We also examined the potential effect of 4 different incentive domains  on those indicators.We examined the effectiveness of providing incentives to participants in lifestyle modification programs to improve diabetes-related health indicators: body weight, body mass index (BMI), blood pressure, cholesterol, and hemoglobin AI2 statistic and the Cochran Q test. We also conducted moderator analyses by using a mixed-effects model to examine differences between subgroups of incentive domains .We searched Medline, Embase, PsycINFO, and Cochrane Library to identify relevant studies published from January 2008 through August 2021. We used a random-effects model to pool study results and examine between-study heterogeneity by using the P < .001), BMI , and both systolic blood pressure  and diastolic blood pressure . A reduction in cholesterol level was noted but was not significant . One study found a significant reduction in hemoglobin A1c . The moderator analyses showed that the incentive effect did not vary significantly between the subgroups of the incentive domains, except on weight loss for the attainment certainty domain, suggesting that a variety of incentive subgroups could be equally useful.Our search yielded 10,965 articles, of which 19 randomized controlled trials met our selection criteria. The random-effects model revealed that, relative to the control group, the incentive group had significant reductions in weight (−1.85kg; 95% CI, −2.40 to −1.29; Providing incentives in lifestyle modification programs is a promising strategy to decrease weight, BMI, and blood pressure. Lifestyle modification programs can improve diabetes-related health indicators . Including incentives can make these programs more effective.We demonstrated the effect of incentives in lifestyle modification programs on multiple diabetes-related health indicators and how this effect might vary by incentive domain .Using incentives in lifestyle modification programs may improve diabetes-related health indicators, independent of incentive domains. Therefore, programs could exercise flexibility by choosing incentive domains that work for their participants.Medscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit.Preventing Chronic Disease. Medscape, LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.In support of improving patient care, this activity has been planned and implemented by Medscape, LLC and AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.Medscape, LLC designates this Journal-based CME activity for a maximum of 1.00 http://www.medscape.org/journal/pcd; (4) view/print certificate.All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 75% minimum passing score and complete the evaluation at Release date: October 27, 2022; Expiration date: October 27, 2023Upon completion of this activity, participants will be able to:Distinguish the most common patient incentive applied in randomized trials included in the current meta-analysisAssess the effect of patient incentives on body weight and body mass indexAssess the effect of patient incentives on blood pressureEvaluate other cardiometabolic variables that might be improved with patient incentivesEDITORRosemarie PerrinEditorPreventing Chronic DiseaseAtlanta, GeorgiaCME AUTHORCharles P. Vega, MDHealth Sciences Clinical Professor of Family MedicineUniversity of California, Irvine School of MedicineCharles P. Vega, MD, has the following relevant financial relationships:Consultant or advisor for: GlaxoSmithKline; Johnson & Johnson Pharmaceutical Research & Development, LLCAUTHORSLaShonda Hulbert, MPHCenters for Disease Control and PreventionAtlanta, GeorgiaCyberData Technologies, Inc.Herndon, VirginiaShannon L. Michael, PhD, MPHCenters for Disease Control and PreventionAtlanta, GeorgiaJasmine Charter-Harris, MPHCenters for Disease Control and PreventionAtlanta, GeorgiaOak Ridge Institute for Science and EducationOak Ridge, TennesseeCharisma Atkins, MPHCenters for Disease Control and PreventionAtlanta, GeorgiaRenée A. Skeete, PhDSapodilla Group, LLCAtlanta, GeorgiaMichael J. Cannon, PhDCenters for Disease Control and PreventionAtlanta, GeorgiaMore than 37 million adults in the US have diabetes, and an additional 96 million have prediabetes, a precursor to type 2 diabetes. Prediabetes is defined as blood glucose levels that are higher than normal, but not high enough to be diagnosed as type 2 diabetes . PreventParticipating in a lifestyle modification program can help a person develop healthy habits and reduce risks associated with diabetes and related chronic conditions. Results from the National Diabetes Prevention Program have demonstrated that a structured, year-long lifestyle modification program can help participants reduce their risk by coaching them on how to make healthy food choices, reduce stress, and increase physical activity ,3. SimilPrevious systematic reviews and meta-analyses have examined whether incentives can improve health behaviors such as smoking cessation ,11, gett1C [HbA1c]) and the effect that incentives might have on them in the context of a lifestyle modification program. We also examined the effect by different types of incentives.In contrast, our systematic review and meta-analysis examined a range of diabetes-related health indicators  checklist  to guidehttps://www.congress.gov/bill/111th-congress/house-bill/4124). The search comprised a combination of key terms related to incentives, lifestyle modification programs, and diabetes-related indicators such as weight, BMI, blood pressure, cholesterol, and HbA1C ; 3) included adults (≥18 y); 4) occurred in high-income countries  provided incentives  to participants; 2) reported on a diabetes-related health indicator(s)  ocWe excluded studies that focused on programs not designed to modify diabetes-related health indicators ; medical interventions for weight loss ; pharmaceutical treatment for weight loss; one-time screenings for preventive services; incentives awarded to health care providers or health systems; or conditions or diseases not of interest . We excluded all gray literature, conference and dissertation abstracts, and public health presentations.2), blood pressure (both systolic and diastolic in mm Hg), cholesterol (mg/dL), and HbA1C (%). If multiple publications described the same study by using data from the same participants, we selected the publication with the most complete data and excluded the others.We used abstraction forms in DistillerSR (Evidence Partners Incorporated) to screen and manage all articles. Reviewers extracted the following information: study characteristics, study populations, incentive domains, and diabetes-related health indicators. The diabetes-related health indicators of interest were body weight , body mass index (BMI) , we extracted the pre- and post- values for diabetes-related health indicators. Using Comprehensive Meta-Analysis Software Version 3 , we calcP values. We used random effects models, which consider between-study variations, to calculate pooled effect-size estimates. We evaluated the overall effect of studies using z statistics with P < .05 considered significant. We assessed the risk for publication bias by visually inspecting funnel plots and assessing the degree of asymmetry in the distribution of effect sizes by using the techniques of Begg and Mazumdar  values, Q statistics, and their associated P values. We interpreted the I2 value, per the Cochrane Handbook . We also examined differences between study quality and types of lifestyle modification programs provided to the incentive and control groups to see how they affected heterogeneity and overall effect size.We assessed heterogeneity by 95% CIs, Handbook  as folloTo assess the impact of different incentive domains, we conducted moderator analyses with categorical variables by using mixed-effects models. We assessed the effect on body weight and BMI for subgroups within 4 incentive domains: including 1) type (cash vs other types); 2) monetary value ; 3) attainment certainty (criteria-based guaranteed vs other), and 4) schedule (fixed vs other). Because at least 2 studies in each subgroup are needed to conduct the analysis, we were only able to conduct the moderator analyses for body weight and BMI and for 4 of the 6 incentive domains.Our initial searches returned 10,965 articles . After rOf the 19 studies included in our review, 14 were conducted in the United States, 2 in Australia, 1 in Singapore, 1 in Scotland, and 1 in South Korea . Most of1c (HbA1c) (28). The quality scores of the studies varied: 4 good (The most frequently reported setting of the included studies was internet-based programs (n = 6) ,37,42,43: 4 good ,39,41,43: 4 good ,40,42; a (HbA1c) . The qua: 4 good  limited.Among the 19 RCTs, the most common incentive type was cash . Most stWe found a significant overall mean effect for providing incentives in lifestyle modification programs for 4 diabetes-related health indicators: body weight, BMI, and both diastolic and systolic blood pressure .Weight. The pooled mean difference for weight was −1.85 kg , indicating that the incentive group lost more weight (−1.85 kg or 4.1lb) than the control group.BMI. The pooled mean difference for BMI was −0.47 kg/m2 , meaning the incentive group decreased their BMI by 0.47 kg/m2 more than the control group.Blood pressure. The pooled mean difference for systolic blood pressure was −2.59 mm Hg , and for diastolic blood pressure it was −2.62 mm Hg  meaning that the incentive group had a greater decrease in their systolic and diastolic blood pressure than the control group.1CCholesterol and HbA. Two studies (P = .37). We did not have at least 2 studies to conduct a meta-analysis for HbA1C; in the only RCT . studies ,38 examionly RCT  examininP value of .03) and BMI . In addition, the Egger et al .The funnel plots of the effect sizes for weight and BMI were asymmetrical, suggesting possible publication bias for studies with nonsignificant effects. This was supported by the significant findings from the Begg and Mazumdar  publicater et al  publicatand Fill  analysisThe funnel plots of the effect sizes were symmetrical for diastolic and systolic blood pressure, and the trim-and-fill analysis suggested no adjustment to the mean effect size, indicating no evidence of publication bias.I2 = 51%; Q = 36.43; P < .01) and BMI , so we conducted subgroup analyses to better understand the potential sources of heterogeneity.We found moderate to substantial heterogeneity for the effect size of incentives on weight  for weight and for BMI . We chose to keep this study in both meta-analyses because it did not change the significance and only slightly lowered the pooled effect sizes .First, we identified potential study outliers as those with standard residuals ≥1.96. One study was identified as an outlier for weight and BMI . When weI2 = 60%) compared with studies rated as good  and limited . For BMI, the assessment was constrained because 6 studies were rated as fair (2) and moderate to substantial heterogeneity (I2 = 61%) compared with the study rated as limited .Second, we assessed heterogeneity as a function of study quality but did not find a consistent pattern. We found that for weight, studies rated as fair ,38,40,42 as good ,39,41,43 limited ,36 , which means that the differences across those studies are due to sampling error, not differences in true effect sizes. For the 5 studies that did not provide the same program, the I2 was 80% and significant , which means the amount of variability across the studies cannot be explained by chance alone. We found similar results for BMI, where the three studies (2) and unimportant heterogeneity , compared with the lower effect size (−0.41 kg/m2) with substantial heterogeneity  for the 4 studies  and systolic  blood pressure, so we did not conduct any further analyses.We found heterogeneity to be unimportant for diastolic , especially those programs associated with the prevention and management of chronic diseases such as type 2 diabetes . ReducinP = <.001) decrease in weight, whereas the other subgroup types showed a −2.03 kg (P = <.001) decrease. However, the differences in effect sizes across most subgroups were mostly nonsignificant. Therefore, it seems reasonable for lifestyle modification programs to use a variety of incentive domain subgroups.The results of the moderator analyses showed that nearly all the subgroups in each incentive domain  had a significant effect on reducing body weight and BMI. Some of the effect sizes were larger than others, suggesting that certain incentive domains might be more effective. For example, for the incentive type domain, the cash subgroup showed a −1.79 kg (1c, and certain settings to determine whether incentives could reduce disparities in the outcomes of lifestyle modification programs (Future studies could consider the effectiveness of various types of incentives for specific populations, cultures, certain health indicators like cholesterol and HbAprograms ,51. Althprograms –55, otheprograms . Similarprograms –12,19 foprograms –58. One programs .Our study has several limitations. Variability across lifestyle modification programs and incentive domains likely contributed to the heterogeneity of our results. Nevertheless, we found no significant differences in effect sizes according to the subgroup analysis for heterogeneity. Also, 2 of the incentive subgroup moderator analyses consisted of 2 studies, so we interpreted those results with caution. Finally, we were not able to include other factors that could influence participation or success, such as race or ethnicity of participants or the coach, the socioeconomic status of participants, or other incentive domains, such as incentive timing , so our Our study has several strengths. We had enough RCT studies to include in a meta-analysis with multiple diabetes-related health indicators, and most of them were considered of good or fair quality, mostly on the basis of limitations of the sample designs and the interpretation of study results. We used subgroup analyses to address heterogeneity, used moderator analyses to understand the effect of several incentive domains on health indicators, and adjusted for potential publication bias. Through these analyses we determined that the observed effect of the incentives could not be attributed to outlier studies or publication bias and that the effect sizes were consistent across incentive domains. Furthermore, for the programs that differed only by the incentive, we observed a strong effect and low heterogeneity in these studies for body weight and BMI. These findings provide more confidence that the use of incentives in lifestyle modification programs for chronic disease can lead to better outcomes.1c. Because our analysis showed effectiveness of incentives on multiple health indicators, we were able to add to the literature regarding the use of incentives to promote lifestyle modification. Chronic disease prevention and management programs can consider incentives as a tool to increase participant success.Using incentives in lifestyle modification programs is a promising strategy for adults at risk for or diagnosed with type 2 diabetes to reduce body weight, BMI, blood pressure, and, potentially, HbA


Access to emergency and essential surgical care is still unmet and accessibility is disproportionately inequitable in Ethiopia and other low-and middle-income countries. The aim of this study was to assess surgical care access in terms of capability, capacity, and timeliness of care in different levels of health care in Ethiopia.A cross-sectional study with retrospective data review was conducted in 172 health facilities from December 30, 2020 to June 10, 2021. Descriptive statistics such as median with interquartile range and proportion were computed using STATA Version 15 statistical software.Within a 90-day interval of the study period, 69,717 major and minor surgeries, and 33,052 bellwether procedures were performed, and major surgeries accounted for 58% of the surgeries. About 1.6%, 23.56%, 25.34%, and 32.2% of both major and minor, and 3.1%, 12.8%, 27.6%, and 45.3% of bellwether procedures were performed in health center OR blocks, primary, general, and specialized hospitals, respectively. Private hospitals performed 17.33% of major and minor and 11.2% of bellwether procedures for the period. The average pre-admission waiting time for surgical patients in primary, general, and specialized hospitals was 9.68, 37.6, and 35.9 days, respectively, whereas, in private hospitals, the average pre-admission waiting time was 1.42 days. On average, surgical patients traveled 5 Hrs, 11 Hrs, 28.4 Hrs, and 21.3 Hrs to access surgical services in primary, general, specialized, and private hospitals, respectively. The surgical workforce to the population served ratio was 7.5, 1.15, and 1.31/100.000 population in primary, specialized and general hospitals, respectively.Most surgical procedures were performed in specialized hospitals, indicating that there is a burden in these health facilities. The pre-admission waiting time for surgical patients was long in higher-level public hospitals. Surgical patients traveled a long distance to access surgical service in higher level hospitals. The ratio of surgical workforce per 100,000 population served was low in all levels of public health facilities in general, and in higher level hospitals in particular. Efforts should therefore be made to strengthen all levels of the health system and improve surgical care access in terms of capacity, capability, and timeliness in the country. Equitable access to surgical care service is still unreachable for billions of people. According to the Lancet Commission on Global Surgery (LCoGS), about five billion people lack access to timely, safe and affordable surgical and anesthesia care services globally . HoweverThe World Health Organization (WHO) Global Initiative for Emergency and Essential Surgical Care launched in 2005, galvanized global commitment for strengthening access to Emergency and Essential Surgical Care (EESC) in LMICs through successful advocacy efforts for the inclusion of EESC as an integral component of the Universal Health Coverage (UHC) packages. In 2015, the World Health Assembly (WHA) Resolution on EESC had motivated countries to prioritize surgical and anesthesia care in their national surgical plans and develop a national surgical plan , 4.Measuring surgical care in terms of capability, capacity, timeliness, safety, and affordability is essential to access the services. In line with this, the LCoGS put forth the following targets to be achieved by 2030. The targets include 80 percent coverage of essential surgical and anesthesia services per country; at least 20 surgical, anesthesia, and obstetric physicians per 100,000 population; 5,000 procedures annually per 100,000 population, and 100 percent protection against catastrophic expenditure from out-of-pocket payments for surgical and anesthesia care [SaLTS I) Strategic Plan 2016–2020 as the national flagship initiative. The SaLTS initiative was designed to improve access to safe surgical care at all levels of the Ethiopian health care delivery system with special emphasis in expanding EESC service in the primary level healthcare units (PHCUs) [In Ethiopia, former study findings showed a substantial unmet need for surgical care in the country. For instance, in 2015 the surgical volume and specialist surgical workforce per 100,000 population were 43/100,000 population and 0.35 surgeons/100,000 population, respectively [ (PHCUs) .SaLTS initiative has been launched, there is no adequate information about surgical care access status across levels of the health system in Ethiopia. Understanding the surgical care access status will be a springboard for the subsequent planning and inform the strategies to achieve universal access to surgical care in the nation. The aim of this study was to assess the status of surgical care access in terms of capability, capacity, and timeliness in different levels of health care including public and private health care facilities in Ethiopia.Ethiopian health care operates on the basis of a three-tier healthcare delivery system. The first level comprises the PHCUs, which include health posts, health centers, and primary hospitals, while levels two and three comprise general hospitals and specialized hospitals including teaching hospitals, respectively . The priHealth facility based cross-sectional study with retrospective data review was conducted in public and private health facilities of Ethiopia from December 30, 2020 to June 10, 2021. Ethiopia is an east African country with estimated population of more than 117 million people in 2021 [P = 0.5); therefore, the sample size was estimated to be 163 public hospitals. As we used a stratified sampling method, the sample size for each stratum of primary hospitals (np), general hospitals (ng), and specialized hospitals (ns) was calculated using the proportional allocation method and it was 105, 43, and 15 hospitals, respectively. In addition, to assess the status of surgical care in the private health sector, private health facilities providing safe surgical care services were included. According to DHSI 2 report, 45 private health facilities were providing surgical care. Thus, the sample size for private hospitals was estimated to be 40. This makes a total of 203 study sites. Each hospital from each stratum was selected by a simple lottery method. However, due to internal conflict and limited transport accessibility in some parts of Ethiopia, we could not be able to access all health facilities that were selected randomly, and we decided to replace some health facilities which were convenient assuming that hospitals in the same strata are homogeneous. A total of 172 sampled health facilities were evaluated in the study, which hold 84.7% of the estimated sample size.A multi-stage stratified random sampling method was used to select study sites . First, lists of all health care facilities providing surgical care were obtained from MOH of Ethiopia’s District Health Information System 2 (DHIS 2) report. Accordingly, 282 government hospitals  were providing EESC during the study period. The required sample size for the study was estimated using a single population proportion formula with a 95% level of confidence, a 5% margin of error, and an assumed proportion of surgical care accessibility  blocks for surgical services after an on-site assessment by a medical professional in the reporting period.Surgical workforce: total number of available surgical workforces including Surgeons , Anesthesiologists or anesthesia care providers, Obstetrician-gynecologist, Integrated Emergency Surgical Officers (IESO), and Nurse Anesthetists.The reviewed data were cleaned, checked for consistency, and entered into the Redcap database, and the data collectors archived cleaned data on a regular basis, every week. Then the cleaned data were exported into STATA Version 15 statistical software package for statistical analysis.p-value of < 0.05 was considered statistically significant.Descriptive statistics: frequency, proportion, and median with interquartile range (IQR) were computed. As the data were skewed, non-parametric tests  were employed to compare the median number of surgical volumes performed by health care facilities level. Kruskal–Wallis test was used for comparing the surgical volume performed among public specialized hospitals, public general hospitals, and public primary hospitals, and the Mann–Whitney test was used for comparing the surgical volume between public and private health facilities. A The study was approved by Armauer Hansen Research Institute (AHRI) ethical review board in Addis Ababa, Ethiopia. Additionally, the Ethiopia MOH issued a letter of support to conduct data review at the selected health facilities. Additionally, letters of support and permissions were obtained from the local health offices authorities to conduct data review at the selected health facilities.A total of 172 health facilities were included in the study. Of which, 9 (5.2%), 77 (44.8%), 38 (22.1%), 16 (9.3%), and 32 (18.6%) were health center OR blocks, primary hospitals, general hospitals, specialized hospitals, and private hospitals, respectively.Within a 90-day interval of the study period, from September 2020 through May 2021 a total of 69,717 major and minor surgical procedures were performed. Of which were 40, 202 (58%) major surgeries and 29,515 (42%) minor surgeries. With regard to the share of facilities, 40.7%, 27%, and 13.3% major procedures were performed at specialized, general, and primary hospitals, respectively. On the other hand, 20.5%, 23.1%, and 37.6% minor surgical procedures were undertaken in specialized, general, and primary hospitals, respectively. Private hospitals performed 18% of major and 16.4% of minor surgical procedures. One percent of major surgery (elective cesarean section) and 2.4% of minor surgeries were performed in health centers OR blocks , respectively (Table P = 0.02). The median number of major surgical procedures that were performed in private hospitals was higher as compared to the number of procedures performed in public health facilities; 118 (IQR: 60–287) versus 93 (IQR: 36–214)   versus 48 (IQR: 24–81), respectively . The median number of Caesarean sections the surveyed public health facilities performed was 105 (IQR: 50–234). Specialized hospitals, general hospitals, and PHCUs reported 373, 165, and 46 median number of Caesarean section, respectively during the study period  . The median number of major surgical procedures performed in specialized hospitals, general hospitals, and PHCUs were 1028, 185, and 46, respectively  and 21 Hrs, respectively. The time length required to get access to surgical care in primary hospitals was exceeded 4 hours Table .Table 6PA total of 8,584 patients were referred for surgical services in a 90-day interval. About 3956 surgical patients were referred from PHCUs to other health facilities. Of these 3540 and 416 surgical patients were referred from public primary hospitals and health center OR blocks, respectively. Public generalized and public specialized hospitals referred 2936 and 1449 surgical patients, respectively. A total of 243 surgical cases were referred out to other health facilities from private hospitals during the same period  collectively account for nearly 50% of the reasons for referral out from the surveyed health facilities , 48.27% of Anesthesiologists or Anesthesia care providers, and 49.4% Obstetricians were available in public specialized hospitals. Fifty nine percent and 30.2% of Integrated Emergency Surgical Officers (IESO) were available in public primary and general hospitals, respectively  of the surgical procedures were major surgeries, and about 41% of which were performed in public specialized hospitals where capacity in terms of human resources, infrastructure, equipment, and supplies are relatively better. On the other hand, public primary hospitals performed a small proportion 13.3%) of major surgical procedures. This is in line with a study in three East African countries that reported low rates of major surgery at district hospitals, ranging from 50 to 450 surgical procedures per 100,000 population . In Ethi.3% of map < 0.001), however, the median number of major surgical procedures which were performed in 32 private health facilities was higher than 136 public health facilities performed during the period. Furthermore, more than a third of open fracture management was undertaken in private hospitals. This may indicate the demand for surgical care services from private health facilities and the significant contribution of private hospitals in reducing the surgical burden. Nevertheless, the private sector in Ethiopia is relatively small  compared to other countries in the region. For instance, 46% and 65% of all health facilities are managed by Private Sectors in the Democratic Republic of Congo and in Kenya, respectively [Despite the fact that only 18.6% of the study facilities were private surgical facilities, the private sector contributed to 17.3% of both minor and major surgical volume for the study period. Although, the median number of major surgical procedures was significantly high in public specialized hospitals as compared to public primary and general hospitals  of the bellwether surgical procedures were performed in specialized hospitals. This is consistent with findings of a study in KwaZuluospitals . The Lanospitals . The proospitals , 17. Howcal care .Our study showed the surgical volume of 289 /100,000 population, 37/100,000 population, and 33/100,000 population over a 90-day interval in PHCUs, general hospitals, and specialized hospitals, respectively. This indicates that the surgical volume in Ethiopia’s public health facilities falls far below the LCoGS target of 5000 surgeries per 100,000 population/year which has been set to be achieved by the year 2030  and RwanThe study revealed that patients traveled about 28Hrs, 21Hrs, and 11Hrs to access surgical services in public specialized hospitals, private hospitals, and public generalized hospitals, respectively. This is still far from the LCoGS recommendation that patients should access a facility capable of performing the Bellwether procedure within two hours . AnotherOn the other hand, our study showed that patients have taken less than one hour to reach the health centers OR blocks. This may be related to the reason that all health center OR blocks are located in Addis Ababa where with relatively better transport access. However, a small proportion, 2.4% of minor surgeries and 3.1% of bellwether procedures were performed in health centers OR blocks for the period. This may be related to the gap in the deployment of IESO at the health center level.The average pre-admission waiting time for patients, who need essential surgical care, was 38 days in general hospitals and 36 days in specialized hospitals. This is longer than the findings of studies from other countries. For instance, a study from Zambia showed that the pre-admission waiting time for surgical patients, who need elective surgery, in teaching hospitals was 9 days . AnotherThis study showed that public primary hospitals referred nearly two-fifths (41%) of surgical patients. Nonetheless, higher levels of health facilities including generalized and specialized hospitals also referred significant proportion of patients who need surgical interventions. Lack of skilled professionals, lack of equipment/instrument, lack of blood, and lack of supplies or medications were the most frequent reasons for patient referrals at all levels of the health system. Likewise, a study from Tanzania showed that the lack of essential equipment, infrastructure, and human resources were significant gaps to provide EESC in first-referral health facilities .Lack of skilled professionals accounts for about one-third of the reasons for surgical referral out and which may likely indicate shortages of surgical workforce in the country. Our study also showed a considerably low surgical workforce to population ratio which was about 1/100,000 population served in higher levels of health facilities. However, the surgical workforce per 100,000 population served in PHCUs  was higher compared to in higher levels of health facilities. This might be related to that PHCUs are supposed to serve nearby communities and lower catchment populations . Unless The study also has strengths. As far as our literature review is concerned, this is the first study in Ethiopia that attempted to assess surgical care access in terms of capability, capacity, and timeliness across levels of the health care system. The study highlighted the surgical care access gap within the health system of the country; therefore, we believe that the results would inform a crucial input for the surgical care strategic plane of Ethiopia and provide a foundation for evidence-based decision-making and evidence-informed policy making. Moreover, the study may be used as baseline data for future studies.Our study has limitations. Although we could collect data from 85 percent of sampled health facilities, because of security situations related to the existing conflict at different places of the country, the data were not collected from all sampled health facilities. Moreover, the study was conducted in the COVID-19 era when the pandemic has been affecting health services provision including surgical care. Therefore, the pandemic might have affected the performance of surgical care services, particularly the surgical volume. This study may share the inherent limitation of secondary data such as inconsistency, incompleteness, and inaccuracy; however, extensive efforts have been made by the research team to ensure the data quality.The study showed that within a 90-day interval (September 2020-May 2021), the majority of surgical procedures were performed in specialized hospitals, indicating that there is a very high burden in these health facilities. Private hospitals substantially contributed for providing the surgical care service. The study revealed long pre-admission waiting time for surgical patients in higher levels of public hospitals. The surgical workforce ratio per population served was low in all levels of public health care facilities in general, and in specialized public health facilities in particular. Substantial proportions of surgical patients were refereed from public primary, generalized, and specialized hospitals to other health care facilities, indicating the weak status of the country’s health system. Surgical patients in Ethiopia traveled a long distance to access surgical services in a higher level of health facilities.Increasing access to surgical services and reducing delays in admission would help to increase the use of the respective services. Strengthening the capacity of primary-level health facilities may decrease the number of referrals and reduce the burden on high-level health facilities. Implementing the national surgical care strategies in private hospitals has paramount importance of the surgical care provision of the nation. Overall, efforts should therefore be made to strengthen all levels of the health system and improve surgical care access in terms of capacity, capability, and timeliness in the country.


Galium verum ethanol extract (GVL gel) and reveal its healing effects in the model of aphthous stomatitis in rats. Rats with oral ulcers were divided into the following groups: control (untreated), gel base , and GVL gel group (the ulcer was treated with GVL gel in the same way as the gel base). Animals from each group were sacrificed on days 0, 3, 6, and 10 for collecting blood and ulcer tissue samples. Healing properties of oral gel were determined by clinical evaluation, as well as biochemical and histopathological examinations. Our findings suggest a significant decrease in the ulcer size in GVL gel group, with healing effects achieved through the alleviation of oxidative stress, reduction in COX-2 immunopositivity, and increase in collagen content in buccal tissue. Significant ulcer repairing potential of GVL gel highlights this oral mucoadhesive gel as a promising tool for prevention and treatment of RAS.Although oral ulcers represent one of the most frequent oral mucosal diseases, the available treatment is not sufficient to provide complete ulcer recovery without side-effects. Therefore, the aim of our study was to prepare a mucoadhesive oral gel based on  Recurrent aphthous stomatitis (RAS) is the most common oral ulcer disease presented as round ulceration with an erythematous band and white-yellowish pseudomembranous center . The ulcGalium verum L.  belongs to the Rubiaceae family and, throughout history, has been known as an active herbaceous plant with multiple therapeutic properties. The effectiveness of this plant is based on several isolated bioactive complexes: iridoid glycosides, phenols, triterpenes, anthraquinones, etc. [p-coumaric acids, as well as quercitrin and rutin, in G. verum aerial part extracts, and those compounds have been highlighted to mostly contribute to the overall therapeutic potential of this plant species. However, the chemical content of the extract is strongly dependent on the harvesting time, method of extraction, applied solvent, etc. [G. verum extracts possess strong antioxidant and antimicrobial activity, we hypothesized that topically applied extract would accelerate the healing of aphthous stomatitis.Despite the fact that corticosteroids and antibiotics are the most effective and recommended in the management of RAS, certain patients do not respond adequately to the treatment, and, more importantly, their long-term use is associated with serious side-effects. Great concern in RAS management is referring to the multiple resistance of microorganisms to available antimicrobials especially in diabetic and cancer patients at risk for poorly healing infected ulcers. Therefore, scientific attention in recent years has been oriented on exploring alternative methods such as phytotherapy. For years, phytotherapy has been used as an approach in RAS treatment since plant-based products contain bioactive compounds with pharmacological activity comparable to currently available synthetic drugs but with better tolerability . Numeroues, etc. . Previount, etc. ,12. To tG. verum extract and explore its efficacy in healing of RAS in rats, with a special emphasis on the role of oxidative stress. The special novelty of our research is in providing an understanding of the influence of a G. verum-based topical product as an innovative therapeutic approach in RAS, which might be implemented alone or in combination with currently available pharmacological agents.Regarding the abovementioned data, the aim of this study was to formulate a mucoadhesive gel based on G. verum was collected on 5 July 2021 in Dobroselica, on the southern precipice of Mt Zlatibor, Serbia. Identification of the plant material was performed at the Institute of Botany and Botanical Garden “Jevremovac”, University of Belgrade, Serbia. The collected plant was dried under dark conditions and powdered (sieve 0.75). Ethanol extract was prepared using the heat reflux extraction method with 100 g of the aerial part of the plant and 500 mL of 70% ethanol as the solvent, at a temperature of 60 °C for 2 h. Afterward, the extract was dried under reduced pressure by a rotary evaporator  in order to obtain dry extract [The plant  extract ,14. The  extract .trans-cinnamic, p-coumaric, chlorogenic, rosmarinic, and ferulic acid, as well as quercetin, rutin, and quercitrin. The compounds of interest were separated on a Nucleosil C18 column  held at 30 °C. The mobile phase consisting out of 1% (v/v) aqueous HCOOH (A) and methanol (B) was delivered in gradient mode according to the following program: 0 min 10% B, 10 min 25% B, 20 min 45% B, 35 min 70% B, 40 min 100% B, and 46 min 10% B, while the flow rate was variable . The elution of compounds from the column was monitored at 280 nm , 330 nm , and 350 nm (rutin and quercitrin), while the quantification was based on calibration curves obtained for analyzed chemical standard substances under the same experimental conditions [A previously described analytical method based on high performance liquid chromatography  was applied for quantitative and qualitative chemical profiling of the obtained extract. Specifically, the extracts were analyzed for the amounts of gallic, caffeic, nditions .G. verum extract, was prepared using 20% w/w of extract, which was incorporated into the carbomer gel to achieve a uniform gel [A simple gel base was prepared using Carbomer 934, propylene glycol, triethanolamine solution, and water as previously described by our research group . Sodium form gel ,18.Sixty male Wistar albino rats (210–270 g) obtained from the Military Medical Academy, Belgrade, Serbia, were included in the experimental study. The animals were housed at a temperature of 22 ± 2 °C, with 12 h of automatic illumination daily, and they consumed commercial rat food  ad libitum. The experimental study was carried out in the laboratory for cardiovascular physiology of the Faculty of Medical Sciences, University of Kragujevac, Serbia. The Ethics Committee of the Faculty of Medical Sciences  approved the experimental protocol. All procedures were performed according to the EU Directive for the welfare of laboratory animals (86/609/EEC) and the principles of Good Laboratory Practice (GLP).To create the oral buccal ulcer model, rats were anesthetized with a mixture of ketamine (5 mg/kg) and xylazine (10 mg/kg) intraperitoneally. Oral mucosal ulcer was performed by exposing the buccal surfaces to glacial acetic acid following a previously established acetic-acid-induced in vivo model in rats . Two dayG. verum-based gel).Immediately after induction of RAS, rats were treated by applying the test formulation three times a day. Depending on the applied formulation, the rats were divided into three groups (20 per group): negative control (ulcer left without any treatment), control group—gel base (ulcer treated with gel base not containing any active agent), and GVL gel  three times daily for 10 days. The animals were sacrificed at different time intervals for 10 days. Five animals from each group were sacrificed on days 0, 3, 6, and 10. After short-term ketamine/xylazine anesthesia, rats were sacrificed by decapitation. Blood was collected for determination of systemic redox status, while buccal tissues were taken for histopathological analysis and determination of tissue redox state.The development and healing of the lesion were photographed and followed every second day by measuring the size of the ulceration using Image J software  starting from day 0 until complete healing. The degree of healing was represented as the percentage contraction of ulcer area, and it was calculated for each animal using the following formula: ulcer healing rate (%) = (A0 − At) × 100/A0, where A0 and At represent the initial ulcer area and the ulcer area at the time of observation, respectively .2−), nitrites (NO2−), and hydrogen peroxide (H2O2), as well as the index of lipid peroxidation (measured as thiobarbituric acid reactive substances (TBARS)). Parameters of the antioxidative defense were determined in the lysate of erythrocytes: activities of superoxide dismutase (SOD), as well as levels of reduced glutathione (GSH) and catalase (CAT).In the moment of sacrificing animals, blood samples were collected from the jugular vein for biochemical analysis. The concentrations of pro-oxidants were determined in plasma: the levels of superoxide anion radical  production, as previously described. Nitrites were measured at wavelength of 550 nm. The levels of superoxide anion radical (O2−) were measured using the nitro blue tetrazolium (NBT) reagent in Tris buffer (assay mixture) with a plasma sample. The measurements were performed at 530 nm. For measurement of hydrogen peroxide (H2O2), we used a protocol based on the oxidation of phenol red by hydrogen peroxide in the presence of horseradish peroxidase. The level of H2O2 was measured at 610 nm [The degree of lipid peroxidation in the sample was estimated by measuring TBARS using 1% TBA (thiobarbituric acid) in 0.05 NaOH, incubated in plasma at 100 °C for 15 min, and read on 530 nm spectrophotometrically. The level of NOt 610 nm .The level of reduced glutathione was determined on the basis of GSH oxidation with 5.5-dithio-bis-6.2-nitrobenzoic acid. The measurement was performed at 420 nm. CAT activity was determined according to previously described method, and detection was performed at 360 nm. For determination of SOD activity, the epinephrine method was used, and detection was performed at 470 nm .g at 4 °C for 15 min. The supernatants were collected and used for oxidative stress analysis. The following parameters were spectrophotometrically determined in supernatants: TBARS, GSH, CAT, and SOD, as previously described [After sacrificing animals, the aphthous lesions were isolated and immediately frozen at −80 °C. A 0.5 g section of each tissue was homogenized in 5 mL of ice-cold phosphate-buffered saline (pH 7.4). Afterward, the homogenate was centrifuged at 10,000× escribed .Presence of epithelial necrosis, no signs of inflammation;The inflammatory reaction has started, with no new capillary proliferation;The inflammatory reaction is prominent with few capillary proliferations on the basis of the ulcer, but no epithelization at the surface;The inflammatory reaction is decreased, new capillary proliferation has reached the surface, and epithelization has started at the surface;The epithelization is complete.The samples of isolated aphthous lesions were fixed in 4% formalin for 24 h. Afterward, tissue sections were dehydrated in increasing concentrations of alcohol (70–100%), cleared in xylene, and embedded in paraffin. Then, 5 μm thick tissue sections were stained with hematoxylin and eosin (H&E) in order to verify morphological changes, as well as with Picro-Sirius Red for detection of collagen. The specimens were analyzed using the following pre-established histological scoring protocol :PresenceCOX-2 in this study was verified by immunohistochemical staining. Tissue sections were deparaffinized and rehydrated through decreasing ethanol concentrations (100%–70%), and then sections were cooked in citrate buffer at a temperature of 95 °C, at pH 6.0, for 20 min. Tissue sections were cooled at room temperature for 15 min, followed by blocking endogenous peroxidase (into 3% hydrogen peroxide) for 10 min and washing in phosphate-buffered saline (PBS) for 5 min. Sections were incubated with protein block  for 5 min, followed by primary antibody COX-2 (1:100)  for 1 h at room temperature. Sections were washed in PBS (3 × 5 min) followed by incubation with primary antibody amplifier Qvanto, Thermo Scientific, USA for 10 min, washed in PBS (5 min) followed by addition of HRP (HRP Polymer Quanto) for 10 min, and then washed in PBS for 5 min. Binding sites were visualized with 0.05% diaminobenzidine . The sections were contrasted with hematoxylin, rehydrated in increasing alcohol concentrations (70–100%), cleared in xylene, and mounted with DPX  . Images t-test) and nonparametric tests  were performed to determine the differences between groups depending on the normal distribution of the data. All results are expressed as the mean value ± standard deviation (SD). A p-value < 0.05 was considered statistically significant.Statistical analysis was performed using the Statistical Package for Social Sciences v23.0 . The Shapiro–Wilk test was used to evaluate the distribution of data. Parametric tests . Elevated levels of pro-oxidant markers in patients with active oral lesions in relation to patients in the remission stage of RAS and healthy controls have been well documented ,38. TherIn addition to biochemical analysis in blood samples, we monitored oxidative stress in the ulcer tissue in order to provide a better understanding of the effect of GVL gel. Our results revealed that application of GVL gel was associated with a significant reduction in TBARS levels in ulcer tissue, which was prominent on days 3 and 6 following ulcer appearance. Moreover, there were significant differences in all measured antioxidant parameters, which were increased in the GVL group compared to the gel base and control group, on days 3, 6, and 9. Such results indicate an important role of GVL gel on oxidative stress in terms of amplification of the antioxidative defense system and a reduction in the concentration of pro-oxidative markers. Several studies support our results showing increased activity of SOD and GSH in mucosal ulcer, by 40% and 54%, respectively, after treatment with plants with a similar phytochemical profile ,40.In order to highlight the mechanisms responsible for healing effects of GVL gel, histological analysis of the buccal mucosa was performed. H&E staining confirmed that GVL gel reduced the duration of the inflammatory process and accelerated healing time. The most prominent beneficial effects were achieved on day 6, which was confirmed by the completely remodeled epithelium and absence of ulcer in rats exposed to GVL treatment. On the contrary, the inflammatory response was still present in other groups at that timepoint. These results are in accordance with macroscopic evaluations, thus confirming the significant role of GVL in promoting ulcer healing.G. verum, as the active ingredient in our mucoadhesive gel, could be explained by the presence of phenolic acids such as p-coumaric, caffeic, and chlorogenic acid, which are known as selective COX-2 inhibitors [It is well known that cyclooxygenase enzymes are essential in the process of inflammation and participate in the process of prostaglandin generation. Since COX-2 is an inducible enzyme that promotes inflammatory prostaglandins at sites of healing and inflammation, we aimed to assess the influence of GVL gel on COX-2 protein expression in buccal ulcer tissue . Our finhibitors . Our resTaking into consideration that collagen contraction is the final stage in wound healing, after inflammation and cell proliferation , we aimeG. verum extract to accelerate oral ulcer healing. The positive effects of this gel are reflected by a significant increase in percentage ulcer contraction throughout the duration of the treatment. Additionally, 10 days of treatment with G. verum gel reduced the generation of pro-oxidants in buccal tissue, thus suggesting a reduction in oxidative stress as one of the mechanisms underlying the healing effects of this formulation. The potential of the gel to decrease COX-2 expression and elevate collagen content further contributes to better buccal mucosa regeneration. This significant influence of G. verum extract-based gel on oral wound healing may be attributed to the additive and/or synergistic activity of the most abundant compounds in our extract such as rutin, p-coumaric acid, quercetin, quercitrin, and gallic, caffeic, and chlorogenic acid. The promising findings of our study highlight GVL as a promising tool for the management of oral mucosal ulceration.Our results for the first time suggest the potential of a mucoadhesive gel based on


Meanwhile, there was no significant difference between meatballs with GLP and TP in AV, A294, GO, and CML (p > 0.05). Correlation analysis indicated that GO, CML, pentosidine, and fluorescent AGEs positively correlated with AV, TBARS, A294, and A420, while GO, CML, pentosidine, and fluorescent AGEs negatively correlated with free sulfhydryl groups. These results manifested GLP could inhibit AGEs formation by inhibiting lipid oxidation, protein oxidation, and Maillard reaction. The possible inhibitory mechanism of GLP on the AGEs included scavenging free radicals, capturing dicarbonyl compounds, forming polyphenol–protein compounds, and reducing the formation of glucose. Therefore, the work demonstrated that the addition of plant polyphenols may be a promising method to inhibit AGEs formation in food.The inhibitory effect of guava leaf polyphenols (GLP) on advanced glycation end products (AGEs) of frozen chicken meatballs (−18 °C) and its possible inhibitory mechanism was investigated. Compared with control samples after freezing for 6 months, acidic value (AV), lipid peroxides, thiobarbituric acid reactive substance (TBARS), A Chicken meatball, as a chicken processed meat product, is popular for its pleasant flavor, convenient processing, and low price, and is usually preserved at −18 °C to reduce the contamination of enzymes and microorganisms and prolong the shelf life ,3. HowevAt present, some inhibitors are used to inhibit the formation of AGEs, and they are divided into synthetic inhibitors and natural inhibitors according to the source. Clinically, synthetic aminoguanidine has been used as an inhibitor and has excellent inhibitory effects, but it is potentially toxic to humans . In contPsidium guajava L.) is a member of the Myrtaceae family and is favored for its distinct flavor, nutritional components, and medicinal value [Guava , pentosidine, and fluorescent AGEs; (4) clarify the correlation of lipid oxidation, protein oxidation, Maillard reaction, and the formation of AGEs; and (5) analyze the possible inhibitory mechanism of the GLP on AGEs. Meanwhile, the hypothesis of this work is that the addition of GLP can inhibit AGE formation in frozen chicken meatballs (−18 °C) by inhibiting lipid oxidation, protein oxidation, and the Maillard reaction.Therefore, the aims of the present work were to (1) explore the effect of the GLP on the lipid and protein oxidation by acidic value (AV), lipid peroxides (POV), thiobarbituric acid-reactive substances (TBARS), and free sulfhydryl groups; (2) investigate the effect of the GLP on the degree of Maillard reaction by intermediate and advanced products; (3) evaluate the effect of the GLP on the AGEs by glyoxal (GO), NFresh chicken breast samples were supplied by a local supermarket . GLP  was purchased from Fufeng Snow Biotechnology Co. LTD . Tea polyphenols (TP)  were obtained from Anhui Red Star Pharmaceutical Co. Ltd. . All other reagents were supplied by Wantai Biomedicals Inc. .The chicken meatballs were prepared according to Shahimi et al. with modifications . Fresh cThe AV of the chicken meatballs during frozen storage was determined following Chinese Standard GB 5009.229-2016.V/V) in a 50 mL centrifuge tube. The mixture was homogenized at 11,000 rpm for 30 s by using a M133/1281–0 high-shear mixer  and then 3 mL 0.5% NaCl solution was added to the mixture. The mixture was centrifuged at 5000 rpm for 10 min and, subsequently, the upper liquid phase was extracted using a 5 mL sterile syringe and injected into another 50 mL centrifuge tube. Then, 5 mL of chloroform: methanol solution  stored at 4 °C, 25 μL ammonium thiocyanate solution , and 25 μL ferrous chloride solution were added into the centrifuge tube, and the solution mixed by vortexing for 3 s with each addition. The absorbance of the mixed solution was measured at 500 nm after reaction for 5 min at room temperature. The standard curve was prepared by using a reduced iron. The POV values were expressed as meq/kg of meat.The content of lipid peroxides in chicken meatballs was measured as described by Pan et al. . The min532 is the absorbance at 532 nm; m is the weight of chicken meatballs sample (g); and “9.48” is a derived constant from the dilution factor and the molar extinction coefficient  of the red TBA reaction product.The TBARS value was evaluated according to the method reported by Li et al. . Minced −1 cm−1. The results were recorded as nmol/mg protein.According to the method described by Zhang et al. , myofibrThe degree of Maillard reaction was measured according to the method reported by Zhu et al. . The absThe measure of GO was conducted according to the method of Zhu et al.  with sliCML was determined by enzyme-linked immunosorbent assay, and specific operations were slightly modified according to the method described by Zhu et al. . StandarThe pentosidine content was determined based on the method described by Joglekar et al.  with modThe fluorescent AGE content was determined based on the steps described by Wu et al.  with minp < 0.05) using a Statistix 8.0 software with the General Linear Models procedure . Figures were plotted by using an OriginPro 2021 . Data regarding the oxidation and Maillard reaction of chicken meatballs during the frozen storage were analyzed using a mixed model according to the analytical method of Biffin, Smith, Bush, Collins, and Hopkins [The data were expressed as mean values ± standard error (SE), and an analysis of variance (ANOVA) with Tukey’s multiple comparisons was performed to analyze data under the significance level . Compared with the control samples, AV values of chicken meatballs with GLP decreased by 12.13%, 13.88%, 27.10%, and 11.08% at 1, 2, 3, and 6 months, respectively, and there was no significant difference compared to samples with TP (p > 0.05). As shown in p < 0.05). Compared with the control samples, POV values of the chicken meatballs with GLP decreased by 12.84%, 8.36%, 23.4%, 8.99%, and 22.3% at 0, 1, 2, 3, and 6 months, respectively. Compared to samples treated with TP, there was no obvious difference in the first month (p > 0.05). As shown in p < 0.05). Compared with the control samples, TBARS values of chicken meatballs treated with GLP decreased by 14.21%, 19.44%, 29.42%, 19.33%, and 19.52% at 0, 1, 2, 3, and 6 months, respectively, while they significantly increased compared with samples with TP (p < 0.05).As shown in The increase in AV values of chicken meatballs was attributed to the fact that ice crystals caused muscle cell rupture during frozen storage and then released a large number of pro-oxidant substances and enzyme, which would make lipid oxidize and hydrolyze into free fatty acids; therefore, the lipid hydrolysis degree of chicken meatballs increased . The risp < 0.05), while the free sulfhydryl groups content of samples with GLP and TP increased by 4.90% and 6.95% compared with control samples after freezing for 6 months. During frozen storage, protein was oxidized, which destroyed sulfhydryl groups and made them convert to disulfide bonds, resulting in a decrease in sulfhydryl content [Protein oxidation stability can be reflected by free sulfhydryl group contents that are the most easily affected functional groups in chicken protein, and most of those (70%) are contained in MP . The hig content ,35. Afte content . Moreove content . Huang e content  also rep294) [294, the higher the intermediate product’s content. As depicted in 294 of all meatballs significantly increased with the increase of frozen storage time; among them, the A294 of samples with GLP and TP significantly decreased compared with control samples after 1 month (p < 0.05). The increase in A294 was on account of the protein structure of chicken meatballs being unfolded, resulting from protein oxidation during frozen storage, and the inherent amino groups inside were exposed, and further reacted with carbonyl groups in residual sugars, causing the increased degree of the Maillard reaction [294 was attributed to both GLP and TP inhibiting the protein oxidation and reducing the exposure amino groups, resulting in the decreased degree of Maillard reaction [The Maillard reaction can produce small, colorless, intermediate products, including sugars, aldehydes, and ketones, which is reflected by the absorbance of samples at 294 nm (A294) . The higreaction . The decreaction . The resreaction , who rev420) [420, the higher the melanoidin content, and the more thorough the degree of the Maillard reaction. As depicted in 420 of all meatballs significantly increased (p < 0.05). The A420 of samples with GLP and TP significantly reduced compared with control samples after freezing for 1 month (p < 0.05), and there was no significant difference between samples with GLP and samples with TP (p > 0.05). The increase in A420 was assigned to the accumulation of melanoidin produced by the Maillard reaction that kept happening during frozen storage [420 was due to GLP effectively protecting the protein structures and avoiding the exposure of free amino acids, thus effectively inhibiting the Maillard reaction [At the advanced stage of the Maillard reaction, fragments of protein polypeptides and polysaccharides condense to form brown melanoidin, whose content can be evaluated by the absorbance of samples at 420 nm (A420) ,39. The  storage . The decreaction . Zhu et reaction  also conGO, a kind of α-dicarbonyl compound, is a crucial precursor substance during the formation of AGEs , which ip < 0.05). After freezing for 6 months, the CML content of control samples significantly increased from 214.13 ng/mL of meat to 335.72 ng/mL of meat. Compared with the control, the CML content of samples with GLP and TP reduced by 4.80% and 6.75% after freezing for 6 months, respectively. The increase in CML content was mainly ascribed to the aggravated Maillard reaction and oxidation forming more GO during frozen storage, and the GO reacting with lysine to produce more CML; meanwhile, the aggravated Maillard reaction also generated more Schiff base that produced rearranged products by Amadori, and then the rearranged products were decomposed to form more CML [CML, a noncross-linked non-fluorescent product, is a kind of typical AGE . As showmore CML . The decmore CML .Pentosidine, a cross-linked fluorescent product, is a kind of representative AGE which is generated by pentose reacting with the lysine and arginine ,49. The Most of the AGEs are fluorescent products whose content is reflected by fluorescence intensity . The hig294, and A420; (2) between GO, CML, and POV; while there was a negative correlation between GO, CML, pentosidine, fluorescent AGEs, and free sulfhydryl groups; and there was no correlation between pentosidine and POV.The correlation of lipid oxidation, protein oxidation, and Maillard reaction with advanced glycation end products formation can be analyzed by the color of grid and Pearson’s r value ,55. As sThe correlation analysis indicated that lipid oxidation, protein oxidation, Maillard reaction, and the formation of AGEs had excellent correlations. Lipid oxidation produced a variety of oxidation products, among which the dicarbonyl compound directly combined with amino acids to produce AGEs . In addiThe possible mechanism for the inhibitory effect of the GLP on the AGEs included scavenging free radicals, capturing dicarbonyl compounds, reducing the formation of glucose, and forming polyphenol–protein compounds. The graphical illustration is shown in (1)GLP could scavenge free radicals produced by lipid oxidation, which stopped the chain reaction of lipid oxidation, thus preventing the formation of dicarbonyl compounds, the precursor of AGEs, and inhibiting the formation of AGEs . Further(2)GLP directly captured dicarbonyl compounds that were the precursors of AGEs to inhibit the formation of AGEs. The benzene ring and phenolic hydroxyl group in GLP electronically conjugated to produce phenoxy anions, which could combine with dicarbonyl compounds, thus reducing the precursor of AGEs ,53.(3)GLP reduced the production of glucose that was the substrate of the Maillard reaction. Polyphenol in guava leaves inhibited the activity of α-amylase, which reduced the decomposition of polysaccharides into glucose, thereby reducing the substrate for the Maillard reaction . In addi(4)Polyphenols in GLP combined with protein to form polyphenol–protein compounds, which reduced the Maillard reaction between proteins and sugars, resulting in decreased AGEs .In conclusion, the effect of the GLP on the lipid oxidation, protein oxidation, Maillard reaction, and AGE formation of frozen chicken meatballs was studied. After adding GLP to chicken meatballs, the lipid oxidation, protein oxidation, degree of the Maillard reaction, and formation of AGEs were inhibited. Correlation analysis indicated that GLP inhibited AGE formation by inhibiting lipid oxidation, protein oxidation, and the Maillard reaction. The possible inhibitory mechanism of GLP on the AGEs included scavenging free radicals, capturing dicarbonyl compounds, forming polyphenol–protein compounds, and reducing the formation of glucose. This work demonstrated that plant polyphenols could be used as a natural source additive to inhibit the production of AGEs in food and provide a theoretical basis for improving the safety of industrial processed food.


The incidence of renal cell carcinoma (RCC) rises globally with the highest rates in developed countries. This indicates not only the impact of advanced imaging, but also an increased prevalence of modifiable risk factors such as smoking, obesity, and hypertension. This review will summarize the epidemiology and genetic variation of RCC, primary prevention-involving risk factors, and secondary prevention through early detection with a focus on biomarkers.With 400,000 diagnosed and 180,000 deaths in 2020, renal cell carcinoma (RCC) accounts for 2.4% of all cancer diagnoses worldwide. The highest disease burden developed countries, primarily in Europe and North America. Incidence is projected to increase in the future as more countries shift to Western lifestyles. Risk factors for RCC include fixed factors such as gender, age, and hereditary diseases, as well as intervening factors such as smoking, obesity, hypertension, diabetes, diet and alcohol, and occupational exposure. Intervening factors in primary prevention, understanding of congenital risk factors and the establishment of early diagnostic tools are important for RCC. This review will discuss RCC epidemiology, risk factors, and biomarkers involved in reducing incidence and improving survival. Renal cell carcinoma (RCC) accounts for about 2.4% of all malignancies in adults, with more than 400,000 new cases diagnosed and about 180,000 deaths worldwide in 2020 according to GLOBOCAN data [Increased detection of early RCC lesions in many patients is due to the widespread use of computed tomography (CT) and magnetic resonance imaging (MRI), and the 5-year survival rate for early RCC detection is as good as 93% ,3. HowevAs it is generally resistant to cytotoxic chemotherapy and radiation therapy, RCC is classically considered an immunogenic tumor, and past immunotherapies have had some success, albeit inadequate . TreatmeHowever, improvement in the prognosis of advanced RCC is likely to be limited even with advances in pharmacotherapy. Therefore, understanding how to reduce the incidence of RCC and detect it early may help reduce the burden of disease, promote prompt treatment, and improve survival rates for this disease that claims 180,000 lives each year [RCC is the ninth most common malignant neoplasm in the United States (U.S.) and has been increasing in recent years . Future RCC is the 12th most common malignant neoplasm worldwide, excluding blood cancers, with approximately 431,000 new cases diagnosed, of which approximately 271,000 are in men and 160,000 are in women, based on 2020 estimates from GLOBOCAN data [About 180,000 people died from RCC in 2020 accounting for 1.8% of all cancer patient deaths according to GLOBOCAN data, of which 116,000 were men and 64,000 were women .Many risk factors for RCC have been reported, including genetic mutations. This section describes risk factors that cannot be changed.Many sporadic RCCs are found in the elderly as it is generally a disease of the elderly. The average age of diagnosis in the U.S. is 64 years of age . Most RCMost neoplasms are more common in males as shown in the GLOBOCAN data, and the same is true for RCC, with 1.5 times as many cases in males as in females .RCC incidence varies by ethnic group in the U.S., with a higher risk of RCC among Native Americans and African Americans, and lower among Asian Americans . FactorsMost RCC is sporadic, but some is due to specific germline gene mutations . TherefoOriginating from tubular epithelial tissue and often metastasizing hematogenously to the lungs or bone, ccRCC is the most common type of RCC . Von HipThe average age of RCC onset in patients with VHL disease is as young as 40–45 years, with a 70% lifetime risk, and the need for scheduled imaging studies for patients . HoweverBAP1 (Breast cancer susceptibility gene 1 associated protein 1 Tumor Predisposition Syndrome).Breast cancer susceptibility gene 1 associated protein 1 (BAP1) tumor predisposition syndrome is an autosomal dominant syndrome associated with increased risk of malignant mesothelioma, uveal melanoma, cutaneous melanoma, basal cell carcinoma, and RCC . BAP1 atAlthough non-clear cell type has also been reported, BAP1-associated RCC subtype is mainly ccRCC . Median Cases of pRCC account for about 10–20% of all RCC cases, and most cases are solitary . Two subHereditary papillary RCC (HPRC) is an autosomal dominant inheritance syndrome and a risk for type 1 pRCC . HPRC haHereditary leiomyomatosis and RCC (HLRCC) is an autosomal dominant hereditary cancer syndrome and a risk factor for pRCC type 2, uterine fibroids, and skin leiomyoma . PatientHereditary paraganglioma-pheochromocytoma syndrome (PGL/PCC) involves pathogenic variants of the succinate dehydrogenase (SDH) gene and is associated with the development of paragangliomas, pheochromocytomas, gastrointestinal stromal tumors, and RCC . SDH is Lifetime risk of RCC for SDHB mutation carriers is estimated to be about 5% . Median Tuberous Sclerosis Complex (TSC) is an autosomal dominant genetic disorder that can cause lesions in various sites, including the skin (angiofibroma), heart (rhabdomyoma), and kidney (angiomyolipoma (AML), cyst, RCC) . TSCs loBirt–Hogg–Dubé (BHD) is an autosomal dominant genetic disorder characterized by benign skin lesions, lung cysts with a high risk of pneumothorax, and multiple cysts in the liver and kidneys . BHD is Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome/Cowden syndrome is an autosomal dominant disorder associated with germline mutations in the PTEN gene . LocatedHyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant genetic disorder that involves mutations in the cell division cycle (CDC73) gene . The CDCOver-the-counter analgesics are frequently used worldwide and have been reported to be associated with RCC risk.An aspirin study found an increased risk in non-US studies , but no difference overall  . HoweverSubstances that have been associated with specific occupational exposures are not associated with renal cancer, such as bladder cancer and malignant mesothelioma. However, trichloroethylene has strong degreasing power, which is used as an organic solvent, and has been used in the past for cleaning, specifically semiconductor cleaning. It has been reported to be associated with kidney cancer. This substance is highly carcinogenic and is a predisposing risk factor for RCC, along with liver cancer and lymphoma .The comprehensive VITamin And Lifestyle (VITAL) study in the U.S. reported that lifestyle disease such as obesity and hypertension, and smoking increased the risk of developing RCC . MoreoveTobacco smoking has been linked to many common cancers including RCC. Tobacco smoke contains a mixture of carcinogens implicated in the etiology of RCC . EpidemiModerate alcohol consumption has been reported to have a protective effect on RCC incidence compared to abstinence . A very In terms of diet, the group with a median red meat intake of 62.7 g per 1000 kcal had an increased risk of cancer with a HR of 1.19  compared with the group with a median intake of 9.8 g . This coConsumption of fruits and vegetables  has been reported to be associated with reduced risk of RCC ,68. HoweThe risk of median daily sodium intake (3.4 g in men and 2.8 g in women) was presumably mediated by the development of hypertension , althougOn the other hand, there is growing evidence that coffee can prevent several chronic diseases, including cancer and metabolic diseases ,72,73 al2; HR 1.71; 95% CI, 1.06–2.79) [2 compared to the counterpart under 22.5 kg/m2 [2 had a HR of 1.99  for cancer risk in the JPHC study, compared with a BMI of 23–24.9 kg/m2. In contrast, overweight women were positively associated with RCC risk, albeit not statistically significant . Interestingly, an increased risk of cancer was also observed in thin men with a BMI < 21 kg/m2 , indicating a U-shaped association not seen in other countries [The VITAL study confirmed that obesity is significantly associated with RCC risk (BMI ≥ 35 vs. < 25 kg/m06–2.79) . The RR 06–2.79) . Another.5 kg/m2 . Men witountries .Hypertension was independently associated with RCC risk   and evidType 2 diabetes has been associated with an increased risk of several types of cancer ,87, but Screening programs improve survival rates by detecting and treating RCC in its early, curable stages. The ideal screening modalities have not yet been determined and there are currently no diagnostic modalities for the early detection of RCC other than incidental radiological discovery although it has been postulated that screening for RCC may be a cost-effective strategy through downstaging the disease, reducing the prevalence of metastatic tumors and associated expenditure relating to systemic therapies. Some candidate molecules in blood and urine have been reported as biomarkers for RCC recently by searching serum microRNAs and urinary proteins or by metabolomics, proteomics, and amino acid profile analysis. There are no results or sufficient evaluations of screening in a large general population, and they have not reached a practical stage.As an alternative to radiologic screening, the use of tumor markers with high sensitivity and specificity is desirable, but no readily available and clinically validated biomarkers for RCC screening are available. However, several urine and serum biomarkers have been proposed as potential screening tools. The collection of this biological fluid can also be attractive due to its quick, easy, and non-invasive method in clinical practice. The most promising urine biomarkers are aquaporin 1 (AQP1) and perilipin 2 (PLIN2). These concentrations are sensitive and specific biomarkers for the early non-invasive detection of clear cell or papillary subtypes of RCC ,90. The Alterations in DNA methylation occur early during cancer development and are observed even in the precancerous state in the case of clear cell RCC (ccRCC) ,100, witme levels might be an indicator of disease progression and metastatic processes [Emerging evidence has suggested that miRNAs may be promising novel biomarkers for the diagnosis of RCC ,104. Therocesses . Cancer-rocesses .Recently, lncRNAs have been shown to contribute to the development of almost all cancer types, including RCC ,122. lncL-carnitine and L-proline betaine could be prognostic markers [L-glutamic acid, lactate, D-sedoheptulose 7-phosphate, 2-hydroxyglutarate, and myoinositol) in a diagnostic predictive model for ccRCC and four metabolites  in a predictive model for clinical stage III/IV ccRCC were extracted. The sensitivity and specificity of the diagnostic prediction model were 93.1% and 95.0%, respectively, with an AUC of 0.966. Sensitivity and specificity of the clinical stage prediction model were 88.5% and 75.4%, respectively, with an AUC of 0.837 [Previous studies have identified metabolites of ccRCC using tissue samples evaluated with the Global Metabolomics protocol . Pathway markers . Others  markers : five meof 0.837 . Guida eof 0.837 . In thisProteomics studies of RCC using a variety of mass spectrometry (MS) techniques have been applied to many different types of samples, including tumor cell lines, serum, tissue, and urine . A high Lipidomics is an independent and emerging field within metabolomics , and lipExtensive research has been conducted to determine whether serum amino acid levels can be a biomarker for RCC. One study reported that the concentrations of 26 amino acids in serum collected preoperatively from 189 RCC patients and 104 age- and sex-matched controls showed statistically significant changes in the concentrations of 15 amino acids, with a decrease in 13 and an increase in two amino acids. Furthermore, the value of AUC was 0.81, based on a logistic regression model using eight amino acids . This same model also had predictive value in terms of overall survival and tumor recurrence in patients with RCC, suggesting that serum amino acid levels may be useful as a screening tool in identifying patients with RCC and predicting outcome . AnotherThe incidence and mortality of RCC vary widely around the world. Hereditary risk factors cannot be modified, but behavioral and environmental factors and comorbidities can be improved. Prevention efforts targeting smoking, obesity, hypertension, diabetes, and occupational exposure are therefore important.Secondary prevention, mainly early detection, is also important in addition to prevention of outbreaks. Adequate follow-up for hereditary diseases and early detection of sporadic cases, which account for the majority of cases, may reduce the number of deaths due to RCC.A significant number of biomarkers for RCC have been studied and reported for diagnostic and prognostic purposes. However, none are yet accurate enough to be widely used in clinical practice. Therefore, further search and elucidation of new markers for RCC and research on existing markers should be continued.


This study aimed to develop an effective support vector machine (SVM) classifier based on the multi-modal data for detecting the main brain networks involved in group separation of premature ejaculation (PE).A total of fifty-two patients with lifelong PE and 36 matched healthy controls were enrolled in this study. Structural MRI data, functional MRI data, and diffusion tensor imaging (DTI) data were used to process SPM12, DPABI4.5, and PANDA, respectively. A total of 12,735 features were reduced by the Mann–Whitney U test. The resilience nets method was further used to select features.Finally, 36 features  were chosen in the training dataset. We got the best SVM model with an accuracy of 97.5% and an area under the curve (AUC) of 0.986 in the training dataset as well as an accuracy of 91.4% and an AUC of 0.966 in the testing dataset.Our findings showed that the majority of the brain abnormalities for the classification was located within or across several networks. This study may contribute to the neural mechanisms of PE and provide new insights into the pathophysiology of patients with lifelong PE. Premature ejaculation (PE) is one of the most common male sexual dysfunction worldwide. According to the International Society for Sexual Medicine and European Association of Urology Guidelines, the definition of lifelong PE was characterized by the following: ejaculation that always or nearly always occurs prior to or within about 1 min of vaginal penetration . In receThe development of neuroimaging techniques, such as structural and functional MRI (fMRI) as well as diffusion tensor imaging (DTI), provides a task-free approach and a reliable measure of the brain mechanism. A significant difference in the caudate nucleus volume was found between patients with PE and healthy controls (HCs) . PatientMultivariable pattern analysis (MVPA) based on machine learning could better utilize the inherent multivariable properties of high-dimensional neuroimaging data to classify new samples, which works by decoding patterns of differences between brain regions/connections by learning discriminant rules from datasets . As one Against this background, we aimed to (1) develop an effective SVM classifier based on the three types of neuroimaging data and (2) detect the main brain networks involved in group separation in order to improve the understanding of PE.A total of 88 right-handed adult men including 52 drug-naïve patients with lifelong PE and 36 matched HCs were enrolled in the present study. Patients with lifelong PE were diagnosed by the guideline of the International Society for Sexual Medicine (ISSM) . For theb = 0 and b = 1,000 s/mm2 with diffusion sensitizing gradients applied along 64 non-linear directions.Individual MRI data were acquired using a 3T MRI system . Participants were asked to lie in the scanner in the supine position, with their eyes closed and without thinking, and the head motion were restricted with foam fillers. The functional MRI images were collected by using the gradient echo with the following parameters: repetition time (TR) = 2,000 msec, echo time (TE) = 30 ms, slice thickness = 3.5 mm, data matrix = 64 × 64, flip angle (FA) = 90°, field of view (FOV) = 240 mm × 240 mm, in-plane resolution = 3.75 mm × 3.75 mm. The scan parameters of the T1 images were as follows: TR = 8.2 ms; TE = 3.2 ms; FA = 12°; data matrix = 256 × 256; in-plane resolution = 1 mm × 1 mm; FOV read = 256 mm; and slice thickness = 1 mm. The scan parameters of DTI data were as follows: TR/TE = 10,000/85.3 ms, FOV = 240 mm × 240 mm, slice thickness = 2 mm, data matrix = 256 × 256, and 70 continuous axial slices with no gap. 2 Diffusion-weighted sequences were acquired using gradient values 1 in accordance with the following procedures: (1) T1 data was normalized to the template space; (2) the processed images were segmented into gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF); (3) quality checks, including displaying one slice for all images and checking sample homogeneity, were carried out; (4) different brain sizes based on total intracranial volume (TIV) by the ANCOVA model were corrected; and (5) the image data with an 8 mm full-width at half-maximum Gaussian kernel were smoothed ied out;  differen2 First, the first five volumes to avoid the effect of the scanning inadaptation were removed. Then, slice-timing and head motion were corrected for the time delay of acquisition and the alignment to the first volume, respectively. We excluded all subjects whose maximum translation was larger than 2 mm or head rotation exceeded 2°. After normalizing to the Montreal Neurological Institute (MNI) space by using the EPI template, images were resampled at 3 mm × 3 mm × 3 mm. The nuisance factors included 24 head motion parameters, the WM, and the CSF signal in the procedure of nuisance covariates regression. Finally, smoothing, detrending, and temporal bandpass filtering (0.01–0.1 Hz).The preprocessing of the fMRI imaging data was accomplished by the DPABI toolbox (DPABI 4.5).Diffusion tensor imaging (DTI) data were processed using the PANDA, which was a pipeline toolbox for analyzing brain diffusion imaging. The individual FA images of native space were registered to the FA template in the MNI space. After that, the resulting warping transformation was applied to write the diffusion metric image, such as mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), into MNI space. In this study, the Anatomical Automatic Labeling (AAL) template with 90 cortical and subcortical regions (45 in each hemisphere) was applied to obtain the mean tensor-based parameters value of each brain region. For network construction, the whole-brain fiber tractography was obtained by a deterministic streamline tracking algorithm. If it turns at an angle of more than 45° or reaches a voxel with a FA < 0.15, the tractography terminates. In addition, the FA matrix, the fiber number (FN) matrix, and the fiber length matrix were computed for network analysis.z-score to standardize all the features. Then, a two-stage feature selection technique was used to select the most discriminating features and improve the reliability of the results. Since the number of matrix features  is much larger than other features, a non-parametric Mann–Whitney U test was used for preliminary selection to make all feature dimensions similar . Considering individual variation, in order to ensure the stability of the retained variables, we adopted the keep-one elimination method. After the Mann–Whitney U test in the first step, we spliced the remaining features with other features as the input for the second feature selection. When applying L1-penalty and L2-penalty simultaneously, the elastic net exhibited the grouping effect, i.e., selecting a group of features with a high correlation and making their regression coefficients to be equal. Due to the simultaneous application of L1- and L2-penalties, the elasticity network exhibits a grouping effect, which is a set of features with high correlation selected so that their regression coefficients tend to be equal. Therefore, 4-fold cross-validation resilience nets were randomly shuffled 100 times with the classification accuracy as a cost function to select the most informative set of relevant features and retain non-zero features.In the current study, we calculated functional and structural measures, including GMV, ReHo, ALFF, DC, FA, MD, AD, and RD, as well as a matrix of the mean value of FA on the fiber, a matrix of the fiber length, and a matrix of the fiber number as the variables in the following statistical analysis. First, we used a A fourfold cross-validation strategy was used to evaluate the classification performance, which included accuracy, sensitivity, specificity, precision, recall, and f1. Specifically, all samples were divided equally into four subsets, with samples from three subsets being used to train a multi-kernel SVM classifier and samples from another subset being used to calculate classification metrics. The entire dataset was randomly shuffled 100 times to avoid any bias introduced by randomly splitting the dataset, and cross-validation was performed after each shuffle. Average classification accuracy, sensitivity, specificity, precision, recall f1, and area under the curve (AUC) were calculated over the 100 runs. The flow diagram for this study is illustrated in The demographics and clinical features  of all participants are summarized in Among the 3 types of data, 12,735 features were reduced by the Mann–Whitney U test. Finally, 36 features  were chosen in the training dataset. After training SVM in the training dataset with the 36 selected features, we got the best SVM model with an accuracy of 97.5% and an AUC of 0.986 in the training dataset. Then, we used the model to predict the status in the testing dataset with an accuracy of 91.4% and an AUC of 0.966 . The resWithin this study, we applied a multivariate pattern analysis to distinguish patients with lifelong PE from HCs. The accuracy was 97.5% and the AUC was 0.99 in the training dataset by applying 36 selected features in 3 types of data, and the accuracy was 91.4% and the AUC was 0.97 in the testing dataset. To the best of our knowledge, this is the first study to develop a multivariate pattern method that combines the resting state sMRI, fMRI, and DTI data in the classification of PE and HCs. Our results showed that the majority of the structural and functional abnormalities that contributed to the classification were located within or across the default mode network, the affective network, the sensorimotor network, the reward circuitry, and the frontoparietal network.Previous studies reported their works on functional or structural abnormalities by using traditional group-level statistical methods. A notable finding using the SVM model has shown important progress in distinguishing patients with PE from HCs . The resThe feature selection process discerned the functional and structural abnormalities in PE largely covering the default mode network and the sensorimotor network. The functional elements of the default mode network comprise supporting emotional processing, self-referential mental activity, and the recollection of prior experiences . The relThe observed group differences in the reward circuit and the affective network are particularly noteworthy when comparing patients with PE with HCs. The reward circuit comprises the ventral tegmental area dopaminergic neurons, which innervate several regions of the part of the ventral striatum, the prefrontal cortex, the amygdala, and the hippocampus, as well as other areas . It playOur main analysis of features revealed that certain regions located in the frontoparietal network  and other regions  were associated with PE. The control system, consisting of several sub-systems , is considered to be involved in highly adaptive control processes, time-extended control processes, and coordinated attention to external stimuli . It is wThe current study has several limitations. First, although the sample of our study was larger than previous studies, the sample size was relatively small. Second, future studies should use longitudinal data that may reduce possible confounders. Finally, besides the AAL-90 atlas, future studies should further detect subtle anatomical differences between different atlases.In conclusion, based on three types of imaging data and machine learning approaches, our study showed that the majority of the brain abnormalities for the classification were located within or across several networks. This study may contribute to neural mechanisms associated with PE and provide new insights into the pathophysiology of patients with lifelong PE.The original contributions presented in this study are included in the article/The studies involving human participants were reviewed and approved by the Northwest Women’s and Children’s Hospital Ethics Committee. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.BG and PL: conceptualization. MG and YW: data curation. BG and RP: methodology. MG, CL, SZ, and KX: investigation. RP, CL, and XZ: software. BG: writing – original draft. BG, YW, PL, and RP: writing – review and editing. MG: funding acquisition. YW, PL, and XZ: resources. All authors contributed to the article and approved the submitted version.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.