to a large number of proteins and lipids b, (ii) d4 to 105 colony-forming units/mL), a high concentration of conjugated BAs (about 10 mM during digestion time) and an FXR level three times higher than the epithelium of the proximal small intestine.BAs and gut microbiota have a mutual interaction. As aforementioned, the molecular structures of primary BAs are modified by the gut bacteria to give rise to secondary BAs or other BA forms that escape the enterohepatic circulation. Nevertheless, also BAs influence the microbiota composition ,55. ConcMoreover Kang et al. recently discovered that the bile acid 7a-dehydroxylating gut bacteria, responsible for the biotransformation of primary BAs into secondary BAs, secrete tryptophan and proline-based antibiotics. Such antibiotics are able to obstruct bacterial pathogens causing diarrhea and colitis and their efficiency is enhanced in presence of DCA and LCA . CommensTo conclude this paragraph, it has to be emphasized that the enteric flora in the human body can have protecting functions, by for example eliciting immune responses, but can be also responsible for pathologies such as inflammatory bowel disease and cancers ,68. TherThe BA ability to penetrate membranes has been boosted up in derivatives, enabling for preparation of active molecule carriers where the BA derivatives (BADs) can work both as monomer  or in aggregates . BAs emulsification properties have been investigated to formulate new drugs for treatment of obesity and other diseases related to slow fat assimilation and high levels of cholesterol . Starting from the regulatory functions of BAs, BADs have also been developed to interfere in several physiological pathways  for the treatment of metabolic syndromes.In the light of their biological origin and the specific interaction with several physiological pathways, BA and BADs have naturally become the protagonist of many biomedical and pharmaceutical studies . For exaBoth natural BAs and a large number of BADs have been proved efficient against many bacteria, parasites, fungi and to induce apoptosis in different types of cancerogenic cells. To mention some examples, it has been known for more than a decade that LCA induces apoptosis in neuroblastoma , breast Antimicrobial activity is mainly based on the ability of BAs to damage membranes resulting from their amphiphilic steroidal structure . In addiBAs can be used in the preparation of polymers with a main interest in drug delivery . The prePolymers formed by BAs as repeating units in the main chain, have also been synthesized with branched or linear architectures , mainly BAs and lipids can form mixed micelles exploited to solubilize hydrophobic drugs and to improve their bioavailability ,128 BA cN-isopropyl acryl amide) (PNIPAM) block and a cationic polymer block of poly(3-acrylamidopropyl)-trimethylammonium chloride (PAMPTMA(+)) and the oppositely charged BA surfactant sodium deoxycholate. Two kinds of mixed aggregates were observed to form at room temperature having a globular morphology or a longitudinally striped tape-like architecture, which have a roughly neutral zeta potential at all compositions of the mixtures  in an associated process that is often observed to be gradual and without a sharp critical micellar concentration. Reported critical micellar concentrations decrease relative to a decrease in the number of hydroxyl groups (increasing hydrophobicity) according with the order cholate < deoxycholate ,151,152,A decrease in the repulsions among the charged heads of deprotonated BAs can be induced by increasing the ionic strength or by decreasing the pH (for carboxylate BAs), thus promoting unidirectional growth of the micelles. Fibrils form because of the growth that can lead to gelation. For example, it is well known that DCA forms gels in water upon lowering pH around neutrality ,153, wit2+ can crosslink BA charge heads promoting micellar growth and gelation for cholate and GDCA. Crosslinking and formation of nanohelices can be induced on CA solution also by other multivalent cations, like those of transition metals [Multivalent cations like Can metals ,161 and n metals ,163,164.n metals  and by Dn metals .Electrolyte-induced wormlike micelle growth and gelation is also observed in lecithin/BA aqueous mixtures ,168. A sThe various self-assembly behavior of natural BA includes the formation of tubular aggregates, provided by LCA at strong alkaline conditions (pH = 12) ,172. It It is important to remark that BAs are chiral molecules, and can selectively interact with enantiomers of additives both in monomeric and micellar form. This ability was reported for the interaction of monomers and micelles of DCA , GCA, anBeside the drug-conjugated derivatives employed in medicine and the polymeric molecules, a broad family of molecules can be synthesized starting from BAs, to provide an expanded set of self-assembling biomaterials . DerivatKeeping the same substituent, the ability to form tubules was reported to be lost for aminoacid substituted derivatives obtained from more hydrophilic BA precursors ,192, wheSeveral BAs functionalized at the carboxylic groups to form different species like hydrazide  and aminBAs are natural molecules ubiquitously found in vertebrates. In humans, they are produced in the hepatocytes from cholesterol modification and, through a cyclic path named enterohepatic circulation, are transported from liver to intestine, lately being transferred to the blood stream by which they are re-absorbed from the liver. The unusual amphiphilic structures allow BAs to exhibit detergent functions towards different compounds, e.g., solubilization of cholesterol, fat dietary lipids and penetration/breaking of membranes. The latter feature, expressed towards bacteria, makes BAs important antibacterial elements that are able to regulate the strength of the gut microbiota. Furthermore, BAs work in the body as hormones, being signaling molecules for the expression of genes and regulators of different metabolic paths. The physiological roles of BAs briefly summarized here and comprehensively overviewed by other specialist reports ,213,214,


The aim of this online cross-sectional study is to identify the sources of scientific information used by Brazilian dentists in clinical decision-making and the barriers that they perceive as important to the incorporation of scientific evidence into clinical practice. A pretested questionnaire created in Google Forms which was made available to participants through links sent by e-mail or shared on Facebook® and Instagram® was used to collect the data between October 2018 and May 2019. Only dentists who were involved in direct or indirect care of patients  were asked to complete the questionnaire. The sample was comprised of 528 dentists ; their mean age was 45.2 years (±12.5) and 30.9% had an academic position. The majority were women (68.0%) and lived in Southern or Southeastern Brazil (96.0%). The sources of scientific information more frequently used by them in clinical decision-making were clinical guidelines , scientific articles  and bibliographic databases . The information resource less frequently used was social media. The most important barriers to the clinical use of scientific evidence were: difficulty in determining whether scientific contents found on the Internet were reliable or not , high cost of access to scientific papers , and lack of time for reading scientific articles . Although Brazilian dentists show a positive attitude towards obtaining scientific evidence from reliable sources, there still remain important barriers to the translation of evidence into practice. This can have significant implications for quality of care and should be further investigated. Incorporating scientific evidence into dental practice requires that dentists apply the best available scientific evidence that may be relevant to a given patient case in the process of clinical decision-making . HoweverThe process by which evidence produced by scientific research is made available for use in clinical and political decisions is called knowledge transfer and exchange (KTE). Unfortunately, there are numerous barriers to KTE, at both the organizational and individual levels. For example, at the organizational level, the professional incentive system for scientists encourages the dissemination of results of scientific studies in high-impact peer-reviewed journals, which are generally published in the English language. This can make it difficult for clinicians in countries where a language other than English is spoken to access updated scientific information in their field. At the individual level, the lack of ability to evaluate the results of scientific studies, negative attitudes towards change and conflicts of interest are often considered as important barriers to the successful transfer of knowledge between producers and users of scientific evidence .Additionally, it is very challenging for dentists to keep up to date with the latest evidence because of the current scenario of large dental research productivity. A total of 104,975 articles were published between 2009 and 2019 in dental journals and indexed by MEDLINE. In view of these numbers, feeling overwhelmed with information and having difficulty in selecting evidence that may be truly relevant and useful for clinical practice are not unlikely [The identification of dentists’ behaviors regarding the search for scientific information as well as barriers they face in this process is an indispensable step for the development of effective KTE strategies. In developed countries, it has been shown that dentists are cautious about making decisions based on documentary sources like systematic reviews of the dental literature and prefer to seek advice from colleagues, dental specialists, or respected dental experts. They also report lacking time, experience, skills, and confidence to find and use evidence-based resources . MoreoveKnowledge about the frequency of use of scientific information resources by Brazilian dentists is scarce, and data regarding the use of clinical guidelines and systematic reviews published in the Cochrane Library are lacking. Furthermore, some potential constraints which may hinder the use of scientific evidence in clinical practice such as the high cost of accessing peer-reviewed papers, difficulty in performing critical appraisal of research articles, and uncertainty regarding the quality of the information found on the Internet have not been investigated yet . Thus, tThe Institutional Review Board of the Pedro Ernesto Hospital of Rio de Janeiro State University (UERJ) approved this cross-sectional study before its outset (CAAE 94336518.9.0000.5259). Data were collected online, and before answering the questionnaire, all participants were requested to click a button stating that they agreed to participate in the study. The reporting follows the STROBE guideline for cross-sectional studies [The participants were alumni of a major Brazilian public university , and dentists recruited via social media . Any Brazilian dentist was considered eligible for the study; there were no exclusion criteria such as age, sex, or graduation year.In order to contact USP alumni we sent e-mails to 5,990 dentists who had at some point enrolled in graduate or postgraduate programs offered by its School of Dentistry. We invited them to participate in our survey regarding the use of scientific evidence in clinical decision-making and provided a link to a Google Form containing the questionnaire. We also asked them to help us with the recruitment of participants by forwarding our e-mail to at least two colleagues who they thought might be willing to participate in the study. After the first email, two reminders were sent to all potential participants.https://pt-br.facebook.com/crescersorrindo), was used for this purpose. The publications on social media regarding the research provided a link to a Google Form containing the questionnaire.Additionally, to promote the study on social media, the researchers used their personal accounts on Facebook® and Instagram®. Also, a business account managed by a group of professors of another major Brazilian public university . We used the formula “n = 100 + 50(i)”, where (i) refers to number of independent variables in the final model, to verify whether this sample size would be sufficient for performing logistic regression analyses with four explanatory variables [An online questionnaire created in Google Forms  was used to collect the data. The questions and responses were developed during directed group discussions. The list of questions to be asked was drawn up by four members of the research team , taking into consideration the objectives of the study and the target population. The sources of acquisition of information for clinical decision-making were based on their own experience and the dental literature –13. BarrFrom May to June 2018, we pretested the questionnaire with 34 dentists who were postgraduate students at the University of São Paulo (n = 21) and the Rio de Janeiro State University (n = 13). Following the pretest, the research team made revisions to the original document regarding wording, sequence of questions, and response options in order to ensure that the questionnaire presented adequate content validity. The final questionnaire was organized into five sections. In the first section, we explained the aims of the study, introduced the researchers responsible for its development, invited potential participants to answer the questionnaire, and requested those who were willing to participate in the survey to click a button stating that they voluntarily agreed to participate. In the second section, we asked respondents about their year of birth, sex, place of residence, and graduation year. We also asked whether or not they were involved in direct  or indirect  care of patients. We requested dentists who did not perform any kind of clinical work to stop filling out the questionnaire at this point. The third section was comprised of questions about respondents’ professional activity. The fourth section included questions about the frequency of use of the following sources of scientific information in the process of clinical decision-making, during the past 12 months: consulting with colleagues, textbooks, clinical guidelines, bibliographic databases , scientific articles, the Cochrane Library, search engines , and social media . The answers to these questions were given on a five‐point frequency scale: never, hardly ever, occasionally, often or very often. The wording of this scale was the same as the one used in the Brazilian version of the Oral Health Impact Profile-Short Form (OHIP-14) . The fifData collection lasted from October 2018 to April 2019 for USP alumni and from March to May 2019 for social media.Descriptive analyses were performed, and distributions of absolute and relative frequencies  were obtained.In order to estimate the percentage of dentists  who used each source of information, often or very often, in the past 12 months, responses were recoded as follows: “often” and “very often” as “yes”  and “never”, “hardly ever” and “occasionally” as “no” . In order to estimate the percentage of dentists  who perceived lack of time, cost of access to scientific papers, insufficient proficiency in the English, lack of confidence to critically appraise evidence, and difficulty in determining reliability of Internet contents as barriers to the use of evidence in practice, their responses were also recoded by grouping “strongly agree” and “agree” into “yes”  and “strongly disagree”, “disagree” and “neither agree nor disagree” into “no” .p-value cut-off point of 0.25 in the bivariate analyses was used for [Student’s t-tests were used to analyze whether there were significant differences between the mean age of those (1) who used the Cochrane Library and those who did not and (2) who perceived difficulty in performing critical appraisal as a barrier to the incorporation of evidence into practice and those who did not. The significance level was set at α = 0.05. Additionally, we performed logistic regression to evaluate the relationship between these outcome variables and age, sex, graduation year and academic position. To select variables for the multivariate models, the used for . All anaWe received 412 responses from dentists contacted through the university’s alumni database and 155 responses from dentists contacted through social media making up a total of 567 responses. Among the 567 respondents, one subject from the USP subsample checked “no” in the box corresponding to the question asking for consent to participate in the study. This questionnaire was excluded and the initial sample totaled 566 respondents. Thus, the response rate from the USP alumni database was 6.9%. We could not calculate overall response rate because the number of dentists who actually received the invitations to participate in the survey via social media was unknown. Thirty-eight of the 566 respondents mentioned that they did not provide clinical care to dental patients, either directly or indirectly. Thus, they did not respond to the questions regarding sources of scientific information used for clinical decision-making and barriers to the use of scientific evidence in clinical practice and we ended up with 528 participants. The age range of the participants was from 23 to 83 years, and the majority lived in Southern or Southeastern Brazil (96.0%), were women (68.0%), and did not hold an academic position (69.1%). Detailed information on sociodemographic characteristics of the study population is depicted in The source of scientific information more frequently used by respondents was clinical guidelines, followed by scientific articles and bibliographic databases. The information resources less frequently used were Facebook®, Instagram®, and YouTube® .Based on the participants’ experience during the past 12 months, difficulty in determining whether scientific contents found on the Internet were reliable or not and high cost of access to scientific papers, were the barriers to the use of scientific information in clinical practice more frequently perceived by them, followed by lack of time for reading scientific articles. Insufficient proficiency in English was the problem less frequently reported .The Cochrane Library was reported to be used often or very often by 17.8% of respondents . The oddt-test, p = 0.02). Additionally, the odds of perceiving difficulty in performing critical appraisal as a barrier to the use of scientific evidence in practice was 57% higher for female than for male participants. After adjusting for age, this association was no longer significant  were. Also, practices widely reported were consulting with colleagues and looking for information on textbooks. Participants considered concerns regarding reliability of online scientific information, financial constraints for accessing scientific papers, and shortage of time for reading scientific papers relevant hindrances to integrating evidence into practice.Evidence-based clinical guidelines (CGs) are important tools for reducing the gap between research and clinical practice and consequently improving the outcomes of dental care . SystemaThe dentists in our sample showed a positive attitude towards CGs. High acceptability of CGs was also shown in a survey with European dentists who acknowledged the multidimensional benefits of CGs to both clinicians and patients and suggested that CGs should be more effectively disseminated through partnerships between National Dental Associations and Universities . HoweverThe high rate of use of bibliographic databases suggests that our surveyed dentists understand that these are important resources for finding peer-reviewed scientific articles. Nevertheless, efficiently navigating electronic databases may be a daunting task . FurtherAdditionally, clinicians may be able to read in English but they still may not master the competencies required to evaluate the quality of published articles before implementing a new technique or changing his/her clinical decision-making . In our Interestingly, in another study with Brazilian dentists about the use of scientific evidence in dental practice , case reTaken together, these findings suggest that availability of affordable preappraised, regularly updated, high-quality scientific evidence in the Portuguese language as well as training in the use of the 6S model to search for evidence  might help to reduce important barriers to KTE encountered by Brazilian dentists .Additionally, the high popularity of traditional methods for the acquisition of scientific information  observed in our study has also been previously reported in studies performed in other countries  –14,31.Experts and colleagues are a quick, cheap, and easy to use source of information which offer psychological benefits that journals and online databases cannot offer . QualitaIt is reasonable to expect that seeking advice from experienced and trusted colleagues may help a dentist to determine whether existing scientific evidence is relevant to his/her patient and that expert opinion may provide valuable guidance when there is no conclusive scientific evidence on the best way to solve a given clinical problem. Nevertheless, one cannot guarantee that the colleague being consulted is more knowledgeable than the dentist asking questions . Skills In the past decade, a couple of innovative initiatives have been implemented, notably in the USA and the UK, to bridge the gap between research and practice and overcome dentists’ mistrust in researchers and clinical trials. In the USA, the National Institute of Dental and Craniofacial Research, National Institutes of Health, successfully funded a number of projects incorporating clinicians into research groups lead by academics in Dental Practice-Based Research Networks (DPBRN) . DPBRN pTextbooks can be useful as the backbone to understanding health problems and diseases. However, the time lag between the publication of research showing beneficial or harmful effects of a given clinical intervention and the incorporation of its results into the text of dental books may turn textbooks into outdated or incomplete sources of scientific information for clinical decision-making ,42. TherTo our great disappointment, search engines  were more frequently used as resources for obtaining scientific information than the Cochrane Library. However, dentists who held an academic position were significantly more likely to search for evidence in the Cochrane Library than those who did not. Thus, it is possible that some close interaction between clinicians and academics, through participation in university-based DPBRN, for example, could benefit clinicians by raising their awareness of the relevance of Cochrane systematic reviews to dental practice and enhancing their adherence to evidence-based treatments ,46. ThisOnline resources contribute to efficient access to both high- and poor-quality scientific publications. Identifying the scientifically meritorious work that directly applies to their patients is the societal responsibility of health professionals . This caSocial media emerged between 1999 and 2006. Facebook was launched in 2004, YouTube in 2005, and Twitter in 2006. Practicing dentists and consultants began to use these platforms within 2 years of their creation . The virOur survey provides relevant information for the improvement of KTE in dentistry, especially in the Brazilian context. Nevertheless, the generalization of our findings to all dentists in Brazil should be made with great caution. Considering that there were 309,088 dentists registered at the National Council of Dentistry (CFO) in August, 2018 , less thIt is also worth noting that the distribution of dentists in the Brazil is highly heterogeneous; the ratio of inhabitants/dentists varies from 601 in the Southeast to 1,800 in the North. Southeastern Brazil concentrates 74% of dentists and Rio de Janeiro and São Paulo are the states with the highest number of dentists in the country. Moreover, the Brazilian dental workforce is predominantly female (55%) . In our Dentists in our sample showed a positive attitude towards obtaining scientific evidence from reliable sources. However, they reported that there still remain important barriers to the translation of evidence into practice. This can have significant implications for quality of care and should be further investigated.S1 Checklist(PDF)Click here for additional data file.S1 Appendix(PDF)Click here for additional data file.S2 Appendix(PDF)Click here for additional data file.


Aspiration is a common sequela post stroke as a result of oropharyngeal dysphagia. It is primarily managed using the poorly empirically supported intervention of thickened liquids. Where evidence is limited, clinicians may rely on clinical practice guidelines to support decision making. The purpose of this systematic review and narrative synthesis was to evaluate the evidentiary bases of recommendations made by stroke clinical practice guidelines regarding the thickened liquids intervention.A systematic review was conducted on stroke clinical guidelines retrieved via searches conducted across a range of databases including Academic Search Complete, CINAHL, MEDLINE, and the Cochrane Library as well as through association websites. Guidelines were eligible for inclusion if they focused on adult stroke populations, made recommendations relating to the thickened liquid intervention and were published between January 2010 and December 2018. Four independent reviewers rated methodological quality using the AGREE‐II instrument. Intervention recommendations were extracted and analysed using the Criteria for Levels of Evidence Reported from the Canadian Stroke Best Practice Recommendations and a novel framework examining the appropriateness of the supporting evidence.Thirteen clinical guidelines were included in the review. Methodological quality was variable with seven rating as good‐excellent overall. Thirty recommendations regarding the intervention were extracted. Of these, 16 recommendations were classed as a recommendation to use the treatment and all guidelines made this recommendation. Much of the evidence used to scaffold recommendations did not directly support the intervention.Despite the limited evidence base for the thickened liquid intervention, there was consensus among stroke guidelines in recommending it. This is despite limited empirical support. Furthermore, much of the evidence used to support recommendations was not appropriate, suggesting less than satisfactory evidence‐based practices in formulating recommendations. In this case, clinical guidelines may not be reliable decision‐support tools for facilitating clinical decision making. AGREE‐IIThe Appraisal of Guidelines for Research and Evaluation Second EditionAustralia 2017The Stroke Foundation of Australia CPGCameroon 2013SEEPD Program of the Cameroon Baptist Convention Health Board, the Bamenda Coordinating Centre for Studies in Disability and Rehabilitation (BCCSDR), and ICDR‐Cameroon of the University of Toronto CPGCanada 2015Heart and Stroke Foundation (HSF‐C)/Canadian Stroke Best Practices Advisory Committee CPGCanada 2018Heart and Stroke Foundation (HSF‐C)/Canadian Stroke Best Practices Advisory Committee CPGCPGsclinical practice guidelinesGermany 2013German Nutrition Society (DGEM) German Society for Neurology, German Geriatric Society CPGIreland 2010Irish Heart Foundation CPGPhilippines 2010The Stroke Society of the Philippines CPGPRISMAPreferred Reporting of Items for Systematic ReviewsPWDpeople with dysphagiaTLthickened liquidsScotland 2010 #118Scottish Intercollegiate Network (SIGN) CPG #118Scotland 2010 #119Scottish Intercollegiate Network (SIGN) CPG #119UK 2013National Institute for Clinical Excellence (NICE) CPGUK 2016Royal College of Physicians (RCP) Intercollegiate Stroke Working Party CPGUSA 2010Veterans Association/Department of Defence (VA/DOD) CPGUSA 2016American Heart Association (AHA)/American Stroke Association (ASA) CPG11.1Stroke is a significant cause of oropharyngeal dysphagia which is known to increase the risk of malnutrition, dehydration, aspiration, pneumonia, and mortality.1.2CPGs are “systematically developed statements that assist clinicians to provide appropriate evidence‐based care” (p. 57).Quality CPGs should reflect evidence based practice and thus contain recommendations supported by current research evidence where present. They should also ideally incorporate clinical expertise and patients' perspectives. This triad of evidence may be especially important in cases where the “existing literature is ambiguous or conflicting or where scientific data is lacking or an issue” (p. 6).The evolution of CPGs as sources of reliable clinical information has naturally resulted in research on guideline quality.1.3The purpose of this systematic review and narrative synthesis is to evaluate the evidentiary bases of stroke CPG recommendations regarding the TL intervention.2There are no specific standardized reporting guidelines relating to systematic reviews of CPGs. To this end, relevant sections of the Preferred Reporting of Items for Systematic Reviews (PRISMA) guidelines2.1A search strategy was developed to identify all stroke CPGs that were published between January 2010 and December 2018. For the purposes of this study, stroke CPGs were defined as CPGs focused primarily on the condition of stroke in both acute and chronic phases and which made recommendations for the rehabilitation of the stroke patient. The search strategies were based on the processes recommended by Moher et al Appendix .31 DatCPGs focused on the rehabilitation of stroke populations;General stroke CPGs which are not intervention specific  or discipline specific ;CPGs making recommendations relating to the intervention of TL for the management of dysphagia in adults (>18 years) post‐stroke;CPGs produced between January 2010 and December 2018;Most recent versions of CPGs; andPublished in English.A sample search strategy for Scopus is presented with the main search terms and related terms Appendix . Core seCPGs should be reviewed or updated regularly, ideally within 3 to 5 years.2.22.2.1The methodological quality of the included CPGs was evaluated using The Appraisal of Guidelines for Research and Evaluation Second Edition (AGREE‐II) tool.2.2.2The AGREE‐II does not assess the quality of the CPG content including the evidentiary bases of recommendations. Thus, the extraction and evaluation of TL specific recommendations were performed across a number of domains. These included the specific recommendations, the evidence supporting the recommendations, grading of the evidence based on the Criteria for Levels of Evidence Reported (CLER) in the Canadian Stroke Best Practice Recommendations33.1A total of 2460 documents were initially retrieved from searches. Hand and Google searching retrieved no additional documents. Following removal of duplicates and initial screening of titles and abstracts, 64 documents were considered for full screening. The reviewers independently applied the inclusion criteria to the 64 documents and 13 CPGs were agreed upon for final inclusion  scoring below this threshold on all domains. Four of the included CPGs  scored >70% on all domains. Thus, over half the included CPGs can be considered high‐quality CPGs and nearly a third excellent quality. For all CPGs, the highest scoring domains  were Domain 1: scope and purpose (85%) and Domain 4: clarity of presentation (81.8%). CPGs performing better overall tended to achieve higher scores for all domains including, for example, Domain 2 (stakeholder involvement) and Domain 6 . On the basis of AGREE‐II evaluations, most CPGs would be recommended for use .55.1Guideline developers should make reasonable efforts to employ the best and most recent evidence when making recommendations and CPGs should preface intervention‐specific recommendations with clear summaries of the evidence‐base.Supporting evidence should be specific to the intervention being recommended. Furthermore, explicit links between supporting evidence and individual recommendations should be consistently employed to enable readers to assess the evidence and encourage guideline developers to provide targeted evidence for specific recommendations.Clear directions and easy access to all supporting documentation are required to enable future researchers and policy makers to fully understand the evidence on which recommendations are being made, including caveats to recommendations.A broader range of evidence should be considered in formulating recommendations especially in cases where the intervention evidence is limited. This may include ethical, contextual, and collective patient evidence.Guidelines developers should consider the use of expert panels with intervention‐specific expertise when evaluating evidence and making and reviewing recommendations. Where recommendations are based on such evidence, this should be explicitly stated to ensure readers understand the nature of the evidence supporting that recommendation and can act accordingly.Care should be taken to ensure that traditional clinical practices are not automatically recommended or assumed to be best practice in the absence of supporting evidence.To ensure that publicly available guidelines remain current, processes for updating CPGs need to be explicit and rigorous. For example, UK 2013 CPG authors designed ongoing external peer review elements to their guideline development process. A process for removal or CPGs is also indicated based on the findings of this review.5.2Individuals, teams, and organizations employing CPGs should be aware that CPG recommendations may not be wholly evidence‐based and should review the evidence where possible to ensure recommendations are evidence‐based.Clinicians may benefit from training in CPG critical appraisal in order to be able to evaluate the supporting evidence used by CPGs. Such investments would maximize the applicability of CPGs as well as increase the number of clinicians who may, in the future, contribute to CPG content themselves.6Systematic methods were used to identify, select, appraise, and synthesize the findings from the included CPGs. The PRISMA standardized reporting guidelines were referenced to illustrate the flow of studies in the review. The interdisciplinary review team reflected a mix of academics and clinicians. This is first review to examine the evidence underpinning recommendations in stroke CPGs.Some limitations are evident. Comparatively, this review includes a small sample size. Possible explanations for this include the use of TL as a core term in the search string and the timeframe imposed to maximize retrieval of the most current versions of CPGs. Additionally, although it is advised that CPGs are updated every 3 to 5 years, this was not the case for a number of CPGs in the review. This means that some included CPGs could not reflect up to date evidence. Furthermore, the inclusion criteria did not capture CPGs published by professional speech and language therapy associations which may reflect deeper discipline‐specific knowledge regarding the research evidence and the intervention itself. This may limit the external validity of the findings. Where possible the evidence referred to in “other guidelines” was also extracted. In some cases this was not possible due to guideline age, lack of access to original documentation or being superseded by a subsequent guideline. Some CPGs, such as Germany 2013, may not have been best reflected in this exercise due to lack of accessibility to guideline development documents.7This study examined the evidentiary bases of recommendations for the intervention of TL for PWD post‐stroke. The quality of the 13 stroke CPGs included in this study was generally good, based on tools examining the development of those guidelines. A discrepancy was highlighted between quality rating tools for guidelines and the narrative evaluation of the evidence underpinning guideline recommendations. Despite the limited evidence base for the TL intervention, there was consensus evident among CPGs in recommending it. Furthermore, much of the evidence used to support recommendations was inappropriate, suggesting less than satisfactory evidence‐based practices in formulating recommendations. CPGs may therefore not be the most reliable decision support tools with which to facilitate evidence based clinical decision making and clinicians may be better served by guidelines that target specific interventions rather than broad‐based instruments. Furthermore, if these findings are reflected for other interventions and in other CPGs, questions should be raised about the value and reliability of guidelines generally.The authors declare no conflicts of interest.Data S1. PRISMA checklist. The PRISMA checklist is an evidence‐based minimum set of items for reporting in systematic reviews and meta‐analyses. It uses explicit, systematic methods that are selected to minimize bias, thus providing reliable findings from which conclusions can be drawn and decisions made. The 27 checklist items pertain to the content of a systematic review and Appendix S1 details the completed checklist for this review.Click here for additional data file.Data S2. Main sources searched for CPGs. This table identified the databased employed in the search and included stroke association and guideline websites.Click here for additional data file.Data S3. Search terms. Appendix S3 highlight the search terms employed in this exercise.Click here for additional data file.Data S4 Extraction Framework. This table provides details of the extraction framework which was developed to support the narrative synthesis.Click here for additional data file.


The global severe acute respiratory syndrome coronavirus 2 pandemic strikingly shows the need for rigorous evidence to inform decisions. During such times of crisis, many decisions are made across multiple sectors and trillions of dollars are spent to deal with its consequences that affect all aspects of economic and societal life. Given the scale of human suffering, thoughtfully designing effective policies, and carefully spending scarce resources on interventions that work during crisis management and recovery, become crucial.However, in many areas of decision making, the use of robust and reliable evidence is not the norm. This has dire consequences: evidence from impact evaluations in different sectors show that about 80% of policy interventions are not effective White, . EquallyNow, more than ever, public policy needs to be informed by the most rigorous, comprehensive and up‐to‐date evidence possible. We, at the Campbell Collaboration, are working on both providing this rigorous evidence and promoting its use to inform decisions about social and public policy. Campbell systematic reviews provide a wealth of rigorous evidence to support social and economic response. These reviews highlight what is known and actionable, and point to critical questions decisionmakers need to ask in planning and implementing social and economic responses.Campbell systematic reviews follow carefully structured, peer‐reviewed procedures to produce high‐quality, theory‐based evaluations of social and economic policies and programmes. They address real‐world problems, often in partnership with relevant stakeholders, and seek to answer what works, why and for whom. Our 12 coordinating groups provide broad coverage of social issues, including ageing, business and management, climate solutions, crime and justice, disability, education, international development, knowledge translation and implementation, methods, nutrition and food systems and social welfare. And our international editorial board supervises the process in order to produce rigorous evidence syntheses and strategic partnerships that encourage their timely consideration for policy.Campbell systematic reviews have influenced national policy discussions on over 40 topics. They inform international guidelines and support the design and scaling‐up of dozens of evidence‐based social and economic policies and programmes .6.Initiatives within practitioner and policy communities, such as priority‐setting, webinars and training.The Campbell response to COVID‐19 has included the following six main strategies to date.Campbell Systematic Reviews welcomes registration of new reviews, with a fast‐track editorial process, to inform the global COVID‐19 social and economic response. Our methodological standards protect against bias and potentially misleading findings. Registration with Campbell protects against research waste since titles and protocols are publicly available and searchable.As the world continues to respond to the COVID‐19 crisis, the policy community needs rigorous evidence on options and alternatives. Evidence from Campbell systematic reviews shows what is known on social and economic policies and programmes. Reviews identify the uncertainties to address via policy experiments, pilot tests and trials. And they identify questions to be answered with further evidence synthesis or primary research. Donald Campbell's vision of an Experimenting Society (Campbell,


Female cyclists are prone to a variety of injuries and illnesses that occur as a result of prolonged contact with a bicycle saddle. Saddle sores are a range of skin ailments on the buttocks, genitals and inner thigh that result from a combination of friction, heat, pressure, moisture and bacteria in the saddle area. Whilst saddle sores are reportedly common, for some cyclists, the condition may cause only mild discomfort. However, for female competitive cyclists, the condition can be an ongoing source of pain and illness affecting participation and performance in the sport. Despite many online sources for health information and products for saddle sores, it is unknown what empirical evidence exists for the prevalence and severity of saddle sores, and for the effectiveness of prevention and treatment methods. This paper outlines the protocol for a scoping review, which aims to describe the empirical evidence for the prevalence, prevention and treatment of saddle sores among female competitive cyclists. Ethics approval has been obtained for this study from Curtin University’s Human Research Ethics Committee no: HRE2019-0120. The findings from this study will contribute to the literature for injury in female sport. Female cyclists are known to experience a variety of injuries and illnesses that occur as a result of prolonged contact with a bicycle saddle ,2,3. SadSaddle sores often begin as minor chafing, or as folliculitis, an inflammation of the hair follicle, and can progress into severe skin abrasion, deep skin infection and abscess . Once esHealth information is now widely disseminated online, and anecdotally saddle sores appear to be well documented across mainstream cycling websites and forums . This maDespite a plethora of online health information on saddle sores, there is little known regarding the prevalence and severity of saddle sores among female competitive cyclists, or the effectiveness of popularised methods for prevention and treatment. An understanding of the empirical evidence may assist physicians, allied health practitioners and coaches to better engage with female cyclists. This paper outlines the protocol for a scoping review, which aims to describe the evidence for the prevalence, prevention and treatment of saddle sores among female competitive cyclists.A scoping review is an exploratory study that brings together evidence from disparate sources regardless of the quality. Scoping reviews do not seek to analyse the evidence, but aim to map the types of evidence, the key concepts and the gaps in research within a defined field . The metsaddle sores’ AND cycling AND review. The search revealed a narrative review of the literature for pelvic floor injuries among female cyclists conducted in 2016 [A preliminary search for existing reviews of saddle sores among female cyclists was conducted during November 2018. The databases searched were: ProQuest, CINAHL Plus with full text, PubMed, Scopus and SPORTDiscus with Full Text and Proquest Dissertations using the terms ‘Saddle sores among female competitive cyclists: a scoping review. The review title was constructed using the population, concept, context (PCC) mnemonic, which defines the population , concept (saddle sores) and context .The objective of the review is to map the available evidence and provide an overview of the prevalence, prevention and treatment of saddle sores among female competitive cyclists.The review asks, ‘what evidence is there on the prevalence, prevention and treatment of saddle sores among female competitive cyclists?’ This is the primary question of the review and provides a clear structure for the search process and inclusion criteria.-Is a primary study;-Indicates the prevalence, prevention or treatment of saddle sores;-Includes a female study population who undertake some level of competitive cycling (elite or novice).Evidence will not be constrained by the date of publication or geographical region. Evidence will be included if the source:-Is a secondary review/discussion/opinion of the literature;-Is anecdotal evidence (no research methodology described);-Does not include female study participants;-Study participants are described as non-competitive, recreational cyclists; or-Non-English language material.Evidence will be excluded if the source:A database search for published and unpublished literature including primary studies and opinion articles; andAn advanced Google search for grey literature.The full search strategy will comprise two components:cycling OR cyclist OR bicycle OR bike) AND . These terms are derived from an analysis of keywords from papers retrieved in the preliminary search and are congruent with the review title, objective and research question. They will be used to conduct a full search of five databases (EMBASE (Ovid), Medline (Ovid), PubMed, SCOPUS, SPORTDiscus) in addition to an advanced Google search. A search of ResearchGate ‘projects’ will also be undertaken. The search will be limited to title and abstract, and no date limits. The review search process will be iterative, allowing for the addition of key words and sources of evidence. The reference list of key papers will be used to search for additional citations not found in the first stage of the study selection. Authors of conference papers or abstracts will be contacted should the search fail to retrieve the study’s full-text version. These authors will be contacted twice within a two-week period to allow for inclusion in the review.The initial search terms are  from search results will be examined by two independent reviewers . In the second stage, the full-text articles for studies that are deemed eligible will be extracted for screening by two reviewers  independent of one another. The eligibility of the final selection of studies will be agreed upon by two reviewers . During the final selection process, any differences in the decisions of the two reviewers will be discussed, and a third reviewer (J.E.L.) will be called upon to resolve any disagreements.The selected studies will be charted according to the source, which may include peer-reviewed literature, unpublished literature and grey literature. A charting form will be used to further map the results by the relevant characteristics: author(s); date of publication; country of origin; aims/purpose, study population and sample size; methodology, outcomes/key findings; and the relevance to the three elements from the scoping review question . Data charting will be calibrated by comparing the results of the two reviewers . The third reviewer (J.E.L.) will be called upon to resolve any disagreements in the charting process.The review methods and results will be presented using PRISMA extension for scoping reviews (PRISMA-ScR) by . This chn = 30), including physiotherapists, competitive cycling coaches, gynaecologists and sports doctors. This stage aims to validate the findings of the scoping study and may also result in additional insights being included in the review and guide recommendations for future research [A consultation exercise will be conducted via an online survey with relevant stakeholders from the Australian cycling community (up to research ,18. A puresearch . Human eThis scoping review seeks to increase understanding of what evidence there is, the main sources of information and the gaps in research in this area. The results may inform further research into saddle sores and the effectiveness of prevention and treatment interventions to guide evidence-based recommendations for female cyclists.


Human activities and anthropogenic environmental changes are having a profound effect on biodiversity and the sustainability and health of many populations and species of wild mammals. There has been less attention devoted to the impact of human activities on the welfare of individual wild mammals, although ethical reasoning suggests that the welfare of an individual is important regardless of species abundance or population health. There is growing interest in developing methodologies and frameworks that could be used to obtain an overview of anthropogenic threats to animal welfare. This paper shows the steps taken to develop a functional welfare assessment tool for wild cetaceans (WATWC) via an iterative process involving input from a wide range of experts and stakeholders. Animal welfare is a multidimensional concept, and the WATWC presented made use of the Five Domains model of animal welfare to ensure that all areas of potential welfare impact were considered. A pilot version of the tool was tested and then refined to improve functionality. We demonstrated that the refined version of the WATWC was useful to assess real-world impacts of human activity on Southern Resident killer whales. There was close within-scenario agreement between assessors as well as between-scenario differentiation of overall welfare impact. The current article discusses the challenges raised by assessing welfare in scenarios where objective data on cetacean behavioral and physiological responses are sparse and proposes that the WATWC approach has value in identifying important information gaps and in contributing to policy decisions relating to human impacts on whales, dolphins, and porpoises. Many scientists and researchers are also now arguing for the development of a compassionate or welfare-inclusive approach to conservation . Conservation has also been the focus of extensive research effort. Some human activities can separately or additionally cause great harm to the welfare of individual wild animals , 2. Howeervation –7.The establishment of a new discipline, “Conservation Welfare,” has been suggested to integrate the perceived competing schools of thought of conservation scientists who generally emphasize “fitness” and welfare scientists who generally emphasize “feelings” . There aentanglement in fishing gear, with others trapped in other forms of marine debris  provides a particularly strong demonstration of this point. Tremendous multinational efforts have been expended in the past 75 years to conserve cetacean species and regulate whaling activities, including the establishment of the International Whaling Commission (IWC) in 1946. The IWC aims to conserve species and regulate whaling activities, and the experts and delegates who attend IWC meetings have amassed a wealth of information on cetacean population numbers and trends, and increasingly they seek to work alongside other scientists to address the full range of human activities that threaten cetacean populations . A recenealth IWC. The lonealth IWC. In addiealth IWC, 16 and ealth IWC, 18 joina large pool of independent scientists would study animal welfare issues in conservation and report on every industry and context that affects animals”  provide advice on all aspects associated with “ivities” . This privities” , which tThe workshop explored the concept of animal welfare arising from the utilitarian arguments of Bentham and others who were primarily concerned with the question of the capacity for suffering in animals . As sociThe workshop recognized that the factors that influence animal welfare are multidimensional, as reflected by the Five Freedoms concept . VersionThe FDM had been applied to assess welfare in other contexts, including wildlife population control e.g., , 28] but but28)] The workshop explored the contexts in which there may be an ethical responsibility for cetacean welfare. For example, a reduction in the availability of food may be due to a period of natural scarcity or to the activities of humans. The negative effect on the animal will be the same regardless of the cause, but there are differences between the two cases. An assessment of animal welfare will indicate the need for an improved diet, but the ethical imperative to provide additional food differs depending on causation. Similarly, the moral imperative for humans to intervene differs if a dolphin is injured in a fight with a shark or by a ship's propeller. The workshop agreed that it is a human responsibility to reduce anthropogenic welfare threats but not a responsibility to attempt to provide welfare enhancements or to attempt to deliver positive welfare. The workshop recognized also that conservation decisions made under such circumstances will employ yet another set of principles, and intervention may be decided not on animal welfare grounds but on factors such as the endangered status of the animal or its genetic value to its population.The workshop participants selected four of the current non-hunting threats to free-living cetacean welfare mentioned above, namely, whale watching, ship strike, entanglement in fishing gear, and marine contaminants. These are of concern to the IWC and were selected because of the potential to include welfare considerations in the development of mitigation policies in these areas. Four independent focus groups were formed, and each evaluated one threat. Each focus group made further decisions about what scenarios to consider following free discussion. There was no systematic attempt to select scenarios, and the decisions would have been influenced by the prior knowledge and experience of the participants. Stranding was not evaluated because developing policy in this area is more difficult, and work in this area is currently focused on developing appropriate emergency responses.The IWC has declared that “there is compelling evidence that the fitness of individual odontocetes repeatedly exposed to commercial whale-watching vessel traffic can be compromised and that this can lead to population-level effects” . An overFollowing free discussion, this group decided to consider four hypothetical case scenarios of cetaceans being struck by ships where the model could be applied: a large whale hit by a large vessel ; a smalThis group decided to consider entanglement in actively used fishing gear  or in dThe group explored three hypothetical case scenarios involving polychlorinated biphenyls (PCBs): pilot whales in the Mediterranean with moderate exposure and killer whales in the Mediterranean with high exposure, as well as an oil spill in the Gulf of Mexico affecting a bottlenose dolphin. Discussion focused around welfare impacts of bioaccumulation on immunosuppression and reproductive suppression including increased abortions and mortality of live-born calves. It was noted that impacts on some domains were secondary or interactive, for example, once an animal becomes diseased (as a result of immunosuppression), then nutrition and behavior may be affected by lack of ability or motivation. Impacts considered in one scenario included a case of calf mortality as a result of toxicity from high levels of PCBs in milk. In this scenario, it was noted that a measure of the welfare status of a female could improve following off-load of PCB burden to her calf (which can be up to 90%) but could also decrease due to a grieving response , 41. ForEach category of threat was considered in detail by a focus group that developed hypothetical scenarios and applied the FDM to its cases, using a 4-point grading scale  for each domain. Focus groups commented informally on their confidence in each evaluation. The groups concluded that the FDM had performed fairly well but identified challenges including the level of detail required to produce appropriate scenarios for consideration. Each group found that the FDM could be applied only where context-specific cases were considered and that it was not useful to assess very general questions. Groups identified the lack of data or knowledge in certain areas (particularly difficulties in extrapolating from single point observations of adverse events) as key constraints for the assessment of welfare of free-living cetaceans. There was no consensus on the grading scheme or how to assess welfare over time, and data on cumulative indicators of stress are scarce. A model developed by Wolfensohn et al.  to captuA 1-day workshop attended by seven participants was held in London in 2018 to consider some of the challenges identified at Kruger. This workshop led to the development of the following operational principles to support the WATWC.Any WATWC should be considered in relation to preexisting frameworks for assessing risks to animal health and welfare . The majProblem formulation is a key issue to be addressed before the FDM can be applied. Problem formulation can start from a consideration of hazards  or from a consideration of outcome measures taken on animals . From a policy perspective, and due to a lack of existing data and difficulties in collecting direct cetacean outcome measures, a hazard-based problem formulation  providesInformation should be provided to assessors on likely levels of exposure, for example, about whether a risk factor (such as a particular type of net) is present all the time or during certain periods only, and the chances that an individual animal in the vicinity would encounter the risk factor. Where data are available, they should be used, otherwise, expert opinion should be sought. If reliable estimates are available, we propose that the number of animals affected should be highlighted in any final report or recommendation. This does not form part of consequence characterization but will be useful in policy decisions.tissue injury stimulates nociceptors to propagate neural impulses to the brain where they may be transduced into the experience of pain” , it is less focused on principles or concerns that relate to captive animals . It also differs from other frameworks by its clear separation of objective  domains 1–4 and subjective (inferred “affective state”) domain 5 while showing how internal physiological and external environmental factors may generate functional affective states. For example, “of pain” . Becauseof pain” ], one ofof pain” . Consideof pain”  or againof pain”  or behavof pain” ] when anThe FDM itself makes no binding recommendations on specific measures, scales, confidence, and aggregation procedures for consequence characterization [although certain operational proposals were suggested by ]. We recZiphius cavirostris) and three concerning the impact of tourism and whale-watching activities on the bottlenose dolphin (Tursiops truncates). Each scenario was accompanied by a fact sheet that provided background information on relevant aspects of cetacean biology, health, and behavior; data about biological effects of the threats; and further reading. Areas of sparse knowledge were highlighted, and care was taken to avoid any leading comments on severity of impact or overall cetacean welfare.Following the operational decisions, we developed six hypothetical demonstration scenarios, three concerning the ingestion of marine debris by Cuvier's beaked whales . They had post-doctoral experience in animal welfare science, previous experience of using the FDM in other contexts, or both. None of the assessors had specific marine mammal expertise, but the primary aim here was to pilot test the scoring framework. We developed an appropriate scoresheet that required scoring the maximum intensity  of harmful impact within Domains 1 to 4 and judgment of the overall harm from the specific event affecting each individual cetacean within the Domain 5 affective state category. The assessors were asked to express confidence in their own scoring using a categorical scale; to score the duration of persistent harm following the specific event; to judge how often similar events would occur; and to assess therefore the overall proportion of life span affected by mild, moderate, or severe harm due to total events of this nature, using categorical scales provided.All assessors returned the completed scoresheets within 2 weeks, independently and without conferring. There was relatively high variation between assessors in the scores provided, and the assessors expressed limited confidence in their own scoring. This was particularly the case for Domain 5 scores where between five and six assessors expressed low confidence around each scenario, and one assessor declined to complete the estimates of life span affected by harm for this reason. Despite this, the assessors found the pilot WATWC easy to use and appropriate in guiding their thinking. The cetacean-specific FDM was considered a useful reference. The assessors felt that reduced general background and more focused information for each scenario would be an improvement. Some minor problems with the scoring sheet and scales were identified, including a lack of clarity about when assessors should consider Domain 5 scores, a lack of a 0% option on the drop-down menu for some scoring options, and a lack of clarity about whether the life span estimates of mild–moderate and moderate–severe harm should sum to 100% . It was also felt that there should be an increased number of categories of life span harm. The assessors liked the 10-point grading scale, which appeared to enable discrimination of impacts without leading to false precision. The feedback from this pilot testing influenced the subsequent format of case presentation and the operational details of the scoring spreadsheet used in the next phase.Orcinus orca) population living off the west coast of USA and Canada, which is subject to intense whale-watching pressure, and where relevant data are available.The pilot WATWC and results from the pilot scoring exercise were presented at a plenary session of the IWC Scientific Committee meeting, Bled, Slovenia, April 2018, and to the Whale Watching Sub-Committee at the same meeting. The committees were asked for assistance in identifying real scenarios for future welfare scoring. The Whale Watching Sub-Committee suggested the Southern Resident killer whale . Care was taken to avoid any leading or suggestive information  while providing pertinent scientific data on the general context, whale biology, and available data on Southern Resident killer whale behavior in the presence of vessel traffic. Two cases for scoring were drafted for a hypothetical pod X based on the data available. Based on feedback from the pilot exercise, the two cases focused on specific individual animals. The two cases  presenteAll assessors completed the assessment independently and without conferring and returned their scores within a period of 8 weeks. The results of the severity scores for Cases 1 and 2 are shown in When scoring the proportion of life span affected, a different assessor  considered a high proportion of life span to be unaffected by harm, being out of step with all other assessors  and air  so that sound pressure levels in air are not the same as sound pressure levels in water.Overall, the feedback received from assessors was that the WATWC had been clear and straightforward to use, but that significant challenges in assessing welfare impacts are raised by scenarios where data on cetacean health and behavioral responses are sparse.Phocoena phocoena)  . Asking Animal affective states have dimensional aspects  that can be studied using preference or motivational tests , 51. AniThe scoring system for our WATWC was relatively simple, and it was greatly improved between the pilot and refined version. A higher level of assessor confidence was achieved when using the refined WATWC, although this may have arisen for multiple reasons, including more detailed case scenarios, the inclusion of real data in the background information, and the greater (average) expertise level of the assessors. Assessor confidence is not a gold standard measure of animal welfare (assessors can be wrong) but, where reliance is placed on expert judgment, it is important. In addition to high confidence, high agreement between assessors was obtained when using the refined WATWC, despite assessors scoring independently. This contrasts with problems that have arisen in other expert elicitation work with cetaceans, leading to uncertain forecasts . ImportaWe note two areas where further consideration of operational aspects of the WATWC might be useful. First, it could be helpful to specify an acceptable level of assessor confidence. Second, it could be beneficial to give more thought to the number and independence of the factors listed within each domain . In deveOur proposals to progress this work are presented in a flowchart in The WATWC could be used next in a variety of ways. It could be used to evaluate scenarios similar to those addressed for the Southern Resident killer whales, for example, to assess the impact of human activities on Hawaii island spinner dolphins which experience the highest exposure rates to dolphin watching in the world  so as toThe datasets generated for this study are available on request to the corresponding author.All authors have made a substantial, direct, and intellectual contribution to the work. LB, CJ, CN, MS, and JV participated in the Kruger workshop that initiated the process. LG, LK, CN, and MS participated in the London workshop that considered operational principles. CN, DN, and MS attended the IWC Scientific Committee meeting. CN, DN, and MS devised test scenarios and background information, and CN compiled and analyzed assessor scores. All authors participated in article preparation and writing and approved it for publication.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.