The HEAR-aware project targets adults ≥50 years who were recently diagnosed with hearing loss and declined hearing aids, but were open for support via a smartphone app on different target behaviors (TBs). The HEAR-aware app, based on Ecological Momentary Assessment and Ecological Momentary Intervention , contains educational materials (“snippets”) tailored partly to the user’s experienced listening situations. The app aims to increase adults’ TB-specific readiness to take action on hearing problems. The present study focused on examining feasibility regarding three novel aspects: (1) the app’s acceptability, mainly regarding its EMA and EMI elements , (2) psychometric properties of 10 new TB-specific stages-of-change (SoC) measures , and (3) the potential of tailoring snippets on a person’s SoC.A nonrandomized intervention study including four measurements with 2-week intervals (T0–T3). (1) The intervention period lasted 4 weeks. App usage data were collected throughout (T1–T3). Usability, usefulness, and satisfaction were measured at T3 (n = 26). (2) Reliability concerned T0 and T1 data, in between which no intervention occurred. Intraclass correlation coefficients (ICCs) were calculated (n = 29). Construct validity was examined by calculating correlations between the different TB-specific scales (at T0), and also between each of them and self-reported hearing disability (n = 29). (3) Person-tailoring by SoC was examined using T0 and T1 data. Linear mixed models were applied to test whether users rated snippets corresponding to their SoC as more interesting and useful than noncorresponding snippets (n = 25).p > 0.05) and 0.74 (p < 0.001), supporting only partly overlap between their underlying constructs. Only the correlation between TB-specific readiness for hearing aid uptake and self-reported hearing disability was significant. (3) Correspondence of a snippet’s SoC with the person’s SoC significantly related to “interesting” ratings (p = 0.006). Unexpectedly, for snippets with a lower SoC than the participant’s, further deviation of the snippet’s SoC from the participant’s SoC, increased the participant’s interest in the snippet. The relationship with “usefulness” was borderline significant.(1) The percentage of participants that complied with the intended usage varied across the five predefined compliance criteria . Median snippet satisfaction scores were reasonably positive (3.5 to 4.0 of 5). Usability was good  and usefulness satisfactory , but showed large variance. (2) The 10 TB-specific scales showed fair-to-excellent reliabilities (range ICCs = 0.51 to 0.80). Correlations between the TB-specific scales ranged between −0.17 ((1) Overall usability, usefulness, and satisfaction scores indicated sufficient app acceptability. The high variance and fairly low compliance showed room for improving the app’s EMA/EMI parts for part of the participants. (2) The 10 new TB-specific SoC measures showed sufficient reliability, supporting that they measured different types of readiness to take action on hearing problems . (3) The unexpected findings regarding tailoring educational app materials to individuals’ SoC deserve further study. Hearing aid fitting is the most common form of rehabilitation for adults with hearing loss (HL), with beneficial outcomes on disability and wellbeing e.g., , 2007. NPrevious studies showed that self-management support programs (SMSPs) delivered via e-health (e-SMSPs) have the potential to reach many adults with valuable knowledge and skills needed to manage the impact of HL on their wellbeing . EffectiPresent e-SMSPs however hold limitations. First, because most of them are not offered independently of hearing aids e.g., , adults The HEAR-aware project aims to address these shortcomings see . It coveThis article reports on a nonrandomized intervention study evaluating different aspects of the feasibility of the app prototype intervention in a group of participants with HL. The results will inform a randomized controlled trial in which the app intervention is examined for its effectiveness . The preEMA is a data capture technique for assessing real-time experiences repeatedly in individuals’ own natural environments . In hearAnother pillar of the HEAR-aware app is the readiness, or SoC concept derived from the Transtheoretical model of health behavior change . This moSoC measures traditionally used in audiology are generic, that is, it is not specified what “taking action on hearing” means. In HEAR-aware, readiness is assumed to be TB-specific: an individual can be in different SoCs for different TBs. Hence, generic measures are not considered suitable . We therLastly, tailoring intervention content to a recipient’s current SoC is assumed to help move them to higher SoCs . For heaIn the next sections, General Methods and Results are presented first. Subsequently, Specific Methods and Results per RQ are presented.The design concerned a nonrandomized intervention study to examine different feasibility aspects.The aim was to include n = 50 participants, which is considered the minimum “adequate” sample size for reliability and validity studies . All parage 50 years or oldera minimum pure-tone threshold of 35 dB HL averaged across 1, 2, and 4 kHz in at least one earvisited a Schoonenberg HoorSupport shop for a hearing test appointment or a subsequent intake appointment no longer than 1 year ago, but was not inclined to pursue a hearing aid trajectoryowned an e-mail accountnever tried a hearing aid or ALDstill did not want a hearing aid at the time of recruitmentowned a smartphone and uses appswas fluent in Dutchwas willing to use the app regularly throughout the day for the study period.All participants provided informed consent. They received €40 for their participation. The Medical Ethics Committee of the Amsterdam University Medical Center (location VUmc), confirmed that ethics approval was not necessary because the Medical Research Involving Human Subjects Act (WMO) did not apply to the study.http://links.lww.com/EANDH/B197) outlines the measurement moments and measures for each of the RQs. Online questionnaires were administered at all four moments and were sent to the participants’ e-mail addresses. They could complete them via their PC, smartphone, or tablet . In the 2-week interval between T0 and T1 no intervention occurred, to facilitate the test–retest reliability analyses (for RQ2.1). App usage data were collected throughout the 4-week usage period (covering T1–T3) and were stored in real time in an online database. Participants received written instructions to download it from Google Play (Android) or App Store (iOS). App start-up and usage were monitored by the researchers in real time via an online content management system. E-mail and telephone assistance were provided in case of technical problems.There were four measurement moments with a 2-week interval between each of them (T0–T3). Table SM1 in Supplemental Digital Content 1 (http://links.lww.com/EANDH/B197). The aims of the app and instructions for use were explained via the app’s introductory screens, explanation at the top of the main “pages,” and collapsible “?”—icons. The introductory screens appeared automatically when starting up the app for the first time but could be re-accessed at any time.The app was hybrid, allowing both Android and iOS smartphone users. It consisted of five main “pages” through which users could navigate via the bottom icons , a push notification invited participants to fill in short EMA surveys, to report on difficult listening situations. This concerned a clickable pop-up message accompanied by sound and vibration. The times could not be changed to the user’s preference because of technical limitations. There were two kinds of surveys: one for the identification of expected, current, or past difficult listening situations (henceforth: identification surveys), and another for evaluating the previously reported difficult listening situations, which had passed by then . Thus, the option to fill out an evaluation survey about a listening situation only appeared after the completion of the identification survey of that particular situation. Note that participants were instructed to continue as usual, and not seek out more difficult listening situations. Participants could also self-initiate surveys instead of responding to a push notification. All survey questions were multiple-choice.http://links.lww.com/EANDH/B197) for all types. Then, users were asked to indicate if background noise was present during this situation. If users reported a listening situation with media, they were also asked to indicate the volume level. Depending on the participant’s answers, the software activated three acoustic labels: (1) type of listening situation, (2) presence of background (yes/no), and (3) presence of loud media volume (yes/no). The app subsequently offered one snippet (see later under “Snippets”) that matched with acoustic labels 1 and 2. When label 3 was activated, a second snippet on potential hearing damage was offered.The identification survey comprised three to four questions and took 1 to 2 minutes. Participants selected one of 15 predefined listening situations . See Table SM2 in Supplemental Digital Content 1 (http://links.lww.com/EANDH/B197). The survey questions were partly based on http://links.lww.com/EANDH/B197). Participants were reminded about any unevaluated listening situations via the afternoon and evening notifications, and via red pictograms . The red pictograms remained visible for as long as situations remained unevaluated. Note that in the same afternoon and evening notification, participants were also asked to add any new situations. Users could also add photos and notes (free text field) to each listening situation. The research team sent reminder e-mails when participants had not added any listening situations in the past 3 (directly after app start-up) or 5 days (later in the usage period).The evaluation survey consisted of 8 to 14 questions, depending on the type of listening situation. Completion took 3 to 4 minutes, corresponding to the 3-minute limit suggested by Both EMA survey forms functioned to elicit awareness of hearing difficulties and the identification survey additionally served to select acoustically tailored snippets. Photographs and notes served to further promote hearing awareness and facilitate evaluation of the listening situations . The shohttp://links.lww.com/EANDH/B197). Snippets varied in length (2 to 10 min. reading/watching time), but most took less than 5 minutes. There were two kinds of snippets: listening situation-induced snippets (81) and standard library snippets (37). The former were offered in response to an entered listening situation (directly after finishing the identification survey) and then became permanently available in the app’s library. Users were invited to directly open the offered snippets, but they could also do that later as they remained retrievable. Each snippet was offered only once. Standard library snippets were available per default in the library.Snippets  were short pieces of educational content and consisted of written text, videos, pictures, sound fragments, or a combination thereof. An example is shown in Figure 1, pane 7, Supplemental Digital Content 1  conversation” with “a lot of background noise,” a snippet was offered that fitted the activated listening situation labels (1) “conversation, 2 to 3 persons” and (2) “speech-in-noise” . Around 33% of the listening-induced snippets that were offered had no label and thus, were not offered in a tailored fashion but were offered randomly. The fact that some, and not all, offered snippets were linked to the entered listening situations was explained in the app’s introductory screens. Snippets were supposed to promote TB-specific readiness and an overall sense of self-management.http://links.lww.com/EANDH/B197). Themes and corresponding TBs were: (1) background knowledge of hearing (no TB), (2) communication strategies (TB communication strategies), (3) coping with hearing loss , (4) understanding by loved ones , (5) hearing at work (no TB), (6) ALDs—to be used without hearing aids (TB ALDs), (7) hearing aids (TB hearing aids), (8) ALDs—to be used with hearing aids (TB hearing aids), and (9) Fun (no TB). The TBs were not visible to the users but the themes were visible.Each snippet covered one or more of the nine app themes that structured the app’s library . This concerned the degree to which they found the snippet: (1) useful, (2) interesting, (3) fun/entertaining, (4) understandable, (5) having the right extent/length, and (6) having a pleasant tone of voice . A five-point Likert scale (1 to 5 stars) was used, with higher scores indicating higher satisfaction . In addition, a maximum of two short reminder e-mails were sent when participants had reviewed ≤50% of the offered snippets in the past week.http://links.lww.com/EANDH/B197). The latter served to motivate (re-)reading of snippets.For each library snippet, the participant’s review scores and the average scores of other participants were visible . Participants’ own statistics and those of others were presented for comparison and to promote hearing difficulty awareness (pane 5).Participants could access an overview of their entered listening situations (My listening situations) with some statistics about them (My statistics), see panes 3; 4, and 5, respectively, of Figure 1, Supplemental Digital Content 1 (http://links.lww.com/EANDH/B198). Twenty-six participated in the full study . Three provided data on the T0 and T1 questionnaires . Characteristics of the 26 app participants are described in Table SR2, Supplemental Digital Content 2 (http://links.lww.com/EANDH/B198). Their mean age was 63.4 years . Mean HL  was 34.2 dB HL (SD = 7.6).Data were collected between July 13, and November 30, 2020. Because of the COVID-19 pandemic in this period, society was partially locked-down, with various government measures being in place. In general, individuals had to keep a ≥1.5 meters distance from nonhousehold members and (large) group gatherings were prohibited or discouraged. In total, 29 participants were included. Reasons for not having opted for a hearing aid earlier are presented in Table SR1, Supplemental Digital Content 2 (http://links.lww.com/EANDH/B197).RQs on acceptability, the corresponding analyses, and more details about the app are outlined later. App usage data and the T3 questionnaire were used to answer these RQs  add at least 1 to 2  listening situations per day, 42 in total; (2) evaluate ≥80% of the added situations; (3a) view ≥80% of offered snippets, (3b) resulting in 33 snippets in total, and (4) view ≥10 standard library snippets. Note that participants were not provided with these or any specific targets, although various app elements  did serve as incentives to stimulate daily usage. Descriptive statistics were used. The compliance criteria were based on To explore a possible impact of the COVID lockdown on the number of encountered listening situations, we included a self-designed item in the T3 questionnaire asking if participants had run into difficult listening situations (far) less, equally often, or (far) more frequently due to the COVID lockdown as compared with before.None of the participants met all five compliance criteria, as described in the following paragraphs.http://links.lww.com/EANDH/B198). Most (86%) were self-initiated; 14% were added in response to the morning push notification. Variance in the number of added situations was high and ranged from 0 to 77 . Two participants (8%) met compliance criterion 1 and added 42 listening situations, in line with 1.5 per day. More specifically, three participants (12%) added at least one situation every day, 11 (42%) at least every other day, and 13 (50%) at least every 3 days. The remaining 13 (50%) added 0 to 22 situations  with relatively long passive periods (4 to 20 days no situations added). Twelve participants (46%) reported having come across (far) less difficult listening situations because of the COVID-19 lockdown. This was against three (12%) reporting (far) more, and 11 (42%) reporting no difference.The 26 participants added 616 listening situations in total . Twenty-two participants (85%) met criterion 2 and reached ≥80% evaluated situations. It was not registered which situations were evaluated in response to a push notification versus which were self-initiated.In total, 648 snippets were offered in response to the 616 added listening situations . The number of viewed snippets ranged from 0 to 65 per participant . The mean percentage of viewed snippets relative to offered ones was 65% per participant . Ten participants (40%) met compliance criterion 3a and viewed ≥80% of the offered snippets. Only 3 participants (12%) met criterion 3b and reached at least 33 viewed snippets.In total, 211 standard library snippets were viewed, ranging between 0 and 37 across participants . Eight participants (31%) met criterion 4 and reached ≥10 viewed snippets.The System Usability Scale (SUS) is a validated, 10-item scale providing a global view of users’ perceived usability of a system or device . It usesThe value/usefulness subscale of the Intrinsic Motivation Inventory IMI;  was usedWe used item 4 of the Dutch-validated International Outcome Inventory-Alternative Intervention IOI-AI; : “ConsidThe mean SUS score was 72.4, indicating “good” overall app usability . The varThis was measured by a self-designed item administered at T3: “Do you think completing the surveys has provided you with more insight in your hearing?” with four response options: no, not more insight; yes, perhaps a bit more insight; yes, moderately more insight; yes, much more insight.Snippet usefulness was measured by review indicator useful  and by one of the EMA evaluation survey questions, that is, “Did the information/tips from the snippet offered earlier today for this particular situation help you in any way?” The four response options were: no, a bit, much, very much. Descriptive statistics were calculated for all snippets lumped together and for different snippet subgroups. Snippet satisfaction was measured by all six review indicators .The majority (77%) indicated that filling out the EMA surveys had provided them with “greater insight in their hearing” .http://links.lww.com/EANDH/B198) shows the distributions of the EMA evaluation survey question (snippet usefulness) responses and median scores on the six snippet review indicators (snippet usefulness and satisfaction).Table SR4 in Supplemental Digital Content 2 (http://links.lww.com/EANDH/B198), snippets had helped the participants to some extent in 65% of the occasions . In 35% of the occasions, snippets were rated as not helpful (“no”). When stratified for acoustical tailoring, acoustically tailored snippets were found somewhat more useful (“no”: 29% versus ≥“a bit” useful: 71%) than nontailored snippets (“no”: 51% versus ≥“a bit” useful: 49%). When stratified into other snippet subgroups, somewhat differing distributions were found, but the general trend was that most snippets were either rated as not useful , or a bit (ranges 30 to 71%).With all review snippets lumped together , four review indicators had a median of 4.0. Indicator “fun/ entertaining” only reached 3.0. Acoustically tailored snippets were found somewhat more fun/entertaining (median 3.0) with a more appealing tone (median 4.0) than nontailored snippets . When stratified into other snippet subgroups (rather than lumped together), similar medians were found . Snippets about ALDs without hearing aids; however, showed a lower median score (3.5) for indicators “useful” and “interesting.”With all review snippets lumped together  of the new measures.We hypothesized low to moderate correlations (0 to 0.60) between the five TB-specific measures and between each of them and their Generic version, for both the Staging Algorithm and The Line. This would support that they partly measure differing types of readiness.As an additional way to examine construct validity, we examined which of the five TBs participants thought about when filling out the Generic readiness measures. We hypothesized that the TBs would differ between participants and also the number of TBs. This would confirm that generic measures may measure different types of readiness, depending on the individual.Consistent with http://links.lww.com/EANDH/B197). Below, all measures are described. The full SoC questionnaires are provided in Supplemental Digital Content 1, http://links.lww.com/EANDH/B197, pages 6 to 12.Data for each of the RQs were obtained at T0 and T1 ” and “nothing specific.”T0 and T1 data were used. The 2-week interval between T0 and T1 (with no intervention) was assumed long enough for respondents to forget their answers, and short enough for readiness to remain stable. Reliability of the 10 new TB-specific SoC scales was determined by calculating ICCs and their 95% confidence intervals (95% CIs) , Spearman’s rho (ρ), or ICC .Data from T0 were used to determine correlations. Depending on the variables involved, this was either a Pearson correlation coefficient , no participants were in precontemplation and few were in the action SoC (n = 4 at both T0 and T1). Most were in contemplation or preparation . The Line Generic and the Staging Algorithm Generic showed good reliability .The means of The Line Generic were 6.7 SD = 1.4) and 6.6 (SD = 1.9) at T0 and T1, respectively  and 6.1 . Four of five TB-specific scales showed good reliability (ICCs = 0.66 to 0.74), but for Hearing Aids, it was fair (ICC = 0.53).http://links.lww.com/EANDH/B198). Exceptions were the Hearing Aids and ALDs scales. These showed a similar picture as of the Generic scale: no participants in the action SoC for ALDs and Hearing Aids and few in precontemplation for Hearing Aids. Three TB-specific Staging Algorithm scales showed good reliability: ALDs, Social Support, and Communication Strategies (ICCs = 0.69 to 0.72). Reliability was excellent on the Hearing Aids scale (ICC = 0.80) and fair on the Emotional Coping scale (ICC = 0.51).In contrast with the Staging Algorithm Generic scale, some participants were in precontemplation and action stages for specific TBs  present correlations between each of the TB-specific scales of The Line (upper part) or the Staging Algorithm (lower part), as well as between them and their Generic scales, respectively. The Generic scales were significantly correlated with Communication Strategies (The Line: ρ = 0.47) and Hearing Aids . Most other TB-specific scales were either not significantly correlated with each other (The Line), or moderately . An exception was the correlation between the Social Support and Communication Strategies scales, which was relatively strong (≥0.60), both for The Line (ρ = 0.74) and the Staging Algorithm (ICC = 0.70).Rows 1 and 7 of Table SR11  had a mean of 1.5 TBs in mind when they reported their readiness to take action on their hearing problems, as measured via the Generic SoC measures . The TBs that most participants thought about were getting hearing aids (n = 20), learning communication strategies (n = 13), and getting ALDs (n = 7). Improving emotional coping (n = 3) and seeking social support (n = 1) were reported less often. Two respondents reported not having any specific TB in mind when filling out the Generic readiness measure. Of that reporting to have had to get hearing aids in mind (n = 20), eight only reported this TB, six, in addition, reported learning communication strategies, three additionally reported both learning communication strategies and getting ALDs, two additionally reported getting ALDs, and one additionally reported emotional coping. Lastly, 14 reported to have “improving self-management” in mind, of which 12 did so in addition to thinking about at least one of the five TBs.http://links.lww.com/EANDH/B198), the correlations with self-reported hearing disability are shown. Only the Hearing Aids scale was significantly correlated with self-reported hearing disability, both for The Line (r = 0.39) and the Staging Algorithm (ρ = 0.45).In the last column of Table SR11  (http://links.lww.com/EANDH/B197).As mentioned, each snippet had content addressing one or more app themes, each of which in turn corresponded to a TB. For RQ3, each snippet was a priori assigned a main TB  and a main SoC that each snippet was deemed most suitable for. Both the TB and SoC assignments were done by the same researcher, who used literature study and a self-designed summary document to assign SoC. SoC assignments of the first 15 snippets, and of any unclear snippets were discussed with a second researcher. Table SM3 of Supplemental Digital Content 1, person, see later under “RQ3 Measures”). These two elements allowed us to determine whether there was agreement between participant’s SoC and the snippet’s SoC, or disagreement, and how far they were apart then . Lastly, as mentioned, users could indicate their snippet satisfaction on six indicators. We used two of them to operationalize “satisfaction,” to address the last RQ:In addition to having assigned the TB-specific SoC for each snippet, we assumed that each participant would be in a particular SoC for a particular TB  would be linked to higher snippet satisfaction scores.We hypothesized that lower SoCThe two scores of review indicators “useful” and “interesting” (scores 1 to 5) were used.difference, SoCsnippet, and SoCperson were used. These are explained first. SoCsnippet. SoCsnippet denoted the main SoC the reviewed snippet tapped into (see earlier). This variable was coded 0 (precontemplation), 1 (contemplation), 2 (preparation), and 3 (action).To calculate SoCperson. SoCperson included the participant’s TB-specific SoC as measured by the TB-specific Staging Algorithm. We chose the Staging Algorithm because The Line has no validated cutoff points. SoCperson was coded similarly to SoCsnippet (0 to 3).SoCperson as measured at T1 or T2. Thus, for snippets reviewed between T1 and T2, participants’ T1 SoCperson score was used in the analyses, whereas for snippets reviewed between T2 and T3, their T2 SoCperson score was used.Each snippet satisfaction rating was linked either to the participant’s SoCdifference. SoCdifference was calculated as SoCsnippet− SoCperson, reflecting the difference between the participant’s SoC (SoCperson), and the SoC the snippet tapped into (SoCsnippet) for the same TB. For snippets without a specific TB, the participant’s Generic SoC Staging Algorithm score was used for SoCperson. Scores for SoCdifference could range from -3 (SoCsnippet was much lower than SoCperson) to 3 (SoCsnippet was much higher than SoCperson). Zero indicated full SoC correspondence and was set as the reference value. SoCdifference was treated as a categorical variable as it showed no linear relationships with “useful” and “interesting.”SoCdifference were assessed using two separate linear mixed models which are robust for non-normally distributed outcomes and for missing values at random. The review indicators “interesting” and “®useful” were entered as continuous outcome variables and the independent variable of interest was SoCdifference. SoCsnippet was included as a corrective factor. To illustrate, the conceptual equation for the outcome “interesting” was: snippet satisfactioninteresting = SoCdifference + SoCsnippet. The overall relationship was considered statistically significant if the coefficient of SoCdifference was significantly associated with satisfaction (p < 0.025). A Bonferroni correction was applied because of the two satisfaction outcomes (0.05/2). Post hoc analyses were used to determine the statistical significance of the estimates for the five individual nonzero SoCdifference values compared with an SoCdifference of 0 .The relationships between the participants’ snippet satisfaction and SoChttp://links.lww.com/EANDH/B198) shows the descriptives of SoCperson and SoCsnippet. Table Table SR12 in Supplemental Digital Content 2 (difference was found (p = 0.006). Post hoc testing showed that only for snippets with a much lower SoC than the participant  there was a significant difference with the reference (p < 0.001). Thus, participants rated snippets with a much lower SoC than their personal SoC  0.85 points more “interesting” as compared with snippets with a SoC similar to their personal SoC . Although not statistically significant post hoc, the direction of the effect also applied to SoCdifference values −2 and −1. Thus, the further away the snippet’s SoC was from the participant’s SoC  the more interesting the participant rated the snippet. This direction was contrary to our hypothesis.For indicator “interesting,” a significant overall association with SoCdifference), the direction was reversed and in the expected direction. Now, snippets with a higher SoC than the participant was associated with lower “interesting” scores. However, these associations were not significant post hoc (p ≥ 0.095).For snippets with a higher SoC than the participant .For “useful” there was a more or less similar trend in the estimates visible as for “interesting.” However, the overall association for “useful” was borderline significant (This study reports on the findings of an intervention study among adults who had been recently diagnosed with HL and declined a hearing aid trajectory but were open to an e-SMSP in the shape of the 4-week HEAR-aware app intervention. Key uncertainties were examined and related to: the app’s acceptability (RQ1), the psychometric properties of ten newly developed TB-specific SoC scales (RQ2), and the potential of using the SoC concept for person-tailoring of educational materials (RQ3). Later, the principal results and study limitations are discussed.p = 0.007).Only 8% of participants met the intended usage of adding ≥1.5 listening situations a day, resulting in 42 snippets in total across the 4-week intervention period. The average participant added about half of that volume . Although this number might be an underestimation as half of the sample underreported difficult listening situations because of the COVID-19 lockdown circumstances, the observed compliance seems generally in line with other EMA research . In contLow satisfaction with the snippets’ usefulness may have limited the compliance somewhat (see further later). In addition, we found anecdotal evidence for other reasons directly or indirectly leading to underreporting of listening situations, in the free text field at the end of the T3 questionnaire . In contrast, the relative usage compliance criteria 2 and 3a  showed higher satisfactory acceptability. Compliance rates for these criteria were 85% and 40% of the participants, respectively, suggesting that once participants had added listening situations and received snippets, they were generally inclined to take the next steps . It should be noted that there was some uncertainty about whether snippets were actually viewed as we used a proxy measure of viewing .Overall usability (SUS) of the HEAR-aware app was good, and overall usefulness (IMI) was satisfactory, albeit with large variances. The majority (77%) of the participants indicated that filling out the EMA surveys had provided them with greater insight into their hearing. This is encouraging, especially because hearing difficulty awareness is considered an important outcome in HEAR-aware. As pointed out earlier , the queSatisfaction with the snippets as measured by the six review indicators was considered sufficient (median scores of 3.5 or 4 of 5). The median snippet usefulness review indicator score was 4. In contrast, usefulness was rated less positive on the EMA evaluation survey question: about one-third of the snippets were not found useful at all (35%). However, the EMA survey asked about the direct helpfulness of the offered information/tips to the particular listening situation, whereas the snippet review score indicated a more general usefulness of the snippet. In line with this, the snippets that were acoustically tailored to the listening situation were rated somewhat more useful on the EMA survey question (at least a bit useful: 71%) than the nonacoustically tailored snippets (at least a bit useful: 49%). Although it was explained in the app’s introductory screens that not all offered snippets were linked to the entered listening situation, the mere fact that the snippets were offered directly after an entered listening situation may have given this impression nonetheless. Anecdotal evidence from the T3 questionnaire supported this: “The predefined connection between the snippets and listening situations was not always useful.” In turn, this may explain some of the suboptimal results found for both usefulness parameters. Lastly, it should be noted that both parameters were administered directly after viewing the snippets, whereas some information may have needed more time to sink in, or may have concerned an unconscious process.A last acceptability-related finding worth mentioning is that the adults reached with HEAR-aware were 5 to 9 years younger and had 7 to 10 dB HL better hearing thresholds than participants in two previous intervention studies  and comparable to the Generic scales. Two TB-specific scales however scored somewhat lower and strictly may be considered insufficient . Although the reliability findings are encouraging, some caution is needed when interpreting the findings. The range for some of the scales was limited. Similar to the Staging Algorithm Generic, no to few participants were in the precontemplation and action SoCs for two TB-specific Staging Algorithm scales . Also, the sample size was 29, which is on the border of being inadequate (n < 30) and doubtful (n = 30 to 49) for reliability and validity testing according to The present study’s results on self-reported TBs of taking action (RQ2.2.2) showed that the Generic SoC measures assess readiness on different, and often multiple TBs per individual. This is consistent with earlier work  and withr < 0.60), thus measuring largely distinct types of readiness. In contrast, the TB-specific Social Support and Communication Strategies scales were strongly correlated (ρ = 0.74 and ICC = 0.70). A strong social circle may make the person with HL feel more confident or comfortable practicing communication strategies. This seems consistent with studies showing that persons with HL with strong social support generally have better outcomes , were rated as more interesting than matching snippets. Although borderline significant, a similar result was found for “useful.” In contrast, we expected lower satisfaction scores with larger SoC-differences. We speculate that educational information with a “too low SoC” for a person may have been considered confirmative and reassuring (possibly boosting self-efficacy). Alternatively, the information may have simply been easier to understand and relate to. Both mechanisms could have subsequently translated into positive snippet satisfaction scores.Unexpectedly, snippets with a lower SoC than that of the participant . Furthermore, neither persons in the action SoC nor the preparation SoC were represented in the positive SoCdifference scores, as no snippets with an action SoC or higher readiness were available in the app. Therefore, it remains unclear if the confirmative and reassuring effect hypothesized earlier plays a role in individuals with a high readiness  only or also in those with lower readiness (contemplation).There were few participants with an SoCdifference and both satisfaction indicators showed a more or less similar trend in the estimates, including the association for positive SoCdifference scores . So, both for “interesting” and “useful,” the direction of this relationship was in the expected direction, that is, participants reported lower satisfaction when the SoC of the snippet was “too high” for them. However, as the overall association was not statistically significant for “useful,” this result remains unsure.The overall association between SoCdifference (via SoCperson or SoCsnippet). Lastly, we assumed that persons would find snippets more interesting and useful when corresponding to their SoC, but this assumption may not be true. Readiness-tailored educational messages may still impact a person’s attitudes and beliefs (and thus bring about movement in SoCs), despite the message not being rated interesting or useful.In summary, part of the SoC-tailoring results were unexpected and called for further study. Moreover, there are many factors possibly influencing why someone finds educational materials interesting or useful and these may have somehow confounded with SoCOverall satisfaction, usability, and usefulness of the HEAR-aware app were reasonable to good, indicating sufficient acceptability. The large variance between participants in these outcomes, and the suboptimal compliance to the app’s EMA/EMI elements indicated room for improvement for part of the participants. The 10 new TB-specific SoC scales generally showed fair-to-excellent test–retest reliabilities, and sufficient construct validity, indicating their promise for use in future studies. The results of this study may inform future research on how to tailor educational app materials to a person’s SoC.We acknowledge everywhereIM for their role in the development and implementation of the HEAR-aware app in the study. We thank Schoonenberg HoorSupport for allowing the use of “HoorSupport,” and VeiligheidNL  for the use of the book “101 vragen over horen,” for snippet content.HEAR-aware concerns a collaboration project co-funded by Sonova AG (Switzerland), Schoonenberg HoorSupport (the Netherlands), and the PPP Allowance made available by Health~Holland, Top Sector Life Sciences and Health, to stimulate public-private partnerships.


There is no international consensus about the optimal approach to screening and diagnosis of gestational diabetes mellitus (GDM). Fasting plasma glucose (FPG) has been proposed as an alternative universal screening test to simplify the diagnosis of GDM. We investigate the ability of the FPG to predict a 2-hour glucose value below the cut-off for GDM, thereby “ruling out” the necessity of a full OGTT and assess the proportion of GDM-related complications associated with the identified FPG level.2013WHO) and 2017 Norwegian criteria (2017Norwegian). We analyzed pregnancy outcomes for women above and below our selected threshold.This study included secondary data from four Norwegian pregnancy cohorts (2002-2013), encompassing 2960 women universally screened with late mid-pregnancy 75g OGTT measuring FPG and 2-hour glucose. For a range of FPG thresholds, we calculated sensitivity to predict elevated 2-hour glucose, number of OGTTs needed and percentage of GDM cases missed, applying modified World Health Organization (WHO) 2013 criteria (2013WHO) and 10.1% (2017Norwegian). A FPG threshold of 4.7 mmol/L had a sensitivity of 76% (2013WHO) and 80% (2017Norwegian) for detecting elevated 2-hour glucose, with few missed GDM cases . When excluding women with FPG <4.7mmol/l and those with GDM based on FPG, only 24% (2013WHO) and 29% (2017Norwegian) would require OGTT. Women with FPG <4.7mmol/l, including missed GDM cases, had low risk of large-for-gestational-age newborns, cesarean section and operative vaginal delivery.The prevalence of GDM was 16.6% (A FPG threshold of 4.7mmol/l as a first step when screening for GDM could potentially eliminate the need for OGTT in 70-77% of pregnancies. Women with FPG below this threshold appear to carry low risk of GDM-associated adverse pregnancy outcomes. Gestational diabetes mellitus (GDM) is one of the most common disorders of pregnancy, responsible for several adverse outcomes in both mother and child during gestation and in the longer term . DespiteAlthough different diagnostic criteria for the identification of GDM are used, the oral glucose tolerance test (OGTT) is endorsed by all diabetes and health organizations as the “gold standard” diagnostic test for GDM. The use of OGTT in a clinical setting, however, poses several challenges. The test is poorly reproducible , time-coFasting plasma glucose (FPG) has been proposed as an alternative universal screening test for GDM , as it iIn light of this context, we aimed to explore the use of FPG to identify women at low risk for GDM and GDM-related adverse outcomes, limiting the need for an oral glucose tolerance test (OGTT). Our primary aim was to investigate the ability of the FPG to predict a 2-hour glucose value below the cut-off for GDM, thereby “ruling out” the necessity of a full OGTT, based on two different diagnostic GDM criteria in a Norwegian pregnant population. The secondary aim was to assess the proportion of GDM-associated complications for the identified FPG level in order to evaluate whether pregnancies ruled out can be safely excluded from further post-load glucose testing.We used secondary data from four Norwegian population-based birth cohort studies with a special focus on GDM. The criteria for the selection of studies have been previously described in detail . ParticiAll women were offered a 75 g OGTT measuring fasting and 2-hour (2-h) glucose levels. In the STORK Groruddalen study  venous b1999WHO) (FPG ≥7.0 mmol/l or 2-h glucose ≥7.8 mmol/l). We retrospectively applied modified 2013 WHO (2013WHO) diagnostic cut-offs  and the 2017 Norwegian (2017Norwegian) cut-offs (FPG ≥ 5.3 mmol/l or 2-h glucose ≥ 9.0 mmol/L) to the same OGTT. Women with GDM by 1999-WHO criteria were informed and referred to their general practitioner or specialist care according to protocol. Women received standard GDM treatment in accordance with either global guidelines in place at the time  criteria , overweight (25-29.9 kg/m2) and obesity (≥30 kg/m2).All participants provided questionnaire data, self-reported –21 or thOutcome data collected at the time of birth were birthweight (grams), gestational age at birth, delivery method , operative vaginal delivery (vacuum extraction or forceps)), preeclampsia or severe hypertensive disorder, and preterm delivery (<37 weeks). As in clinical practice in Norway, LGA  was calculated using Norwegian national references , while m2013WHO criteria and the 2017Norwegian criteria. Elevated 2-h glucose was used instead of the diagnosis of GDM since the latter also includes those diagnosed based on FPG. Using standard definitions, we assessed diagnostic accuracy measures such as sensitivity, specificity, and negative predictive value (NPV) of a range of threshold values of FPG (varying from 4.4 to 5.0 mmol/l). The number of OGTTs needed was analyzed after excluding women who had GDM based on FPG alone . In addition, we calculated the proportion of missed GDM cases (women with GDM according to the 2-hour glucose but “ruled out” and excluded from the OGTT because of the specified FPG threshold). In the process of selecting the “optimal” FPG threshold, options that demonstrated good/acceptable sensitivity were considered (The area (AUC) under the receiver operating characteristic (ROC) curve was used to analyze the discriminative power of FPG to predict an elevated 2-h glucose value, using the modified nsidered . The thr2 statistic for categorical data and ANOVA for continuous variables. Data are presented as frequencies and percentages for categorical variables and mean and standard deviations (SD) for continuous variables.Characteristics of the women were categorized by FPG-status, and the groups were compared using XTo examine the risk of pregnancy complications among missed GDM cases , we stratified women further into two groups: FPG below or FPG at/above the proposed threshold (4.7 mmol/l). For both strata, multivariable logistic regression models were performed for the pregnancy outcomes LGA, cesarean section and operative vaginal delivery, with elevated 2-h glucose (categorized as less than or at/above 9.0 mmol/l) as the main exposure. We adjusted for pre-specified confounders such as maternal age, pre-pregnancy BMI, ethnicity, parity, cohort, smoking and gestational age at birth. The effect estimates for 2-h glucose (less than or at/above 9.0 mmol/l) is presented as odds ratios (OR) with 95% confidence intervals (CI). The level of significance was set as 0.05. Statistical analyses were performed using statistical package IBM SPSS .2013WHO criteria for GDM, while 10.1% met the 2017Norwegian criteria. More than 80% of all GDM cases were identified by elevated FPG, both by the modified 2013WHO (≥5.1 mmol/L) and the 2017Norwegian (≥5.3 mmol/L) criteria, while 16.0% and 17.6% were identified by elevated 2-h glucose alone [2013WHO (≥8.5 mmol/L) and 2017Norwegian criteria (≥9.0 mmol/L)] ] Table S22017Norwegian criteria and slightly lower  when the modified 2013WHO criteria were used to define GDM. A separate ROC analysis for women with non-European background gave an AUC of 0.70 (95% CI 0.6-0.8) using the 2017Norwegian criteria  were assessed graphically Figure 12017Norwegian diagnostic criteria  and total cesarean section was observed in women with FPG <4.7 mmol/L and the highest proportion in the elevated FPG groups. None of the women with FPG <4.7 mmol/l and GDM by 1999WHO criteria received insulin or other antidiabetic medication.2013WHO and 2017Norwegian criteria respectively); 63% of participants had FPG below this threshold and could be “ruled-out” from further testing regardless of criteria used. Importantly, this group appears to carry a low risk of a range of pregnancy complications commonly associated with GDM. Furthermore, because FPG is included in the diagnostic criteria, we could identify (“rule-in”) over 80% of GDM cases using FPG alone in our sample. This implies that if a rule-in/rule-out approach was used, OGTT would be needed in only 24-29% of our population, i.e. only those with FPG in the range 4.7-5.0/5.2 mmol/L.Using data from a Norwegian sample offered universal mid-pregnancy GDM screening, we found that a FPG threshold of 4.7 mmol/L demonstrated an acceptable sensitivity of 76-80% to predict an elevated 2-hour glucose value (using modified FPG thresholds previously suggested as the preferred cut-off to avoid unnecessary OGTT’s include 5.0 mmol/l in Mexican adolescents (14), 4.8 mmol/l in Swedish women (16), 4.4 mmol/l in both an Arab (12) and Chinese population (15), and 4.3 mmol/l in studies from South Asia  and Belg2013WHO or 2017Norwegian criteria, 7-8% of GDMs identified with universal OGTT would be missed. Others have reported higher rates of “missed GDM” for the same threshold. Van Gemert et al. compared the use of a preliminary FPG ≥4.7 mmol/l to universal OGTT, reporting that 29% of women who would otherwise be diagnosed with GDM by 2013WHO criteria could be missed  study . BroadlyWe have previously reported that selection criteria for BMI and age currently used in Norway would result in recommending OGTT to about 70% of women with European ethnicity in our sample . The resHowever, the proposed screening strategy requires certain logistics to be in place in order to make the implementation successful. Ideally, the fasting venous sample would have to be analyzed without delay by a measure with acceptable validity and reliability and at the same facility. This should be followed by an immediate decision as to whether a full OGTT is required, thereby avoiding prolonged waiting time and enabling women to complete the test on the same day as the fasting blood test. Moreover, our study is centered on GDM diagnosis made late in pregnancy. In light of a recent RCT indicating potential benefits of early screening , the matOur study has several strengths. We merged previously collected maternal and offspring data from four cohorts, allowing more powerful and flexible analyses. Moreover, there is no pre-selection bias as an OGTT was offered to all included women. Importantly, most previous studies that have explored the performance of FPG provide limited or no information on adverse pregnancy outcomes.1999WHO criteria were routinely treated. This implies that conclusions drawn about likely clinical outcomes for women classified as “missed GDMs” may be inaccurate, as patients had a known diagnosis and received care, although none of these women received pharmacological treatment. Nonetheless, our results are comparable to those of McIntyre et al., which used a population blinded to OGTT results in their retrospective analysis of FPG and pregnancy outcomes (2013WHO criteria (The main limitation of our study is that glucose results were not blinded and women with GDM diagnosed by outcomes . Additiooutcomes . This macriteria , and a hOur study suggests that a two-step approach to GDM screening, with an initial universal FPG and exclusion of low-risk women from further testing, could potentially limit the use of OGTT to less than 30% of all pregnancies. A FPG threshold of 4.7 mmol/l appears to identify women at low risk of both elevated 2-hour glucose and GDM-associated adverse pregnancy outcomes. Additional studies are needed to validate our findings and confirm the safety of this screening approach, including long-term health outcomes, especially in populations where a higher proportion of women are diagnosed with GDM from post-load values.line.sletner@medisin.uio.no.The data analyzed in this study is subject to the following licenses/restrictions: The datasets analyzed during the current study are not publicly available due to the dataset containing clinical data which cannot be shared publicly, and as the study is part of a PhD work. The data are available from the corresponding author on reasonable request. Requests to access these datasets should be directed to Line Sletner, The studies involving humans were approved by Norwegian Regional Ethics Committee South East. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.AR: Data curation, Formal Analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. LS: Supervision, Data curation, Writing – review & editing. AJ: Conceptualization, Investigation, Data curation, Supervision, Writing – review & editing. NØ: Supervision, Data curation, Writing – review & editing. SS: Data curation, Writing – review & editing. EQ: Data curation, Writing – review & editing. AP: Formal analysis. LRS: Supervision, Data curation, Writing – review & editing.


While inhaled corticosteroids (ICS) may increase pneumonia risk in patients with chronic obstructive pulmonary disease (COPD), the impact of ICS on pneumonia outcomes is debated. We examined whether ICS use is associated with adverse outcomes among COPD patients with community-acquired pneumonia (CAP).Population-based cohort study of all COPD patients with an incident hospitalization for CAP between 1997 and 2013 in Northern Denmark. Information on medications, COPD severity, comorbidities, complications, and death was obtained from medical databases. Adjusted risk ratios (aRRs) for pleuropulmonary complications, intensive care unit (ICU) admissions, and 30-day mortality in current and former ICS users were compared with those in non-users, using regression analyzes to handle confounding.Of 11,368 COPD patients with CAP, 6,073 (53.4%) were current ICS users and 1,733 (15.2%) were former users. Current users had a non-significantly decreased risk of pleuropulmonary complications  compared to non-users (3.2%). This was also observed among former users . Similarly, decreased risks of ICU admission were observed among current users [aRR = 0.77 (0.57–1.04)] and among former users [aRR = 0.81 (0.58–1.13)]. Current ICS users had significantly decreased 30-day mortality  compared to non-users (12.6%), with a stronger association observed among patients with frequent exacerbations [0.58 (0.39–0.86)]. No significant association was observed among former ICS users [0.89 (0.75–1.05)].Our results suggest a decreased risk of death with ICS use among COPD patients admitted for CAP. Chronic obstructive pulmonary disease (COPD) is a strong predictor of hospitalization for community-acquired pneumonia (CAP). In a cohort study of patients aged 40 years and older, the annual incidence of hospitalization for CAP was 9.4% in patients with COPD versus 0.5% in patients without COPD . The incExisting data on the association between ICS and outcomes in patients with pneumonia are conflicting. Sellares et al. reported that both COPD and non-COPD patients who used ICS before CAP had a lower incidence of parapneumonic effusion . WhetherWe therefore undertook a large population-based study in Denmark to evaluate ICS use as a prognostic factor for clinical outcomes in COPD patients hospitalized for CAP. To overcome possible collider bias, we controlled meticulously for confounders, and also included a COPD comparison group consisting of former ICS users who likely have a risk factor profile close to that of current ICS users with COPD.International Classification of Diseases, Tenth Revision (ICD-10): J10–J18, A37, A481, A709], or with a primary diagnosis of lung abscess, pyothorax, or pleural effusion  coded with a secondary diagnosis of pneumonia. To focus on community-acquired infections, we excluded patients with any recent inpatient hospitalization within 1 month before pneumonia admission ]. COPD was further subcategorized according to (1) known duration of COPD, defined as time since first hospital diagnosis of COPD ; (2) history of frequent COPD exacerbation, defined as ≥2 exacerbations treated with oral steroids or ≥ 1 exacerbation leading to hospital admission during the last year ; and (3) airflow limitation (GOLD 1–4), based on forced expiratory volume in the first second (FEV1) values recorded in the DNPR during the last 2 years . For addWe defined current ICS users as persons who had filled their most recent ICS prescription within 180 days prior to the index date. Former users had redeemed their most recent prescription ≥181 days before the index date. Non-users were persons with no redeemed ICS prescription before the index date (reference group). To explore robustness of findings, we performed a sensitivity analysis by repeating the current user analyzes for patients who filled an ICS prescription within 90 days before the index date. Using mean defined daily doses (DDD) over a 1-year period before the index date, ICS use was categorized as low dose (≤0.5 DDD), medium dose (0.5 to 1 DDD), or high dose (> 1 DDD)  see Sup.We defined the following main outcomes: (1) a composite outcome of any in-hospital pleuropulmonary complication including parapneumonic complicated pleural effusion , coded as a discharge diagnosis during the incident hospitalization for pneumonia; (2) death within 30 days following the index date. Among patients hospitalized starting in 2005, we also looked at (3) risk of intensive care unit (ICU) admission see .We computed the cumulative incidence of pleuropulmonary complications, ICU admissions during the index hospitalization for pneumonia, and cumulative mortality during 30 days post-admission. Unadjusted and adjusted risk ratios (RR) with 95% confidence intervals (CIs) among current and former ICS users were computed for (1) pleuropulmonary complications, (2) death within 30 days, and (3) ICU admission, using ICS non-users as reference. The RRs were adjusted for a range of confounders, using modified Poisson regression for both in-hospital outcomes and 30-day mortality  see Sup. In an aThe total study cohort included 11,368 COPD patients with a first-time diagnosis of CAP between 1997 and 2013. Among them, 6,073 (53.4%) were current ICS users, 1,733 (15.2%) were former users, and 3,562 (31.3%) were non-users. Compared to non-users or former ICS users, current ICS users were of similar age, had fewer comorbid conditions, and had more use of concurrent medications. Current ICS users had longer COPD duration, more frequent exacerbations, and more prevalent use of systemic steroids and inhaled bronchodilators than non-users. Only 19.9% of our study population were using a dual bronchodilator therapy [long-acting beta agonists (LABA) and long-acting muscarinic antagonists (LAMA)], mainly in the ICS group. In the subgroup with available airflow limitation measurements in the registries (6.9% of cohort members), 72.0% of current ICS users were in the GOLD 3 or 4 spirometric grade compared to 43.1% of non-users and 45.5% of former users. Characteristics of the study cohort are summarized in Among the 11,368 patients with COPD and CAP, 315 (2.8%) were registered with a pleuropulmonary complication. Proportions of patients with pleuropulmonary complications were 3.2% among ICS non-users, 2.6% among current users, and 2.5% among former users. The crude RR was 0.80 [95% CI: 0.63–1.01] in current ICS users and 0.79 [95% CI: 0.56–1.11] in former users, compared with non-users. The adjusted risk of pleuropulmonary complications was non-significantly decreased with an adjusted risk ratio (aRR) of 0.82 [95% CI: 0.59–1.12] for current ICS users, yet was also decreased at 0.78 [95% CI: 0.55–1.10] for former ICS users see .Stratified analyzes are presented in Thirty-day mortality was 9.1% in current ICS users, 12.1% in former users, and 12.6% in non-users. Baseline characteristics according to survival at day 30 are presented in Among the 6,165 COPD patients who had available data on ICU admissions in the DNPR during 2005–2013, 403 (6.5%) were admitted to an ICU . The ICUWe found an approximately 20% reduced risk of pleuropulmonary complications and ICU admission in COPD patients with CAP who were current ICS users. However, these reductions were statistically non-significant and were also observed among former ICS users. Conversely, we found a stronger and significant association between current ICS use and decreased 30-day mortality from CAP, especially among patients with frequent exacerbations, which was not observed in former ICS users.per se. However, longer time since diagnosis of COPD may be related to survivor bias. Also, uncontrolled confounding by contraindication for ICS use, for example polypharmacy and general frailty , may have played a role. Compared to ICS non-users, current and former ICS users also may have had a higher baseline risk of pneumonia, and been admitted with less severe pneumonia less likely leading to complications (surveillance bias) ] (ce bias) . This isce bias) .Compared to ICS non-users, we observed a significantly decreased 30-day mortality among current ICS users [aRR 0.72 (95% CI: 0.62–0.85)], while mortality was not materially decreased among former ICS users. This difference in mortality was consistent during the periods 1997–2004 and 2005–2013. In comparison, a meta-analysis of six RCTs by Festic et al. reported a slightly decreased, yet imprecise, risk ratio of 0.91 [0.52–1.59] for pneumonia fatality (pneumonia deaths/number of COPD patients with pneumonia) . In addiSince ICS are infrequently used as monotherapy in COPD, and are most often used in combination with LABA or LAMA, any association of ICS with mortality might be confounded by a potential beneficial impact of these bronchodilators. We therefore adjusted for bronchodilator use (presence or absence) in our analysis, and still observed a clearly lower mortality with ICS use. Among ICS users, stratified analysis showed that the aMRR tended to be lower in patients who used one type of long-acting bronchodilator [LAMA only or LABA only: aMRR = 0.73 (0.53–1.00)] or a dual bronchodilator therapy [LAMA & LABA: 0.71 (0.34–1.45)] compared to those who did not used long-acting bronchodilator [aMRR = 0.83 (0.68–1.01)]. Of note, only 19.9% of our study population were receiving a dual bronchodilator therapy (LAMA & LABA). This low prevalence is partly explained by our study period (1997–2013), that started way before the first LAMA therapy was approved in Europe .One of our major findings was that among COPD patients without frequent exacerbations, ICS users had only a modest  decrease in pneumonia mortality [aRR 0.80 (95% CI: 0.68–0.95)], whereas frequent exacerbators with ICS use had an aRR as low as 0.58 [95% CI: 0.39–0.86]. Although other potential risks and benefits of ICS must obviously be considered in any treatment decision, our results are in line with current COPD treatment guidelines indicating that ICS should be used in patients with a history of exacerbations despite optimal treatment with long-acting bronchodilators , 27.ex vivo inhibition of human alveolar macrophage innate immune response to bacterial triggers  of ICU admission codes in the DNPR is 87.2% (95% CI: 75.6–94.5) . The facStrengths of our study include its large sample size, use of routinely collected clinical data, and a population-based design with access to individual-level information. Follow-up was virtually complete for pleuropulmonary outcomes and death. The DNPR maintains records on all hospitalizations since 1977, including dates of admission and discharge, and up to 20 discharge diagnoses, coded by physicians according to ICD-10. A previous study, based on medical history, clinical symptoms and findings, and spirometry results reported that the PPV of acute COPD discharge diagnoses is 92% (95% CI: 91–93%) for presence of underlying COPD . AlthougOur study also has limitations. Our observation that ICS users had fewer comorbidities but more concurrent medications may suggest better treatment, better access to medical care in general, and perhaps higher socioeconomic and educational status. We lacked data on socioeconomic variables, on markers of pneumonia severity (severity scores and blood gas results) and on hospital medications that could have had an impact on the outcomes, e.g., systemic steroid use and antibiotics. All of these variables could represent potential confounders that we were unable to adjust for. We had no data on blood eosinophil count, which may predict the magnitude of any ICS effect in preventing future exacerbations; of note, the GOLD guidelines proposed a threshold of >300 Eosinophilic cells/μl for initiating ICS treatment in combination with LAMA or LABA . AssessmUnmeasured confounding by indication for ICS use may be present in our study since our adjusted analysis could not fully account for reduced FEV1, as information on compromised airflow was missing for many patients . However, it is unlikely that lung function would be associated with both pneumonia outcomes and use of ICS independently of the many other markers of COPD severity for which we were able to adjust. Still, as in any observational study, residual confounding may have affected our risk estimates.Among COPD patients with CAP, we observed a modest and non-significantly decreased risk of pleuropulmonary complications and ICU admission among current ICS users. This was also seen in former ICS users however, and may be driven by residual confounding. In contrast, 30-day mortality was significantly decreased among current ICS users but not former users, particularly among those with frequent exacerbations. Our results are consistent with current GOLD recommendations suggesting that ICS use be limited to patients with a history of exacerbations despite optimal treatment with long-acting bronchodilators.The datasets presented in this article are not readily available because Danish data protection legislation does not allow researchers to share raw data from the registries with third parties. The data sources used in this study can be accessed by researchers through application to the Danish Data Protection Agency and the Danish Health Data Authority. Requests to access the datasets should be directed to Danish Data Protection Agency and the Danish Health Data Authority.The studies involving human participants were reviewed and approved by Danish Data Protection Agency (record number 2016–051-000001). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.DB, LW, RT, JM, NS, PD, CA, VJ, and HS contributed substantially to the study design, data analysis and interpretation, and the writing of the manuscript. All of the authors critically revised the manuscript for important intellectual content and gave final approval for the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.This work was supported by a research grant from the Fonds de Recherche en Santé Respiratoire and the Fondation du Souffle [FR2017]. The funding body had no role in the design of the study, collection, analysis, interpretation of data, nor in writing the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Vernonia amygdalina (VA), one of the highly researched species in the Asteraceae family, has proven to possess potent antidiabetic properties. Several phytochemicals identified in multiple extracts from VA are purported to be responsible for the antidiabetic potential of the plant. In this review, we discuss the therapeutic potential of VA in diabetes and its associated complications. We appraise the current evidence and further suggest potential areas that could be effectively exploited in future VA research on diabetes.Diabetes mellitus (DM), a complex heterogeneous metabolic disorder characterized by a defect in the function of insulin, is on the rapid rise globally. Sustained hyperglycemia which is a major sign of DM is linked to the generation of reactive oxygen species which promotes adverse complications of the disorder. Traditional herbal treatment of DM is a common practice in Africa and other tropical parts of the world.  This usually results in low or no insulin, causing hyperglycemia. On the other hand, type 2 DM, the more common type, which is more prevalent [Diabetes mellitus (DM) is a chronic heterogeneous metabolic disorder represented by the incidence of hyperglycemia due to a defect in function or secretion of insulin . There arevalent .According to the World Health Organization (WHO), about half a billion individuals are living with the disorder globally. The majority of these individuals are found in low- and middle-income countries . Though Dietary and lifestyle modifications play a huge role in the treatment of type 2 DM , 10. HowVernonia amygdalina (VA) [Many herbal plants have antidiabetic properties, and their use especially in developing countries is on the rise . Bioactiina (VA) . Here, wVernonia amygdalina (VA) is commonly known as bitter leaf due to its bitter taste. It is a small shrub that grows between 3 and 7 meters high and mostly found in tropical Africa and also grown in other Asian countries [ountries –19. Otheountries . Traditiountries .Extracts from the leaves and roots are also used in the indigenous treatment and management of several diseases such as malaria and diabetes , 23, as Since VA is easily accessible and used in various food preparations, it can be an economical source of medication for the treatment of diabetes . Neverthβ,13-dihydrovernolide [Amaranthus hybridus, Gnetum africanum, Gongronema latifolium, Ocimum gratissimum, Pterocarpus mildbraedii, Pterocarpus santalinoides, Piper guineense, Solanum macrocarpon, Talinum triangulare, Telfairia occidentalis, Vernonia amygdalina, and Vitex doniana) consumed in Nsukka, Southeastern Nigeria, for their hypoglycemic potential, VA showed significantly high antidiabetic activity, compared with the other plants. VA significantly lowered fasting blood glucose level by 70.6% (520.00 ± 7.80 mg/dl-150.00 ± 2.16 mg/dl) 24-hour posttreatment [Decoction of the leaves of VA has been used for indigenous treatment of diabetes . Severalernolide . When anreatment . Other sreatment , 56 haveDiabetic dyslipidemia refers to the disruption in the levels of serum lipids, i.e., low high-density lipoprotein cholesterol (HDL-C), elevated low-density lipoprotein cholesterol (LDL-C), increased VLDL-triglycerides, and the prevalence of small dense LDL , 58. ThiAll these studies further establish the antilipidemic potential of VA in diabetes-associated dyslipidemia.2O2 levels and malondialdehyde observed in diabetic control rats showed decreased levels when compared with the MLVA-treated group. The major antioxidant in the kidney, glutathione (GSH), was reduced significantly in diabetic control rats. However, treatment with MLVA restored GSH levels near the normal values indicating the potential antioxidant properties of VA. Activities of glutathione S-transferase (GST) and superoxide dismutase (SOD), major enzymatic antioxidants, were significantly higher in rats treated with MLVA than normal control and diabetic control rats. This study demonstrated that MLVA has the potential to prevent the progression of diabetic nephropathy through its antioxidant effects [Diabetic nephropathy has become the leading cause of end-stage renal failure in both developed and developing countries. About 20%-40% of all diabetic patients usually suffer from diabetic nephropathy, however, if left untreated, 80% and 40% of type 1 and type 2 diabetic individuals, respectively, are likely to develop definite nephropathy . In diab effects . Similar effects .Chronic hyperglycemia has been associated with increased oxidative stress which plays a significant role in associated complications of diabetes. Damage to hepatic cells as a result of long-term diabetes has been linked not only to oxidative stress but unusual inflammatory responses . The arrβ-cell destruction in the islets of Langerhans [β-cells of the pancreas in STZ-induced diabetic rats. This was evidenced by the reduction in glucose levels posttreatment indicating the potentiation of insulin secretion [β-cells from VA-treated rats showed no vacuolation and less degranulation compared to diabetic control rats. Higher levels of insulin were also detected in this study, and this is indicative of the pancreatic β-cell protective effect of VA. Increased insulin sensitivity and similar pancreatic β-cell regeneration have also been reported in another study [One significant pathological characterization of DM is pancreatic cell destruction leading to pancreatic ngerhans , 67. Thingerhans . A studyngerhans  revealedngerhans . In yet ecretion . In addiecretion  also reper study . Thus, tMultiple studies , 63 haveκB, in the treated rats compared to the negative control group. This demonstrates ameliorative effects induced by the extracts in the renal tissues and, thus, validates the renal regenerative effect reported in the study [Furthermore, immunohistochemical studies of the renal tissue reported by Adeoye et al.  demonstrhe study .Overall, all these studies highlight the potential of VA extract tissue ameliorative effect in diabetic models and hence confirm the restoration of necrotised and degenerated parenchymal cells of the organs in the studies above.μg/ml, were incubated with α-glucosidase (from Saccharomyces cerevisiae) at 0.35 U/ml and 0.1 M PBS (pH 6.8) for 10 min, at 37°C with the addition of 4 mM p-nitrophenyl-α-D-glucopyranoside (p-NPG). After detection of absorbance values at 405 nm for 45 min, the aqueous and Soxhlet root extracts expressed the maximum inhibition potential with an IC50 of 5.6 μg/ml and 39.8 μg/ml, respectively. At 5 μg/ml of the aqueous root extract, the enzymatic activity reduced by 48% and a 100% at 100 μg/ml showing an absolute inhibition potential. The aqueous leaf extract also showed inhibition potential in a concentration-dependent fashion [α-glucosidase activity in a concentration-dependent manner  [μg/ml significantly inhibited α-glucosidase activity in a dose-dependent manner indicating the antidiabetic property of VA [Alpha-glucosidase is an enzyme that catalyzes the hydrolysis of complex carbohydrates to simple sugars like glucose. This leads to increased postprandial blood glucose levels. Due to its activity, it is one of the major enzymes targeted for the treatment of diabetes . Alpha-g fashion . In a mo fashion , the biod 50 μM) . Similarty of VA . Resultsμg/ml). All doses of the extracts showed significant antiglycation effects and proved to be antihyperglycemic agents [μM–100 μM) inhibited AGE formation in ribose-, fructose-, and glucose-induced BSA glycation. This occurred in a concentration-dependent manner with IC50 values of 58 μM (−Log IC50 = 4.24 ± 0.02), 19.6 μM (−Log IC50 = 4.71 ± 0.04), and 40.4 μM (−Log IC50 = 4.39 ± 0.05), respectively [μmol Trolox equivalent antioxidant capacity (TEAC)/μmol compound). Overall, this study showed that the antioxidation and antiglycation potential can be attributed to the presence of the bioactive compound, luteolin [in vitro against 2,2-diphenyl-1-picryl hydroxyl (DPPH) radical [The formation of advanced glycation end products (AGEs) in associated complications of diabetes is linked with hyperglycemia and oxidative stress . Reportsc agents . Moreoveectively . In compluteolin . In yet luteolin . Similar radical .Gluconeogenesis is a series of metabolic reactions that results in the production of new glucose molecules aiding glucose balance in the body, especially in a state of starvation , 75. TheFurthermore, increased tyrosinase and amylase activities have been associated with an increased risk of type 2 DM , 80. TheOverall, these studies suggest that inhibition of gluconeogenesis is one of the mechanisms by which VA exerts its antidiabetic potential.The expression of glucose-6-phosphate dehydrogenase (G6PD), a major enzyme in the pentose phosphate pathway (PPP), was determined. The PPP through the action of G6PD produces nicotinamide adenine dinucleotide phosphate (NADPH). NADPH plays a role in maintaining cellular antioxidative defence systems by acting as a reducing agent , 82. Hepβ-cell survival, decreases insulin resistance, and enhances glucose metabolism and uptake by upregulating the levels of glucose transporter 4 (GLUT-4) [AMPK is a biomolecule that plays a key role in energy homeostasis in the body . It is r(GLUT-4) . These a(GLUT-4) .Vernonia amygdalina in multiple preclinical studies. Its ethnopharmacological use as antidiabetic agent in humans is lacking and, thus, yet to be explored. We suggest that well-designed clinical studies be conducted to validate the antidiabetic properties of VA in human participants in regions where this medicinal plant is frequently used among indigenous communities, such as Ghana and Nigeria. Moreover, the synergistic effect of VA and other known antidiabetic medicinal plants such as Allium sativum [Several studies have proven the antidiabetic properties of  sativum  could be sativum .Furthermore, very few of the studies used the identified phytochemicals to confirm the antidiabetic potential of VA. Hence, characterization of the bioactive agents responsible for the antidiabetic activities is warranted. More relevant to the field of drug design, the mechanism of action of these bioactive agents and their synergistic properties could potentially provide a platform for the design of potent antidiabetic drugs from VA in the near future.Lastly, there is a general lack of data on interaction between VA and approved antidiabetic drugs. Some diabetic patients combine pharmaceutical drugs with herbal medicines such as VA when treating their ailment . HoweverVarious medicinal plants have been reported to exhibit antidiabetic properties, and VA is no exception. In this review, we summarized the various therapeutic potential of VA in the treatment of diabetes and its associated complications such as nephropathy and dyslipidemia. VA has demonstrated hypoglycemic abilities via several mechanisms in animal models and could therefore be potent in human studies.


Epidemiological studies support an association between obesity, metabolic syndrome (MetS), and periodontitis. Still, understanding of the effects of low-grade inflammation in obese subjects on periodontitis and influence of MetS remains incomplete. The aims of this cross-sectional study were to explore the association between obesity related variables and periodontitis, and assess if MetS is a risk indicator for periodontitis in a sample of obese adults.2 referred for obesity therapy at the Obesity Centre at Haukeland University Hospital (HUH), Bergen, Norway. The subjects had prior to enrolment completed a 5-month lifestyle intervention course as part of a 2-year managing program. According to the revised National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) classification of MetS, 38 subjects were recruited to the MetS group and 14 subjects to the non-MetS group. Medical data including peripheral blood samples were obtained from records at HUH at the time of enrolment. Probing depth, clinical attachment level, tooth mobility, furcation involvement, bleeding on probing (BoP) were recorded and intraoral bitewings evaluated at a full-mouth periodontal examination. Associations between risk variables for obesity/MetS and periodontitis were explored using linear and logistic regression models.The study sample comprised 52 adults with a body mass index (BMI) of ≥ 30 kg/mIn the present sample 79% of the subjects were diagnosed with periodontitis. The prevalence of stage III/IV periodontitis was 42.9% in the non-MetS group vs. 36.8% in the MetS group (p = 0.200). In the non-MetS group 29.8% of the sites displayed BoP vs. 23.5% in the MetS group (p = 0.048). For stage III/IV periodontitis, the effect of age appeared to be significant for obesity related variables and MetS . None of the other analyses showed significant association with the outcome variables.In the present sample of obese subjects, periodontitis occurred independently of MetS. Reaching a certain BMI level, suggested association between MetS and periodontitis might be non-significant due to the dominating impact of obesity related variables undermining the effect of other systemic factors.The principal clinical trial, entitled “Obesity and Oral Diseases”, was prospectively registered in ClinicalTrials.gov with registration NCT04602572 (20.10.2020). Overweight and obesity increasing globally are considered major challenges to human health services . In 2016Metabolic syndrome (MetS) represents an assembly of functional disturbances including obesity, increased waist circumference, increased insulin levels/blood glucose, hypertension and/or low high-density lipoprotein (HDL)/high triglycerides (TG) count. Each is considered a risk factor for the development of other diseases . Co-occuPeriodontitis is a chronic non-communicable, inflammatory disease encompassing tooth supporting gingival tissues and alveolar bone triggered by dysbiosis of oral microbiota and host immune response . PeriodoElevated levels of inflammatory biomarkers including high-sensitivity C-reactive protein (CRP)  and proiPeriodontitis and MetS share inflammation as a common feature and subjects affected by either disease may display elevated levels of circulatory cytokines. Both TNF-α and IL-6 have been considered important mediators for periodontitis . IncreasThe aims of the present cross-sectional study were to explore the association between obesity related variables and periodontitis, and assess if MetS is a risk indicator for periodontitis in a sample of obese adults. We hypothesize that MetS deteriorates the periodontal inflammatory status in these subjects.The study protocol and informed consent following the Helsinki Declaration of 1975 (version 2008) was approved by the Norwegian Regional Ethics Committee . The principal clinical trial, entitled “Obesity and Oral Diseases”, was prospectively registered in ClinicalTrials.gov with registration NCT04602572 (20.10.2020). Study subjects were informed of the nature, scope, and consequences of participating in the study before signing the informed consent. The present article is written according to Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. All methods were carried out in accordance with relevant guidelines and regulations.The present cross-sectional study enrolled subjects from the Obesity Centre, Section of Endocrinology, Haukeland University Hospital (HUH), Bergen, Norway, January 2021 through September 2021. Medical data and fasting blood samples were collected at enrolment. A clinical periodontal examination was performed at the Department of Clinical Dentistry, University of Bergen, January 2021 through December 2021. Enrolled subjects were informed of any periodontal pathology and recommended to seek dental care from a local dentist or periodontal specialist of choice.One examiner (AT) unaware of group assignment performed all clinical examinations. Prior to initiation of the study, two separate calibration exercises were performed: 1: Examiner AT was calibrated with an experienced periodontist (KNL) and 2: Examiner AT performed an exercise to assess intra-examiner reproducibility for the primary outcome variables probing depth (PD) and clinical attachment level (CAL). In a study sample of five subjects (100 teeth/600 sites), PD and CAL were examined twice, 10 min apart, at six sites per tooth. Intraclass correlation coefficients (ICCs) were calculated separately for each site. ICC for repeated measures ranged between 0.84 and 0.93 for PD and between 0.82 and 0.95 for CAL.The pre-study sample size calculation was based on change in PD. A difference of 0.5 mm was considered clinically relevant . Standar2 having completed a 5-month lifestyle intervention course as part of a 2-year managing program. Consecutive subjects were screened for eligibility according to inclusion/exclusion criteria by a senior consultant. Fifty-two out of 129 screened subjects were enrolled  ≥ 30 kg/mStudy exclusion criteria included leukaemia/neutropenia, HIV/AIDS, pregnancy, use of immunosuppressive drugs, mental illness , Sjögren’s syndrome, obesity caused by endocrine disease , bulimia nervosa, and present/past history of head and neck cancer. In addition, subjects treated for periodontitis or used systemic antibiotic/anti-inflammatory medication within the last 6 months were also excluded.2. The blood sample for testing MetS diagnosis parameters  and CRP were all collected at HUH in the morning after 12 h fasting. Subjects were excluded if group allocation was not possible based on predefined MetS criteria.Enrolled subjects were assigned into a non-MetS or a MetS group Fig.  accordinUpon arrival for the clinical examination, study subjects completed a multiple-choice questionnaire including demographic items, general health, medication, smoking, oral health/hygiene, and dietary habits. Questions were repeated orally if there were missing answers resulting in a 100% response rate. The questionnaire, tested internally to ascertain that all items were easily understood, was constructed by the research group experienced in the items selected. Participants were classified as either current smokers (had smoked ≥ 100 cigarettes in their lifetime and currently smoked), former smokers , or never smokers (had not smoked ≥ 100 cigarettes in their lifetime) .The following clinical parameters were recorded: PD ; and CAL  using a periodontal probe  at six sites per tooth rounded up to the nearest mm . Bleeding on probing (BoP), sites showing bleeding on gentle probing was estimated at four sites per tooth  . FurcatiPeriodontitis was diagnosed and classified using the 2017 World Workshop on the Classification of Periodontal and Peri-implant Diseases and Conditions . In shorMean values and standard deviations were used to describe continuous variables. For categorical variables frequencies and percentages were used. Quantitative variables such as PD and CAL were sectioned into three distinct groups: 0–3 mm , 4–5 mm For continuous variables at patient level, two-group t-test was used to test statistical differences, while chi-square tests were used for the categorical variables. Continuous variables were analysed using linear regression models reporting beta coefficients with 95% confidence intervals (95% CI). The categorical (dichotomous) outcome variables were analysed using logistic regression models, reporting odds ratios (ORs) with 95% CI. For tooth and site-specific outcomes variables, the regression analyses were performed using cluster robust variance estimates to adjust for multiple measures per individual. Stata version 17  was used for the statistical analyses. P-values less than 0.05 were considered statistically significant.A total of 52 subjects (1456 teeth/8736 sites) meeting study inclusion criteria were examined . Five (35.7%) and six (42.9%) subjects in the non-MetS group were classified as stage I/stage II and stage III/stage IV (p = 0.25). In the MetS group the numbers were 16 (42.1%) and 14 (36.8%).Table The outcomes of unadjusted and adjusted logistic regression analyses for interdental PD (on site level), CAL (on site level), and stage III/stage IV periodontitis (on patient level) are shown in Tables When adjusted for obesity related variables and MetS, the effect of age on stage III/stage IV periodontitis, persisted to be significant Table  and 4.2, the occurrence of periodontitis was not found to be associated with MetS. The data analyses revealed a higher percentage cases with severe periodontitis in the non-MetS group (stage III/stage IV: 42.9%) compared with the MetS group (stage III/stage IV: 36.8%). Similar distributions of PD and CAL were observed in the two groups. Interestingly, a significantly higher percentage BoP was observed in the non-MetS compared with the MetS group. For staging of periodontitis, the effect of age appears to be significant both for obesity related variables and MetS.In a sample of obese subjects with a mean BMI of 41.5 kg/mWe hypothesized that MetS would promote a more severe periodontal conditions in obese subjects. However, the prevalence of periodontitis was similar (78.6% in non-MetS vs. 78.9% in MetS), the non-MetS group exhibiting a slightly higher prevalence severe periodontitis (42.9% in non-MetS vs. 36.8% in MetS). Moreover, BoP was more prevalent in the non-MetS group . The questionnaire, however, exploring personal oral hygiene routines disclosed comparable findings (73.7% in the MetS vs. 71.4% in the non-MetS group).A study on the prevalence and severity of periodontitis in a Tromsø, Norway, normal-weight population , reported a prevalence of 49.5% . DespiteA study from northern Finland  investig2) or a non-MetS (mean age 58.2/mean BMI 27.0 kg/m2) group [The association between prevalence of periodontitis and MetS was investigated in Vietnamese subjects allocated to an MetS (mean age 57.8/mean BMI 28.3 kg/m2) group . Subject2 and > 25 kg/m2. However, no information on mean group BMI was available. The overall prevalence of periodontitis in our study groups approximated 79%. This may indicate that exceeding a certain level of overweight/obesity the association between MetS and periodontitis becomes less significant as the dominating impact of obesity relates variables undermines the detrimental effect of other systemic factors.A Brazilian case-control study also reported a risk association between MetS and periodontitis . The preThe regression analysis showed a tendency toward significant impact of gender on the development of stage III/stage IV periodontitis when adjusting for MetS variables (p = 0.083). Age had a significant effect on the prevalence of stage III/stage IV periodontitis. The effect of age might be expected as periodontitis is an irreversible, cumulative disease , 37. As The unbalanced distribution of subjects within the two groups, with a lower number of subjects included in the non-MetS group, might undermine the statistical power of the study. In the present study, staging and grading were primarily based on clinical measures such as CAL, PD, furcation involvement, and bitewing radiographs. Registration of plaque would give a more nuanced understanding of all clinical parameters and particularly BoP. The rather high mean BMI of our study sample may undermine the likelihood of detecting intergroup differences. Only about 15% of the obese population will not develop obesity related co-morbidities . In addiThe strength of this study is the full-mouth periodontal evaluation, and the periodontal examination performed by only one examiner with high ICC values, improving the disease detection accuracy. The sociodemographic, oral hygiene habits, laboratory and clinical data were rather comprehensive and relevant.In the current sample of obese subjects, periodontitis occurred independently of MetS. The data analyses showed that a higher percentage cases with severe periodontitis was found in the non-MetS group (stage III/stage IV: 43%) compared with the MetS group (stage III/stage IV: 37%). A significantly higher percentage of BoP was detected in the non-MetS group. For stage III/stage IV periodontitis, the effect of age appears to be significant both for obesity related variables and MetS. Apparently, when a certain BMI level is reached the suggested association between MetS and periodontitis seems to be inferior due to the dominating impact of obesity related variables possibly undermining the significance of other systemic factors.