According to the Strength of Recommendation Taxonomy (SORT) criteria, level A can be established to conclude that patients with OLP can be rehabilitated with dental implants.A systematic review was conducted to answer the following PICO question: “Can patients diagnosed with oral lichen planus (OLP) be rehabilitated with dental implants as successfully as patients without OLP?”. A systematic review of the literature was done following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements to gather available and current evidence of oral lichen planus and its relationship with dental implants. The synthesis of results was performed using a Binary Random-Effects Model meta-analysis. Summary measures were odds ratios (ORs), frequencies, and percentages comparing the survival rate of dental implants placed in patients with OLP vs. those in patients without OLP. The electronic search yielded 25 articles, after removing the duplicated ones, 24 articles were selected. Out of the 24 articles, only 15 fulfilled the inclusion criteria. According to the results of the meta-analysis, with a total sample of 48 patients with OLP and 49 patients without OLP, an odds ratio of 2.48 (95% CI 0.34–18.1) was established, with an I Oral lichen planus (OLP) is an autoimmune and chronic inflammatory disease ,2,3. TheThe prevalence of this inflammatory disease involves 1–2% of the population, the epidemiology od OLP was evaluated in 1987 by Axell and Rundquist , on thisTherefore, OLP usually appears in women and in the age group of 50 to 70 years old. The meta-analysis carried out by Aghbari et al.  concludeSince OLP is a mucosal disease, it has been suggested to affect the ability of attachment to the titanium surface; and although some conditions are considered as risk factors for dental implants, there are only a few absolute contraindications for this rehabilitation option . Taking this statement into account, oral rehabilitation with dental implants in patients with OLP needs to be questioned; in fact, surgical injury due to the implant insertion procedure should be avoided during active, erosive phases of OLP. Frequent follow-ups are needed in order to rule out inflammatory tissue response interfering with long-term survival of implants . Excellent results in patients without general pathologies have been reported with survival and success rates of implant, in a long-term follow-up . FurtherHowever, other factors such as smoking and the level of oral hygiene can affect osseointegration and lower dental implant success rates . The main aim when treating patients with OLP is to avoid irritating factors for the mucosa, since this disease may appear in either asymptomatic or symptomatic forms. Patients may refer to burning or occasional pain ,2,3,4.This systematic review was conducted to answer the following PICO question: “Can patients diagnosed with OLP be rehabilitated with dental implants with the same survival rate as patients without OLP?”. A systematic review of the literature was done following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements  to gatheThe following terms were searched in PubMed and Cochrane;  AND “Dental Implants” [Mesh]. Inclusion criteria were articles written in English or Spanish, meta-analyses, systematic reviews, randomized-control trials, cohort studies, and case reports. On the other hand, exclusion criteria were animal studies, in vitro studies, and descriptive reviews.The primary outcome of this article was to establish whether patients with OLP had the same survival rate as patients without OLP. Furthermore, secondary outcomes such as the protocol and recommendations for patients with OLP who were rehabilitated with dental implants were reviewed. The following data were extracted from the included studies (when available) by two independent reviewer authors (A.T.-M. and C.S.-H.): authors, year, study design, number of subjects, gender, age, OLP type, OLP location, OLP duration (in years), previous biopsy, number of implants, type of prostheses, survival rate, follow-up (in months), malignant transformation, and OLP treatment. Discrepancies were resolved with the other authors , and finally data were validated by J.L.L.The selected studies were assessed following the Strength of Recommendation Taxonomy (SORT) criteria .A quality assessment of the publications included for the systematic review was not applicable due to the entity of included publications. Blinding of participants and personnel (performance bias) and blinding of outcome assessment (detection bias) were not applicable, since most publications were case reports. Due to selective reporting within case reports, attrition bias (incomplete outcome data) and reporting bias (selective reporting) were assumed to be high.The synthesis of results was performed using a Binary Random-Effects Model meta-analysis. Summary measures were odds ratios (ORs), frequencies, and percentages comparing the survival rate of dental implants placed in patients with OLP vs. those in patients without OLP. Forest plots were produced to graphically represent the odds ratio of successful placement of the dental implant in patients with OLP and among patients without OLP . 2 statistics. Each outcome was combined and calculated using the Review Manager software. Heterogeneity was assessed by the IThe electronic search, in PubMed and Cochrane databases, yielded 25 articles, after removing the duplicated ones, 24 articles were selected. Out of the 24 articles, only 15 fulfilled the inclusion criteria. As shown in A total of 110 patients were examined, with an age range of 51 to 81 years old. There were a total of 83 female patients (75.45%) and 27 male patients (24.55%). Not all the studies evaluated the type of OLP, although a total of 72 patients were divided by the type of OLP. The most common OLP type was erosive OLP (42 cases—58.33%), followed by the reticular OLP (22 cases—30.55%) and the atrophic type (8 cases—11.11%). Regarding the location of OLP, a total of 29 locations were mentioned; the most common location was the buccal mucosa (22 cases—75.86%), following the gingiva (5 cases—17.24%), the tongue (1 case—3.44%), and the palate (1 case—3.44%). From the 15 articles selected, only 8 ,23,24,25Regarding the type of prostheses, it was analyzed in most of the articles, and a total of 113 prostheses were analyzed, the most used type of protheses was the fixed partial (95 rehabilitations—84.07%), the second most used was the fixed complete rehabilitation (10 rehabilitations–8.84%), and the overdenture (8 rehabilitations–7.07%). Concerning OLP treatment when patients were being rehabilitated with dental implants, it was only considered in 6 articles ,23,24,25Regarding malignant transformation, 5 articles stated a malignant transformation ,18,19,20Regarding the 8 patients who were diagnosed with oral squamous cell carcinoma, only 4 of them ,19 had aMoreover, 3 patients (37.5%) reported a previous malignant pathology, 3 patients (37.5%) reported not having any history of OSCC, and for the 2 remaining patients (25%) it was not reported. 2 was used to assess heterogeneity between studies.According to the results of the meta-analysis, with a total sample of 48 patients with OLP and 49 patients without OLP, an odds ratio of 2.48 (95% CI 0.34–18.1) was established. Indicating that patients with OLP had a 2.48 times higher survival with dental implants in comparison with patients without OLP, and the IBased on our systematic review of the literature and answering our PICO question: rehabilitation with dental implants in patients with OLP is a valid treatment option with a survival rate of 93.88%. This survival rate is similar to the survival rate of implant rehabilitation in patients without any pathology or systemic condition, which is 92% or 95%, depending on the prosthetic rehabilitation . In order to maintain this high survival rate, frequent follow-up appointments and oral hygiene instructions should be established to eliminate inflammatory tissue response (peri-implant mucositis and peri-implantitis) .Although the most common type of OLP is the reticular type , followeWe would like to point out, that we were surprised by the fact that none of the articles mentioned previously reported any case of re-activation of OLP or an atrophic or erosive stage after the placement of dental implants. Furthermore, although the malignant transformation rate calculated (7.3%) is substantially higher than the one reported by Aghbari et al.  in patieAdditionally, we were surprised by the fact, that not all the studies that reported malignant transformation, reported the time that elapsed between the OLP diagnoses and the development of OSCC, and again, the frequency with which the patients were evaluated was not mentioned. Another notable matter is the fact that only 53.33% of the studies analyzed related performing a biopsy to diagnose the OLP. However, both clinical and histopathologic criteria need to be present to diagnose OLP, according to the modified WHO diagnostic criteria of OLP and oral lichenoid lesions, proposed by van der Meij and van der Waal . TherefoRegarding the meta-analysis, an odds ratio of 2.48 was established, indicating that patients with OLP have a higher survival rate in comparison with patients without OLP. However, these results are based on only 2 studies ,25, sincAccording to our results, implant rehabilitation in patients with OLP is not contraindicated, and survival rates are comparable to those of patients without OLP. Given the foregoing , our wor(i) Initially, we would like to remark on the importance of a detailed medical history, a photographic register, and a biopsy to confirm the OLP diagnosis. (ii) Secondly, and in agreement with Hernández et al. , no implThe guideline that we propose is deflazacort 30 mg 2 days pre-operative, 15 mg 3 days post-operative, and 7.5 mg for 3 more days. We propose deflazacort since it is a synthetic glucocorticoid characterized by high efficacy and good tolerability, widely used in autoimmune disease and dermatology . From here, we agree with other studies ,24 and w(iii) Finally, meticulous oral hygiene and frequent, regular appointments  are impoThe limitations of this systematic review include the fact that most studies were case reports, which means low-level evidence, and the fact that case series did not provide data separately. Additionally, the published cases provided a short follow-up, therefore longer follow-ups would mean a more reliable prognosis.Therefore, with the discrepancies presented in the current literature along with a lack of treatment guidelines and the small sample analyzed, caution should be exercised when drawing a conclusive statement.According to the SORT criteria , level AMore studies with longer follow-up and higher levels of evidence, such as randomized-controlled trials, are needed.


Mobile health and self-management interventions may positively affect behavioral change and reduce hospital admissions for patients with chronic obstructive pulmonary disease (COPD). However, not all patients qualify for these interventions, and systematic, comprehensive information on implementation- and compliance-related aspects of mobile self-management apps is lacking. Due to the tendency to target digital services to patients in stable phases of disease, it is especially relevant to focus on the use of these services in broad clinical practice for patients recently discharged from hospital.This study aims to evaluate the effects of a mobile health and self-management app in clinical practice for recently discharged patients with COPD on use of the app, self-management, expectations, and experiences (technology acceptance); patients’ and nurses’ satisfaction; and hospital readmissions.A prototype of the app was pilot tested with 6 patients with COPD. The COPD app consisted of an 8-week program including the Lung Attack Action Plan, education, medication overview, video consultation, and questionnaires (monitored by nurses). In the feasibility study, adult patients with physician-diagnosed COPD, access to a mobile device, and proficiency of the Dutch language were included from a large teaching hospital during hospital admission. Self-management , technology acceptance (Unified Theory Acceptance and Use of Technology model), and satisfaction were assessed using questionnaires at baseline, after 8 weeks, and 20 weeks. Use was assessed with log data, and readmission rates were extracted from the electronic medical record.P=.04). The COPD app was rated on a scale of 1-10, with an average score by patients of 7.7 (SD 1.7) and by nurses of 6.3 (SD 1.2). Preliminary evidence about the readmission rate showed that 13% (5/39) of patients were readmitted within 30 days; 31% (12/39) of patients were readmitted within 20 weeks, compared with 14.1% (48/340) and 21.8% (74/340) in a preresearch cohort, respectively.A total of 39 patients were included; 76.4% (133/174) of patients had to be excluded from participation, and 48.9% of those patients (65/133) were excluded because of lack of digital skills, access to a mobile device, or access to the internet. The COPD app was opened most often in the first week , but its use decreased over time. The self-management element knowledge and coping increased significantly over time , and fine-tuning its adoption in clinical pathways.Clinicaltrials.gov NCT04540562; https://clinicaltrials.gov/ct2/show/NCT04540562. Chronic obstructive pulmonary disease (COPD) affects over 250 million people worldwide  and almoSelf-management interventions are also recognized to be important in reducing exacerbations  and hospMobile apps are increasingly being used to provide patients with health and self-management interventions, for example, for remote monitoring of patients’ health status -17, selfUntil now, much attention has been given to the effects on clinical health outcomes ,25-27 anSelf-management interventions, which are increasingly supported by mobile apps in recent years, may improve disease management in patients with COPD and may decrease hospital admissions. However, not all patients qualify because of reasons such as socioeconomic status, internet access, and skills. Systematic, comprehensive information on implementation- and compliance-related aspects of mobile self-management apps is lacking. Additional evidence about the effectiveness of mobile self-management apps is needed, especially regarding factors affecting the use in clinical practice for high-use patients, such as those recently hospitalized due to an exacerbation.COPD app) in clinical practice for patients with COPD, after discharge from the hospital, on app use, self-management, expectations and experiences (technology acceptance), patients’ and nurses’ satisfaction, and hospital readmissions.The objective of this study is to evaluate the effects of a mobile health and self-management app , frequency of notifications they would prefer, the readability, the frequency of new information, and their sociodemographic characteristics. Before starting the feasibility study, results from the pilot testing were used to improve the COPD app.Pilot testing was used to receive feedback on a prototype of the COPD app. A total of 6 patients, admitted to a large teaching hospital  for a COPD exacerbation, were provided with a tablet and access to the app. Patients received assignments such as Patients were recruited from a large teaching hospital . To be eligible, patients must be older than 18 years, diagnosed for COPD by a physician, admitted to the hospital for a COPD exacerbation , have access to a smartphone or tablet, have a working internet connection, being able to use a smartphone or tablet, and be proficiency in Dutch language. Patients with cancer or (severe) cognitive or psychiatric conditions were excluded. At least one hospitalization for COPD exacerbation in the year preceding this study was also a criterion for accrual, but it only applied during the first month (of the inclusion period) because the number of eligible patients was too low.Patient Journey App software (PJA version 4.0) [Facetalk [Patients were informed about the study by a pulmonary nurse and the researcher during hospital admission. Patients received the study information letter and were asked to sign the informed form. They also received support to download apps. The ion 4.0)  was usedFacetalk  for videFacetalk -43.The COPD app provided patients with an 8-week self-management program. The app had 3 views: timeline, information page, and contact page see . The staLung Attack Action Plan, (2) Medication Overview, (3) Information and Education, (4) Questionnaires, and (5) Consultations, in week 4 and 8  nd 8 see  and 2.Longfonds) [I am doing well today (green), I feel worse (yellow), No improvement after 2 days (orange), and The situation is threatening (red). All levels included advice about symptoms , medication, physical activity, and nutrition. Patients could access and use the Lung Attack Action Plan at any time using the COPD app. It was also possible to request contact with a pulmonary nurse after using the Lung Attack Action Plan. The nurse received a notification email and would contact patients within 2 working days.The Lung Attack Action Plan was provided by the Lung Foundation (ngfonds)  and was Patients had access to an overview of their personal daily and extra medication.A total of 5 information categories were included in the timeline: the COPD app, the condition COPD, physical activity, nutrition, and advantages of smoking cessation. For each topic, a general page was accessible, including more specific topics. Patients were provided with information, in text and video, about the COPD app , COPD condition , nutrition , physical activity , and smoking cessation .Patients were asked to fill out the weekly Clinical COPD Questionnaire (CCQ) and the Hospital Anxiety and Depression Scale (HADS) at weeks 1 and 8, using the app or via email. The results were monitored by nurses. The HADS was used to measure anxiety and depression The HADS is a 14-item screening list that consists of two 7-item subscales. The items are rated on a 4 point Likert scale (range 0-3) ,46. The A video consultation was planned after 4 weeks with a pulmonary nurse, and a face-to-face consultation was planned after 8 weeks with a nurse practitioner or a pulmonologist. Patients could also request additional video consultations and telephonic consultations using the COPD app.The information page contained an overview of the information elements: Lung Attack Action Plan, the COPD app, condition COPD, nutrition, physical activity, smoking cessation, and information about video consultation. The information elements were presented in a list format, with a search function. See The contact page presented 2 elements for patients: (1) the Lung Attack Action Plan and the option to request contact with a pulmonary nurse or (2) directly request telephonic contact with a nurse. Nurses received an email and contacted the patients within 2 working days. See Use of the COPD app is measured with log data. Use is reported as the number and percentage of patients and the number of times, described as page clicks, the app and the information items were opened. The number of times the Lung Attack Action Plan, contact request, and CCQ questionnaires were used is described with absolute and relative numbers.Patients completed questionnaires about satisfaction with app use, the information provided, and user-friendliness. This is assessed on a 7-point scale . Patients were also asked about their overall satisfaction on a scale of 1 to 10 . See The Partners in Health (PIH) scale was used to measure self-management ,49. The Questionnaires covering constructs of the Unified Theory of Acceptance and Use of Technology (UTAUT)  model weAfter all patients were included and completed the 8-week self-management program, we asked involved pulmonary nurses about their experience with the COPD app, video consultation, experience with monitoring the CCQ scores, and their satisfaction with for example efficiency and time investment.A hospital readmission was defined as admission for at least 24 hours. The number of hospital admissions was obtained from the electronic medical record (EMR) after 30 days, 8 weeks, and 20 weeks. This was compared with the readmission rate from the previous year, November 2017 to November 2018.Patients’ age, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage, and comorbidities were extracted from the EMR. Their marital status, education, internet use, smartphone or tablet skills, and need for support using a smartphone or tablet were assessed using a questionnaire.Use was assessed using log data, extracted from the app software, after 8 and 20 weeks. Patients completed a baseline questionnaire during hospital admission, covering aspects of self-management (PIH), expectations with the COPD app, internet use, smartphone or tablet skills, and sociodemographics. After 8 weeks and 20 weeks, a questionnaire was sent on self-management, experiences with the app, and  satisfaction. After 30 days, 8 weeks, and 20 weeks, the readmission rate was assessed, and data were extracted from the EMR. See Data analysis was performed using IBM SPSS V22.0. Descriptive statistics were used to report the baseline characteristics, app use, expectations and experiences, satisfaction, and number of readmissions. Changes in self-management over time were analyzed using a linear mixed model. Using a linear mixed model allowed for the inclusion of cases with missing data. The relation between app use and self-management was analyzed using linear regression. Normally distributed variables were reported as mean and standard deviation, and non-normally distributed data were reported with medians and interquartile ranges (25th-75th percentiles).Commissie Mensgebonden Onderzoek Arnhem–Nijmegen.The study was approved by the local ethical committee A total of 6 patients participated in the pilot testing of a prototype of the COPD app: 3 men and 3 women. The age range was 58-78 years. A total of 4 patients used the internet  every day and 2 patients (less than) 1 day per week. Moreover, 3 patients used a smartphone or tablet  every day, 1 patient multiple days per week, and 2 patients never. Furthermore, 3 out of 6 patients perceived their smartphone or tablet skills not good or not bad, 1 bad, and 1 good. In addition, 3 (out of 6) patients did not miss information items in the COPD app.The information was categorized per day in the prototype, meaning that a new information item was presented daily. During the assignments and observations, we found that it was not easy for patients to find information because the timeline was very long. A total of 4 (out of 6) patients preferred to receive all information items in 1 overview, ordered by information category . On the basis of the findings, we categorized the information per category  instead of per day. To increase ease of use, the 8-week program was classified per week instead of per day. Patients’ opinion about the frequency of receiving a notification varied. Therefore, we decided to send a weekly reminder about the Lung Attack Action Plan and a reminder to fill out the weekly CCQ questionnaire.Inclusion took place from November 19, 2018, to December 13, 2019. A total of 174 patients were assessed for eligibility. Moreover, 81 patients did not meet the inclusion criteria because they had no access to a smartphone or tablet (n=41), were not able to use a smartphone or tablet (n=19), no working internet connection (n=5), no proficiency in Dutch language (n=9), cancer, (severe) cognitive disability or psychiatric condition (n=7), or other reasons . In total, 28 patients declined to participate. Moreover, 2 patients signed the informed consent form, but they were excluded because the COPD app could not be installed on their smartphone or tablet. In total, 39 patients started the intervention. One patient died during the first 8 weeks, and 1 patient died before 20 weeks. Therefore, 39 patients were included in the analysis until 8 weeks, 38 patients were included in the analysis at week 8 and from week 8 to week 20, and 37 patients were included in the analysis at 20 weeks .The baseline characteristics of the population included in the feasibility study are presented in The use of the COPD app, questionnaires, and consultations is described in more detail below and is presented in The use of the COPD app varied widely across patients. The app was opened most often during the first week . However, use decreased over time. The app was opened by the majority of patients during the first 8 weeks, varying from 100% (39/39) in the first week to 79% (31/39) in week 8. Patients read information most frequently during the first week, especially regarding the functionalities in the COPD app , physical activity , the condition COPD, nutrition, and the Lung Attack Action Plan . See In total, 29 patients filled out all the weekly CCQ questionnaires , 3 answered the CCQ during 8 weeks, 4 answered the CCQ during 7 weeks, 1 answered the CCQ during 6 weeks, and 2 answered the CCQ during 2 weeks. A total of 35 patients filled out the HADS in week 1 (after discharge) and 33 after 8 weeks. Two patients reported that they did not want to fill out the questionnaires anymore during the study, and 1 patient died 7 weeks after discharge. The monitoring of the scores was used inconsistently, and therefore, the results do not offer a meaningful contribution.A total of 17 patients attended the planned video consultation 4 weeks after discharge. For 13 other patients, this was replaced by a telephonic consultation because of problems with the video consultation system ; 2 patients did not want a video consultation; 1 patient visited the hospital instead; 1 patient’s consultation was canceled because of hospital readmission; 1 patient left the digital waiting room because the nurse was too late; 1 patient was not available; and for 3 patients, a reason for cancelation was not reported.A total of 27 patients attended their face-to-face consultation after approximately 8 weeks. For 11 other patients, the appointment was canceled because patients did not show up (n=5), because of readmission (n=3), two patients canceled the appointment, and 1 patient died. For 1 patient, this consultation was replaced by a telephonic consultation because the patients did not feel fit enough to come to the hospital.In total, additional contact with a nurse was requested 19 times. A total of 9 patients used the Lung Attack Action Plan 15 times (13 times code yellow and 2 times orange), and 3 patients used the contact form 4 times to request contact with a nurse. See The COPD app was rated, on a scale of 1 to 10 , with a 7.7 (SD 1.7) after 8 weeks and 7.0 (SD 2.4) after 20 weeks. Patients thought the app was easy to use and well-structured . Almost all patients reported that the Lung Attack Action Plan was easy to find  and easy to use , and more than half of the patients thought it actually helped them . The majority of patients also thought that the information was understandable , and all the patients  were satisfied with the information about nutrition. According to 33% (9/27) of patients, too much information was available in the COPD app. The majority of patients were satisfied with the video consultations  and thought it saved them time . See P=.04). However, there was no significant change in the recognition and management of symptoms (P=.14). See Knowledge and coping increased significantly over time (knowledge and coping (P=.75) and recognition management and adherence (P=.92).No relation was not found between use of the app, the number of times the app was opened (mean page clicks during week 1-8), and the self-management elements Patients’ expectations with the COPD app were relatively high. However, only 2 aspects improved over time. After using the app, more patients thought that it takes no effort to use it and that they had enough skills to use it. However, most aspects related to receiving support using the app decreased over time. See The use of the COPD app and monitoring of the weekly questionnaires were evaluated with 3 nurses. They rated the COPD app, on a scale of 1 to 10 , on average with a 6.3 (SD 1.2) Most of them were satisfied with the app  and the information provided  and thought that better care was provided using the COPD app . However, use of the COPD app did not save time . They received a lot of questions from patients , and they mentioned that it took them a lot of time to explain it and answer questions . They also reported:Unfortunately not applicable for our target population, the app is good.How simple it seemed to use, how difficult it appeared to be for patients.Only 1 nurse would recommend the COPD app to more patients. The nurses would not recommend it to their colleagues.The nurses were less satisfied with monitoring the results of the questionnaires and rated this with a 5.3 (SD 0.58), on a scale of 1 to 10 . Only 1 nurse thought that monitoring the results of the questionnaires fitted well in their work process. They commented:Plan more time for nurses to monitor the questionnaires.It is often unclear for patients what they have to fill out. Sometimes patients were surprised when they got a call, because they felt good.The nurses were less satisfied with the video consultations and mentioned the following:This was very difficult, very unclear for patients, took a lot of time and often a telephonic consultation was needed.Many patients did not understand how to start a video consultation.In total, 39 patients were included in the study. A total of 12 patients  were readmitted 22 times during the study period (20 weeks), of which 5 patients  were readmitted 1 time in the first 30 days. Within 8 weeks, 8 patients  were readmitted 11 times. In the total study period (until 20 weeks), there were 22 readmissions for 12 patients . The main reasons for readmissions was COPD exacerbations, and 1 time it was due to a patient’s home situation.In the year preceding the study, from November 2017 to November 2018, 340 patients were admitted 478 times to the hospital. In total, 48 patients  were readmitted 77 times within 30 days. There were 103 readmissions within 8 weeks for 61 patients , and 74 patients  were readmitted 129 times within 20 weeks.knowledge and coping increased significantly over time (P=.04), but a relation with app use was not found (P=.75). No significant change was found in recognition and management of symptoms, adherence to treatment (P=.14), or in relation with app use (P=. 92). Patients rated the COPD app on average with a 7.7 (SD 1.7) and nurses with a 6.3 (SD 1.2). Preliminary evidence about readmission rate showed that 13% (5/39) of patients were readmitted within 30 days, 21% (8/39) within 8 weeks, and 31% (12/39) within 20 weeks compared with 14.1% (48/340), 17.9% (61/340), and 21.8% (74/340), respectively, in a preresearch cohort.In this study, a mobile self-management app for high-risk patients with COPD was evaluated in daily clinical practice. The COPD app was opened most often in the first week , but its use decreased over time . Information, especially on physical activity , was read most often during the first week. The self-management element The use of mobile apps itself is not applicable to all patients ,52. In tUntil now, the effects of self-management interventions on patients recently discharged from the hospital were scarcely evaluated  in combiSocial support is seen as a facilitator for use ,52. The A positive effect was found on knowledge and coping, which may partly be explained by the selection criteria for this study, as patients with cognitive disability and lack of skills with a mobile device were excluded. In addition, the provision of timely information using a mobile device can positively influence knowledge . Self-maPatients were satisfied with the COPD app, user-friendliness, and information. However, nurses addressed some concerns, for example, the increased workload and (lack of) integration in the work process. It is common that the degree of satisfaction between patients and health care professionals can differ. In general, patients report more favorable outcomes because mobile interventions are often provided as an extra service in addition to their usual care. For that same reason, health care professionals are generally less satisfied, especially because they often see it as an increase in workload . The nurCOPD management requires a multidisciplinary approach that is fragmented , and thiDue to accrual issues, especially related to device availability and internet access, the COPD app was evaluated in a small sample, so we could not reach the power originally calculated for this trial. In addition, nurses found it difficult to comply with the contacting rules, so there were inconsistencies in the follow-up monitoring using the CCQ questionnaires. Some patients were only contacted a limited number of times when they had a high score on the CCQ questionnaire. After approximately 20 patients, we decided to send nurses a notification by email with the scores, and they were asked to take up contact (if necessary). As a consequence of the team setting, only 3 nurses were involved in this study, and we have to be careful about the related outcomes. Preliminary evidence on readmission rates was provided based on an earlier cohort, but this was not a matched exercise. Therefore, definitive conclusions on this aspect cannot be drawn.The integration and use of a mobile self-management app for recently discharged patients with COPD in clinical practice is affected by multiple factors and is only feasible for a relatively small number of patients after hospital discharge. Patients were very positive about the COPD app; however, its use decreased over time. The findings of this study showed a significant positive change in the self-management element knowledge and coping. Nurses expressed concerns about integration in their work processes and increased workload. Tailored interventions, patient support, and active adoption by professionals are important elements to ensure successful mHealth interventions. Therefore, future research on digital self-management interventions in clinical practice should focus on including more difficult subgroups of target populations, on a multidisciplinary approach, on technology-related aspects (such as acceptability), and on finetuning its adoption in clinical pathways.


Background: Previous studies have proved that low-level vagus nerve stimulation (LLVS) could suppress acute obstructive sleep apnea (OSA), which is associated with atrial fibrillation (AF).Objective: This study investigates the underlying electrophysiological, neural, and cardiomyocyte injury mechanisms on acute OSA-induced AF, examining whether LLVS can attenuate or reverse this remodeling.Methods and Results: Eighteen mongrel dogs received endotracheal intubation under general anesthesia and were randomly divided into three groups: the OSA group , the OSA+LLVS group , and a control group . In the OSA+LLVS group, the atrial effective refractory period was significantly lengthened while the sinus node recovery time and AF duration decreased after the 4th hour, and the expression level of Cx40 and Cx43 was significantly increased compared to the OSA group. Norepinephrine, TH, and ChAT were significantly decreased in the OSA+LLVS group compared with the OSA group. Mitochondrial swelling, cardiomyocyte apoptosis, and glycogen deposition, along with a higher concentration of TNF-α, IL-6 were observed in the OSA group, and the LLVS inhibited the structural remodeling and expression of inflammatory cytokines.Conclusion: LLVS decreased the inducibility of AF partly by ameliorating sympathetic hyperactivity and atrial myocyte injury after acute OSA-induced AF. Obstructive sleep apnea (OSA), the most common and severe form of sleep disordered breathing, is an important potential risk factor for the initiation and maintenance of atrial fibrillation AF; . PreviouRecently, increasing evidence shows that sympathovagal imbalance plays a crucial role in the maintenance of AF, and neuromodulation through rebalancing sympathovagal activity has become a research hotspot. Previous studies have shown that low-level vago-sympathetic trunk stimulation (LLVS) at voltages that do not slow the sinus rate or AV conduction, could decrease AF inducibility and AF duration, and prolonged ERP induced by acute OSA on a rabbit model , but no This study established a 6-h OSA model in dogs to examine changes in electrophysiological parameters, autonomic nervous activities, systemic inflammation, and myocardial damage and explore the possible mechanisms. In doing so, we aimed to provide underlying theoretical support for LLVS as a treatment for acute OSA-induced AF.All experiments were reviewed and approved by the Animal Use and Management Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University (IACUC-20170706-09) and were confirmed to adhere to Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health .via intramuscular injection with a mixture of Zoletil  and xylazine , followed by sodium pentobarbital (50–80mg/kg) as needed every 2h to maintain anesthesia. We assessed the effect of anesthesia by observing the disappearance of the eyelash reflex and tongue drag resistance. All dogs were safe and stable throughout the experiments. Standard surface electrocardiography and arterial blood pressure were continuously monitored using a Lead-7,000 . At the end of the study, animals were euthanized and heart tissues were harvested for further examination.A total of 18 healthy male mongrel dogs  were used in this investigation. Each animal was anesthetized n=6), the OSA+LLVS group , and the control group . All animals were randomly divided into three groups: the OSA group , AF duration time, sinus node recovery time (SNRT), atrial-His interval , and His-ventricle interval  were measured at baseline and during the OSA process. AERP was measured by applying 8 consecutive S1 stimuli (S1-S1-330ms) followed by premature S2 stimuli with 10 times diastolic threshold, which was gradually decreased until capture no longer occurred. The SNRT, which indicated the function of the sinus node, was recorded between the last paced beat and the first spontaneous atrial depolarization  by a Grass stimulator . The threshold voltage was set to a voltage that did not slow the sinus heart rate or AV conduction . The pH value, partial pressure of oxygen (PaO2), and partial carbon dioxide tension (PaCO2) were calculated using an i-STAT300 Analyzer . All the arterial blood samples were analyzed within 10min of being collected.Arterial blood for blood gas analysis was drawn from the femoral artery A blood pressure monitoring device was inserted into the left femoral artery. Blood pressure changes were recorded throughout the experiments. The systolic pressure of the arteries was analyzed. The blood pressure monitoring device was one part Lead-7000 .During the 6th hour of OSA, the left vagal nerve and LSG activity were recorded during the 2min of apnea and followed 40s of re-ventilation with PowerLab . The Analysis Module of Lab Chart 8.0/proV7 software  was used to analyze the signals. More detailed outlines of these processes are reported in our previous studies .Transthoracic echocardiography was administered at baseline, the 3rd hour, and the 6th hour with a phased-array system . The following parameters were recorded: left atrial end-diastolic diameter (LA), right atrial end-diastolic diameter (RA), and left ventricular fractional shortening (FS). Each measurement used an average of three consecutive cardiac cycles.Venous blood was drawn at baseline in the 3rd hour and the 6th hour to measure the concentration of norepinephrine , TNF-α , and IL-6  using ELISA kits, respectively. The detection procedure was performed according to the manufacturer’s protocols.At the end of the study, left atrial (LA) tissues were harvested and fixed in 10% neutral buffered formalin for 24h at 4°C. They were then dehydrated, embedded in paraffin and consecutively cut at 5-μm thicknesses, and mounted on glass. These sections were used for staining with HE, PAS, TUNEL, and silver following the manufacturer’s protocols . A microscope  was used to study histological changes. The area of the interstitial fiber was calculated using image analysis software . The apoptotic rate of cardiomyocytes was calculated by the number of apoptotic cells/total cell number ×100%. The nerve density was calculated as positive nerve area/total area ×100%.To detect ultrastructural changes in LA and LSG, transmission electron microscopy  was constructed. Briefly, tissues were processed by being fixed , stained (1% uranyl acetate), dehydrated (ethanol), and embedded (epoxy resin).2/mm2). Connexin-40 , and connexin-43  were also detected, with quantitative analysis of integrated optical density (IOD) also conducted.Immunohistochemistry staining was performed to evaluate the nerve fiber density of the LA tissues. Paraffin-embedded tissue sections were incubated with anti-TH , anti-ChAT , and anti-PGP9.5  antibodies overnight at 4°C. After being washed with PBS, the sections were incubated with peroxidase-conjugated rat anti-rabbit IgG  for 20min at room temperature, and they were finally evaluated with a microscope at ×200 magnification . Image Pro Plus 6.0 software  was used to analyze the image. Nerve fiber density was calculated as the ratio of positive nerve area to the total area (μmΔΔCt−). The primers used for RT-PCR are presented in At the end of the experiment, all dogs were euthanized, and the left atrial tissues were obtained. The mRNA expression levels of ion channels were measured by qRT-PCR. Total RNA was extracted using TRIzol reagent  and then reverse-transcribed to cDNA using a PCR Kit  according to the manufacturer’s instructions. An RT-PCR amplification reaction was performed as follows: 55 amplification cycles of 10s at 95°C, 20s at 58°C, and 20s at 72°C. The specificity of amplification was confirmed by melting curve analysis. A housekeeping gene (β-actin) was used to correct the expression level of the target gene, and the calculation was performed by a comparative method  and analyzed using SPSS 19.0 software. Two-way repeated-measures ANOVA with p>0.05). A marked reduction in PaO2, with obvious increases in PaCO2 and pH, were observed post-apnea (p<0.05). The alterations were not affected by LLVS intervention. The above experimental data indicated that the OSA model was successfully established , an analogous pattern also emerged in the first 3h in the OSA+LLVS group , but after the 4th hour, the trends of all the parameters gradually reversed and returned to their baseline values . The Cav1.2 channel was less expressed in the OSA group and the OSA+LLVS group than in the control group (p<0.01). The Kir2.1 channel and the Kir3.1 channel were highly expressed both in the OSA group and the OSA+LLVS group compared with those in the control group (p<0.01), and no significant difference was observed between the OSA group and the OSA+LLVS group (p>0.05). There was no significant difference in the Kir3.4 channel expression between the control and experimental group (p>0.05). Compared with that of the control group, the expression of the HCN4 channel in the OSA group and the OSA+LLVS group decreased (p<0.01), but there was no significant difference between the two groups.To clarify the changes in ion channels that are associated with AF, the qRT-PCR was administered . The Navp<0.05; Changes in the atrial structure were evaluated by echocardiography at baseline, in the 3rd hour and the 6th hour. In the OSA group, the LA gradually became swollen and spherical, deviating from its original oval shape, and the LA diameter significantly increased. This structural change was also represented in the OSA+LLVS group at the 3rd hour. After the LLVS treatment was administered from the 3rd hour to the 6th hour, the shape of the LA gradually changed from sphere to oval, and the LA diameter decreased ,B. ConveTransmission electron microscopy was used to observe the ultrastructural changes of cardiomyocytes. We found that the mitochondria in cardiomyocytes evidenced swelling to different degrees in the OSA group compared to those in the control group, and LLVS intervention was able to attenuate the swelling of the mitochondria to a certain extent .To evaluate changes in myocardial tissues, HE staining was conducted. The atrial myocytes in LA and RA were arranged tightly and orderly in the three groups, and neither showed any significant difference ,B.TUNEL staining was used to evaluate atrial cardiomyocyte apoptosis, the OSA group had more brown-stained nuclei compared with the control group, meaning that apoptosis in the OSA group was more serious, LLVS could attenuate cardiomyocyte apoptosis in the atria ,D.p<0.05; PAS staining was conducted to evaluate glycogen deposition in atrial tissues. In contrast to that in the control group, glycogen deposition was not only observed at the junction of cardiomyocytes but also in cardiomyocytes in the OSA group. After LLVS treatment, glycogen deposition was attenuated p<0.05; ,F.In conclusion, acute OSA-induced AF could change the structure of LA, and this remodeling could be reversed by LLVS treatment.ELISAs were used to detect the concentrations of TNF-α and IL-6. The concentrations of TNF-α and IL-6 in the OSA group were significantly increased compared to those in the control group, and these levels decreased in the OSA+LLVS group, indicating that LLVS could inhibit the expression of inflammatory cytokines .This study had the following findings: (1) LLVS reversed OSA-induced vagosympathetic nerve overdriving, including the high expression of ChAT, TH, PGP9.5 and enhanced silver staining in LA tissues, as well as a high concentration of NE. Additionally, both parasympathetic and sympathetic activity increased significantly during apnea, and a high state of sympathetic activity after ventilation was observed. (2) LLVS increased ERP, decreased AF duration, and AF inducibility in the process of OSA-induced AF. The present study is the first to report prolonged SNRT, high expression of Cx43 and Cx40, and ion channel expression abnormality in the acute OSA-induced AF, which could be attenuated by LLVS treatment. (3) Systemic inflammation, glycogen deposition, cardiomyocyte apoptosis, and mitochondrial damage in LA cardiomyocytes were also reported in the acute OSA-induced AF model for the first time, whereas LLVS treatment weakened these harmful effects. In a word, LLVS intervention could attenuate the parameter changes mentioned above, and these effects may occur through modulating the ANS and systematic inflammation.There is considerable evidence that ANS plays a crucial part in the initiation and maintenance of AF . In the The present study revealed a change in ion channels in the acute-induced AF. As is widely known, ion channel abnormality plays a very important role in the processes underlying the occurrence and maintenance of AF. Several studies have reported that higher expression of Nav1.5 , Kir2.1 This study investigated changes in the electrical parameters of AF as a consequence of OSA. Previous research has shown that a shorter ERP is strongly associated with a high incidence of AF . SNRT, rRecently, increasing evidence has pointed to a role played by inflammatory agents in the initiation of AF . Serval +, Na+, Ca2+, and HCN4) and Cx43 and Cx40. All these changing parameters ultimately shorten the ERP, increase AF susceptibility and atrial conduction heterogeneity, promoting AF initiation and maintenance. In our present study, although hypocapnia and hypoxemia were not attenuated after LLVS was administered, the sympathetic neural hyperactivation was modulated, and the systemic inflammation was inhibited, also improving the remodeling of myocardial tissue structure, ion imbalance, and abnormal Cx43 and Cx40 expression, while ultimately inhibiting AF occurrence  In apnea, thoracic expansion generates a negative intrathoracic pressure, which is subsequently transmitted to the thin-walled atrium and leads to LA stretching, which has been recognized as one of the highest risk factors of AF . (2) In currence .The present study has several limitations. First, the invasiveness of LLVS limits its clinical application. A noninvasive low-level transcutaneous auricular branch of the vagus nerve electrical stimulation has been shown to decrease AF inducibility . Second,In summary, this study found that OSA induced sympathetic overactivity, enhanced LA sympathetic innervation and systematic inflammation, myocardial mitochondrial swelling, glycogen accumulation, and myocardial apoptosis. We hypothesize that both neural and structural remodeling promoted ion abnormalities, Cx43/Cx40 disturbances, and conduction heterogeneity. Since all of these effects could be attributed to the initiation and maintenance of AF, the present study indicates that LLVS could reverse the related parameters to a degree. This approach might therefore provide a novel option and potential therapeutic target for AF in acute OSA.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by the Animal Use and Management Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University.YG, JX, QM, and HS contributed to the animal experiments. YG and LZ contributed to the statistical analysis and interpretation. GC, XZ, LZ, and BT contributed to the funding acquisition, conception, and design of the study. All authors contributed to the writing, critical reading, and approval of 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.


The glyoxalase system was discovered over a hundred years ago and since then it has been claimed to provide the role of an indispensable enzyme system in order to protect cells from a toxic byproduct of glycolysis. This review gives a broad overview of what has been postulated in the last 30 years of glyoxalase research, but within this context it also challenges the concept that the glyoxalase system is an exclusive tool of detoxification and that its substrate, methylglyoxal, is solely a detrimental burden for every living cell due to its toxicity. An overview of consequences of a complete loss of the glyoxalase system in various model organisms is presented with an emphasis on the role of alternative detoxification pathways of methylglyoxal. Furthermore, this review focuses on the overlooked posttranslational modification of Glyoxalase 1 and its possible implications for cellular maintenance under various (patho-)physiological conditions. As a final note, an intriguing point of view for the substrate methylglyoxal is offered, the concept of methylglyoxal (MG)-mediated hormesis. The glyoxalase system, which was first described over a hundred years ago, consists of two cooperating enzymes named Glyoxalase 1 (Glo1) and Glyoxalase 2 (Glo2) ,4. The iGlo2 is encoded by the hydroxyacylglutathione hydrolase gene and, like Glo1, it is expressed in nearly all living cells in order to hydrolyze S-D-Lactoylglutathione, the intermediate product of the glyoxalase cycle, into D-Lactate and (recycled) GSH ,9. InterN-(1-carboxyethyl)lysine (CEL) purin-9(8)one (MG-dG) [Increased levels of MG can lead to an intracellular accumulation of advanced glycation end products (AGEs) and to increased amounts of glycated DNA adducts. Both events are associated with many pathological events in humans, such as obesity and diabetes, atherosclerosis, various cancer types and neurodegenerative diseases ,18,19,20ne (CEL) ,25. Rega (MG-dG) . CedG ha (MG-dG) .Caenorhabditis elegans (C. elegans), an overexpression of Glo1 results in an increase in mean and maximum lifespan by ~40% [The regulation of Glo1 activity and expression is complex and still not well understood. However, what we know is that Glo1 has a metal responsive element, an insulin-responsive element, an antioxidant responsive element, and it is a hotspot of copy number variation ,29,30. D by ~40% . In bovi by ~40% . Consist by ~40% ,38. On t by ~40% . Hypergl by ~40% ,17,18,40 by ~40% . Last bu by ~40% .As already mentioned, in many types of cancer the situation is quite different. Due to the vast amounts of glucose consumption resulting from the increased proliferation rates of most tumors, Glo1 is necessary to protect the cell from harmful MG. In malignant cells with a high proliferation rate, it is undoubtedly proven that Glo1 protects those cells from the increased formation of MG due to a high glycolytic flux within the context of the Warburg effect ,44,45. TIn prostate cancer, Glo1 is also linked to the maintenance of the metastatic phenotype by controlling the epithelial to mesenchymal transition . The assThis review will not focus on the past, where most of the studies have shown that the high global abundance of Glo1 is a result of a necessity to detoxify MG and prevent accumulation of AGEs and DNA modifications. This review will summarize the importance of alternative detoxification mechanisms for MG, spotlight the overlooked post-translational modifications (PTMs) of Glo1, and emphasize antioxidant aspects of MG-derived AGEs  and the hormetic potential of MG itself. Herein, we put very recent findings into new contexts of MG-derived damage under (patho-) physiological conditions and this will hopefully leave the reader with a challenging and eye-opening new perspective of the glyoxalase system.Escherichia coli it has been shown that there is also a glyoxalase-like enzyme  that is independent of any cofactor, converting MG into D-Lactate [Due to its highly conserved role, the glyoxalase system has been viewed as a crucial enzyme system to maintain cellular viability ,8,14. Th-Lactate . When it-Lactate ,62. Anot-Lactate ,64 The s-Lactate . However-Lactate .Drosophila revealed that Glo1 KO flies first become hyperinsulinemic in a young state, develop elevated total-body triglyceride with normal circulating glucose levels once they are matured, and then acquire hyperglycemia when they are in a mature state. The flies showed early on mildly increased MG and MG-H1 levels. This led to the authors’ hypothesis, that MG is not the cause of late diabetic complications due to increased formation of AGEs and DNA modifications, but rather more the reason for insulin resistance due to hyperglycemia similar to what is observed in type 2 diabetic patients [Unfortunately, the first attempts to abolish Glo1 activity failed, due to a high amount of copy number variants using the approach of gene trapping mutations . Neverthpatients . In the patients ,70. The patients . Howeverpatients . In thispatients . Previoupatients . Consequpatients . Obviouspatients ,74. It hpatients ,75,76,77In a mouse models with a global Glo1 KO, others were able to show that the expected damaging effects of Glo1 loss are rather mild or non-existent ,74. One In summary, and to put the new findings into context, various in vivo studies of Glo1 KO models show that Glo1 is not an indispensable enzyme and thus, the glyoxalase system is neither. It is also a fascinating example that with increasing complexity and advanced evolution, nature may establish a backup system, which can compensate and substitute genetic mutations of highly conserved enzymes. This may not be perfectly the case in crude organisms, such as yeast and worm, but to some degree in flies and fish, and finally with perfection in a mammalian organism . This leArabidopsis thaliana, for instance, a phosphorylation of Glo1 was observed within the context of enhanced stress resistance [Arabidopsis thaliana [Despite the extensive research on the glyoxalase system, and in particular Glo1, investigating PTMs of Glo1 in mammals have not been a focus in the field. Studies regarding the PTMs of Glo1 are rare and the consequences of those are unfortunately not well understood . Howeversistance . Furthersistance . Plants sistance ,80. Furtthaliana .139) even within the human Glo1 protein. The S-nitrosylation is also associated with a strong inhibition of Glo1 activity [Yeast, which was exposed to the mating factor, also induced the phosphorylation of Glo1, whereas S-nitrosoglutathione inactivated Glo1. Further studies identified a nitric oxide responsive element at a cysteine residue  [m; higher Vmax) and it is also protected from rapid proteasomal degradation by ubiquitination [The most studied PTM of Glo1 is the phosphorylation. There are five different putative phosphorylation sites identified for Glo1, whereas Threquences ,84. The ll death . A recenCamKIIδ) . Moreovetination . Given ttination . Interestination . An impotination . This cotination ,33,34,41tination .The PTM of an enzyme is usually a quick and precise way to adapt in a flexible way to various intracellular conditions . NowadayAs pointed out at the beginning of this review, the intracellular concentrations of MG must be maintained at low levels in order to prevent cellular damage ,16,17,18However, recent studies draw a slightly different picture. Sub-toxic doses of MG seem to be linked to a beneficial effect called hormesis. The concept of hormesis was first introduced by the pharmacologist Hugo Schulz, who observed that the growth rate of yeast could be stimulated by small doses of toxins . ExampleArabidopsis thaliana [2O2 [Drosophila fly, which recapitulates the progression of type 2 diabetes, the authors expected reduced longevity. Instead of that, it was reported that the Glo1 KO and potentially the mild increase in MG are associated with a significant lifespan extension [Undoubtedly, MG increases ROS even at low levels, because of its high reactivity towards amino acids and nucleotides . It moduthaliana . In yeasana [2O2 . Interesana [2O2 . The effana [2O2 . Going hana [2O2 . It is aana [2O2 . In contana [2O2 . Furtherxtension . This rextension .The nature of a biphasic dose–response relationship (hormesis) has been assessed in human tumor cell lines as well. Hormetic-like relationships in malignant cells have been reported for endogenous agonist , antitumor drugs  or phytochemicals  . The horWith respect to MG adducts, there is another example of an unexpected experimental result within the glyoxalase metabolism. Besides MG-H1, which accounts for more than 90% of MG protein modifications, there is also the possibility that MG-H3 is formed  Figure . AlthougThis review showed that the glyoxalase system is surprisingly not an indispensable system to maintain cellular viability. Especially in mammalian organisms, the loss of the glyoxalase system is compensated efficiently by enzymes of the AKR and ALDH family. Those enzymes can play a pivotal role within the context of MG mediated damage in healthy cells or malignant cells. Undoubtedly, and this has been shown herein, there is room for studying the glyoxalase metabolism from alternative points of view. This includes PTMs of Glo1, hormetic effects of MG and MG-derived AGEs, or even the intriguing concept that the glyoxalase system may reflect a regulator of cell division. It is a pity that many studies have focused relatively blindly on the cause-and-effect model between Glo1 and MG, which has been described in detail in the introduction of this review. This is further supported by the idea that there is so little literature published on Glo2 in the last 10 years . This r


Diabetic retinopathy (DR), caused by small vessel disease, is the main cause of blindness in persons with diabetes. Taiwan is one of the Asian countries with the highest prevalence rate of DR. The purpose was to investigate the related risk factors of DR in elderly patients with type 2 diabetes mellitus (T2DM), in Lee’s Endocrinology Clinic. 792 T2DM patients over 60 years old were invited to have an outpatient visit at least every three months, and all of them were asked to undergo a standardized interview and collect their blood samples. Significant factors were being female (adjusted hazard ratio (HR): 1.287; 95% CI, 1.082–1.531), higher glycated hemoglobin (HbA1c) , higher mean low density of lipoprotein cholesterol (LDL-c) , and chewing betel nut . This study showed that gender, the behavior of chewing betel nut, HbA1c, and LDL-c are important factors for the development of DR in elderly patients with T2DM. It is suggested that patients should control their HbA1c and LDL-c and quit chewing betel nut to prevent DR. This suggestion applies especially to female patients. Diabetes is a common chronic metabolic disease worldwide. Patients with diabetes need to strictly control and manage their lifestyle to maintain their blood index such as blood glucose, pressure, and lipids to prevent vascular neuropathy and diabetic neuropathy. Without proper management, it might accelerate disease deterioration into cerebrovascular and coronary artery diseases, and diabetic retinopathy (DR). In addition, the complications pose a significant threat to the worsening of symptoms ,2. In 20In 2011, the proportion of diabetes patients over 20 years old was around 8.0%, and it was estimated that more than 1.4 million patients were diagnosed with diabetes in Taiwan. The National Health Insurance medical expenses for diabetes are around nearly USD 0.6 billion per year, accounting for about 4% of Taiwan’s National Health Insurance Fund. Various complications and diseased organs are consequences of diabetes, including kidney disease, heart disease, stroke, diabetic retinopathy, vascular disease, etc. For example, hemodialysis was about USD 1.1 billion per year, which is the highest among medical expenses associated with diabetes. Furthermore, the proportion of hemodialysis patients caused by diabetes had reached 40.0%, which increased the medical resources burden worldwide . The medDR caused by small vessel disease was the main cause of blindness in persons with diabetes . It is aThe prevalence rate of DR was 23.0% in Asia-Pacific, 12.1% in Hong Kong, 25.4% in Singapore, and 15.8% in Korea . SeveralFrom July 2016 to December 2017, in Lee’s Endocrinology Clinic, we recruited 792 patients who met these criteria and invited them for a standardized interview that included a dilated fundus examination. An ophthalmologist performed the dilated fundus examination (DFE) to evaluate and determine whether the patients with T2DM had progressed to DR. Inclusion criteria of study samples were as follows: (I) patients who were over 60 years of age and (II) patients who performed regular clinic visits for diabetes checkups and DFEs at least every three months during this study. Exclusion criteria of study samples were as follows: (I) patients who had monocular or bilateral blindness before or during the study, (II) patients who had glaucoma not caused by diabetic diseases, and (III) patients who were failing to follow up or unwilling to be involved in this study.2). T2DM duration in patients with DR was defined as the time (in years) from the onset time of diabetes to the time of first diagnosis at each stage of DR progression; diabetes duration of T2DM patients without DR was defined as the time (in years) from the onset time of diabetes to the time of the latest DFE. Health habits of participants included smoking, drinking, chewing betel nut, and regular exercise behavior. Smoking behavior was defined as smoking any type of cigarette at least once a day for a period of 6 months or longer. Drinking behavior was defined as drinking any type of alcoholic beverage at least three times a week for a period of 6 months or longer. The behavior of chewing betel nut was defined as chewing areca nut at least once a day for a period of 6 months or longer. Regular exercise behavior was defined as exercising regularly, at least three times a week, for a period of 6 months or longer. Blood pressure (systolic blood pressure and diastolic blood pressure) was measured with a digital automatic blood pressure monitor with the participant seated after resting for 5 min. The levels of creatinine, fasting plasma glucose, TG, CHOL-T, and HDL-c were measured on an analyzer with an enzymatic assay. HbA1c was measured on an analyzer using high-performance liquid chromatography. The eGFR was estimated in accordance with the formula (186 × Creatinine^(−1.154) × Age^(−0.203) ) [We asked participants to fill out a brief questionnaire at the scheduled outpatient visit. The brief questionnaire included questions on gender, education level, body mass index (BMI), diabetic duration, family history of diabetes, and health habits. We collected patents’ blood samples during the outpatient visit to check for glycated hemoglobin (HbA1c), fasting plasma glucose, triglyceride (TG), total cholesterol (CHOL-T), high density lipoprotein cholesterol (HDL-c), low density lipoprotein cholesterol (LDL-c), and the estimated glomerular filtration rate (eGFR). The education level of participants was classified as follows: no qualifications, elementary school, and junior high school or higher. BMI was measured as weight divided by height squared ) . Moreovefemale)) .To obtain a better view of the fundus of the eye, we performed DFE on all participants. The procedure included an eyesight test, automatic optometric examination, and air puff test. It is a diagnostic procedure that employs the use of mydriatic eye drops (such as Mydrin-P) to dilate or enlarge the pupil. The value of intraocular pressure must be reported as normal before the dilated eye exam. The ophthalmologist used the mydriatic eye drops, delivering the eye drop every 5 min thrice. After 30 min, the patient’s pupil would stay open with its size naturally enlarged, enabling the ophthalmologist to use ophthalmoscopy to view the eye’s interior, allowing for assessment of the retina, blood vessels, optic nerve head, and other features. It also allowed the ophthalmologists to diagnose and monitor the degree of DR in a more detailed manner once the digital images from all participants were obtained.p-value < 0.05 was considered to be statistically significant. Statistical analysis was performed using IBM SPSS Statistics 24.The participants’ characteristics were described by absolute and relative frequency for categorical variables and mean and standard deviation for continuous variables. In inference statistic methods, an independent sample T-test was used to analyze the difference of the mean for continuous data between the patients with and without DR. A chi-square test was used to analyze the difference in the proportion of categorical variables between the patients with and without DR. Pearson product–moment correlation coefficients were applied to test the correlations between each risk factor. Finally, the significant factors in each statistic testing were considered in the model. The optimal multivariate Cox regression model was determined by stepwise model selection. Those results were reported as hazard ratios (HR) with a 95% confidence interval (CI). A In this study, 792 patients with T2DM were effectively enrolled. Their average age was 67.85 (SD = 6.53). During the follow-up period, DR was diagnosed in 611 patients (77.15%). In this study, there were 339 male patients and 453 females. About 493 patients reported a history of diabetes in their family, 149 patients reported drinking behavior, and 79 patients were addicted to chewing betel nut. A family history of diabetes was reported by 493 patients, 149 patients reported drinking behavior, 79 patients were addicted to chewing betel nut, 108 patients reported no educational qualifications, 189 patients were addicted to smoking behavior, and 453 patients reported regular exercise behavior.2 = 8.99, p = 0.003), a family history of diabetes , and a behavior of chewing betel nut . However, there was no significant association between education level, smoking behavior, drinking behavior, or regular exercise behavior and the development of DR.According to the results in p < 0.001), TG , CHOL-T , and LDL-c  were associated with the development of DR in elderly patients with T2DM. Moreover, we also found that HbA1c had a significant positive correlation with TG, CHOL-T, and LDL-c, and the correlation coefficients were 0.147, 0.248, and 0.220, respectively. The correlation coefficient for TG versus CHOL-T was 0.337, for TG versus LDL-c was 0.193, and for CHOL-T and LDL-c was 0.845; the p-value of each group was under 0.001 significant rate. However, factors such as BMI, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, HDL-c, and eGFR were not significantly associated with the development of DR in elderly patients with T2DM.In Integrating the results from This study found that factors such as gender, the behavior of chewing betel nut, HbA1c, and LDL-c were important predictors of DR in elderly patients with T2DM. The risk of DR in female patients was higher than that in male patients. The risk of retinopathy in patients with a behavior of chewing betel nut was higher than that in patients without a behavior of chewing betel nut. Patients with higher HbA1c and higher LDL-c had a higher risk of developing retinopathy. Most of our findings were consistent with risk factors reported in existing literature; additionally, we observed the behavior of chewing betel nut to be a unique risk factor to the Taiwanese population.Regarding gender, other studies previously reported that women are more likely to develop retinopathy than men ,30. EstrThe results of a recent study of relationships between diabetes duration and risk of DR in patients with T2DM showed that the prevalence of retinopathy was 1.1% at the first time of diagnosis, 6.6% for diabetes duration of less than 5 years, 12.0% for diabetes duration between 5 and 10 years, 24.0% for diabetes duration between 10 and 15 years, 39.9% for diabetes duration between 15 and 20 years, and 52.7% for diabetes duration over 20 years. Therefore, the prevalence of DR in patients rises substantially when their diabetes duration is over 10 years . Some stLopez et al. (2017) found that patients with a family history of diabetes had a higher chance of developing DR; the number of patients with a family history of diabetes was about 63.4% . GeneticIn terms of blood biochemical values pertaining to blood pressure and BMI, the results of this study showed that HbA1c, TG, CHOL-T, and LDL-c were highly associated with the risk of DR in elderly patients with T2DM. On the other hand, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, HDL-c, eGFR, and BMI were not significantly associated with the risk of DR. A study explained that higher HbA1c increases the risk of DR and that hyperglycemia causes injury to body organs, such as nerve damage (neuropathy), kidney damage (diabetic nephropathy), and even damage to the blood vessels of the retina (diabetic retinopathy), potentially leading to vision loss . StrattoMoreover, this study found that the behavior of chewing betel nut, which is a common social interaction throughout Asia, is significantly associated with the development of DR in elderly patients with T2DM and is an essential predictor of DR. Some studies found that the behavior of chewing betel nut was associated with newly diagnosed T2DM and the occurrence of chronic kidney disease and increases the risk of cardiovascular disease ,25,26. OThis study found that the characteristics in the high-risk group of developing DR were being female, a family history of diabetes, and the behavior of chewing betel nut. Therefore, it is suggested that patients with these factors should always keep their HbA1c, LDL-c, TG, and CHOL-T in a normal range and quit their behavior of chewing betel nut to prevent developing DR. Moreover, integrated care focusing on more coordinated and integrated forms of care provision may play an important role in the care of patients with diabetes mellitus. Not only do blood glucose, blood pressure, and blood lipids have to be regularly controlled and managed for patient with diabetes, but related complications of diabetes should also be regularly screened. However, anyone who has diabetes mellitus is always under the risk of developing DR; some may be diagnosed with DR after having diabetes mellitus for several years. Thus, it is important to enable clinical care personnel to promote regular health examinations for T2DM patients by exploring and understanding the important predictors of DR in patients with T2DM. Early intervention for vision problems is useful to prevent severe vision loss. Doctors should also allocate patients to appropriate hospitals or clinics in time for patients to attend to routine pupil examinations and consultations. Nurses should also implement the education of health guidelines individually. It will be helpful to improve the self-management abilities of patients who are under a high risk of the progression of DR.This research was a hospital-based study, and the patient recruitment might not represent overall diabetes patients. We cannot exclude the residual confounding factors due to unmeasured factors. To better understand the relationship between DR and relative risk factors, it is necessary to have a more extensive population study. Our study showed that gender, the behavior of chewing betel nut, HbA1c, and LDL-c are important factors for the development of DR in elderly patients with T2DM. We suggested that patients should control their HbA1c and LDL-c and quit chewing betel nut to prevent DR, especially female patients. However, our study presents that the behavior of chewing betel nut is one of the potential risk factors for DR in elderly patients with T2DM, a result that is very different from the other studies. Therefore, the relationship between chewing betel nut and the risk of DR in diabetic patients needs further investigation.


Background: Food insecurity is defined as the limited or uncertain availability of enough food forpermanent active and healthy life. Upper gastrointestinal (GI) cancers (esophagus and stomach) areone of five most common cancers in Iran. This study aimed to determine the association of foodinsecurity and upper GI cancers in newly diagnosed patients.Study Design: Case-controlstudy Methods: Overall, 120 patients with upper GI cancers as cases and 120 patients with orthopedic, earnose-throat(ENT), and neurologic diseases as controls were recruited from Imam Khomeini Hospital,Tehran, Iran in 2013. The patients were newly diagnosed using endoscopy or imaging or biopsymethods. They were individually matched for age, sex, and residential area. The general and UnitedStates Department of Agriculture (USDA) household food security questionnaires were completed.The univariate and multivariate conditional logistic regression tests were applied using the Stata 11SEstatistical software.Results: The food insecurity prevalence was 69.2% and 43.3% in cases and controls, respectively.Food insecurity, low economic level and family history of cancer were significantly associated withcancer (P<0.05).Conclusions: Food insecurity was one of the important risk factors for upper GI cancers that healthcare providers should consider it. According to the 1996 World Food Summit (WFS), food security exists when all people, at all times, have physical and financial access to adequate, safe and nutritious food to achieve their dietary essentials and food inclinations for a dynamic and healthy life2. Food secure peoples do not live in hunger or dread of starvation3. Then again, food insecurity as indicated by the United States Department of Agriculture (USDA) is a circumstance of constrained or unverifiable availability of nutritionally satisfactory and safe foods or restricted or indeterminate ability to obtain acceptable foods in socially worthy ways4. Therefore, four columns of food security are availability, access, utilization, and stability3.The concept of food security was attended in the early years of 1970s over the food crisis and several studies evaluated its various perspectives5. The food insecurity and poor health status can prompt each other. Continuous and periodic food deficiencies may be the more effectively trigger health challenges that can augment, in turn, food insecurity6.Food insecurity with inadequate intakes of essential nutrients may prompt mental and behavioral dysfunction in children and adults and reduce resistance to diseases. Inability to purchase nutritious and adequate food and its mental and emotional stresses affect human health detrimentally, and even result in aggravation of other underlying diseases caused by other risk factors. Food insecurity is indirectly in relationship with poor health status, certain chronic diseases, adulthood obesity, hypertension, abnormal blood glucose levels, dyslipidemia, increasing levels of C‐reactive protein, depression, decreasing ability in daily activities, heart failures, gum disease, asthma and cognitive decay7. The food insecurity prevalence was 14.7% in America, 10% in Canada, 50% in Malaysia, 11% in Indonesia, 35% in the Philippines, 70% in Bolivia, 73% in Burkina Faso, 5.7% in Finland, 43% in Pakistan, and nearly 50% in Iran5.Increasing food insecurity over the past decade, particularly in developing countries was because of economic levels decline that raise fuel and food costs8. The upper gastrointestinal (GI) tract (esophagus and stomach) cancers were one of the five most common cancers in Iran9.Cancer as a debilitating disease shortens the lifetime and contributes to various individual and social harms. The importance of cancer as a main cause of death is increasing. Cancer was ranked as the second cause of mortality after cardiovascular diseases in the world10. In a study among cancer patients, the food insecurity prevalence was significantly higher than general peoples11. The relationship between food insecurity and some diseases, including obesity/overweight, diabetes, depression, and other mental and physical illnesses has been demonstrated5.Attention to the effects of food insecurity on health and social and psychological consequences, evaluation of its perspectives is essentialConsidering the increasing food insecurity and upper GI tract cancers in Iranian population, possibility of relationship, and no previous studies, we determined the association of food insecurity and upper GI tract cancers in newly diagnosed patients.This case-control study was conducted at Imam Khomeini Hospital of Tehran, Iran, from Jan-Dec 2013. The case group included 120 newly diagnosed patients with upper GI tract cancers admitted in the surgical ward of Central Institute of Cancer. The control group was 120 non-cancerous patients at one of the Orthopedics, Ear-Nose-Throat (ENT) and Neurology Departments. The age, sex and residential status  were matched between two groups.Ethical clearance as a master’s thesis was obtained from the Ethics Committee of Tehran University of Medical Sciences (RegNo.139). Before the data collection, a written informed consent form was taken from the patients.13.All of the participants completed the general and USDA household food security status questionnaires by interviewing. The Persian version of USDA household food security questionnaire and the general questionnaire were used already14 and 0.72 in Iran12. Furthermore, the adapted model of HFSSM in Isfahan survey gave internally valid household-level measures of food insecurity among adults and children. The scattering of items over a notable range of severity alongside passable item-fit statistics showed high average item difference and good fit to the Rasch measurement model. The other studies in several countries including Bolivia, Brazil, Colombia, Mexico City, Trinidad and Tobago, Ecuador, and Canada have been conducted to validate the HFSSM. Their results were similar in confirming the proportionality of the HFSSM to measure the severity of household food insecurity using different internal validity tests and methods14.The value of Cronbach's alpha for USDA household food security survey model (HFSSM) was 0.80 in USThe questions of general questionnaire included age, sex, residential area, economic levels, ethnicity, education levels, health insurance, history of GI ulcer, family history of cancer, body mass index (BMI), family size, number of children, marital status, history of smoking at 6 months consecutively, and history of specific diseases .The inclusion criteria were patients with upper GI cancers , diagnosis duration less than 6 months, and age more than 20 yr. The exclusion criteria were disability to answer, cooperate or remember  and psychotic diseases.The methods of diagnosing upper GI cancers were endoscopy, imaging, or biopsy/cytology depending on the doctor opinion.Before beginning, a pilot study was conducted among 19 newly diagnosed cancer patients to clarify the research perspectives.13.The economic status was determined based on nine items: car ownership, house ownership, washing machine, LCD TV, dishwasher, side-by-side refrigerator, handwoven carpets, computers/laptops, and microwave oven. The three economic levels were low/poor (< 3 items), moderate (4-6 items) and good/wealthy (>7 items)4.According to the 18-item USDA food security status questionnaire, food security is classified into four groups: food secure, food insecure without hunger, food insecure with moderate hunger, and food insecure with severe hunger. In this study, participants were divided into two food secure and food insecure groups. The scoring range of food security was 0 - 18 according to the numbers of positive responses 2, 18.5-24.99 kg/m2, 25.0-29.99 kg/m2, and ≥30 kg/m2 as underweight, normal, overweight, and obese, respectively).Weight and height were obtained from medical records and BMI was calculated  aged 71.1 ± 32.6 yr. Patients with gastric, esophageal or both cancers were 79 (55 men and 24 women), 30 (10 men and 20 women) and 11 (7 men and 4 women) and patients with neurological, orthopedic and ENT diseases were 33 (13 men and 20 women), 51 (35 men and 16 women) and 36 (24 men and 12 women), respectively.The residual areas of 27.5%, 11.7%, and 60.8% of any groups were the center of Tehran, the around of Tehran, and the other cities, respectively.The mean ± standard deviation (SD) of age, weight, and height in cases and controls were 60.23±11.48 yr and 60.42±11.99 yr, 59.71±12.53 kg and 67.67±9.72 kg, and 163.19 ±9.64 cm and 166.96 ± 8.18 cm, respectively.The food insecurity prevalence was 69.2% in cases and 43.3% in controls. The mean ±SD of food security score in cases and controls were 3.297±2.437 and 1.848±2.081, respectively.According to the univariate conditional logistic regression model, the food security, economic status, education status, ethnicity, health insurance status, GI ulcer history , family history of cancer, body mass index and family size differed significantly between two groups. The majority of cancerous patients were in food insecurity, lower economic levels, non-Fars ethnicity, illiterateness, family size≥3 peoples, GI ulcer history or family history of cancer, and health insurance coverage status. The other factors, including marital status, smoking history, and history of specific diseases did not have significant differences between the two groups .Ultimately, risk factors of upper GI cancers were food insecurity, family history of cancer, and lower economic levels .11.69.2% of the patients with upper GI cancers and 43.3% of the controls had food insecurity. The food insecurity, family history of cancer, and lower economic level were significant risk factors for upper GI cancers. In only a cross-sectional study among 115 cancerous patients (various types of cancer) in Kentucky, with and without hunger food insecurity prevalence were 9.6% and 7.8%, respectively. These rates were more than in general peoples of Kentucky13. Moreover, the food insecurity prevalence in the United States between 1995 and 2012 varied from 10.1% to 14.7%5. The food insecurity prevalence in other studies on general peoples using USDA household food security questionnaire was reported less than this study15. These differences may be the result of the different methods and participants.The current study was the first on the food security status of cancer patients in Iran. The average food insecurity prevalence in the past studies on general population in Iran was about 45%Food insecurity, family history of cancer and lower economic level were the most relevant risk factors for upper GI tract cancers. The odds ratio of cancer in peoples with food insecurity, low economic level, and family history of cancer were 2.57, 2.42, and nearly 2 times, respectively.5. Insecure food insecurity creates anxiety and worry, because of the social and biological importance of food that increases the probability of growing usual mental disorders. Besides, anxiety and worry can provoke encountering food insecurity and using nutritionally inadequate and high-calorie foods 18. Therefore, food insecurity may increase risk of nutrient deficiency and consequently the risk of cancer.The grades of food insecurity are concern about adequate food and reducing the size and number of meals, decreasing the size and number of meals, weight losing, feeling hunger, and reducing the size or number of the children’s meals. Recently, the paradox of food insecurity and health conditions has been concentrated in literatures. The food insecure populations often have the limited available budget, leads to purchase and consume cheaper and nutritionally insufficient foods  that might contribute to obesity, and an increased susceptibility to chronic illnesses including cancer, type 2 diabetes, depression and other medical condition such as acne, dyspepsia and so on21. In coastal areas of Iran, the incidence of esophageal and gastric cancer was lower in high-income peoples22. Furthermore, food insecurity was associated with the lower economic levels15. The income level is an important factor to access to adequate food in the society and peoples with good economic status have more choices of food23. Recently, Iranian politicians and policymakers have focused specially on resistance economy to improve the economic status24.The risk of adenocarcinoma and esophageal squamous cell carcinoma increases with low socioeconomic level according to previous studies in Iran and other countries25. In addition, family history of digestive tract cancer was significantly associated with the higher risk of gastric cancer (cardia and non-cardia), but did not increase the risk of esophageal cancer. Family history of breast cancer was considerably associated with the risk of both esophageal and gastric cardia cancers26. The family history of the mouth, oral cavity, pharynx and stomach cancers increases risk of esophageal cancer significantly27. In Iran, family history of esophageal cancer in the first-degree relatives was associated with the higher risk of esophageal cancer28. In contrast, neither the family history of esophageal cancer, nor the family history of stomach or other digestive tract cancers in the first-degree relatives did increase risk of the esophagus carcinoma. However, the risk of stomach cardia adenocarcinoma is moderately increased with a family history of gastric cancer in the first-degree relatives29. This inconsistency may be, because of the differences between populations and some associated conditions.Family history of cancer was a risk factor for gastric cancer and larger massesThe other study variables including ethnicity, education levels, health insurance, history of GI ulcer, BMI, family size, marital status, history of smoking, and history of specific diseases were not significantly associated with upper GI cancers.31. The data on weight and BMI of patients before cancer incidence were not accessible.Unlike this study, the BMI and risk of upper GI cancers were inversely related in several previous literatures32.The demographics of upper GI cancers have been altering drastically on the recent decades. Its occurrence differs broadly based on socioeconomic status, BMI, and history of GI ulcer, smoking, and underlying diseases. Comprehending the etiology and epidemiology of upper GI cancers will prompt interventions for averting and screening in high-risk populacesHelicobacter pylori infection, dietary pattern, being overweight or obese before of cancer incidence, stomach lymphoma, gastroesophageal reflux disease, Barrett’s esophagus, achalasia, tylosis, Plummer-Vinson syndrome, workplace exposures, injury to the esophagus, and few viral infections, could not be verified in this study.Some risk factors of upper GI cancers including The selective revealing or suppression of information by subjects may be as a potential reporting bias, that the statistical methods addressed it partly.The strengths of the study are case-control design, the nobility, obtaining an informed consent form (in Persian) from all the participants, selecting the newly diagnosed cancer patients, individually matching for age, sex, and residential area, conducting a pilot study before the beginning, and no bar to receiving the other health care services of the center.The limitations of the study are self-reporting, limited types of upper GI cancers, slow patient recruitment because of the eligibility criteria, a single center, and lack of cooperation of some patients in the end, which lead to patients be replaced.The implications of the work for practice and research are the selecting controls, the difficulty of obtaining reliable information about an individual’s exposure status over time, the difficulty of identifying the newly diagnosed cancer patients, poor mental condition and impatience of cancer patients, and expecting of some patients for financial supports.The food insecurity prevalence in patients with upper GI cancers was high. The food insecurity, poor economic status, and family history of cancer may be some risk factors for upper GI cancers. The noticing to comprehending of food insecurity effects on health reduces the burden of it. Even so, other studies are still needed to find association of food insecurity with other cancers or health problems. It is necessary to assess the food insecurity prevalence in different provinces of Iran and investigate diseases associated to it in future studies to depict an obvious illustration of food insecurity.Ethical issues  have been completely observed by the authors.Tehran University of Medical Sciences (RegNo.139) supported this master’s thesis. Cooperation of participants and Cancer Research Center is acknowledged.The authors declare that there is no conflict of interest.None.The food insecurity prevalence is notably higher in patients with upper GI cancers.The proof of upper GI cancers increases with lower food security and economic levels. The family history of cancer increases upper GI cancers.