We previously developed draft MEDLINE and Embase (Ovid) geographic search filters for Organisation for Economic Co-operation and Development (OECD) countries to assess their feasibility for finding evidence about the countries. Here, we describe the validation of these search filters.We identified OECD country references from thirty National Institute for Health and Care Excellence (NICE) guidelines to generate gold standard sets for MEDLINE  and Embase . We validated the filters by calculating their recall against these sets. We then applied the filters to existing search strategies for three OECD-focused NICE guideline reviews  to calculate the filters' impact on the number needed to read (NNR) of the searches.The filters both achieved 99.95% recall against the gold standard sets. Both filters achieved 100% recall for the three NICE guideline reviews. The MEDLINE filter reduced NNR from 256 to 232 for the NG103 review, from 38 to 27 for the NG140 review, and from 631 to 591 for the NG146 review. The Embase filter reduced NNR from 373 to 341 for the NG103 review, from 101 to 76 for the NG140 review, and from 989 to 925 for the NG146 review.The NICE OECD countries' search filters are the first validated filters for the countries. They can save time for research topics about OECD countries by finding the majority of evidence about OECD countries while reducing search result volumes in comparison to no filter use. A search filter is a set of premade, reusable search terms with known performance characteristics , 2. TheyValidating filters is important because it allows conclusions to be made about the generalizability of a search filter's performance , 2. ValiPrecision and number needed to read (NNR) are measures of search filter efficiency. Precision is the percentage of retrieved records that are relevant, and NNR is the number of records that must be screened to retrieve one relevant record . ManuallThe Organisation for Economic Co-operation and Development (OECD) is an international agency that works in collaboration with high income, democratic countries to develop policies for reducing inequality and poverty in all nations . There aIn NICE guidelines, evidence about countries with similarities to the UK is often required. OECD countries are usually used as a proxy for similar countries. The purpose of creating the draft OECD filters was to assess their feasibility for finding evidence about OECD countries. The draft version of the filters used in the development study were promising, as they retained most OECD country evidence while reducing search result volumes .Following the development study, we updated and finalized the draft filters for the validation process . The purThe NICE OECD countries' search filters take the unusual approach of finding evidence about OECD countries by excluding evidence about non-OECD countries. Detailed information about the structure and content of the filters is available in our previous paper . BrieflyThe NICE OECD countries' search filters are composed of a set of subject headings for non-OECD countries that are applied to a separate set of OECD country subject headings with the NOT Boolean operator, as outlined below :Subject headings about non-OECD countries (combined with the OR Boolean operator)Subject headings about OECD countries (combined with the OR Boolean operator)1 NOT 2The filters must be applied to search strategies with the NOT Boolean operator, as in the following example :Search strategyNICE OECD countries' search filter1 NOT 2The filters work by excluding database records that have only the non-OECD subject headings, which are listed in the filters, and retaining all the remaining database records to find OECD country evidence. The filters retain database records that are indexed with only OECD country subject headings, that are indexed with both OECD and non-OECD country subject headings, and that are not indexed with either OECD or non-OECD country subject headings .The Venn diagram in Using the geographic subject headings to retrieve evidence directly would result in relevant OECD evidence being inadvertently missed. This is because some database records do not have any geographic subject headings. Because of this, we took a cautious approach of excluding unwanted geographic subject headings to retain relevant evidence in order to maximize the filters' retrieval.As explained in our previous paper , creatinThe aim of the NICE OECD countries' search filters is to improve the effectiveness and efficiency of literature searches when evidence about OECD countries is required. Our objectives were 1) to create novel validated OECD countries search filters that retrieve evidence about OECD countries from MEDLINE and Embase (Ovid) with high recall and 2) to reduce NNR in comparison to no filter use. The target for recall was set at 90% in line with previous filter studies .Search filters are validated using a gold standard (GS) set of known, relevant references , 2. The We identified the OECD country-related references for the MEDLINE and Embase GS sets from the evidence reviews of thirty NICE guidelines that were published between December 2018 and December 2019 (see Appendix 1 for the NICE guidelines).We screened the evidence tables for the reviews that informed each NICE guideline to identify references that had been categorized with an OECD country or a group of countries that included at least one OECD country. There were too many unique OECD country references to list them in a single search string . InsteadWe found 2,065 references that were available in MEDLINE (see Appendix 4) and 2,023 references that were available in Embase (see Appendix 5). We used these references to form the GS sets for each database.A sample size of at least 100 relevant references is suggested to provide a reasonable confidence interval for a filter that aims to retrieve at least 90% of all relevant references . Both thWe validated the filters by calculating their recall against their GS sets. To do this, we applied the MEDLINE and Embase filters to each of the thirty-three saved OECD country search strings in turn using the NOT Boolean operator (see Appendix 3 for an example). We recorded the recall results individually and then added them together to form an overall recall result, given that there were no duplicates in the GS (see Appendix 2). Recall was calculated as  × 100 to express as a percentage [After the filters were validated, we conducted a case study to evaluate the efficiency of the filters using “real life” searches. The filters had been validated for sensitivity using lists of individual references from thirty different guidelines. This did not demonstrate their impact on reducing the screening workload for search topics.For the case study, we used the original MEDLINE and Embase search strategies from three NICE guideline evidence reviews that were based on OECD country evidence. No geographic restrictions had been applied to the original search strategies. The three NICE guideline evidence reviews topics that we used are below:Evidence review 3: Increasing uptake in clinical risk groups NG103 Flu vaccination: increasing uptake.Evidence review P: Contraception after abortion NG140 Abortion care.Evidence review C: Facilitating the return to work of employees on long-term sickness absence and reducing risk of recurrence NG146 Workplace health: Long-term sickness absence and capability to work.We reran the original Embase searches on December 15, 2020, and reran the original MEDLINE searches on December 18, 2020. The rerun search strategies contained date limits that matched the time frame of the original search strategies. We calculated the original search strategies' recall and NNR for retrieving the included references for the reviews. We then applied the OECD countries' filters to the strategies using the NOT Boolean operator and compared the recall and NNR of the filtered strategies for finding the included references. Recall was calculated as  × 100 to express as a percentage , with prThe validated NICE OECD countries' geographic search filters for MEDLINE and Embase can be found in Appendix 6.We validated the MEDLINE and Embase filters by calculating their recall against the MEDLINE and Embase GS set references. The filters both met the >90% target for high recall. Both filters achieved 99.95% recall  .The filters both missed one reference that concerned OECD and non-OECD countries , 18. TheIn the case study, the versions of the search strategies with the filters applied achieved 100% recall for the included references that were found by the original search strategies .For the NG103 evidence review, the MEDLINE filter reduced NNR from 256 to 232, and the Embase filter reduced NNR from 373 to 341. For the NG140 evidence review, the MEDLINE filter reduced NNR from 38 to 27, and the Embase filter reduced NNR from 101 to 76. For the NG146 evidence review, the MEDLINE filter reduced NNR from 631 to 591, and the Embase filter reduced NNR from 989 to 925. On average the filters reduced the volume of references to be screened by 8% .The search strategies and search result volumes for the MEDLINE filter can be found in Appendix 7. The details for the Embase filter can be found in Appendix 8.The NICE OECD countries' geographic search filters for MEDLINE and Embase are the first validated filters to find evidence about OECD countries. To our knowledge, the filters are also the first validated, standalone search filters to be composed entirely of subject headings. In addition, the filters are the first validated, standalone filters to make exclusive use of the NOT Boolean operator with the aim of excluding irrelevant evidence to retain relevant evidence.The filters found almost all the OECD country evidence in the NICE evidence reviews from MEDLINE and Embase while reducing search result volumes by a modest but useful amount. The Cochrane Handbook estimates that 500–1,000 abstracts can be screened in an eight-hour period . The 8% We acknowledge that databases additional to MEDLINE and Embase are used for systematic literature searches . AlthougThe principles behind the filters can potentially be used to find evidence for a variety of other country groupings. For example, for research topics that require evidence about BRICS   or WorldThere are currently only three validated geographic search filters for the UK, Africa, and Spain in the published literature –9, 22–24As detailed in our previous paper on the development of the filters , we acknAs in the development study , the valIn our previous study, we noted that the geographic search filters may need to be updated to reflect changes in OECD membership, MeSH, and Emtree OECD and non-OECD country terms as well as changes to the names of the countries . HoweverThe NICE OECD countries' search filters for MEDLINE and Embase are the first validated filters to find evidence about OECD countries. The filters find the majority of evidence about OECD countries while reliably reducing search result volumes in comparison to no filter use. They can therefore potentially save time for research topics about OECD countries.


Four anthocyanin compounds predominated in fruit samples of American cranberry cultivars: cyanidin-3-galactoside, cyanidin-3-arabinoside, peonidin-3-galactoside, and peonidin-3-arabinoside. They accounted for 91.66 ± 2.79% of the total amount of the identified anthocyanins. The total anthocyanin content detected via the pH differential method was found to be by about 1.6 times lower than that detected via the UPLC method. Hierarchical cluster analysis and principal component analysis showed that the ‘Woolman’ cultivar distinguished from other cranberry cultivars in that its samples contained two times the average total amount of anthocyanins (8.13 ± 0.09 mg/g). The group of American cranberry cultivars ‘Howes’, ‘Le Munyon’, and ‘BL-8’ was found to have higher than average levels of anthocyanidin galactosides (means 3.536 ± 0.05 mg/g), anthocyanidins (means 0.319 ± 0.01 mg/g), and total anthocyanins (means 6.549 ± 0.09 mg/g). The evaluation of the antioxidant effect of cranberry fruit sample extracts showed that the greatest radical scavenging activity of the cranberry fruit extracts was determined in the fruit samples of ‘Woolman’ (849.75 ± 10.88 µmol TE/g) and the greatest reducing activity was determined in ‘Le Munyon’ (528.05 ± 12.16 µmol TE/g). The study showed a correlation between the total anthocyanin content and the antiradical and reductive activity of the extracts in vitro (respectively, R = 0.635 and R = 0.507,  Vaccinium macrocarpon Aiton) is a perennial evergreen plant of the Ericaceae A.L. de Jussie family growing in natural habitats in North America [The American cranberry  grow in the natural cenopopulations of raised bogs and intermediate-type wetlands [In the climatic conditions of Lithuania, small cranberries  , flavan-hia coli . The effhia coli . Studieshia coli  and ovarhia coli  cancer chia coli .Anthocyanins and anthocyanidins are one of the most important groups of biologically active compounds in cranberry fruit. Pappas and Schaich have found that in samples of freshly harvested cranberries, their levels could vary from 13.6 to 171 mg/100 g . About 9Yan et al. found that cyanidin-3-galactoside isolated from cranberry fruit extract was capable of scavenging free radicals and inhibiting the oxidation of low-density lipoproteins . Ho et aSeeram et al. found that the anthocyanin fraction in cranberry fruit extracts inhibited inflammatory processes , and craCranberry fruits, both fresh and processed, are used in the production of food supplements, juice, and in the confectionery industry ,8. CranbThe studies of the qualitative and quantitative composition of anthocyanins in cranberry samples are important for the evaluation of the quality of food products, food supplements, and pharmaceuticals. The preparation of high commercial value raw material of cranberry fruit should be based on the evaluation of phytochemical profiles, especially anthocyanins and their distribution in cultivated or wild cranberries.Vaccinium oxycoccos) and American cranberries (Vaccinium macrocarpon) and their cultivars, determining the regularities of the accumulation of biologically active compounds, the optimal time of berry harvesting, and the selection of the most promising cranberry cultivars for introduction.Determination of anthocyanins content in cranberry fruit are important for the evaluation of fruit samples of small cranberries   were also acquired.Acetonitrile , methanol , formic acid , reference standards for delphinidin-3-galactoside, cyaniding-3-galactoside, cyaniding-3-glucoside, cyaniding-3-arabinoside, peonidin-3-galactoside, peonidin-3-arabinoside, peonidin-3-glucoside, malvidin-3-galactoside, malvidin-3-arabinoside, cyanidin chloride, peonidin chloride, and malvidin chloride were purchased from Extrasynthese . ABTS 2,2′-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid), Trolox , potassium peroxydisulfate, sodium acetate , ferric (III) chloride hexahydrate , TPTZ -s-triazine) , acetic acid , hydrochloric acid , potassium chloride, and ethanol 96% (Vaccinium macrocarpon Aiton) (The fruits examined in the present study were mature and ripe fruit of different cultivars of American cranberry (n Aiton)  grown inv/v) ethanol containing 1% hydrochloric acid in an ultrasonic bath for 15 min at 80 kHz and 565 W at room temperature. The extract was collected and filtered through a membrane filter with a pore size of 0.20 µm. The prepared extracts were stored in dark glass vials at −20 °C.About 1 g (precise weight) of the lyophilized cranberry powder was extracted with 20 mL of 70% (+ solution (absorbance 0.800 ± 0.02) was mixed with 5 µL of the 5-fold diluted cranberry extract. A decrease in absorbance was measured at a wavelength of 734 nm after keeping the samples for 30 min in the dark. A standard curve  was produced by using standard Trolox solutions of 4000–48,000 μmol/L concentration.An ABTS∙+ radical cation decolorization assay was applied according to the methodology described by Re et al., 1999  and modi3·6H2O (0.02 M in water), and an acetate buffer  at the ratio of 1:1:10. A volume of 3 mL of a freshly prepared FRAP reagent was mixed with 10 µL of the cranberry extract. After 30 min, the absorbance was read at 593 nm using a UV-vis spectrophotometer. A standard curve  was produced by using standard Trolox solutions of 400–24,000 μmol/L concentration.The ferric reducing antioxidant power (FRAP) assay was carried out as described by Raudone et al. . The worThe total anthocyanin content was determined according to the pH differential method as described by Lee et al. . During pH1.0 − (A520 − A700)pH4.5; MW (molecular weight) = 449.2 g mol−1 for cyanidin-3-glucoside; DF = dilution factor; l = cuvette path length in cm (1 cm); ε = 26,900 mol extinction coefficient, in L × mol–1 × cm–1 for cyanidin-3-glucoside.The anthocyanin pigment concentration, expressed as cyanidin-3-glucoside equivalents, was calculated as follows:The analysis of the qualitative and quantitative composition of anthocyanins in cranberry fruit was performed using the UPLC methodology validated by Vilkickyte et al. . The ideData analysis was performed using Microsoft Excel 2016  and SPSS Statistics 27 . All experiments were carried out in triplicate, and presented as the mean value ± SD. Significant differences between samples were determined using ANOVA with Tukey’s test for multiple comparisons. The variability of the results were evaluated using coefficients of variation (CV). Principal component analysis (PCA) and hierarchical cluster analysis applying the between-groups clustering method with Euclidean distances were performed to elucidate the groupings of cranberries. Correlational analysis was performed using Pearson coefficient. Level of significance α = 0.05.Increasing consumer awareness creates the demand for the products with health-promoting effects and capabilities of prevention of various pathological processes. To assure the quality of such products, it is important to study the chemical composition of cranberry fruits and to conduct qualitative and quantitative evaluation of their biologically active compounds . The chrFour anthocyanin glycosides, namely cyanidin-3-galactoside, cyanidin-3-arabinoside, peonidin-3-galactoside, and peonidin-3-arabinoside, predominated in the studied samples of cranberry cultivars grown in Lithuanian  in a ranp < 0.05). Statistically significantly lower levels of cyanidin-3-galactoside  were found in fruit samples of cranberry cultivars ‘Bergman’, ‘Howes’, and ‘Le Munyon’, respectively. The lowest cyanidin-3-galctoside levels (0.29 ± 0.01 mg/g and 0.38 ± 0.01 mg/g) were determined in the samples of the ‘Early Black’ cultivar and the ‘BL-22’ genetic clone, respectively (p < 0.05).In our study, the highest amounts of cyanidin-3-galactoside (1.92 ± 0.02 mg/g) were determined in cranberry samples of the ‘Woolman’ cultivar (p < 0.05). Lower levels of cyanidin-3-arabinoside  were found in fruit samples of cranberry cultivars ‘Crowley’, ‘Howes’, ‘Le Munyon’, and ‘Mc Farlin’, respectively. The lowest cyanidin-3-arabinoside content (0.40 ± 0.02 mg/g) was found in fruit samples of the ‘BL-22’ genetic clone (p < 0.05).The highest content of cyanidin-3-arabinoside (1.51 ± 0.01 mg/g) was determined in cranberry samples of the ‘Woolman’ cultivar (p < 0.05). Statistically significantly lower levels of peonidin-3-galactoside (2.35 ± 0.02 mg/g and 2.41 ± 0.03 mg/g) were determined in cranberry samples of the ‘Howes’ cultivar and the ‘BL-8’ genetic clone, respectively. The lowest content of peonidin-3-galactoside (0.49 ± 0.02 mg/g) was determined in samples of the ‘Early Black’ cultivar (p < 0.05).The highest content of peonidin-3-galactoside (2.74 ± 0.03 mg/g) was determined in fruit samples of the ‘Woolman’ cultivar (p < 0.05). The lowest peonidine-3-arabinoside levels (0.50 ± 0.01 mg/g and 0.47 ± 0.02 mg/g) were determined in cranberries of the ‘Early Black’ cultivar and the ‘BL-22’ genetic clone, respectively (p < 0.05).The highest levels of peonidine-3-arabinoside  were determined in fruit samples of the genetic clone ‘BL-8’ and ‘Woolman’ and ‘Crowley’ cultivars, respectively (p < 0.05), while no cyanidin was detected in fruit samples of the ‘Searles’ cultivar. Peonidin content ranged from 0.17% to 3.53% in cranberry fruit samples. The highest levels of peonidin (0.184 ± 0.01 mg/g and 0.192 ± 0.01 mg/g) were found in fruit samples of ‘Howes’ and ‘McFarlin’ cultivars, respectively (p < 0.05). The lowest aglycone peonidin content (0.006 ± 0.00 mg/g) was determined in cranberry samples of the ‘Searles’ cultivar (p < 0.05). Malvidin content ranged from 0.21% to 2.60% in cranberry samples. The highest content of the anthocyanidin malvidin (0.107 ± 0.01 mg/g) was found in fruit samples of the ‘Howes’ cultivar, and the lowest (0.012 ± 0.00 mg/g) in fruit samples of the ‘Crowley’ cultivar (p < 0.05). These results suggest that genotypes have characteristic variation in the amounts of individual anthocyanins and anthocyanidins.The analysis of the quantitative composition of the anthocyanin complex in cranberry fruit samples showed that aglycones formed a small part of the anthocyanin complex. The highest content of one of the anthocyanidins, cyanidin (0.133 ± 0.01 mg/g), was determined in fruit samples of the ‘McFarlin’ cultivar (p < 0.05). Lower total anthocyanin levels  were found in cranberry samples of ‘Howes’, ‘Le Munyon’, and ‘Crowley’ cultivars and in the ‘BL-8’ genetic clone, respectively. The lowest total anthocyanin levels (1.95 ± 0.11 mg/g and 2.21 ± 0.15 mg/g) were found in fruit samples of the ‘Early Black’ cultivar and the ‘BL-22’ genetic clone, respectively (p < 0.05).The highest total anthocyanin content (8.13 ± 0.09 mg/g) was determined in cranberry samples of the ‘Woolman’ cultivar  was found in fruit samples of the ‘Early Black’ cultivar, and the maximum total content of anthocyanins (5.09 ± 0.24 mg) was found in fruit samples of the ‘Woolman’ cultivar. The total anthocyanin content in the fruit samples of American cranberry cultivars ‘Bergman’, ‘Crowley’, ‘Howes’, ‘Le Munyon’, and ‘McFarlin’ grown in New Zealand’s climatic conditions ranged from 1.34 mg CGE/g to 1.90 mg CGE/g and were about 1.5 times lower than the total anthocyanin content found in our study in samples of the abovementioned cultivars .The total anthocyanin content in cranberry fruit samples determined via the pH differential method was about 1.6 times lower than the total anthocyanin content determined via the UPLC method. The coefficient of variation of the total anthocyanin content in cranberry fruit samples determined via the UPLC method was 33.57%, while that determined via the pH differential method was 37.45%.Grace et al. in their study have found that the total anthocyanin content (expressed as CGE) in American cranberry fruit samples detected via the application of the pH differential method was 1.4 times lower than that detected via the HPLC method . Lee et p < 0.05). A very strong significant correlation between the total anthocyanin content in cranberry fruit samples assessed via the pH differential method and the UPLC method was also found in other studies, the correlation coefficients being r = 0.98, r = 0.925, and r ≥ 0.99 (p < 0.05) [The results obtained using pH differential methods and UPLC were highly corresponding and correlated  ,54,55. TThe analysis of the similarity of the composition of anthocyanins in American cranberry cultivars introduced and grown in Lithuanian climatic conditions was based on the quantitative composition of anthocyanins determined in the samples of different cultivars and was carried out by performing a hierarchical cluster and principal component analysis. The cluster analysis of the samples of different cultivars of American cranberry was performed on the basis of the quantitative composition of anthocyanins delphinidin-3-galactoside, cyanidin-3-galactoside, cyanidin-3-glucoside, cyanidin-3-arabinoside, peonidine-3-galactoside, peonidin-3-glucoside, peonidin-3-galactoside, peonidine-3-arabinoside, cyanidin, malvidin-3-arabinoside, peonidin, and malvidin. Fruit samples of cranberry cultivars were divided into three clusters .Fruit samples of cranberry cultivars ‘Baifay’, ‘Early Black’, ‘Early Richard’, ‘Holiston’, ‘Prolific’, ‘Searles’, ‘Bain-6’, ‘BL-12’, and ‘BL-22’ were assigned to cluster I because their total anthocyanin content was by 1.7 times lower than the average total anthocyanin content. The total amount of anthocyanins found in the fruit samples of the cluster II cultivars  was close to the mean anthocyanin content. Cluster II is considered to consist of cranberry cultivar samples which have higher than average levels of anthocyanidins . Cluster III consisted of one American cranberry cultivar ‘Woolman’. The total anthocyanin content in cranberry fruit samples of the ‘Woolman’ cultivar was twice the mean total anthocyanin content in the studied cultivars.A principal component analysis (PCA) was performed to evaluate the quantitative variation of the identified anthocyanin group compounds in different American cranberry cultivars . Two maiAmerican cranberry cultivars located in the negative squares of PC I and PC II  coincided with cluster I in the cluster analysis, which had a lower-than-average total anthocyanin content. The cranberry cultivars ‘Bergman’ and ‘Crowley’ formed the second group of similar cultivars with above-average total anthocyanin content and below-average total anthocyanidin  content. The total anthocyanin content in the samples of the hybrid cultivars ‘Bergman’ (a hybrid of ‘Early Black’ and ‘Searles’) and ‘Crowley’ (a hybrid of ‘Mc Farlin’ and ‘Prolific’) was higher than that in samples of the precursor cultivars ‘Early Black’ and ‘Searles’, and ‘Mc Farlin’ and ‘Prolific’, respectively. Diaz-Garcia et al. found that fruit samples of the second- and third-generation cycle cultivars contained higher levels of anthocyanins than the samples of the early selection attempts did .The American cranberry cultivar ‘Woolman’ was far removed from other cranberry cultivars in the PCA chart because the total anthocyanin content found in it was almost two times higher than the mean total anthocyanin content. Exceptionally high levels of cyanidin-3-galactoside and peonidin-3-galactoside were determined in samples of the cranberry cultivar ‘Woolman’, but the total content of anthocyanidins  was lower than their mean total content in cultivar samples. In our previously published study, samples of the cranberry cultivar ‘Woolman’ differed from samples of cultivars ‘Baiwfay’, ‘Drever’, ‘Bain’, ‘Bergman’, ‘Searles’, ‘Holliston’, and ‘Piligrim’ in that they contained high levels of phenolic acids and dihydrochalcones and low levels of flavonols and flavan-3-ols .The total content of anthocyanidin galactosides in fruit samples of the group consisting of the cranberry cultivar ‘Hobelman’ and genetic clones ‘Ar-2’, ‘Bain-MC’, and ‘BL-15’ was close to the mean total amount of galactosides in the studied cultivars, and the total content of anthocyanidins  was higher than the mean total amount of anthocyanidins. The cranberry cultivar ‘Mc Farlin’ was far from other cultivars in the PCA chart because its fruit samples contained two times the average amount of aglycones . The group of American cranberry cultivars ‘Howes’, ‘Le Munyon’, and ‘BL-8’ located in the positive quadrant of PC I and PC II was characterized by higher anthocyanidin galactoside and total anthocyanidin contents compared to the mean total anthocyanidin and galactoside contents.Recently, many studies have been conducted on phenolic compounds in plant matrices as natural antioxidants with protective antioxidant properties as well as on the application of these phenolic compounds for prophylactic purposes . The antThe strongest antiradical activity detected by using the ABTS method (849.75 ± 10.88 µmol TE/g) was found in samples of the cranberry cultivar ‘Woolman’ . The strOszmiański et al. have investigated the antioxidant activity of fruit extracts of ‘Howes’ by applying the ABTS and FRAP methods . Howeverp < 0.001), and for the FRAP method . Oszmiański et al. determined similar correlation coefficients for the ABTS (r = 0.675), FRAP (r = 0.614), and DPPH (r = 0.602) methods. Chaves et al. have found that the total anthocyanin content determined in the samples of blackberries, blueberries, and strawberries correlated with the antiradical capacity of the extracts determined by the DPPH and ABTS methods  [The correlation between the total anthocyanin content and antioxidant capacity was determined for the ABTS method  . The antBifidobaterium spp. and Lactobacillus spp., and the inhibition the growth of pathogenic bacteria, such as Staphylococcus aureus and Salmonella typhimurium [Akkermansia population and induced features of the prevention of metabolic phenotypes linked to obesity. Furthermore, treatment with cranberry extract was found to lower content of intestinal triglyceride and to reduce inflammation and oxidative stress of the intestinal tract [Scientific studies confirm that antioxidant activity mechanisms are interrelated with the biological activities expressed in the body and substantiates that the bioavailability of phenolic compounds is highly important for their bioactivities in vivo . The dathimurium ,64. Gutpal tract . The benCranberry’s phytochemical profile is genotype-dependent and this study provides new knowledge on the variation in the composition of anthocyanins and anthocyanidins in different cranberry cultivars. Moreover, this study allows for the assessment of the quality of cranberry fruit and the use of high-quality cranberry raw material for food and health promotion. Four anthocyanin compounds predominated in fruit samples of American cranberry cultivars: cyanidin-3-galactoside, cyanidin-3-arabinoside, peonidin-3-galactoside, and peonidin-3-arabinoside, and they can be regarded as qualitative profile markers of American cranberry products. The chromatographic profiles are species-characteristic and can be applied for cranberry authenticity studies.The fruits of American cranberry cultivars ‘Woolman’ and ‘Le Munyon’ distinguished with the highest content of anthocyanins, and their extracts had the strongest antioxidant activity. The cultivation of cranberry cultivars ‘Woolman’, ‘Howes’, and ‘Le Munyon’ in Lithuanian climatic conditions could be carried out in gardens and collections. The results of this study allow for evaluating the qualitative and quantitative composition of anthocyanins and anthocyanidins in fruit samples of the grown cultivars and for ensuring the preparation of high-quality cranberry raw material. High-quality phytochemically characterized American cranberry extracts rich in natural antioxidants can be used in the production of high-added-value products, food supplements, and other functional ingredients for nutrition and health.


Despite high rates of critical incidents (CIs) in working class occupations, there is a significant gap in our understanding of responses to these events. In this study, we aimed to inform a response training module by synthesising the key elements of pre-, during- and post-incident responses to CIs and suicide in the workplace. A rapid review identified studies on responses to CIs or suicide deaths in the workplace published between January 2015 and June 2020. A systematic search of six databases  and grey literature was performed. Studies were excluded if the focus was on non-colleagues. Two reviewers independently conducted record screening, a review of the full text and assessed study quality. The existing evidence was synthesised and interventions were categorised using Haddon’s Matrix. Five studies were included, reporting on CIs across a range of workplace settings, including railways, factories, police and military, along with external critical response units. Overall, study quality was assessed as being poor. Most of the evidence focused on the pre-incident and post-incident stage. There is little evidence on responses to CIs in the workplace. Evidence-based education and training is necessary to establish organisational responses to assist with supporting workers exposed to workplace CIs. Critical incidents (CIs), including work-related death and injuries, remain a significant public health issue. Recent global estimates report that approximately 350,000 deaths per year are due to fatal incidents, with an additional 313 million workers involved in non-fatal occupational incidents either resulting in serious injuries or requiring at least four days’ absence from work . In AustThe witnessing of injuries  and suicide or hearing about these types of events from colleagues can leave employees and their employers susceptible to adverse psychological outcomes such as post-traumatic stress disorder (PTSD) . FactorsThe levels of preparedness to CIs in the workplace vary. Although most workplaces, particularly government organisations, have formal policies and procedures in place, some organisations also choose to outsource their management of critical events. One example involves an early intervention strategy known as employee assistance programmes (EAPs), providing employees with immediate emotional support following traumatic events . An alteWith regard to suicide postvention—which is defined as: “those activities developed by, with, or for suicide survivors, in order to facilitate recovery after suicide, and to prevent adverse outcomes including suicidal behaviour” —there isThere is very little evidence on the type of training workplaces should consider in the management of workplace CIs. Some organisations focus on preventative measures such as pre-incident resiliency training. This approach, which has been implemented in the emergency sector, is focused on developing psychological resiliency and education and awareness among employees in regard to how resiliency can act as a protective factor when exposed to traumatic events . A studyTo date, due to a focus on the prevention of death by suicide and CIs in the workplace, there has been little attention given to the issues of workplace responses to death by suicide and CIs on an individual level and at the broader organisational level, or of how blue-collar industries are managing responses to these traumatic events.The aim of this study was to identify the key elements of responses to CIs and death by suicide in the occupational setting. This was achieved by performing a rapid review of the published peer-reviewed literature on responses to CI and key informant interviews with construction workers and managers about their responses to CIs and deaths by suicide in the workplace. The results of the rapid review only are included here; the broader study findings will be published in the future. Together, these findings informed the development of recommendations for the development of a postvention and CI response training module for Mates in Construction (MiC).Identify all of the relevant evidence regarding workplace responses to CIs and suicide in the workplace published between 2015 and 2020;Assess the quality of this evidence using the National Health Medical Research Council Hierarchy of Evidence  and the Synthesise the existing evidence to identify the key elements necessary for the development of an effective workplace programme and;Apply results to a Haddon’s matrix framework to categorise the intervention strategies identified in the review.To achieve these goals, this rapid review aimed to:This rapid review of evidence was commissioned by Mates in Construction (MiC) Australia to inform the development of critical response training for the period after a suicide or critical incident. Rapid reviews “streamline traditional systematic review methods in order to synthesize evidence within a shortened timeframe” . StudiesThe following six databases were searched for articles published from January 2015 to June 2020: Medline/Web of Science; Cumulated Index to Nursing and Allied Health (CINAHL)/EBSCO; PsycINFO/ProQuest; Sociology Collection/ProQuest; Academic Search Complete/EBSCO and, Business Search Complete/EBSCO. An example of a search string used to retrieve articles in Medline (Web of Science) is included in Prior to searching the literature, test searches of search strings and databases were conducted. In any quality review, the pre-testing of the search strategy serves a dual purpose. Firstly, testing of keywords and corresponding medical subject headings (MeSH) or synonymous terms (if available) ensures the maximum retrieval of relevant material, while minimising the number of irrelevant records. Secondly, the testing of search strings across a variety of databases guides the process of identifying which database contains information that will help to answer the research question. As a result, eligible studies were identified by searching the titles and abstracts of records using the following search string:  AND (bereavement OR grief OR mourning OR trauma OR postvention) AND (workplace OR workforce OR employment OR employee OR co-worker OR colleague). Truncation, using asterisk symbol (*) to search variant endings of a word, and/or proximity operators were applied to each of the search terms.Studies were included in the review according to the following a priori criteria: (1) reported on deaths or CIs within the workplace environment; (2) included responses to the incident ; (3) full text available in the English language and published between 2015 and 2020, and, (4) contains original data  or a review of original data.Despite widespread use of the term “critical incident”, no standard definition exists. In the published literature, definitions of the term “critical incident” vary widely depending on the context in which it is being used. A further complication is the frequent use of the term “traumatic event”, which is often used interchangeably with “critical incident”. In a paper on CIs in the police force, Maguen  defined Studies were excluded if: (1) the focus was on patient or client death ; (2) the study did not contain empirical evidence ; or (3) the paper was a protocol.Once the searches of the electronic databases and desktop grey literature were completed, the titles and abstracts of the identified records were imported into Endnote x9 bibliographic software. Duplicate citations were removed using Endnote’s duplicate identification tool. A rigorous manual review was also undertaken for any remaining duplicate records. Following this, unique records were imported into Covidence systematic review software  for screData extraction from the included studies was completed by two reviewers  using a Microsoft Office Excel 2007  coding template, custom made for this project. Categories of data retrieved included country, study design, type, workplace setting, target group, number of subjects, intervention name and description, primary outcome measures and a summary of key results.Quality appraisal tools determine the reliability of evidence used in systematic reviews by assessing the internal validity of research studies . EvaluatThe Haddon’s Matrix conceptual framework was applied to capture the key elements of the intervention across time and function. Haddon’s Matrix is a framework that is widely applied in the field of injury prevention and offers a practical approach to recording risk and/or protective factors across time . The coln = 17); no intervention (n = 11); not co-worker (n = 6); published prior to 2015 (n = 4); study examined the impact of CIs on co-workers, not an intervention (n = 2); and response to patient or client (n = 2). Following the full-text review, five records met the eligibility criteria and were included , Canada (n = 1) and Korea (n = 1). Four of the five studies utilised a quantitative methodology and one utilised mixed methods. Three of the four quantitative studies used a cross-sectional design and one was a case series. The one mixed methods study used a quantitative cross-sectional design and a qualitative survey  programme was developed by a social worker to help employees recover from exposure to workplace deaths . A furth Suicide  by Carso Suicide  (2020).  Suicide . HoweverThroughout the grey and academic literature, one finding was commonly reported—that the presence of clear messaging and information about the incident is received positively, whereas poor communication increases distress. Gulliver et al. , recommeAlthough workplace deaths are investigated by the appropriate authorities, recommendations about specific interventions to support the workplace are not apparent among the publicly available outcomes from these authorities. For example, in our national search of coroners’ findings, we located the inquest into the death of Colin Arthur Greaves . In thisCurrent models used to address exposure to trauma in the workplace include critical incident stress management (CISM), otherwise known as critical incident stress debriefing (CISD) or psychological debriefing. There is little evidence of the effectiveness of this approach. Rather, many suggest that this approach is not beneficial and can be harmful, including the US National Institute for Health and Care Excellence (NICE) , which rThe major strength of this study was that a broad literature search was performed and a systematic approach was taken to minimise the likelihood that studies that met the eligibility criteria were missed. Two experienced reviewers screened the studies, extracted data and assessed study quality. However, this review was limited by several factors. First, as a rapid review it was time limited and to ensure it is contemporary a date limitation of the past five years was applied. Thus, papers published prior to 2015 were not retrieved. However, our prior review of evidence on postvention, which systematically reviewed all suicide bereavement and postvention evidence over a 50-year period to 2015, provided a solid foundation. Very few papers met our inclusion criteria. This limits the findings of this paper; however, it also demonstrates the very small evidence-base for organisational responses to critical incidents and suicide. Of those papers included, the evidence was generally poor, limited by study design (as per NHMRC evidence ranking) and was all ranked at the lowest level. The quality of evidence reported utilising the JBI appraisal tools  was of mDespite the small number of studies in this review, there was evidence that some interventions warrant consideration for an organisational approach to CIs. However, it should be noted that few of the studies evaluated these interventions and, as a result, additional examination of the effectiveness of interventions is required. This is specifically needed in order to establish evidence-based education and training for workers, on CI preparedness, and for managers and senior leadership, on support for workers exposed to CIs. The following five recommendations are for consideration and are intended to provide practical guidance in order to develop an organisational approach to prepare for, respond to and recover from CIs.Consistent with a multifactorial approach, interventions could be activated at the relevant temporal phase of CIs—preparedness, response and recovery at both the worker, management and whole-organisation level. As suggested by the authors, these combined interventions could be documented, delivered and monitored through a detailed critical incident preparedness, response and recovery plan (CIPRRP). A CIPRRP could be developed in collaboration with appropriately qualified occupational health and safety practitioners, and could have representation at all levels of the organisation and include business and human continuity protocols. This would ensure that the CIPRRP was based on best-practice principles of occupational health and safety and that there was input from workers, managers and senior leadership in order to maximise investment in the plan. The plan should be managed through a governance structure, be accessible to all staff to ensure transparency and be regularly reviewed  and updated.Measures to evaluate whether a CI was managed in accordance with the CIPRRP should be included in the plan. This could be conducted for both simulated and actual CIs as a mechanism of examining adherence and to identify areas of improvements. Outcomes relating to the evaluation of simulated and actual CIs should be disseminated to all members of the organisation to maintain transparency and as a mechanism of organisational engagement. How, by whom and when such a plan is developed should be included in any training.Peer support programmes have been implemented in a number of workplaces and were an intervention present in one of the included studies. Further examination of the elements of peer support programmes and their effectiveness in contributing to worker recovery following exposure to a CI may be required to determine whether it should be included in a CIPRRP. Where peer support is used, there is emerging evidence that normalisation of experiences is a useful activity. However, the evidence as to how benefits are monitored and potential challenges are addressed need to be carefully considered.CI preparedness could also include all members of organisations receiving practical and evidence-based training on the nature, impact and recovery from CIs. Additional training could be provided to managers and senior leadership on how to support workers exposed to a CI, and that support should be provided at every layer of the organisation. Evidence of participation and passing of an assessment testing workers and managers knowledge could be linked to performance plans to maximise compliance by employees with poor engagement in occupational health and safety.Consideration could also be given to senior leadership receiving regular external psychological support or at specified intervals following a CI. This will ensure that support is provided by senior leadership to managers that are supporting workers, as well as for senior leadership, as the impact of CIs can be felt beyond directly exposed workers. This training should ideally be undertaken at the time of induction to an organisation and also include regular CI simulations (with post-simulation debriefings) and refreshers.The organisational expectations on workers’ and managers’ responses to CIs should be outlined in detail in the CIPRRP and be communicated via an education and training programme, preferably with practical activities and an assessment. Elements that could be considered for inclusion comprise: (1) how workers should respond immediately prior to and during a CI, for example, the extra-and intra-organisational communication of the occurrence of a CI, the provision of first aid to injured co-workers, etc.; (2) extra-and intra-organisational communication by managers and senior leadership; (3) how and what support will be provided to workers in the immediate period following the CI, including, transportation away from CI site (where relevant and possible), including peer and professional psychological support during the period of compassionate leave, along with any human resource and legal considerations.Studies identified a number of intra- and extra-organisational interventions to support recovery for workers exposed to CIs and for and organisations impacted by CIs. The CIPRRP could include a suite of clinical and non-clinical psychological support programmes that could be offered to individuals and groups of workers. Organisations should offer access to psychological interventions immediately following exposure to the CI, throughout compassionate leave and for a period following the return to work, as the willingness to engage may change over time. There is good evidence for the effectiveness of psychological reprocessing techniques, particularly for symptoms of post-traumatic stress .At the organisational level, the CIPRRP could include a protocol that for actual CIs, a whole-organisation post-CI seminar or debriefing be delivered to facilitate worker and organisational recovery and promote transparency in the response and recovery process. Protocols could also be included in the CIPRRP that receive input from external occupational health safety professionals, invited (as required) to assess organisational and worker recovery and to provide any recommendations on future interventions required.There is a profound lack of available evidence relating to interventions aimed at preventing workplace trauma. This can lead to poor practices that could increase distress in already vulnerable individuals. Monitoring individuals in the post-incident period has received the most attention; however, how and for whom this is done has not been specified. Our analysis of the reviewed studies emphazies that a broader approach to managing critical incidents in occupational settings, which highlights the pre-incident, incident and post-incident temporal pathway, would assist in mapping when and where training should be considered to alleviate adverse outcomes. The focus on the incident as being the primary point for intervention fails to identify the lessons learnt, or training and development opportunities for when incidents occur in the future. Similarly, considering the individual level, as well as the policy and procedural levels, will assist in the integration of training to support workers post-CI or suicide events on-site or among a work crew.


Recommendations to prevent morbidity and mortality in children was a high priority for the editorial group of a WHO pocket book for primary health care in the European region. However, the benefit of preventive interventions is not always clear and recommendations differ across countries and institutions. Here, we summarize the existing recommendations and the most recent evidence on ten selected preventive interventions applied to children under five years to inform this group. In addition, we reflect on the process and challenges of developing these summaries.For each intervention, we systematically searched for current recommendations from the WHO, the United States Preventive Services Task Force, the workgroup PrevInfad from the Spanish Association of Primary Care Pediatrics, the Centers of Disease Control and Prevention, and the National Institute for Health and Care Excellence. Then, we systematically searched the sources above and the Cochrane library for relevant systematic reviews. For each topic, we reported the recommendations and the strength of the recommendation when and as reported by the authors. We summarized the main findings of systematic reviews with the certainty of the evidence as reported. Categorising the ten preventive interventions in three groups allowed narrative comparisons between similar types of interventions and between groups.For the single interventions of providing vitamins D and K and topical fluoride there is overall a high degree of consensus between institutions for the evidence of their effectiveness. For the multiple interventions to prevent sudden infant death syndrome and unintentional injuries consensus was more variable as evidence of effectiveness is harder to ascertain. For the screening interventions the summaries of recommendations and evidence varied too. While institutions generally agreed in recommending for vision screening and against universal screening for language and speech delay and iron deficiency, they had some differences for pulse oximetry and autism.The transparent and independent process shed light upon how institutions use existing evidence in their settings – common and different positions were accounted for and became visible. We also identified gaps and duplications of research. Our approach was a crucial starting point for developing the respective sections in the pocket book.The online version contains supplementary material available at 10.1186/s12887-021-02638-8. Preventable morbidity and mortality among children constitute a critical global health matter. Preventive interventions are specific population- and individual-based interventions, which aim to protect, promote, and maintain health and well-being, and to minimize the burden of diseases, associated risk factors and disability . PreventThe World Health Organization (WHO) European Region is developing a new pocket book for primary health care for children and adolescents in Europe. To this end, the Integrated Management of Childhood Illness (IMCI) and recommendations around common childhood diseases are being revised, so that the pocket book provides updated recommendations applicable to the European setting, to ensure provision of quality services at primary health care level.In this review, we aimed to summarize the existing recommendations and the most recent evidence on ten selected preventive interventions applied to children under 5 years of age to inform the WHO editorial group to make recommendations for health promotion in primary health care. The ten selected preventive interventions were: vitamin D prophylaxis in infancy, vitamin K prophylaxis in newborns, prophylaxis of caries with fluoride for children under 5 years, sudden infant death syndrome (SIDS) prevention, prevention of unintentional injuries in children under 5 years, vision screening in newborns and early childhood, newborn screening for critical congenital heart defects, screening of iron deficiency anaemia in early childhood, screening for autistic spectrum disorder (ASD) in early childhood, and screening for language and speech delay in children under 5 years.In addition, we reflected on the process and challenges of developing recommendations based on available evidence and other determining factors, according to the type of recommendations.Pre-selection of preventive interventions: during the autumn meeting of the European Confederation of Primary Care Paediatricians (ECPCP) in October 2018 in Vilnius the 25 delegates representing ten countries completed a survey about the estimated magnitude of the benefit of 22 preventive interventions.Exclusion of the interventions with high consensus on benefit: a steering group reviewed the survey results and identified six interventions with high consensus of benefit and decided to focus on those with controversial benefit.The steering group presented survey findings to the WHO editorial core team of the pocket book to reach a final consensus and selected ten preventive interventions for evidence synthesis, based on priority research and feasibility criteria including time constraint.The list of preventive interventions that we reviewed is neither an exclusive nor a comprehensive selection of preventive interventions for children under 5 years of age. We selected preventive interventions suitable for primary health care settings common in the European region, and applicable to primary health care physicians including paediatricians and other primary care providers. We followed a multi-step process with the aim to select most relevant topics for child health where evidence of benefit is controversial and for which evidence synthesis is most needed for decision making.For each topic, we formulated several key questions following the Participants, Intervention, Comparison, Outcomes (PICO) format whenever this was applicable. The main focus of the key questions addresses the effectiveness of the preventive interventions. We also assessed the balance between benefits and harms of the preventive interventions whenever this was applicable and feasible.Firstly, we gathered existing recommendations for each preventive intervention, from sources we deemed relevant with potential applicability to the European context. We then intended to gather all available evidence to assess effectiveness and safety of the preventive interventions. We developed a research protocol that includes the search methods prior to starting the search.For each topic, we systematically searched for current recommendations from the WHO, the United States Preventive Services Task Force (USPSTF), the workgroup PrevInfad from the Spanish Association of Primary Care Pediatrics (AEPap), the Centers for Disease Control and Prevention (CDC) in the US, and the UK’s National Institute for Health and Care Excellence (NICE) websites, by using key words (specified for each topic in the corresponding article) and by manual search –6. We liWe selected these sources in agreement with the expert group members in charge of developing the preventive chapter for the WHO pocket book for primary childcare. For topics with no or a limited number of recommendations by the above institutions and sources, we searched for additional sources that we cited in the corresponding article.We systematically searched for systematic reviews commissioned or cited by the WHO, USPSTF, PrevInfad and NICE to inform their recommendations, published from 2010 up to date. For each topic, we also searched the Cochrane library for identification of relevant systematic reviews, by using key terms in titles, abstracts and keywords . We screFor each topic, we cited the recommendations identified from the different sources and the strength of the recommendation when and as reported by the authors. USPSTF classifies their recommendations in one out of five grades to describe the strength of the recommendation Table  8]. Pre. Pre8]. We summarized the main findings of systematic reviews in a narrative way and in summary tables. We also reported the certainty of the evidence as reported by the review authors. Cochrane authors used the GRADE approach for assessing the certainty of the evidence . This coNo statistical analysis was performed from the gathered evidence.Single pharmacological interventions for preventing undesirable outcomes (primary prevention): vitamin D supplementation for preventing rickets and infections, vitamin K for preventing haemorrhage disease of the newborn, and fluoride for preventing dental caries.Multiple interventions for preventing an undesirable outcome (primary prevention): interventions addressing risk factors and promoting beneficial measures for preventing SIDS and unintentional injuries.Screening interventions to detect a condition early (secondary prevention): vision screening in newborns and early childhood, use of pulse oximetry for newborn screening of critical congenital heart defects, screening of iron deficiency anaemia, screening for ASD, and screening for language and speech delay.We classified the ten preventive interventions into three groups, to allow narrative comparisons among similar types of interventions, and for reflection on the process and the challenges of developing recommendations based on available evidence:We present the evidence synthesis for each of the ten preventive interventions in separate articles of this Supplement, including a comprehensive list of references of all the included sources. Table We summarized the main characteristics of the supporting evidence (such as source of the evidence and main findings), the certainty of the evidence, the recommendations across the reviewed documents and the strength of the recommendations in Tables Three articles of this Supplement reviewed single interventions. We found that all the international institutions we looked at  recommend supplementation with vitamin D for preventing rickets, administration of vitamin K for preventing the haemorrhage disease of the newborn, and use of topical fluoride for preventing caries. The strength of the recommendation for the main statement is strong or grade B for each intervention and is based on moderate to high certainty of the evidence for vitamin D supplementation and use of fluoride. Between the three interventions , there are substantial differences in the time when trials or systematic reviews that support the evidence were conducted. For example, studies assessing the effectiveness of vitamin K for preventing the haemorrhage disease of the newborn were conducted in the 1960s and 1990s, while assessment of the use of topical fluoride for preventing caries come from more recent trials (up to 2014) with a systematic review conducted in 2019.Although all institutions recommend these interventions in general, we noted a lack of data and an overall lower certainty of the evidence to inform specific aspects for each of these three interventions including doses and duration of supplementation. For example, there is a lack of evidence to inform whether vitamin D supplementation should be given only during the first 12 months of life or beyond, to inform what is the optimal regimen of oral vitamin K (doses and number of doses), or to inform which fluoride concentration is optimal in toothpastes for preventing caries and for limiting adverse effects.Two articles of this Supplement assessed the impact of several interventions for preventing either SIDS or unintentional injuries. In both cases, there were no randomised controlled trials (RCTs) and the evidence came from retrospective analyses (mainly case-control studies) and surveillance data only. Certainty of the evidence varied from low (mainly) to high, and the strength of the recommendation varied from strong to weak or insufficient  for the risk factors assessed. Overall, the different institutions recommend similar preventive interventions based on the available evidence and good practice recommendations based on common sense.Five articles of this Supplement summarize the evidence and existing recommendations for screening interventions.For vision screening, we found that all the institutions we looked at recommend screening all newborns for congenital cataract and retinoblastoma through ocular inspection and red reflex examination. Although the screening has low sensitivity, it is a harmless examination that is widely accepted due to the severity of both diseases, and both diseases clearly benefit from early detection and treatment. All institutions also recommend vision screening among children between three and 5 years of age, based on indirect evidence of moderate net benefit.All the institutions we looked at recommend against universal screening for detecting iron deficiency anaemia and against universal screening for detecting language and speech delay . The strength of the recommendation for both screening interventions was judged as strong, and was based on the lack of a suitable screening tool and the lack of evidence of benefits from early interventions applied to children detected by screening. The American Academy of Pediatrics is the exception, and recommends universal screening for detecting iron deficiency anaemia despite the lack of evidence.For the remaining two screening interventions, institutions have discrepant views. Some institutions do not recommend pulse oximetry in all newborns because its less than optimal sensitivity leads to false positive results that require unnecessary referral of cases representing a burden to families and the health system. Institutions recommending it however argue that most of the patients with false positive tests may have other severe clinical conditions and would benefit from prompt recognition and treatment, at least within the first 24 h of life. Views of institutions on universal screening for detecting ASD are conflicting too. Although screening tools do identify children aged 12 to 36 months with ASD accurately, and small studies show a benefit of early treatment, no evidence on the effectiveness of interventions applied to children with ASD detected through screening was found.Overall, we found that there is high consensus among institutions for recommending single preventive interventions, for which there is moderate to high evidence that such interventions are effective. However, for these single interventions, the lack of data or the low certainty of the evidence regarding doses, frequency or duration of supplementation results into less clear recommendations and ultimately lesser consensus between institutions. Indeed, while no institution is arguing that vitamin K is effective for preventing haemorrhagic disease of the newborn, national policies are recommending different regimens with regard to route, dose and frequency. This is likely to be explained by the limited data from studies that would directly compare different regimens. In this case, we acknowledge that prospective and comparative trials are challenging to be conducted in the future, due to the low incidence of the outcome and above all due to the severity of the outcome.For SIDS and unintentional injuries, assessing the effectiveness of preventive interventions is difficult due to the nature of the outcome (death or severe morbidity) and the multiple causes involved. For obvious ethical reasons, no RCT can be performed to assess the impact of selected risk factors on the outcome. Evidence is therefore mainly based on retrospective case control studies and surveillance data. This leads to difficulties in differentiating associations from causality between risk factors and outcomes. Furthermore, the multi-causality of the outcome  adds difficulties in establishing the contribution of each risk factor. In addition to the association between risk factors and the outcome , there is overall limited evidence assessing the effect of the recommendations through knowledge, attitude and practices.The assessment of screening tools seemed to be more controversial than for the single or multiple interventions, with a higher degree of disagreement between institutions. This is likely to be explained by the fact that more aspects must be considered when evaluating the balance between benefits and harms of universal screening than of single interventions. For interventions, the main factors to assess and balance are the effectiveness of the intervention to prevent the undesirable outcome and potential adverse effects associated with the intervention. In contrast, for screening, there is a need to assess the effectiveness of the screening tool to detect the condition, the potential harms derived from the screening tool and treatment, and the treatment effectiveness. In addition, outcomes following early detection and treatment versus the time of presenting signs or symptoms must be considered. Furthermore, the significance and consequences of false positive and false negative cases vary between settings with different prevalence of the disease and with different health care system. As the complete set of criteria for a good screening programme that was adopted by the WHO needs to be assessed, economic and other health system related factors need consideration too .Apart from the immediate findings, the approach we used for this evidence synthesis is valuable in several other ways.First, providing both aspects (summaries of existing recommendations and evidence) transparently and independently informs clinicians, researchers and policymakers about important research gaps. Where are formal systematic reviews required and where is field research needed? When we reviewed preventive interventions, it became clear that field research through new trials is needed most. Examples are trials to elucidate the optimal duration of vitamin D supplementation for preventing rickets, studies to determine the benefits of early detection and treatment of children with ASD compared with those identified with developmental concern, or research to find a suitable screening tool for iron deficiency anaemia.Second, the review proved to be a unique opportunity to summarize what is already known across ten controversial and highly important preventive interventions for child health in a single document. It is a crucial starting point when a group or institution intends to develop or update recommendations. Indeed, this approach not only allows the identification of research gaps, but also areas for which recent systematic reviews have already been conducted and areas for which no further evidence might be required. In addition, we noticed that sometimes several institutions committed their own systematic reviews in order to inform the development or update of a recommendation, leading to several groups conducting independent systematic reviews in parallel and addressing the same research question. This represents a potentially avoidable duplication of work, wasting resources.Third, our approach may facilitate ownership of the prevention chapters in the pocket book by institutions such as paediatric societies. We systematically looked at existing recommendations from credible European institutions, national and international, but also non-European institutions, for generalizable and applicable conclusions. By taking into consideration their views and positions and by making our methods clear, the content of the final product may become more acceptable to the target audience. Moreover, presenting an overview of the existing recommendations also sheds light on how various European institutions use and apply existing evidence to their settings – common and different approaches and positions become visible.Finally, we complemented the European-focused summary of existing recommendations with an independent body of evidence from relevant systematic reviews of the Cochrane library. Separating the evidence from the recommendations allows the editorial group to gauge how different institutions considered factors such as acceptability, feasibility, potential harms, cost and others.This review has limitations. There was a limited timeline that was defined by the editorial group and editorial process of the WHO pocket book. To address this, a single author was identified for conducting the literature search, data extraction and data synthesis. When we found no systematic review addressing one of our key questions, or when a systematic review was found but was outdated, it was not possible to conduct a needed systematic review ourselves. In addition, it was not possible to assess the methodological quality of included systematic reviews and guidelines using the AMSTAR-2 tool and the AGREE tool respectively.The strengths of this review are the alignment to the principles of good evidence synthesis for policy – inclusive, rigorous, transparent and accessible , 14. ThiThe practice of well childcare in European countries consists of promotion of healthy nutrition and lifestyles and different methods in primary and secondary prevention of diseases. The rationale for this supplement is a response to a concrete need: to provide a WHO editorial group with a summary of evidence about selected preventive interventions with controversial benefit from a wide range of resources. This paper describes the methods used in each of the following articles, summarizes and analyses the existing recommendations and the underlying evidence for single and multiple preventive interventions and screening. In addition, it identifies lessons learnt from the process that might be useful for similar endeavours.Additional file 1. List of abbreviations.


At Robert Koch Institute’s Department of Infectious Disease Epidemiology, approaches for applying the principles of evidence-based public health (EBPH) have been particularly successfully implemented in the Immunization Unit and in the Unit for Healthcare-associated Infections, Surveillance of Antibiotic Resistance and Consumption. Furthermore, both units participated in the international Project on a Framework for Rating Evidence in Public Health (PRECEPT) which has been funded by the European Centre for Disease Prevention and Control (ECDC).The Immunization Unit hosts the Executive Secretariat of the German Standing Committee on Vaccination (STIKO). In 2011, STIKO has adopted a new Standard Operating Procedure (SOP) for the development of vaccination recommendations. Main aim was to provide a methodological framework to guide this process by applying the principles of EBPH. The SOP comprises ten consecutive steps, starting with a prioritization process of relevant topics, and ending with the publication of the recommendation and a related paper on the scientific background. Following the principles of EBPH, systematic reviews and meta-analyses are performed to address key issues. The methodology of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group is a core element of the SOP and is used to assess the quality of evidence on vaccine efficacy/effectiveness and safety, including population effects. In addition, STIKO has started to use Evidence-to-Decision Tables to support the decision-making process. Since 2012, ten recommendations on new vaccines or revisions of previous recommendations have been successfully developed using the SOP, accompanied by publication of background papers and of the respective systematic reviews in peer-reviewed journals .At the Unit for Healthcare-associated Infections, Surveillance of Antibiotic Resistance and Consumption, the EBPH approach has been used to perform systematic reviews on the burden of healthcare-associated infections . As an eThe latter review was part of the PRECEPT project. PRECEPT defined a methodology for evaluating and grading evidence in public health, with a particular focus on infectious disease epidemiology, prevention and control, taking different domains and question types into consideration . The met


Sense of presence has been often explored in the context of virtual reality (VR) and immersive visual technologies; however, standardized and objective measures of the sense of presence have been difficult to find. Studies attempting to find physiological correlates of sense presence using electroencephalography (EEG) have reported mixed results. In the present study, we used brain event‐related potentials (ERPs) elicited by auditory stimuli to identify an objective physiological index of sense of presence during VR, attempting to replicate the findings of previous studies and explain the heterogeneity of results reported in the literature. Participants in our experiment were asked to experience an immersive virtual environment using a modern head‐mounted display while passively hearing task‐irrelevant frequent standard and infrequent deviant tones as in a classic auditory oddball paradigm. Subsequently, they were asked to complete a battery of questionnaires aimed to estimate their sense of presence during the VR. EEG and questionnaire data from three‐seventh participants were analyzed. ERP components evoked by the auditory stimuli were then analyzed. Late ERP components (after 450 ms from stimulus onset) registered over central brain areas were associated with the sense of presence as measured with questionnaires, while earlier components were not associated with presence. The use of different questionnaires and the content of the VR environment may both be a plausible explanation for heterogeneous results as reported in previous studies. The present study showed that late ERP components recorded over the central brain may represent good electrophysiological correlates of the subjective sense of presence. We validated a method to indirectly index sense of presence using EEG. We found linear association between event‐related potentials to task‐irrelevant stimuli during the VR simulation, and reported self‐presence. The present finding will help to establish new methods to objectively evaluate sense of presence. Modern immersive systems generally consist of wearable displays (HMDs) and handheld controllers, allowing users to visualize and interact with a simulated environment. The headset provides computerized images on two screens, one for the view of each eye  experiences in a continuous, direct, and non‐invasive way. Finding a continuous and objective measure of sense of presence would allow researchers to better understand the development of the sense of presence over time and facilitate the quantification of the quality of experience of VR users. Furthermore, this measure would enable researchers to identify strategies to positively modulate the sense of presence, possibly increasing the quality of experience provided by the VR systems and promoting their acceptability  to find evidence of an association with a subjective sense of presence for one or more electrophysiological indexes and (2) to attempt to explain mixed results as reported in previous EEG studies . The participants were reported to be generally healthy. The study was conducted with the understanding and written consent of each participant and in accordance with the Declaration of Helsinki. The experimental protocol was notified and approved by the Norwegian Centre for Research Data (NSD) prior to data collection. All participants were required to be proficient in English, and all the materials used in this study were in English. It was also a prerequisite that the participants declared to have a normal  vision. All the participants declared to have no diagnosis of psychiatric disorders and/or history of epileptic seizures or current intake of psychotropic drugs. None of the participants declared to be familiar with the game prior to the experiment.N = 20; Kober & Neuper, N = 40; Terkildsen & Makransky, N = 34).From the initial 40 participants, three of them were eliminated from any analysis. Two of them had their data compromised by technical problems . One of them was excluded as it asked to withdraw from the experiment due to excessive simulation sickness after only 2 min of the experiment. The analyses were based on the data from the 37 remaining participants . The final number of participants in our study was in line with one of previous similar studies . The developer and copyright holder of the software gave consent for the use of the game as well as for disclosing images of it in activities aimed at scientific communications.The VR scene presented a first‐person roller‐coaster ride. The ride is part of the selection of rides available in a customer‐oriented videogame (“Epic Roller Coaster” B4T games). Such type of VR was chosen for the ability to induce, even after short use, a high sense of presence as previously shown  situated 45 cm behind the subject's position at 20 cm to each other. In line with the argument of Terkildsen and Makransky , speaker2.4After giving written consent, the participant entered the laboratory, sat in a chair, and was fitted with the EEG electrode cap equipment and the VR headset. Prior to the start of the VR scenario, 2 min task‐irrelevant ERP stimuli were played to habituate the subjects to the occurrence of the background sound. As we did not have any a priori hypothesis on brain activity during this pre‐exposure time, EEG data was not recorded until the beginning of the VR stimulation.The subjects were instructed to press the start button on the control device, at which point the recording of EEG began. The experimenter exited the experimental room after instructions were provided. The stimulus played for 8 min. At the end of the VR exposure, the EEG cap was removed, and the participant could stand up and exit the testing room. In the adjacent room, subjects were asked to fill out the set of questionnaires. One researcher provided instructions about the questionnaires and was available for questions.2.5The PQThe pre‐session questionnaire consisted of a consent form, including demographic questions of the participant's age and sex. Furthermore, three different PQs were used. These questionnaires were selected for their wide use in the literature  and external (system) factors , from 64 silver cloride (Ag/AgCl) active electrodes arranged in a 10/20 configuration cap . CPz was used as a reference electrode, and the ground electrode was placed on AFz. Electrode gel was used to increase the conductivity throughout the experiment, and the impedance levels of each electrode were set below 50 kΩ before the beginning of the experiment.2.6.1For the ERP analyses, data‐pre‐processing pipeline script was created considering the suggestions of the Makoto's preprocessing pipeline  for further inspection. ERPs figures and scalp map topographies were plotted using BVA. Based on previous studies ERP components latencies were established. Upon further examination of the ERPs .Statistics were computed using IBM SPSS Statistics v. 26 and Matlab (R2014). To assess the brain activity differences between high and low levels of sense of presence participant groups, univariate repeated measure analysis of variance (ANOVA) 2 × 3 analyses were calculated. The analyses were computed using the sense of presence group as a between‐subject factor (low vs. high sense of presence group) and electrode position  as a within‐subject factor. The analyses were performed separately for each ERP component of interest and the different grouping resulted from different questionnaires. When the sphericity assumption was violated (Mauchly's test of sphericity), Greenhouse–Geisser correction was used. Corrected p < .05. Standard correlation statistics were one‐tailed, as the direction of the relationship between the variables was deductible from the results reported in previous investigations and from a theoretical point of view. As few variables were examined and all were selected a priori to the investigation to increase comparability with previous studies using a similar experimental design, it was decided not to correct multiple comparisons when analyzing the different questionnaires individually.All the statistical tests performed used the significance level of 33.1The results of the questionnaires evaluating the sense of presence were first descriptively analyzed. For the PQ, the mean score was 4 SD = 0.81), for the SUS the mean was 3.99 (SD = 1.14), for the MPS(sp) the mean was 3.06 (SD = 0.85), and for the MPS(se) the mean was 2.55 (SD = 0.86). These scores are generally in line with the results reported in previous studies . As previous analyses showed no interaction effects between the sense of presence group X electrode position, and to avoid multiple comparisons, instead of computing correlations for each one of the three electrodes separately, the ERP component amplitudes relative to the three studied electrodes  were averaged together, creating a new variable for each ERP component . Furthermore, the effect of sense of presence was shown not to greatly different between these electrode locations when analyzed independently  attempting to clarify if it is possible to establish psychophysiological correlates of sense of presence during immersive VR experience. At the same time, this study attempted to understand and clarify the heterogeneity of experimental results reported in previous investigations . Even if the participants were not instructed tasks or interaction with the VR environment, analyses of questionnaire data suggested participants experienced a good level of sense of presence , MPS(se)), and the median scores of these were used to assign participants into groups. The results of the questionnaires' scores correlated (moderate to high correlation). In the published literature is common that only one type of questionnaire or rating score is used to evaluate the sense of presence in VR, with the important exception of Kober and Neuper , where PNevertheless, when we used the questionnaires’ scores to divide the participants into the high and low sense of presence groups based on overall median scores, as done in previous studies . The difference in results between the different questionnaires may be due to the different construct of sense of presence analyzed. While PQ, SUS, and MPS(sp) evaluate spatial/physical presence , the MPS(se) estimate the different construct of self‐presence Lee, .Statistical differences in the early ERP components N1 and MMN were not found in PQ and SUS questionnaires grouping. However, when grouping was established on MPS sub‐categories, the low sense of presence group showed a more pronounced N1 component, compared to the high sense of presence group (for the MPS(sp)), and the same was shown for the MMN component (for the MPS(se)). These differences were not statistically significant but approached significance.Further correlation analyses were carried on, aiming to understand a possible linear association between the mean amplitude of the components and subjective sense of presence. For those analyses, participants were not grouped. SW1 and SW2 components showed a generally moderate linear association with all the questionnaires, and the association was statistically significant in all the correlations. Instead, none of the association analyses with early components  and questionnaire results showed to be statistically significant. These findings support the idea that even if highly correlated, different questionnaires could evaluate somewhat different sorts of sense of presence, especially when the grouping strategy based on post hoc questionnaire results is used . In an auditory oddball task study  amplitude in the SWs, when the low sense of presence group was compared with the high sense of presence group, in line with the attentional allocation theories aforementioned Kok, .However, the study of Terkildsen and Makransky  did not According to Terkildsen and Makransky , the stuTerkildsen and Makransky  proposedNevertheless, the VR environment used in our study was chosen purposefully for not promoting challenge‐based immersion (as the participants do not have to perform any task in the VR environment), but our results are only partially in line with those of Terkildsen and Makransky . TherefoThe heterogeneity of results obtained with the division in groups of the sample showed how this strategy for data analysis could be problematic, especially in EEG studies where the number of participants is generally not very high. The result of the present study shows that correlational analysis may provide more robust results.4.3In our study, the late components amplitudes (SWs) elicited by the deviant tones were shown to be decreased for the high sense of presence group, compared to the low sense of presence group, as their involvement in VR captured most of their cognitive capacities. The low sense of presence group, as it was less involved in the VR, had more attentional resources available to process the deviant tones, and therefore showed an increased (more negative) SWs amplitude. The SW modulation was shown to be reliable for every grouping strategy using a different questionnaire.The other ERP components analyzed  did not consistently show to differ between the two groups and were found to correlate with the sense of presence only when the groups were estimated using the MPS questionnaires. The N1 component is associated with the allocation of early perceptual processes  elicited by deviant tones has sometimes been analyzed in the context of the auditory oddball paradigm, and it is thought to be related to post‐perceptual cognitive processes as a response to specific auditory stimuli . Hence, our findings, even though in line with these reported by the scientific literature that used traditional systems  to mediate the VR environment, may not be completely comparable. Even though increasingly popular . This may have impaired the validity of the inventory to measure the construct. As our environment did not contain social interactions or social components, the social sub‐component of the MPS questionnaire was also eliminated as irrelevant.An important limitation of the interpretation of the data based on the median split is that the median split resulted in quite even  or rather uneven (MPS) subgroups used for the ERP comparison. This is a limitation that affects all the studies where a median split is used, as several participants may show results right in the median score, and therefore they need to be removed or assigned to one of the groups. Future studies that plan to utilize the median split analysis method using the experimental design described in the present article may attempt to mitigate the problem of data bias by recording, analyzing, and comparing the ERPs in response to the pre‐VR exposure auditory oddball. Such analysis would help to clarify whether observed differences in the ERPs are truly due to the experience of the sense of presence or simply due to pre‐existing differences between the groups. Unfortunately, in the present study–that was designed following the description of the experimental paradigm proposed in Terkildsen & Makransky, Due to the particular nature of the VR environment we used in this experiment, our results are difficult to generalize to environments where movements and interactions are required from the user. Such aspect also reduces the ecological validity of our study in respect to videogames or training and teaching‐oriented VRs, where actions are requested from the user.Finally, the role of simulator sickness and other types of discomfort mediated by immersive HMDs  of interest. However, a data‐driven approach to the electrophysiological data  may be more sensitive to aspects of the physiology of sense of presence that is reflected in early attentional activities. Furthermore, we show that the method of participants grouping based on the median score of the questionnaire–as used in several previous studies–may critically affect the results and that participants’ grouping based on different questionnaires–even when these questionnaires correlate–may be accountable for the heterogeneous results reported in the literature. Different questionnaires may be indicated to explore different aspects of sense of presence, and therefore are associated with different physiological phenomena. However, our reported findings in this respect are inconclusive. The late, negative slow waves recorded over the central brain areas showed a good linear association with the questionnaires used, and this association was found to be robust to outlier values for the SW1 component. Nevertheless, no linear association was found for subjective reports of sense of presence and early brain activity. Taken together, our results suggest that the late ERP components of the EEG, recorded from the central brain area, are (among the ones investigated) the most reliable electrophysiological correlate of the subjective sense of presence.Simone Grassini was responsible for the study idea, the experimental design, the management of the lab work, the data analysis, the training of junior lab. assistants, and for writing the present manuscript. Karin Laumann provided funding for the project, gave feedbacks at every stage of the study, and commented on earlier drafts of the present manuscript. Virginia de Martin Topranin and Simone Grassini assisted in the development of the experimental design, had the responsibility to test the participants in the laboratory, and commented on earlier drafts of the manuscript. All the authors have read and approved the final version of the article.https://publons.com/publon/10.1002/brb3.2269.The peer review history for this article is available at Supporting informationClick here for additional data file.