Currently, the adaptation of scientific evidence in clinical problem solving is based on the evidence-based medicine method. Medical students and health professionals should have an adequate knowledge of this method and thus provide adequate health care and increasingly provide high quality scientific publications that can be subsequently integrated in different clinical scenarios. Several scales and tools have been proposed as guides to recognize the different levels of quality of the available evidence, their degrees of recommendation and the biases and fallacies that may occur both in the clinical and research areas, with the aim of identifying the best available evidence. However, few students and professionals are aware of them and make proper use of them. Therefore, it is necessary to synthesize these tools in an understandable and practical way. •The student's knowledge and use of medical evidence is indispensable.•It is necessary to train the medical student in scientific publication.•The medical student must recognize biases and levels of evidence. This apThe medical student is an actor that in the last decade has gained great relevance in this process, since it participates more and more actively in the creation of evidence through scientific research from medical schools, contributes to the design of strategies for the improvement of medical education, cooperates with the dissemination of scientific knowledge in events of social appropriation and circulation of new knowledge, and has become more critical regarding the outcomes of global health . This haAlthough there are studies that have demonstrated the substantial and positive impact of medical research and scientific publication during undergraduate medical school on the professional career , there iBased on the above, the objective of this review is to design a practical guide for the use of evidence in scientific publication for medical students, to serve as a basis for their training and practice in research and scientific publication in medicine.2A non-systematic literature search was carried out in the PubMed and Scopus databases, using the keywords “medical evidence”, “scientific publication”, “medical student”, “evidence-based medicine”, and synonyms, which were combined with the Boolean operators AND and OR. The search was performed until July 2021. Clinical trials, original studies, reviews, commentaries and letters to the editor were included. The only exclusion criterion was the unavailability of the full text. Finally, 48 articles were included. Additionally, a reverse search was performed, finding 16 articles, finally using 64 references.2.1The term “evidence-based medicine” emerged in the early 1990s through a campaign proposed by a movement formed by a group of epidemiologists from McMaster University in Canada, known as the “evidence-based medicine movement” ,26. The This process allowed the birth of scales to assess study biases and determine how valid the results were within the study design , and how feasible it is to extrapolate those results to the general population  . It alloHowever, in order to adopt this approach in the context of medical practice, a series of steps must always be followed: The first is to establish a clinical question; subsequently the best existing evidence about it must be sought; then it is required to assess the results according to their level of evidence; apply them in practice according to the clinical judgment of the health professional, and finally re-evaluate the performance of the entire process . Steps i2.2It can be said that the scales of evidence-based medicine are the first tool that the student should know. This will allow them to obtain updated and quality information from the study of their academic content in basic sciences, to the analysis of decision-making algorithms and therapeutic decisions during their clinical practice. This is because not all studies have the same weight to support a good recommendation in the clinic . Current2.2.1This classification system is based on evaluating the evidence according to the different clinical scenarios and types of studies . Because, with level 1 corresponding to the best available evidence, and level 5 to the lowest quality . Al. Al40]. 2.4.1The presence of biases significantly reduces the certainty and significance of the results obtained by the studies and given to the recommendations, therefore, they do not guarantee the effect of an intervention and must be recognized in order to avoid errors in clinical practice. In this order of ideas, it is important to reinforce knowledge about biases in medical students and health professionals in order to improve medical care and to critically review the available scientific evidence . To this2.5It is difficult to define the term “fallacy” in a unified definition, since over time many concepts have been attributed to it. However, it basically refers to an argument that seeks to persuade or defend what is false; in other words, it is a lie, a deception or an invalid reasoning . Fallaci2.6Several studies have shown that those medical students who research and publish before graduation tend to continue publishing after graduation and even publish much more than those who begin their research involvement as physicians . BecauseDespite the enormous importance of scientific skills, the number of student researchers is very low, mainly due to the lack of scientific training and incentives in their faculties , added tOn the other hand, there is the “scientific racism” of scientific journals, where some of them undervalue the work done by the medical student, and in order to maintain a high impact factor and h-index, they prefer to accept manuscripts written by recognized professionals with high metric indicators, regardless of the research value of the other manuscripts received . In addi2.7Knowing the levels of evidence, biases, fallacies, quality of information and the relevance of training as a research-based physician, the basic scientific writing process also allows to recognize errors during the process of creating and publishing a scientific article. Some of the recommendations to take into account when carrying out a scientific publication is that during the literature search, references should be as recent as possible and obtained from databases such as PubMed, MEDLINE, Scopus, Web of Science (WoS), Science Citation Index (SCI), or Scielo (for Latin America and the Caribbean), which have metrics that guarantee less bias in the publication of articles in indexed journals . The acrThe title of the article should be neither too short nor too long, ideally a concise and complete title, easy to read and characterizing all the information provided in the article, to arouse the reader's interest . The absOn the other hand, in the results section, the key findings of the study are presented, one by one, in an objective manner, using tools such as graphs or tables . FinallyIt is necessary to always keep in mind that the process of scientific writing is a road full of obstacles, where many times you will fall and will not be able to express your ideas in the best way. However, the more you travel this road and learn to use technical language, to interpret evidence, to collect and understand estimates, among other items, the easier the road will be to overcome. The medical student may be discouraged at the beginning of this journey, but should remember that at the end of the road, there is a priceless treasure, the knowledge and expertise to use evidence to their advantage, and it is the key that can guarantee good final results as a professional.2.8One of the main goals of evidence-based medicine is the stimulation or early motivation of medical students in the field of research by the different academic entities, based on a formal scientific education, where students participate actively, in order to achieve a real commitment on the part of these students . There aA fundamental strategy to achieve this objective is the collective establishment of interest groups , active In this order of ideas, one of the main objectives would be the design of a mixed curriculum that includes a strong component of scientific research for medical students, which facilitates their approach to scientific evidence. There is a need for universities to liaise with student societies and to encourage students who stand out for their commitment to evidence-based medicine, and to recognize the value of evidence-based medicine in the academic community. Financial support, infrastructure, academic content and teaching support during the design and maintenance of interest groups and solid research projects with significant results are a priority to improve the indicators of disease burden, health education and a good cost-intervention balance in the near future.3Scientific research is an indispensable tool for medical students and health personnel in general, since it favors the development of skills and competencies for decision making in clinical practice based on a critical assessment of the available evidence, in order to respond effectively to the needs of patients. Recognition of biases, fallacies, and the advantages and disadvantages of undergraduate research are aspects to consider during the training and design of strategies in evidence-based medicine education and medical research. Evidence is not an absolute, but it is the best tool we have in our hands today.It is not necessary.None.All authors equally contributed to the analysis and writing of the manuscript.Name of the registry: Not applicable.Unique Identifying number or registration ID: Not applicable.Hyperlink to your specific registration (must be publicly accessible and will be checked): Not applicable.Sabrina Rahman. Independent University, Dhaka, Bangladesh.None.


Plasmodium vivax. The mechanisms underlying this intense tropism are not clear. We hypothesised that immature reticulocytes, in which P. vivax develops, may display high densities in the spleen, thereby providing a niche for parasite survival.A very large biomass of intact asexual-stage malaria parasites accumulates in the spleen of asymptomatic human individuals infected with P. vivax and Plasmodium falciparum undergoing splenectomy for any clinical indication in malaria-endemic Papua, Indonesia (2015 to 2017). Infection, parasite and immature reticulocyte density, and splenic distribution were analysed by optical microscopy, flow cytometry, and molecular assays. Nine non-endemic control spleens from individuals undergoing spleno-pancreatectomy in France (2017 to 2020) were also examined for reticulocyte densities. There were no exclusion criteria or sample size considerations in both patient cohorts for this demanding approach.We examined spleen tissue in 22 mostly untreated individuals naturally exposed to Plasmodium infection . Significant splenic accumulation of immature CD71 intermediate- and high-expressing reticulocytes was seen, with concentrations 11 times greater than in peripheral blood. Accordingly, in France, reticulocyte concentrations in the splenic effluent were higher than in peripheral blood. Greater rigidity of reticulocytes in splenic than in peripheral blood, and their higher densities in splenic cords both suggest a mechanical retention process. Asexual-stage P. vivax-infected erythrocytes of all developmental stages accumulated in the spleen, with non-phagocytosed parasite densities 3,590 times  higher than in circulating blood, and median total splenic parasite loads 81 (IQR: 14 to 205) times greater, accounting for 98.7% (IQR: 95.1% to 98.9%) of the estimated total-body P. vivax biomass. More reticulocytes were in contact with sinus lumen endothelial cells in P. vivax- than in P. falciparum-infected spleens. Histological analyses revealed 96% of P. vivax rings/trophozoites and 46% of schizonts colocalised with 92% of immature reticulocytes in the cords and sinus lumens of the red pulp. Larger splenic cohort studies and similar investigations in untreated symptomatic malaria are warranted.In Indonesia, 95.5% (21/22) of splenectomy patients had asymptomatic splenic + reticulocytes and splenic P. vivax-infected erythrocytes of all asexual stages accumulate in the same splenic compartments, suggesting the existence of a cryptic endosplenic lifecycle in chronic P. vivax infection. Findings provide insight into P. vivax-specific adaptions that have evolved to maximise survival and replication in the spleen.Immature CD71 Dr. Anstey and co-authors found that P. vivax-infected immature reticulocytes and erythrocytes accumulate in the same splenic compartments, suggesting existence of a cryptic endosplenic lifecycle in chronic P. vivax infection that maximizes survival and replication in the spleen. Plasmodium vivax parasites in the spleen of people living in malaria endemic areas, greater than with Plasmodium falciparum.There is a surprisingly large biomass of intact P. vivax accumulates so intensely in the spleen is not known.Why P. vivax requires very young red cells (immature reticulocytes) for invasion and replication.P. vivax and immature reticulocytes were evaluated in spleens from people undergoing splenectomy in malaria-endemic Papua.The accumulation of P. vivax parasites and immature reticulocytes accumulated in the same splenic compartments.P. vivax accumulated in the spleen at magnitudes unexplainable by replication occurring in the circulation alone, with the proportion of each stage in the spleen consistent with the duration in their lifecycle.All stages of P. vivax lifecycle can take place in the spleen in chronic malaria.Taking advantage of the large physiological splenic reservoir of immature reticulocytes, the majority of the Chronic vivax malaria should be considered predominantly an infection of the reticulocyte-rich spleen, with secondary involvement of the intravascular compartment.The spleen is not solely a compartment for parasite destruction and clearance.P. vivax survival in the spleen.Specific adaptations have likely evolved to maximise  Plasmodium falciparum (Pf) and Plasmodium vivax (Pv), affects 228 million people with over 400,000 deaths each year /histidine-rich protein-2 [HRP2]) Combo RDT as per manufacturer’s instructions . Giemsa-stained slides of peripheral blood and sliced-spleen blood were examined by 2 expert microscopists for the presence of Plasmodium-infected erythrocytes as previously described ) compared to circulating peripheral blood  ), followed by a small intravascular component  where Pv transmission stages are accessible to the vector.Splenic and peripheral parasite biomasses were estimated based on spleen weight and total blood volume, respectively (see  = 0.10) . Our conFig 3C). Total biomass ratios in these compartments indicated that splenic asexual Pv biomass was a median 81 times (IQR: 14 to 205) higher than circulating in peripheral blood, while the median spleen-to-circulating peripheral blood biomass ratio in Pf was 12 . Although such ratios do not include Pf-IEs sequestered within non-splenic blood vessels, approximately 10-fold higher ratios observed in Pv suggest greater splenic tropism with infection by this species.We have previously reported  that splPlasmodium to grow ex vivo was examined by relative changes in asexual stage frequency in concordance with the known parasite lifecycles. Growth of splenic parasites was observed in 8 of 12 Pf-infected individuals (S1 Table), in line with previous findings , 11 times higher than the median in matching peripheral blood by flow cytometry . To provide insight into potential mechanisms of splenic accumulation, a microsphiltration assay was used to examine reticulocyte deformability. Reticulocytes in the spleen and post-splenectomy peripheral blood were found to be more rigid compared to those in peripheral blood on the day of splenectomy . Here, normalised immature CD71+ reticulocyte counts determined by flow cytometry  were significantly higher in fractions representing splenic content in comparison to peripheral blood . In 4 of the spleens where examination of CD71 subpopulations was performed, an enrichment of CD71-negative, low-, intermediate-, and high-expressing reticulocytes was clearly apparent in splenic effluents compared to peripheral blood .To confirm that the splenic reticulocyte reservoir was not only restricted to infected spleens, reticulocytes were examined in uninfected control spleens by ex vivo flushing from 9 patients undergoing elective spleno-pancreatectomy in France . Immature CD71+ reticulocytes accumulated in all splenic compartments compared to peripheral blood and were expectedly more concentrated in each of the compartments than any of the Plasmodium stages . These cells predominated in the red-pulp cords and sinus lumens in Pv-infected spleens .The locations of non-phagocytosed IE stages and immature CD71Fig 5A). Overall, a median of 73% of Pv rings/trophozoites were observed in the cords and 20% were in the sinus lumens . As such nearly all splenic Pv rings/trophozoites (93%) colocalised in the red-pulp with immature CD71+ reticulocytes (88% of which were in the red pulp cords and sinus lumens). Pv schizonts in the spleen were found at lower densities and were absent in peripheral blood . Their distribution varied widely with medians of 54% in the red-pulp cords and 46% in the PFZ . The PFZ was the only compartment found to contain the very few Pv gametocytes that were observed in the spleen of a single individual .In Pv infection, rings/trophozoites predominated over other Pv stages in each of the splenic compartments . Closer examination of infected CD71-stained spleen sections uncovered a considerable proportion of immature CD71+ reticulocytes that were in close contact with and apparently adherent to endothelial cells lining the luminal side of the sinuses . Counting of apparently adherent versus non-adherent reticulocytes in these spaces indicated that a significantly higher proportion of immature CD71+ reticulocytes in the red-pulp were apparently adherent in the sinus lumens of Pv-infected spleens (p = 0.02), while proportions of adherent and non-adherent sinus lumen reticulocytes in Pf were generally similar . Ratios of adherent-to-non-adherent immature CD71+ reticulocytes showed twice as many apparently adherent cells in Pv (IQR: 1.2 to 4.0), significantly higher than the 1:1 ratio in Pf .The opportunity to histologically evaluate an uninfected spleen in our Papuan cohort revealed an apparent enrichment of immature CD71+ reticulocytes in the splenic red-pulp in asymptomatic Pv infections is strongly suggestive of an endosplenic asexual lifecycle, of greater magnitude in Pv. The greater proportion of immature CD71+ reticulocytes apparently adhering in the sinus lumen in Pv may reflect an additional population of target cells for invasion, statically located in the direct path of merozoites released from rupturing Pv schizonts upstream in the cords and PFZ. Differences in the splenic compartmentalization and numbers of schizonts and gametocytes between Pv and Pf may reflect different pathophysiological mechanisms contributing to their splenic retention and modes of pathogenesis/transmission.Taken together, the accumulation and colocalization of all asexual-stage malaria parasites and immature CD71Plasmodium contains a substantial hidden biomass of intact IEs, with densities hundreds to thousands of times higher than in circulating peripheral blood [+ reticulocytes and asexual-stage Pv were concentrated and colocalised predominantly in the splenic red-pulp, consistent with a role for the human spleen in both reticulocyte maturation and Pv growth and replication. The distinct distribution of schizonts and greater adherence of sinus lumen reticulocytes in Pv-infected spleens, are consistent with recently described spleen-specific Pv cytoadherence [The swollen spleen of nonfebrile humans exposed to al blood . Expandidherence ,68, and Our findings indicate an intrasplenic Pv pool 80-fold greater than the whole parasite population in circulation. This substantial difference cannot be explained numerically by parasite replication events in the circulation alone, with our deductive calculations (outlined in the Results) indicating that splenic retention of 90% of Pv-IEs from circulation would achieve an intrasplenic parasitaemia of 0.03%, 40 times lower than what we observed in our cohort. Even adding a parasite multiplication rate in peripheral blood of 10 to the calculation, the resulting intrasplenic Pv parasitaemia is still 4-fold lower than observed in vivo. Of note, this assumed multiplication rate of 10 is likely an overestimate in light of our observation that a proportion of retained Pv-IEs are phagocytosed. A cryptic asexual Pv lifecycle outside the peripheral blood is therefore by far the most robust explanation of our observations.+ reticulocytes accumulate in the spleen. Further non-histological studies are warranted to confirm the apparent adherence of reticulocytes in the sinus lumen. Our observations in uninfected controls also suggest that the human spleen is a natural physiological niche for maturation of immature reticulocytes. Human erythropoiesis occurs physiologically in the bone marrow but in contrast to murine models [Previous studies in animals –37 and he models ,70, is ee models ,72. WhetApart from the increased rigidity of late/segmenting Pv schizonts   relative to rings/trophozoites (85% to 100%) in Pv-infected spleens is in line with their short duration in the Pv lifecycle (2.4 to 6 hours), with schizonts estimated to represent 5% to 12% of the 48-hour Pv lifecycle [Plasmodium development, with its dense population of immature reticulocytes especially favourable for Pv [Our findings on the splenic accumulation and colocalization of different asexual stages of Pv and immature CD71ifecycle ,65. Secoe for Pv ,31. Thate for Pv  is specuThirdly, we speculate that the schizonts located in the fast-circulation PFZ may serve as a second source of merozoites to invade both adherent and non-adherent immature reticulocytes that accumulate downstream in the sinus lumens. A lower chance of closely interacting with immune cells is an advantage of being in these compartments compared to the cords, but with a faster flow rate similar to peripheral circulation, it is possible that invasion events are less likely to be successful in these spaces despite an equal number of immature reticulocytes being available as the cords. This would be supported by the disproportionally large number of early asexual stages, representing successfully invaded reticulocytes, in the cords (73%) compared to sinus lumens (20%). Reticulocytes infected in the sinus lumens will eventually exit the spleen and circulate. We therefore hypothesise that maintaining a presence in the fast circulation of the spleen may partly be an adaption to maintain transmission, whereby a proportion of invaded reticulocytes are destined to circulate as gametocytes. Presence in compartments of the fast circulation may also allow Pv to survive during periods of immune activation or destabilised tolerance in the splenic cords. In settings such as acute infection, where the immunotolerant conditions reflected in our cohort is not yet acquired or has been lost, a greater proportion of Pv circulate. While these hypotheses remain speculative, our findings to date are consistent with Pv having evolved multiple mechanisms to maximise their survival and replication in the spleen.+ reticulocytes [Reports in humans –22 and fulocytes , and knoulocytes ,78,79, iulocytes  suggest ulocytes  which maPlasmodium is developed in the cords of the spleen, induced by sustained high antigen loads. This is evidenced by a large number of pigmented phagocytes and non-phagocytosed IEs in our cohort. We speculate that, in addition to phagocytosis of active parasites, a proportion of the pigment engulfed by phagocytes may come from rupturing schizonts [Plasmodium infection and direct in vivo evidence for the long-hypothesised clearance of untreated parasites. These data complement previous observations on the central role of the spleen in clearing parasites following treatment with antimalarials [With the entire intraerythrocytic asexual Pv lifecycle likely taking place predominantly in the spleen, our study provides a new framework to explore innate and adaptive immune responses to Pv and Pf. Human studies on the role of the spleen in malaria immunity are urgently needed to inform vaccine development. We hypothesise that immunotolerance to chizonts  and may chizonts . Neverthalarials , postmoralarials ,25,27, talarials  and untralarials ,59 IEs sOur study has several limitations. We report parasitaemia findings in semi-immune individuals with chronic asymptomatic infection, the majority with enlarged spleens. Our study also had a small sample size. These limit the interpretation and generalizability of our findings and warrant larger studies including in acute symptomatic malaria. Splenic trauma or rupture are rare during clinical malaria and performing splenic studies in untreated clinical disease may require indirect, noninvasive evaluation. Recent positron emission tomography and magnetic resonance imaging in experimental human volunteer infection studies indicate greater splenic tropism and metabolic activity in early Pv infection compared to Pf , suggest+ reticulocytes, both colocalised in splenic environments where invasion-reinvasion events would form a cryptic endosplenic lifecycle. Like Pf, quantifying circulating parasitaemia alone will significantly underestimate total-body Pv biomass in asymptomatic infections. This hidden biomass is likely a significant contributor to anaemia and challenges the assumptions underlying prevailing mathematical models of malarial anaemia derived from circulating parasitaemia and the proportions of uninfected-to-infected RBCs lost in chronic infections from both Plasmodium species [In conclusion, our findings provide a major contribution to the understanding of malaria biology and pathology. The spleen sustains a very large biomass of non-phagocytosed asexual Pv parasites, concurrent with the increased availability of immature CD71 species ,85, partS1 Fign = 6 Giemsa-stained spleens were read by 2 expert microscopists to validate non-phagocytosed IE counts, including the ability to distinguish into the different splenic architectural zones and parasite stages (d). Each reader examined spleen sections from different spleen biopsies in the same patient. IE, infected erythrocyte; RBC, red blood cell.Each spleen was weighed and recorded to nearest gram (a), then sliced in half using sterile disposal blades (b). One half of the spleen was sliced longitudinally (c) and used for downstream experiments, while the second half was processed into paraffinised spleen tissue blocks. A subset of (TIF)Click here for additional data file.S2 Fig+ reticulocytes (retics) in P. falciparum- and P. vivax-infected spleens were stained by immunohistochemistry with antibodies against the CD71 transferrin receptor; additional examples of retics are shown (c). A 3-colour flow cytometry stain was used to quantitate retics in SW obtained from the flushing of normal spleens in France, identified as CD45−thiazole-orange+ cells, with or without CD71 expression (d). A 3-colour flow cytometry panel was used to phenotype retics in the Indonesian cohort, identified as CD45−SYTO61+ cells with or without CD71 (e). Numbers per thousand RBCs were determined for total, immature CD71+ and mature CD71− retics in PB and sliced SB samples . Bars represent medians. FS, forward scatter; PB, peripheral blood; RBC, red blood cell; SB, spleen blood; SW, spleen wash; TO, thiazole-orange.Heated and normal RBCs were used for quality control of microsphere tips and gated as shown (a). Retention rates (mean ± standard error) of >95% and <5% for heated and normal RBCs, respectively, satisfied minimum requirements (b). Immature CD71(TIF)Click here for additional data file.S3 FigEach patient’s spleen was photographed for macroscopic records. Images not available for patient #13. Spleen weights presented in grams.(PDF)Click here for additional data file.S4 FigP. vivax-  and P. falciparum-infected spleens  showing non-phagocytosed IEs (red arrowhead), pigmented phagocytes (green arrowheads) in the cords and sinus lumen. Giemsa-stained sections from the ex vivo perfused spleen (P. vivax-infected spleen sections showing merozoites/mature stages staining red (d). IE, infected erythrocyte; PvAMA1, Pv apical membrane antigen-1; RP, red-pulp; sl, sinus lumen; WP, white-pulp.Representative images of Giemsa-stained spleen sections from d spleen  were rea(TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.


A case study describes application of the procedural and CR decision model in a complex homicide case. The model demonstrates the power and efficacy of the application of SPJ to forensic decision-making and is relevant to other types of forensic assessment .Forensic psychologists commonly utilize unstructured clinical judgment in aggregating clinical and forensic information in forming opinions. Unstructured clinical judgment is prone to evaluator bias and suboptimal levels of inter-rater reliability. This article proposes Structured Professional Judgment (SPJ) methods as a potential remedy. Following a review of canonical forensic assessment models, the prevalence of bias in forensic judgments, and inter-rater agreement in criminal responsibility (CR) determinations, this article presents a SPJ model for CR evaluations translated from violence risk assessment methodology. A systematic user-friendly methodology is described, applying procedural checklists, application of a mental state at time of the offense (MSO) model using structured data collection methods, aggregation of empirical evidence guidelines, and  Criminal responsibility (CR) evaluations are complex forensic mental health evaluations requiring collecting, aggregating, and interpreting data from multiple sources , schizophrenia (k = 0.46), and attenuated psychotic symptoms syndrome  yielded intraclass correlations of 0.98–0.99 for the Positive Symptom Scale, and 0.83–0.90 with the Negative Symptom Scale. The General Psychopathology Scale yielded intraclass correlation coefficients of 0.95–0.98 . Of those categories only 14% had a good or very good reliability, which means that only 4% of the DSM-5 categories have been shown to have acceptable reliability. Since the inter-rater reliability of the majority of the DSM-5 categories remains untested, this raises serious questions about diagnostic reliability in the clinical assessment of MSO evaluations for diagnoses and to a lesser extent for clinical features.p < 0.01). Community-based psychologists and court-based examiners reached a “fair” level of agreement . Psychiatrists and court-based examiners reached consensus with “fair” levels of agreement . A study of Hawaii's court-appointed three panels using a separate sample aggregated agreement coefficients for CR yielded an ICC of 0.51. Average pairwise Cohen's k was 0.391  CR language focused on cognitive and volitional capacity. A Hawaii study of 150 independent CR reports conducted by court-appointed three examiner panels yielded “fair” levels of agreement .In a second more rigorous study examining five types of reliability coefficients in 150 cases in a non-crossed data measurement design, reliability of CR decisions in panels of three independent court-appointed examiners was marginal ,gathering information,considering the relevance of risk factors that are present,developing a formulation of risk based on findings,developing a risk management plan, andcommunicating summary judgments.Hart address the interpretive “gap” between steps 3 and 4 by specification or guidance for formulation of risk and scenario planning  checklists for structured application for procedures ;b) structured data gathering organized around a priori predictorsc) data aggregation utilizing predictors using an unweighted aggregation model ; andpost-hoc hypothesis testing using the ACH  structured analytic techniques to consider evidence sources, credibility and relevance and H Heuer, .The application of the SPJ model to CR forensic decision-making provides a systematic, individualized, and evidence-based exposition and analysis of factors supporting the forensic judgment.KDC was referred by his public defender for a CRWhen asked why he had killed the decedent, he could not describe his thoughts or feelings, only that “something had built up” inside of him and then “I just did it.” Immediately before the stabbing, he had overheard IL telling his mother that someone was hanging dogs and cats in the woods behind the house, which angered him because it upset his mother. Around 17:00 h the decedent walked to the back lanai by himself to smoke “clear.” KDC discussed what IL had said to his mother. His mother thought KDC was acting “strange.” From the police interrogation transcript, when asked why he killed him, KDC reported that “I just got weak.” He denied feeling angry at the decedent or frustrated, “…just weak, and I could not feel my arms.” The detective wrote, “He said it was a buildup of the decedent's behaviors and he just got weak and could not tolerate them anymore” and he stabbed IL multiple times in the chest.The Emergency Department medical clearance conducted at a local hospital several hours after the stabbing indicate altered mental status . The police interrogation and closing investigative reports conducted the next day demonstrated bizarre thinking. Jail mental health records described psychotic mentation and he was started on antipsychotic medications. By the time of the examination his symptoms had remitted. Both police and ER medical reports described his behavior as “strange,” that his affect was odd, and that he was talking non-sensically. KDC made an audio-recorded and transcribed statement to a police detective the next day describing the stabbing in detail. He said he was afraid that IL was going to kill him and his mother, if he did not kill him first. The mother stated that she was afraid of KDC in the days prior to the stabbing, that his thinking and behavior were strange and frightening, thinking that he might “erupt” at any minute. She reported that he had been up at night, that his manner was agitated and suspicious, that he was hearing “things,” and looking outside the house saying that “someone was out there.” She had observed KDC's psychotic behavior many times over a period of months. She was extremely worried that he had stopped going to treatment, was not taking his antipsychotic medications and that something bad could happen.KDC has a well-documented history of multiple psychiatric hospitalizations, the great majority of which involved flagrantly bizarre behavior  associated with positive methamphetamine toxicology screens. The record includes records from several psychiatric hospitalizations for methamphetamine-induced psychotic disorderA psychological assessment indicated borderline intellectual abilities, no current clinical signs of psychosis, including negative findings on a Rorschach Test. His PAI was invalidated due to over reporting. The case material and clinical assessment material were coded using the PANSS (at time of offense and at assessment) and RCRAS. The PANSS profile indicated the presence of positive symptoms: hallucinations and or delusions at the time of the offense. The RCRAS indicated the offense involved loss of control under the influence of acute methamphetamine intoxication and chronic methamphetamine psychosis (see note 4 below). At the time of the forensic examination, his symptoms had remitted but to cessation of methamphetamine and medication compliance.post-hoc hypothesis testing matrix. The matrix has summary weighted scores based on degree of consistencies and inconsistencies with the primary and alternate hypotheses. Individual a priori predictors and evidence sources are rated with respect to predictor credibility and relevance. The logic of ACH is examination of data which disprove the primary hypothesis (that KDC was CR). prior to the acute intoxication and commission of the crime. Given the weight of the predictors and the evidence, post-hoc hypothesis testing indicates a high degree of confidence may be placed in the findings, and the opinion may be proffered to a reasonable degree of psychological probability.In terms of the Hawaii two-prong insanity statute, the SPJ aggregation model and review of evidence presented in Based on the credibility and relevance ratings, the evidence database is sufficient to render legally admissible opinions under the Hawaii Rules of Evidence . The evidence aggregation model  yielded The final CR decision derived from the SPJ approach parallels summary risk ratings (SRR) in violence risk assessment instruments, although it does not yield a numerical value. The final CR decision may be applied to any clinically derived final judgment to yield a total score  vs. persistent methamphetamine-induced psychosis at the time of the offense  reliable retrospective clinical diagnosis at the time of the offense, (4) structured data aggregation, (5) linkage between clinical, functional, and legal elements, and (6) post-hoc hypothesis testing of case data. The value of the structured decision model is the a priori specification of robust predictors, weighting of evidence using relevance and credibility ratings, application of predictors to case material, and a post-hoc hypothesis testing procedure to verify opinions, and reduce confirmatory bias. The model externalizes what forensic clinicians already do in an explicit structured procedure. The methodology, based on robust SPJ principles, adheres to a core empirical foundation. A similar methodology may be applied to other forensic decision-making tasks, e.g., competency to stand trial or post-acquittal conditional release.This paper is a pilot description of a structured prediction model for CR opinions applying the principles of SPJ and a transparent data aggregation procedure. Key issues in the CR prediction model include the (1) use of checklists to outline and standardize procedures; (2) structured data collection focused on robust post-hoc control for hypotheses testing and control for confirmation biases. It makes explicit the strengths and weaknesses of the evidence and decision model, assists in the use of the model as probative evidence, and reduces but does not eliminate the gap between data and inference making.Judgment is inevitable in the forensic decision making process. The application of SPJ methodology, including use of empirical guidelines, and rigorous hypothesis testing closes but does not eliminate the gap between evidence and decision. The SPJ methodology organizes and structures the assessment process. The aggregation of empirical predictor model yields sturdy evidence-based decisions. The ACH provides This report provides a conceptual foundation for SPJ decision making for forensic CR opinions. The aim of the project is the “translation and dissemination of the science of risk assessment into the field where such evaluations regularly occur” (Guy et al., The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.All authors listed have made a substantial, direct and intellectual contribution to the work, 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.


Access to evidence and practice knowledge precedes use, but availability does not guarantee reach and uptake by intended audiences. The CareSearch project provides online palliative care evidence and information to support health and aged care professionals as well as patients, carers and families to make informed decisions about care at the end of life. Already established in the palliative care sector, CareSearch commenced planning to extend its reach, and ensure website use is maximised for different audiences. This paper reports on the development of the Engagement Framework which will be used to guide and deliver an Engagement Project which will actively seek feedback and insights from intended users in a structured process. The process for developing the Engagement Framework commenced with a literature review of approaches used in knowledge translation, implementation science, and social marketing. The Engagement Framework comprising eight steps was then developed. The Engagement Framework outlines the series of tasks to be undertaken by team members when working with three target groups . A process/formative evaluation collecting data using qualitative methods is also described for use in the subsequent Engagement Project. The evaluation will explore the experiences of project participants as well as staff implementing the engagement activities. The three target groups will enable a cross-case comparison of the strengths and weaknesses of the approach. Planning, implementing and evaluating engagement with intended audiences, offers one mechanism to identify ways to increase interaction and integration with knowledge users. CareSearch is a nationally established project in Australia providing online evidence and information relevant to palliative care for use by any health professional regardless of setting, and by those affected by the need for palliative care. It aims to support health and aged care professionals, patients, carers and families to make informed decisions about care at the end of life by providing access to trustworthy information and best available evidence. CareSearch is funded by the Australian Government Department of Health . Since iPalliative care is an area of increasing importance to communities, policy makers and the health system given an ageing population, increasing care complexity relating to disease burden and comorbidities, and the diversity of individual needs of people who are at the end of their life ,4. The ATo help capture the complexity of its work, particularly for evaluation and strategic development, CareSearch has developed a program logic . In thisStakeholder engagement has always been a key “input” for CareSearch. In addition to formal governance groups, stakeholders have been engaged to contribute to the quality of content, to improve cohesiveness and reduce duplication in the sector, to contribute to information sharing and skill development across the sector, and to support the promotion of CareSearch resources.Web metrics reported at the end of 2018 demonstrate significant use, with palliAGED receiving over 10,000 visits monthly and CareSearch receiving over 100,000 visits each month. There are over 8000 people registered to receive newsletters and over 4000 followers of the CareSearch and palliAGED Twitter accounts. The CareSearch blog provides different perspectives on palliative care issues with between 300 and 4300 “reads” per article. Data from multiple sources including newsletter registrations, promotional orders and evaluation surveys all indicate that the resource is being accessed across Australia [Evidence is at the core of CareSearch activities . EvidencHaving become an established presence in the palliative care sector, CareSearch is seeking to extend its reach, and to ensure that the utility of the website is maximised for all target groups. In an extensive review of evaluations of seven large knowledge mobilisation agencies, Davies et al. , noted oA growing literature on the role of website design and user testing has highlighted the importance of design elements such as website architecture, content utility, and readability in supporting website use and engagement ,13,14,15Therefore, CareSearch successfully sought funding from the Australian government to design, implement and evaluate a structured engagement activity conducted with three different target groups . These three groups represent some of the audiences with which the CareSearch project engages and highlights potential differences in terms of needs, awareness and knowledge of end-user groups. As part of this process, CareSearch will identity issues and considerations around the specific context influencing palliative care awareness and online knowledge use for each target group. CareSearch will use this to inform activities and strategies in the engagement phase to support the utility of the website and, ultimately, uptake of online CareSearch resources by these groups.The development of a formal Engagement Framework fits into the CareSearch Model at a similar point to other stakeholder activities. The intended consequence of implementing the 2018–2020 structured engagement activity is that CareSearch staff will gain a deeper understanding of the context in which people seek information . These iThe aim of this paper is to report on the development of an evidence-based approach to understanding context to support a targeted engagement approach to influence reach and uptake of online resources. The engagement framework will then be applied in individual studies with each group and these findings separately reported.The initial step in developing the proposed Engagement Framework involved a review of the purpose and requirements of the project as proposed in the grant application. This was undertaken in a detailed meeting between the two authors . This meeting clarified that the three target groups were fixed and reflected priorities for the project in terms of intended user groups. The Engagement Framework needed to include workshops with sector participants to understand context and determine actions to be implemented by the CareSearch project staff prior to a follow up workshop to evaluate the effect of these actions. This meeting also recognised that the intent of the Engagement Framework was to drive and monitor the engagement activities and hence was a first activity in its own right.We reviewed literature from a range of disciplines and perspectives to develop the engagement framework and the reporting aspects of the project.The literature on Knowledge Translation (KT) offers a lens through which to understand the current engagement activity. KT looks at the processes, actors and strategies used to move research and evidence into practice and use to improve outcomes for individuals, systems and societies . A recenProcesses for engaging stakeholders have also emerged through the practice of KT and are being adapted and adopted more widely. In describing the “Deliberative Dialogues” approach, Lavis et al.  describeBased on our review of the literature, we determined that it was important to develop a good initial understanding of the context in which the three target groups were operating prior to bringing people together to talk about the specific issues affecting awareness and use of the CareSearch website. In the absence of this initial step, the process of identifying stakeholders is likely to be limited by the lack of the very context knowledge that is being sought. The purpose of the engagement framework is to go beyond CareSearch’s existing types and levels of stakeholder engagement and extend understanding of context for the three target groups.Following the literature review, the CareSearch Director and evaluation researcher met again to finalise the Engagement Framework and to formalise a template for documenting information about the group and context based on relevant elements identified in the literature review. The proposed approach was then formally reviewed by the CareSearch and palliAGED Advisory Groups to determine face validity.Prior to working with stakeholders directly, a systematic analysis of context was undertaken based on public documents and grey literature. Each analysis sought to document as much as possible about the context prior to a face-to-face workshop, and to support identification of potential stakeholders to attend the workshop.Step 1: Pre-workshop preparation—completion of analysis of context template see ○Step 2a: identifying potential participants○Step 2b: selecting participants○Step 2c: inviting participants○Step 2d: preparing participantsStep 2: Organising WorkshopsStep 3: Stakeholder Workshop 1: Understanding context and developing potential actionsStep 4: Stakeholder (extended group) webinar: Workshop 1 overview and initial action ideasStep 5: Confirming Action plan and developing operational workplansStep 6: Implementing Action planStep 7: Stakeholder Workshop 2: Action Plan implementation update and assessmentStep 8: Stakeholder Workshop 3: Final (joint) assessment of Engagement ActivityThe Engagement Framework includes the following steps:Engagement Framework Development October 2017–March 2018Engagement Project Establishment: March 2018–June 2018Participant recruitment, workshops, action plan, feedback and reporting: July 2018–June 2020Data analysis: July 2020–December 2020Implication assessment and action planning for CareSearch and palliAGED website and future project communications and end-user engagement: January 2021–December 2021The engagement activity will be implemented by one part-time (0.6FTE) coordinator for each target group and a project manager. The proposed schedule for work is as follows:To support the activity of the Engagement Project focused documentation is required. The process, purpose and timing of this documentation development is described below.Step 1: Pre-workshop preparation—completion of template for analysis of context. CareSearch staff will use the template designed for the engagement activity to prepare a document that strengthens and summarises their understanding of the contexts in which palliative care evidence may be accessed and used by the three target groups. The task will be informed by a range of approaches.The field of implementation science has grown rapidly in response to the recognition that knowledge, skills and behavioural intent are not sufficient in and of themselves to lead to behaviour change. From this perspective, context influences the likelihood that evidence will be used in practice. It has been reported that there are over 60 different models of “knowledge transfer and exchange” in use across the fields of health care, social care, and management , and a nExternal—including: the presence and nature of national and local policies and legislative or regulatory mechanisms; incentives and penalising consequences; commonly held values and beliefs; buy-in by stakeholders at different levels; infrastructure; technology; economic climate and financing models; and public awareness.Organisation—including: culture and leadership, which contribute to organisational readiness; resources including time, funding, staff, and technical support; processes and systems; relationships between workers and patients; skill mix and clarity of roles and responsibilities; and team involvement including collaborative working and shared vision.Professionals—including: professionalism including skills and self-efficacy; underlying philosophy of care; attitudes, motivation, and experience; and competencies, including those acquired through training.Intervention—including: the nature and characteristics of the “intervention” including its complexity, evidence of its benefits, cost-effectiveness, and compatibility to the setting; implementability; and safety and data privacy concerns being addressed.Jacobson et al.  offered Social marketing approaches to analysing situation and influencing factors offer another perspective for understanding context. Used in public health, “social marketing approaches can be used to help engage end-users in the development, implementation and evaluation of policies and programmes” . Within All of the above approaches offer some guidance to the task of documenting the context in which the three target groups access and use evidence and resources, but none is perfectly aligned. Therefore, we adapted and combined relevant elements to design a template that CareSearch staff will use to develop an initial description of context for each target group. While the template reflects other approaches, it does not map directly to them. However, the template recognises the different spheres of influence on behaviour described by Lau , JacobsoThe template will also address issues around the online aspect and its relationship to the user group. Some of the elements that are used to describe context for the Patients, Families and Carers (PFC) target group will be different to those used to describe the aged care and allied health groups. There are no pre-defined boundaries to the PFC target group, although some may be developed for the purpose of the engagement activity. For example, the PFC target group may focus on people who have current or recent experience of palliative care and/or end of life.Step 2a: Identifying potential participants: Potential participants will be identified for each of the three target groups through targeted invitations to individuals or organisations identified in the context document and through a general call for interested people made on the CareSearch website. All potential participants identified will be documented. See Step 2b: Selecting participants: The CareSearch team will assess each potential participant’s inclusion, indicating “yes”, “maybe”, or “no”. Ratings will be compared at a team meeting and a final set of 20–25 participants will be invited with the aim of having 15–20 participants attending Workshop 1.Step 2c: Inviting participants: The coordinator for each target group will contact potential participants by telephone or email to invite them to participate. In some instances, the coordinator will need to explain why the person has been invited, as they may not see the immediate relevance in attending a workshop organised by CareSearch around palliative care knowledge.Step 2d: Preparing participants: Stakeholders who agree to participate will be provided with a range of CareSearch/Palliative Care in Aged Care Evidence (PCACE) resources intended for use within their target group. Each group will be provided with a sector specific resources pack. This will be a targeted summary of online resources perceived to be relevant from within CareSearch including webpages, evidence resources, learning modules, videos, examples of case studies etc. Participants will be asked to familiarise themselves with the web resources and website prior to attending a workshop. They will also have further information about what to expect at the workshop, including what the boundaries of disclosure of information that is shared will be.Step 2: Organising WorkshopsStep 3: Stakeholder Workshop 1: Understanding context and developing potential actions. Through a facilitated process, a workshop will be conducted with each target group separately during which participants will be asked to validate  the perceptions that CareSearch has about context and identify gaps in the description of barriers and facilitators to reaching the target groups and encouraging them to access and use PC evidence and prioritise potential areas for action. While similar domains will be explored with all groups, the questions used to generate discussion and descriptions will differ for the health professional groups and the patient, family and carer group. Following the workshops, notes will be collated, and ideas generated will be analysed to identify themes for areas of action to be included in draft Action Plans.Step 4: Stakeholder (extended group) Webinar: Workshop 1 overview and presentation of initial action ideas. A webinar will be held with each group and all potential participants will be invited to attend. The focus of the webinar will be on presenting a summary of discussions and ideas generated at the workshop, and inviting participants to comment, including challenging or adding to actions and strategies. Inviting all potential participants extends the reach of the engagement activity and provides some continuity of participation if future workshops have space available for new invitees because past attendees cannot attend. It is anticipated that between 5–20 participants will attend the Stakeholder Webinar.Step 5: Confirming Action Plan: CareSearch staff involved in the Engagement. The Action Plans will be finalised using structured processes and discussion, including assessment of the feasibility of implementing actions within the 12-month time-frame of the project. It is expected that there will be common areas of action. The final action plans will also identify indicators that can be used to assess the impacts of the action plans. Examples of possible measures include webmetric tracking, website pattern usage, impact on digital referrals or measures of reach and uptake in target audiences.Step 6: Implementing Action Plan: CareSearch staff will implement the Action Plans. The evaluation plan will be developed further based on the contents of the Action Plans.Step 7: Stakeholder Workshop 2: Action Plan implementation update and assessment. Each group of stakeholders will be invited to attend a second workshop during which the status of implementation of the Action Plan will be reviewed and the findings of the evaluation will be presented. Stakeholder participants will be asked for their reflections on the impacts of the Action Plan, and their perceptions of the extent to which the Action Plan implemented reflected the original workshop.Step 8: Stakeholder Workshop 3: Final (joint) assessment. Representatives from the three focus groups will come together to attend a final workshop during which they will be invited to reflect on the process and their participation in the stakeholder engagement activity.The engagement framework is intended to provide a structured approach to understanding the context that affects the reach and uptake of evidence in each target group to inform development of clear priority actions that CareSearch can implement and evaluate. The overall goal of implementing and evaluating the engagement activity is to consider whether this approach adds value to the work of CareSearch , and whether it increases reach and utility of the website and uptake of resources to support implementation of evidence in the target groups .What differences, if any, were there in the effectiveness?How do participants experience the workshops? What worked well; what could be improved?Is the structured and consistent approach to understanding context that was implemented (through structured desk-top review and stakeholder workshops) an effective way to become more familiar with target groups?Do the workshops lead to Action Plans that include novel prioritised actions and strategies that CareSearch can implement?Do the actions and strategies developed through the engagement activity achieve their intended impacts?What is the overall assessment by key stakeholders of cost-benefit?The key evaluation questions are:○Prior knowledge  of CareSearch○Prior knowledge of palliative care, experiences○Expectations of engagement activity○Experience of participationIndividual participant surveys following Workshops 1 and 2 with a focus on assessing:○CareSearch team members as part of regular meetings to monitor the process, document decisions, and identify issues as they arise○CareSearch team members individually after Workshops 1 and 2, and at the end of the project, to capture key experiences around implementation of the engagement activity○Workshop participants at the completion of the engagement activity—through facilitated discussions at Workshop 3Semi-structured interviews and/or group discussions—to be conducted with stakeholders at multiple time points, including:○Context analysis reports○Lists of potential workshop participants○Workshop notes○Action Plans○Documents developed as part of Action PlansReview of documents used to conduct the engagement activity, including:Assessment of Routine Data collected by CareSearch, including Webmetrics. There may be potential to compare trends for web contact associated with the three target groups and those target groups that are not the focus of the engagement activity; however, note that the three target groups were chosen because of the potential challenges of reach and implementation, so the potential to attribute change or differences to the engagement activity may be limited.With the Engagement Framework described, it was then possible to outline data elements and data collection methods that will be used to capture aspects of the Engagement Project activity. These will form the results and findings of the Engagement Project as it is undertaken. Data collection activities will include:Ethics approval for the evaluation has been given by La Trobe University Science, Health and Engineering College Human Ethics Sub-Committee (HEC18116).Key steps of the engagement activity framework have been implemented and collection and analysis of data is currently underway.There is a lot of emphasis on stakeholder engagement in policy and practice, but little evidence to demonstrate that a systematic approach to understanding context based on literature review, mapping and stakeholder workshops can lead to novel actions ,38. DespMore importantly this paper outlines a framework to investigate how context and target group characteristics can reflect barriers and facilitators to dissemination, participation and utilisation of online health information. There is increasing use of online health information by health consumers and health professionals in medical and care decision making. Understanding how to build awareness of the value and relevance of online evidence to discrete groups or sectors and how to identify and measure change in reach and uptake of such evidence, could be instrumental in improving the use and value of evidence-based practice within the health system and the community. The results will make an important contribution to the evidence base for digital translation of evidence and inform our understanding of factors, contexts, and characteristics influencing evidence use.The creation of context prior to the workshops will enable an assessment as to whether a preliminary review is sufficient to develop an effective and useful understanding of the context for online information use, or whether direct face-to-face engagement with the studied group itself reveals additional, and critical, information. By simultaneously studying the process and outcomes of engagement with three discrete groups we will be able to explore what is common and what is unique about the nature of digital audiences and whether action strategies need to be target group specific or are universal in nature. It is also anticipated that the study will provide valuable insights into the contribution of marketing and communication strategies to digital translation.The structured engagement framework and associated evaluation provide rich opportunities to assess not only the influence of the characteristics of the target groups but also the influence of staff involved in the project on the engagement process. The evaluation will consider whether and how a focus on engagement influences the delivery of online health information. This is particularly critical for virtual projects where opportunities for incidental interaction with intended audiences may be more limited .There is a rich and varied literature relating to KT, digital health processes and consumer/end-user engagement. Our literature review was selective and may have missed relevant materials. The development of the engagement framework was time sensitive as it was a precursor to the dependent activity of participant selection, workshops and action plans. Hence there may be elements that could inform the framework that have been missed. The framework depends on engagement from the targeted audiences and it is not known if there will be sufficient interest in participation. The framework assumes that it will be possible to identify common and unique elements from the different audiences that could assist in developing specific content and/or communications strategies.It should also be noted that the framework was designed for a single website with the specific health focus of palliative care. This will limit unthinking generalization of the framework. However, the CareSearch Project is designed to serve a broader audience group, form those affected by the need for palliative care, to those providing palliative care in any health care setting.Despite these limitations, there is both a practical and a theoretical need to understand more about how different users engage with and respond to digital content and to the mechanisms by which such content is promoted and distributed.While evidence retrieval and synthesis activities are critical to the development of trustworthy online health information, we also need to address how to support the use of evidence in practice. A structured approach not only enhances the value of our interaction with intended users but provides us with the ability to evaluate the effectiveness of the framework approach and its contribution to online knowledge translation.


Snoring is a common phenomenon which is generated by vibration of soft tissue of the upper airway during sleep. Due to the high incidence of isolated snoring and the substantial burden for the patient and the bed partner, a thorough examination and appropriate therapy are required. Many recommendations for the treatment of isolated snoring are either not evidence-based or are derived from recommendations for the management of obstructive sleep apnea. Therefore, the aim of this study is the identification and description of open questions in the diagnosis and treatment of isolated snoring and the illustration of areas for further research.In the context of the development of the new version of the German guideline “Diagnosis and treatment of isolated snoring in adults,” a multidisciplinary team of experts performed a systematic literature search on the relevant medical data and rated the current evidence regarding the key diagnostic and therapeutic measures for snoring.The systematic literature review identified 2293 articles. As a major inclusion criterion, only studies on primary snoring based on objective sleep medical assessment were selected. After screening and evaluation, 33 full-text articles remained for further analysis. Based on these articles, open questions and areas for future research were identified for this review.Several major gaps in the literature on the diagnosis and treatment of isolated snoring were identified. For the majority of diagnostic and therapeutic measures for snoring, high-level scientific evidence is still lacking. Snoring as an isolated phenomenon is very common. The symptom is generated by vibration of the soft tissue of the upper airway during sleep. According to the International Classification of Sleep Disorders ICSD-3), isolated snoring is categorized under sleep-related breathing disorders, but must be differentiated from obstructive sleep apnea, either by home sleep testing (HST) or polysomnography (PSG) , 2. Acco, isolateDue to the high incidence of snoring and the substantial burden for the patient and the bed partner, a thorough examination and appropriate therapy for snoring are required. It is still part of ongoing discussion and investigation, whether or not isolated snoring is a cardiovascular risk factor. In a comparison of 377 subjects with isolated snoring after PSG exclusion of OSA with 264 healthy subjects, no difference regarding fatal and non-fatal cardiovascular events “could be detected after adjustment for the common risk factors . HoweverThe role of isolated snoring as potential risk factor for cardiovascular diseases remains unclear—also in the diagnosis and especially in the treatment of snoring, many recommendations are either not evidence-based or derived on recommendations for the management of patients with OSA, despite the fact that snoring in the context of OSA is not equivalent to snoring as an isolated phenomenon. Therefore, the discrimination between isolated snoring and snoring as part of OSA is essential in order to indicate the appropriate treatment. Thus, the aim of this review is the identification and description of current gaps in the evidence of diagnosis and treatment of isolated snoring and the illustration of areas for further research.In the context of developing the new version of the German S3 guideline on “diagnosis and therapy of snoring in adults,” a multidisciplinary team of ten experts defined multiple topics in the management of snoring, for which the evidence should be evaluated , 11. TheIs the application of drug-induced sleep endoscopy (DISE) beneficial regarding the therapeutic outcome?Is the application of pressure catheter beneficial regarding the therapeutic outcome?What is the evidence for the effectiveness of positional treatment of isolated snoring?What is the evidence for the effectiveness of myofunctional treatment of isolated snoring?What is the evidence for the effectiveness of weight loss in the treatment of isolated snoring?What is the evidence for the effectiveness of a treatment with a mandibular advancement device (MAD) in isolated snoring?Is the application of individual MAD superior compared to ready-for-use MAD in the treatment of isolated snoring?Does the effectiveness of MAD in the treatment of isolated snoring depend on the amount of advancement/protrusion?What is the evidence for the effectiveness of soft palate surgery in the treatment of isolated snoring?What is the evidence for the effectiveness of nasal surgery in the treatment of isolated snoring?ClinicalTrial.gov, starting from the year 2000, has been conducted. This time, restriction has been chosen since a differentiation between isolated snoring and OSA has not been done consequently in earlier publications.In January 2018, a literature search was conducted for existing Cochrane reviews in the Cochrane library under the term of “snoring” without date restriction. Additionally, a literature research for existing guidelines or systematic reviews under the term of “snoring” and the limits of “guideline,” “systematic reviews,” “human,” “adults,” “English,” and “German” was performed. In February 2018, a systematic literature research by a certified librarian  in the databases of PubMed, Cochrane Library, Web of Science Core Collection, and https://www.cebm.net/2009/06/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/).The results from the systematic literature research have been thematically separated and allocated to the authors. In the first step, all abstracts were screened by at least two authors and excluded if obviously irrelevant for the single topics. Abstracts were included, if at least one author defined them as relevant. In the second step, all relevant abstracts were reevaluated on the basis of the full-texts and were either included, if again at least one of two authors defined the articles as relevant, or excluded, if still irrelevant for the single topics. At this stage, the reason for exclusion was documented. The selection was limited to English or German articles, adult patients in whom OSA was objectively excluded (AHI < 5/h) and, in the case of articles evaluating therapeutic modalities, to studies with at least ten patients. The information flow through the different phases of the systematic review is depicted as flow diagram according to the PRISMA recommendations . The artQuestions on the diagnosis and treatment of isolated snoring, which could not be answered by the existing literature, were identified and described as current gaps and areas for future research.No existing Cochrane reviews on isolated snoring could be identified. A clinical practice guideline of the American Academy of Sleep Medicine and the American Academy of Dental Sleep Medicine on the application of oral appliances could be identified and was included in the particular statement . Two sysDISE allows the identification of the origin of snoring sounds and the differentiation from OSA, but pharyngeal pressure catheters have not been under evaluation in patients with isolated snoring . The raiNo evidence was available for the effect of positional therapy in the treatment of isolated snoring in adults, since all screened abstracts and full-texts on this topic were excluded mainly due to imprecise in- or exclusion criteria . The only evidence on positional therapy for isolated snoring was available on positional therapy of the head, which is reported to be effective in the subjective and objective intensity of snoring (evidence level 1b) . In a cuThe literature research on myofunctional therapy for isolated snoring in adult patients did not reveal any evidence for or against the recommendation of this treatment.Studies evaluating the effect of weight loss on snoring intensity in patients with isolated snoring without OSA have not been conducted so far. Since body weight is a risk factor of snoring, therapeutic efficacy may be presumed, although this has not been demonstrated to date. This is of particular interest, since weight reduction is a standard recommendation in subjects with isolated snoring (evidence level 5).In contrast, with placebo-controlled trials, evidence on the effectiveness of a treatment with a MAD in adults with isolated snoring was available and further studies also demonstrated the beneficial application of MAD for this indication (evidence level 1b) –23. One The available literature provided limited evidence on the effect of nasal surgery in patients with impaired nasal breathing on the intensity of snoring. Four case-control studies have been identified, which evaluated the effect of nasal surgery on the subjective and objective snoring intensity (evidence level 3b) –28. In aWith 16 publications meeting the inclusion criteria, evidence on the effectiveness of soft palate surgery in the treatment of isolated snoring in adults was available. Different surgical approaches have been under investigation: Uvulopalatopharyngoplasty, uvulopalatoplasty, modifications such as radiofrequency-assisted or laser-assisted uvulopalatoplasty, radiofrequency therapy of the palate and palatal implants. Due to a randomized, placebo-controlled trial, the highest level of evidence is available for radiofrequency therapy of the soft palate (evidence level 1b) . CompariThe identified gaps in the literature regarding diagnosis and treatment of isolated snoring in adults and possible areas for future research are summarized in Table As part of the development of the current version of the German guideline on the diagnosis and treatment of isolated snoring in adults and the associated systematic literature research, striking and partially unexpected gaps in the related literature were identified. This review was conducted in order to illustrate the areas of missing evidence, both in diagnosis and treatment of this common disorder, and thereby stimulate prospective clinical trials.Although in the first round of the evaluation many abstracts were identified, screened and numerous full-texts were evaluated, only few studies met the inclusion criteria of this evaluation. The most frequent reason for exclusion of many articles was the insufficient differentiation between isolated snoring and snoring as part of OSA. Although a number of studies performed a home sleep test or polysomnography to rule out OSA, cutoff values that did not sufficiently differentiate isolated snoring from OSA were frequently used, which led to the inclusion of patients with snoring in combination with mild to moderate sleep apnea. Therefore, it is highly recommended, in accordance with the ICSD-3, to conduct either a home sleep test or polysomnography with an AHI of < 5 events per hour as cutoff at baseline as inclusion criterion both for diagnostic and therapeutic studies in isolated snoring .Subjective snoring intensity including subjective scoresUnwanted effects/morbidityQuality of lifeAcoustic snoring analysis including objective methods of investigation and classificationCosts of the procedureThe multidisciplinary working group further defined relevant outcome parameters which should receive special attention (the ranking corresponds to the importance of the parameter):With regard to the most important outcome parameter, the subjective snoring intensity, a particular characteristic, has to be taken into account. Usually, the primary outcome parameters are patient-relevant endpoints and therefore in the focus of guidelines or the evaluation of the effectiveness of diagnostic or therapeutic procedures. In isolated snoring, however, the subjective evaluation of the snoring intensity is not evaluated by the patients for obvious reasons, but by the bed partners. The affected individuals usually do not suffer from their own snoring, but from the extent of the annoyance of the environment. This justifies why, in the present case, the subjective harassment of the bed partners was selected as the most important endpoint, as it is also customary in the international context. However, evaluation with subjective scores is prone to bias and only the reflection of the current bed partner. The authors around De Meyer et al. demand the development of a model for assessing snoring, which includes both properties of the sound, but also physiological aspects, such as the annoyance influenced by personality aspects, sensitivity to noise, and environmental factors .Visual analogue scales offer the ability to classify snoring by volume and frequency. Similar to questionnaires, such as the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale, visual analogue scales do not enable the differential diagnosis of isolated snoring and OSA, but allow the longitudinal documentation  , 34. TheSnoring is an acoustic phenomenon that can be described by objective parameters. The acoustic detection of snoring sounds should be done by air conduction (sound transmission through the air), since this is the only way to ensure that frequencies above 1000 Hz are adequately reproduced. The measurement of snoring sounds by body contact microphones or dynamic pressure measurement (sound transmission through the body), as it usually is the case in HST and PSG, leads to a reduction of the intensity spectra above 1000 Hz . The acoIn conclusion, several gaps in the literature regarding the diagnosis and treatment of isolated snoring, and therefore areas for further research, have been identified. Future studies on these topics should pay attention to differentiate between isolated snoring and snoring in the context of obstructive sleep apnea with the help of sufficient objective testing. According to current standards, patients with an AHI above 5 events per hour should not be included in studies on isolated snoring. Another difficulty is the selection of the optimal endpoint in these studies. Usually, visual analogue scales are applied to evaluate the baseline snoring intensity and the effect of the particular treatment. No distinct objective evaluation method has gained general acceptance to date, even though the evaluation of the snoring intensity is usually done by the bed partner and therefore prone to multifactorial bias. With this regard, the authors (a) emphasize the particular need of randomized-controlled trials, since the majority of the existing literature is of low evidence, (b) indicate the reliable exclusion of OSA in studies on isolated snoring, and (c) encourage the application/establishment of validated outcome parameters.


The implementation of REGULATION (EC) No 1924/2006 has led to the formation of a list of health claims that can be used in food supplements (EU 432/2012). However, such supplements are often composed of plant preparations with claims omitted from this list. The peculiarity of plants is related to their long history of use, that could allow claims based on traditionally recognized health effects. In addition, the scientific literature has been enriched over the years through clinical studies that have assessed the bioavailability and efficacy of bioactive components, and investigated their mechanisms of action. Based on existing recognized models which aim to classify research according to the level of scientific evidence, Synadiet developed a three-grade model  for assessing plants health claims. In this paper, the applicability of the model is illustrated through an example for which a Grade B health claim attesting the possible contribution of red clover isoflavones to the improvement of blood lipid levels in postmenopausal women has been attributed. The model appears able to be easily extrapolated to claims pertaining to other plants. If adopted by consensus at European level, this model could initiate the implementation of a positive list of health claims on plant preparations. When it comes to substantiating claims about human health, there can be no question that the highest possible standard of proof is required. However, regarding health claims of food supplements related to plants, to date, there is a status quo concerning their evaluation (pending authorization). This does not provide a satisfactory solution either for consumers or for the industry. The intent of the work performed by Synadiet was to propose a model based on graded claims, where the level of proof provided is evaluated by a standardized methodology and where traditions of using plant-based products are taken into account. This attempts to conciliate the requirements of European public health authorities and the concerns of the industry, while keeping in mind consumer protection in terms of provided information.Aesculus hippocastanum L. [Ginkgo biloba L. for cognitive disorders [Pygeum africanum Hook f. in benign prostate hyperplasia [Plants have been utilized since time immemorial for the relief of human illnesses. Many have been used in allopathic drugs or as phytomedicines and have a long history of use. This is the case, for example, for tanum L.  in venouisorders , Pygeum erplasia , etc. Noerplasia . The samerplasia ,6. The vTo be able to simultaneously take into account traditional effects and also new evidence from clinical studies that have been, and continue to be, conducted on plants, it seems desirable to shift towards a graded evaluation system, such as the U.S. FDA Qualified Claims . This vitraditionally used for” and does not raise wording difficulties (its definition will be given hereafter), contrary to level A and B claims which require clear and precise wording, supported by the appropriate strength of evidence to substantiate them.Therefore, Synadiet has formulated a proposal for a graded health claims system for plant-based products. This model, presented in With regard to Grade A, in With regard to Grade B, Synadiet proposes the following level of corresponding evidence: “Convergent body of evidence including at least one randomized controlled study (Level Ib) that does not fulfil the quality criteria established for Grade A, or one controlled study without randomization  (Level IIa), or one other type of quasi-experimental (non-controlled) study (Level IIb) and eventually evidence from observational studies (Level III)”. This definition has the advantage of paying attention to observational studies which reflect the use of plant-based products in real life and the fact that many such substances already have a long history of daily use and were commercialized before today’s requirements for proving health claims. Additionally, clinical textbooks can be provided, which describe how constituents identified in plant preparations work in the body, supporting evidence such as animal and in vitro studies that provide more information surrounding the mechanism of action and consumer satisfaction tests. Grade B can be sustained by several studies that constitute the body of evidence.On that basis, the wording for Grade B recommendations would be, for example, “can contribute to the decrease in xxx” or “can contribute to the improvement of xxx”; Grade A wording would be “decreases xxx”, “relieves xxx” or “improves xxx”.With regard to Grade C, “traditionally used for xxx”, it is based on authoritative reference texts corresponding to Level IV evidence, defined as “Evidence from authoritative reference textbooks, scientific opinion from scientific organizations, regulatory authorities and documented history of uses, e.g., classical texts, published documents from scholars or experts that report the traditional use of the ingredient concerned”. Traditional use is restricted to products for which a long-lasting use of at least 25 years can be documented.Each type of graded claim will be related to the parts of the plant, the type of preparation and the conditions of use.Trifolium pratense (red clover) and cardiovascular health. The use of systematic reviews as a standardized method to identify, select and critically appraise relevant research enables the synthesis of the current body of knowledge on targeted plant efficiency and safety issues. A systematic review was conducted to apply the graded evidence claim methodology according to the EFSA Guidance [To illustrate the applicability of the model described above, a case study has been performed regarding the assessment of the pending health claim related to Guidance  based onTrifolium pratense (red clover) and cardiovascular health is justified (ID 2496) [Trifolium pratense is beneficial for the cardiovascular system”, with the following conditions of use: “1000–2000 mg of red clover in tablet or capsule form for 6 weeks”. Two types of bibliographic references were used for this study. On the one hand, references were addressed to EFSA in 2008 to support the claim  . The pro by EFSA ). On theSixteen studies were initially referenced for EFSA in 2008 in order to substantiate the claim . Among tRegarding the literature search from 2008 to 2017, ten studies were highlighted. Three studies conducted in mouse models were considered not relevant for the justification of the claim, because they were performed on animal disease models (type II diabetes and hepatic steatosis models). In addition, three clinical studies where no significant beneficial effect was observed on cardiovascular system parameters, and one clinical study conducted to assess the association of red clover isoflavones with other substances (probiotics) were also excluded, because they could not contribute to the justification of the claim. However, these studies were taken into consideration for the conclusion of the grade of the health claim. As a result, among the ten studies, four were selected for substantiation of the claim .Trifolium pratense (red clover) and cardiovascular health is justified. The diagram in To summarize, according to all the data available in the literature, thirteen studies were analyzed in order to investigate whether the pending health claim relative to Among the thirteen clinical studies where beneficial health effects were highlighted, some were considered as more relevant regarding the justification of a claim, even if all contributed to the level of evidence. It should also be noted that among the thirteen publications, four publications actually referred to only two distinct clinical trials: ,24 referisoflavones” equivalent and were between 40 mg/day and 80 mg/day. The duration of investigations was between one month and eighteen months. We also noticed that in the majority of the cases, no sample size calculation was specified. Regarding statistical results, ten studies showed statistically significant results between groups, which is a relevant level of evidence [2 for Chedraui et al.) and studies with a very small sample size were considered with caution during discussion [Trifolium pratense [Regarding the study populations, all investigated the effects on menopausal women, one additionally included pre-menopausal women , and twoevidence ,24,32,33scussion ,15,21. Ipratense ,32,33.Trifolium pratense is beneficial for the cardiovascular system” as it stands, based on the studies reviewed. Indeed, these were generally conducted on a small sample size and on populations mainly composed of menopausal women . Conclusions should therefore consider that the active ingredient has not been tested in the general population. Consequently, claims of health benefits should be worded focusing on postmenopausal women population, who can be considered at risk because of hormonal imbalances due to their physiological situation. It would also be interesting and possible to test the effects of red clover supplementation on a population with hypercholesterolemia/triglyceridemia/hypertension, if they do not require a prescribed drug management regime. Indeed, it would be relevant to target this population  to be able to observe physiological effects. A randomized, placebo-controlled clinical study in a population characterized as “at risk” based on their blood status and assessing changes in lipid parameters could be interesting.It seems difficult to confirm the proposed claim “cardiovascular health” axis refers to several physiological effects in the cardiovascular system; therefore, there are many criteria for assessing cardiovascular health. Indeed, the EFSA’s guidance allows claims related to changes in the blood lipid profile, reductions in blood pressure, endothelial function, reduced platelet aggregation, or homocysteine for cardiovascular health [cardiovascular health” axis in general. Regarding the doses and duration of supplementation, the doses proposed for the health claim labelling submission were “1000–2000 mg of clover”, without specifying the composition of the extract. Notably, in France, “l’arrêté plante” recommends a maximum consumption of 1 mg/kg of body weight per day in “aglycone” equivalent. The doses tested were also heterogeneous between studies, making the drawing of a general conclusion difficult. Regarding the chemical forms used , they were not always specified in the publications; therefore, we can question the bioavailability and efficacy of these different plant polyphenols. Moreover, it would be more appropriate to express the dose in “red clover isoflavones” rather than “red clover” in the condition of use. Regarding the duration of investigations, they were consistent with EFSA guidance requirements , as well as with pending claims (six weeks of consumption).Moreover, the studies were heterogeneous in terms of the evaluated parameters, making the comparison and correlation of studies difficult. The “r health . TherefoIn the assessment, it is also important to consider the strength of the evidence where some studies have failed to present any significant effects on cardiovascular parameters. This may be the consequence of an absence of an effect or a low statistical power . A meta-analysis would increase this power, including the difficulty of finding a common criterion relevant to all studies. In addition, it should be noted that cardiovascular parameters were presented as the main criterion for only one study , and forThe results of these studies do not enable a consensus to be formed as to the overall effectiveness of red clover on the cardiovascular system . Clinical studies are needed to investigate the effect of this plant extract on cardiovascular health by focusing on specific parameters, such as the concentrations of LDL-c, HDL-c, and triglycerides, which would be able to provide beneficial clinical data for the consumer. In addition, six studies of level Ib did not show any significant results on cardiovascular parameters, and thus were also taken into consideration when assessing the grade of this claim.Trifolium pratense “can contribute to” certain health benefits. The wording of the claim may be: “Isoflavones of red clover can contribute to lowering LDL-cholesterol in postmenopausal women, with a proposed dose of 50–80 mg/day of red clover isoflavones. Lowering LDL-cholesterol helps reduce the risk of cardiovascular disease”. This is with the support of studies from Clifton-Bligh et al. (2015), M. Terzic et al. (2012), M. M. Terzic et al. (2009), and Chedraui et al. (2008). This grading system has taken into account the evaluation criteria, the studies’ populations, the conditions of use of the product, and the relevance of the statistical data.In conclusion to this study case, the body of evidence mainly constitutes “Ib-type” studies, which could lead to a Grade B claim that The Grade system enables the classification of publications by the level of evidence according to their designs . However, critical reading is necessary for assessing the relevance of the results obtained and the conclusions of a study: study design, suitability of primary and secondary outcomes, sample size calculation, population characteristics set analysis , statistical analyses considering identification and control of potent bias, etc. Consequently, Synadiet’s model also takes into account overall parameters related to the quality of the results.Regarding the current health claim regulations for food supplements, there is a risk that the absence of information that arises from an all-or-nothing evaluation could lead to consumers being given false information or even being misled about many products . The current system, whereby 80% of products do not carry health claims, exposes consumers to the continued absence of any advice about the products for which there are no claims. Considering this situation, it seems that an evaluation able to consider the levels of evidence appears to be a good solution from a scientific and regulatory point of view. This is the direction in which the U.S. Food and Drug Administration has been moving for years . Our sugGrading health claims on plant food supplements according to the strength of evidence of the clinical studies conducted is not easy because all graded systems are linked to a predominant position attributed to the RCT, as well as to a level of scientific requirement that includes not only good-quality RCTs, but also meta-analyses or systematic reviews. The major difficulties in highlighting systematic reviews or meta-analyses on plant-based supplements are that: (1) clinical studies for food supplements are not mandatory for market declarations and are therefore less frequently conducted than for drugs; and (2) the heterogeneity of trial data characteristics has increased the difficulty of pooling clinical trials; for example, extracts are not always well defined and reported in studies, doses and populations are not the same, etc. In addition to this, the high level of evidence based on meta-analysis or on systematic review of RCTs are not even required for the market authorization of drugs and therefore there is no reason why they should be required for plant food supplements. Moreover, during the conduct of the study case, it appeared necessary to add some requirements to the Synadiet’s grading system, especially on the level of evidence and methodological aspects of the study.Trifolium pratense shows, firstly, that the methodology is applicable and efficient to lead to a conclusion based on convincing arguments. Secondly, our graded approach also highlights that each health claim needs to be analyzed case by case by a careful literature review. It also demonstrates that a graded system with an intermediary position, which is Grade B, “can contribute to”, can be interesting to enhance the existing scientific evidence, with distinctions between the levels of proof. Indeed, Grades A, B and C can then be easily discriminated, because Grade A use action verbs, and Grade B uses the conditional, “can”. In addition, traditional uses are taken into account with Grade C, which can be used with proper documentation. To accurately assess the reliability of the model, Synadiet conducted several other case studies on pending botanical health claims and concluded that “a minimum of 120 mg Bacosides from a Bacopa monnieri extract standardized in Bacosides (USP method)improves cognitive faculties and memory” (Grade A) when assessed on healthy subjects over a period of twelve weeks; and “Harpagophytum procumbens L. is traditionally used for maintaining joint health” (Grade C). It was also concluded that the available data were not sufficient to substantiate any claims regarding the benefit of Plantago lanceolata L. on the mobility and flexibility of joints.The case study conducted on It should be noted that this case study also raised different requirements for labelling and assessing a claim; the targeted claims need to be fully identified in terms of population, conditions of use, and assessment parameters . Statistical analysis reliability is also taken into account.Our graded approach for evaluating health claims about plant-based food supplements provides reliable information to consumers, in contrast to “all-or-nothing information”. This graded approach is, to date, the most highly developed which fits with the purposes of the Regulation (EC) No 1924/2006 of the European Parliament and of the Council of 20 December 2006 on nutrition and health claims made on foods, which were clearly implemented to protect the consumer. As presented, clinical studies play a key role in the evaluation of health claims . More than a tool to substantiate current health claims, this model of graded health claims will stimulate food supplement developers to invest in clinical research.