Ghrelin is an orexigenic hormone primarily released by the stomach and has 2 isoforms: acylated ghrelin (AG) and de-acylated ghrelin (DAG), that appear to have different functions in humans.To perform a systematic review and meta-analysis of the association between plasma concentrations of total ghrelin (TG), AG, and DAG and perceptions of hunger in healthy adults.1) sample contained adults ≥18 y of age, 2) body mass index [BMI kg/m2] was ≥18.5, 3) ghrelin was sampled through blood, 4) subjective hunger was measured on a validated scale, 5) study reported a Pearson product correlation of ghrelin or had relevant figure(s) for data extraction, 6) participants were healthy with no overt disease, 7) protocols contained no physical activity or weight loss medication that suppressed appetite, 8) interventions were conducted without environmental manipulations. Moderators assessed were age, BMI, percentage of body fat (%BF), macronutrient content of test meals, energy intake , sex, and ghrelin isoform .The following criteria were used for inclusion: n = 1799, age: 31.4 ± 12.0 y, BMI: 26.0 ± 4.75 kg/m2) and measured AG , DAG , and TG . The overall model indicated that ghrelin concentrations and perceptions of hunger were moderately correlated , and ghrelin isoform significantly moderated this relationship . Other significant moderators included age , BMI , %BF , energy intake , and percentage of carbohydrates of test meals .The analysis included 47 studies (110 trials, Ghrelin is associated with perceptions of hunger in humans, and this relationship is strengthened when AG is isolated; thus, AG may have a large impact on hunger signals in various populations. Future research should attempt to understand the role of DAG in hunger sensations. This meta-analysis is the first to assess the relationship between ghrelin isoform and perceptions of hunger. Our findings indicate the importance of distinguishing between ghrelin isoforms and highlight several gaps in the literature that should be examined in future studies.Ghrelin, discovered in 1999, is the growth hormone stimulating peptide .While TG concentrations fluctuate with a diurnal rhythm, secretion can be affected by meal timing and macronutrient content ,4, and oAG can cross the blood-brain barrier and bind to GHSR1a receptors in the area of the hypothalamus, which promotes appetite . AG medi1) there was an association between endogenous ghrelin concentrations and perceptions of hunger in humans and 2) if the direction and strength of this relationship differed by isoform. We also included meal content to investigate the potential effect of food intake.Therefore, we sought to determine if Sample demographic variables were included in this analysis to explore possible moderators of this relationship. The results from this analysis will advance the scientific field, especially the potential role of ghrelin as a therapeutic target for the management of obesity and its associated comorbidities.This systematic review and meta-analysis were performed in accordance with PRISMA guidelines . This reElectronic databases  were searched by 2 authors (KCA and FH). Articles published through November 2022 were included. The search used the following terms: (ghrelin) AND (relationship) AND (hunger). Reference lists of all relevant studies, along with reviews and book chapters, were also examined. Articles were limited to studies published in the English language.1) sample contained adults ≥18 y of age, 2) BMI was ≥18.5 kg/m2, 3) ghrelin was sampled through blood, 4) subjective hunger was measured on a validated scale, 5) study reported a Pearson product correlation of ghrelin or had relevant figure(s) for data extraction, 6) participants were healthy with no overt disease, 7) protocols contained no physical activity or weight loss medication that suppressed appetite, and 8) interventions were carried out without any environmental manipulations. Two authors  independently completed the study selection and identified studies for inclusion. Any disparities in the initial study selection were resolved by 2 tie-breakers (EEG and SK).For the purpose of this meta-analysis, the term “article” was used synonymously with “study” and “trial” as the unit included in the meta-analysis. Articles often contained multiple eligible trials comprised of a ghrelin and appetite measure. First, the titles and abstracts of the articles were screened for eligibility. The following criteria were determined a priori for article inclusion: 1) author, publication year; 2) continuous variables: sample size, age, Pearson product correlation between ghrelin and subjective hunger, BMI, %BF, and if applicable, macronutrient content of the meal  and EI ; and 3) categorical variables: sex, ghrelin form .For studies that met the inclusion criteria, the following data were extracted and tabulated: If the ghrelin and hunger correlation value was not reported, the study author was contacted. When authors did not respond to follow-up, ImageJ software   was utilP ≤ 0.05. Descriptive data are presented as mean ± SD unless otherwise noted.The meta-analysis was performed using R software version 4.0.2 and the “metafor,” “metaviz,” and “ggplot2” packages, versions 3.0.2, 0.3.1, and 3.3.5, respectively . The sigI2 statistics was used to assess the amount of heterogeneity at each level of the model, with the following interpretation: Values <25% indicate low risk of heterogeneity, 25–75% indicates moderate risk of heterogeneity, and >75% indicates considerable risk of heterogeneity [Due to the possibility of correlation variation being affected by sampling distribution skewness, correlations between ghrelin and hunger were transformed to a Fisher’s Z correlation coefficient to normalize skewness . A 3-levogeneity .Subsequent to estimating the overall effect, we examined the robustness of the pooled results via publication bias and sensitivity analysis. Sensitivity analysis was performed using Cook’s distance to determine potentially influential studies  . Fisher’s Z values from subgroup analyses were transformed back into a correlation coefficient for interpretation. Meta-regressions were also used to determine if the following continuous variables impacted the pooled correlation coefficient: Age, BMI, %BF, meal information EI, %CHO, %FAT, %PRO. The regression coefficient (ß) is reported along with 95% CI.n = 52; only females n = 12; both sexes n = 46) and measured TG . The full characteristics of included trials are in The PRISMA flow diagram outlining this process is presented in P < 0.001, 2 = 56.4%, P < 0.0001) and moderate between-study (level 3) heterogeneity .The overall model indicated that ghrelin concentrations and subjective hunger ratings had a positive, moderate association (Fisher’s Z = 0.47 (which transforms back to a correlation coefficient of 0.43), 95% CI: 0.28–0.57; . It is unclear why these studies had such an effect on the model beyond that most of them contained trials with negative correlations and/or strong correlations. All other studies removed during the sensitivity analysis had no substantial effect on the overall model. Visual inspection of the sunset plot (r = 0.40), and the R-Index was calculated at 15.5%, which suggests a low probability of replication. The Fisher’s Z needed for achieving 66% of median power is 0.67. Given the data, we would expect 34.08 statistically significant trials, and we observed 51, yielding a P value of <0.001.Cook’s distance identified several influential studies  Supplem. When thset plot  revealedr = 0.60, P < 0.001) and TG , but not DAG  but not females  had a moderating effect on the association between ghrelin concentrations and hunger. Concerning meta-regressions, age , BMI , EI , and %CHO  were significant, whereas %FAT and %PRO were both not significant .Moderator data is listed in n = 12) that measured DAG. Since DAG contributes a larger percentage to plasma TG, the moderating effect we report with TG may suggest that DAG also has a weaker association with hunger ratings. Furthermore, while GHSR1a receptors, only utilized by AG, are found in the hypothalamus [The purpose of this systematic review and meta-analysis was to investigate the relationship between endogenous ghrelin concentrations and perception of hunger in healthy adults. We report that ghrelin concentrations display a moderate, positive relationship with subjective hunger ratings. Importantly, our moderator analysis revealed that ghrelin form may influence this relationship: studies measuring AG increased the strength of the overall association, while studies measuring TG had the opposite effect, and DAG had no effect. However, this may have been impacted by the low number of trials  only sampled males, which suggests that our ability to assess this moderator was underpowered. Although there is a wealth of literature describing sex differences in eating behavior, such as food choices, dietary restraint [We also found that sex was a moderator that trended toward significance, specifically that males impacted the relationship between ghrelin and hunger, while females did not. However, the majority of studies  impacts this correlation, along with age, BMI, %BF, EI, macronutrient content, and timing of study meals. This review highlights several gaps in the literature. Future work should be dedicated to the study of the relationship between perceptions of hunger and ghrelin concentrations as a primary aim, as most of the studies included in the current analysis were underpowered to investigate this relationship. In addition, the individual forms of ghrelin should be evaluated and should include samples that contain both sexes across the lifespan, with particular consideration to individuals with obesity. As both ghrelin and the perception of hunger are involved in regulation of body composition, meal timing, and EI, exploring the mediators of this relationship is also critical for metabolic health and weight management interventions.The authors’ responsibilities were as follows – KCA: conceptualized the project, analyzed data, performed the statistical analysis, and wrote the paper; FH and EEG: conceptualized the project, analyzed data, and wrote the paper; SK: conceptualized the project, and wrote the paper, and all authors: read and approved the final manuscript.The authors report no conflicts of interest.The authors reported no funding received for this study.Data in the manuscript are available upon request.


Allergic rhinitis is a chronic and refractory disease that can be affected by a variety of factors. Studies have shown an association between cesarean section and the risk of pediatric allergic rhinitis.The PubMed, Springer, Embase, Cochrane Library, and Web of Science databases were searched to retrieve all studies published from January 2000 to November 2022, focusing on the relationship between cesarean section and the risk of pediatric allergic rhinitis. A meta-analysis was conducted to find a correlation between cesarean section and the risk of pediatric allergic rhinitis. A subgroup analysis was performed, considering the region and family history of allergy, after adjusting for confounding factors. Pooled odds ratios (ORs) were calculated, publication bias was assessed using a funnel plot, and heterogeneity between study-specific relative risks was taken into account.The results showed that cesarean section was significantly associated with an increased risk of pediatric allergic rhinitis . Subgroup analysis stratified by region indicated that cesarean section increased the risk of pediatric allergic rhinitis, with the highest increase in South America  and the lowest in Europe . The results of the subgroup analysis stratified by family history of allergy indicate that family history of allergy was not associated with the risk of pediatric allergic rhinitis.An association exists between cesarean section as the mode of delivery and the increased risk of pediatric allergic rhinitis, and cesarean section is a risk factor for allergic rhinitis. The gloAllergic rhinitis is a chronic and refractory disease that can be caused by a variety of factors. Studies have shown an association between C-sections and the risk of allergic rhinitis in children. In this study, systematic review and meta-analysis were conducted to investigate the relationship between cesarean section and the risk of allergic rhinitis in children. The results may guide pregnant women to choose their delivery methods, suggesting that choosing a natural delivery may reduce the risk of allergic rhinitis in children, especially in high-risk areas.2.https://www.crd.york.ac.uk/prospero/#recordDetails(CRD42022378094) on 3 December 2022.The protocol of this meta-analysis was prospectively registered at 2.1.The relationship between cesarean section and the risk of pediatric allergic rhinitis was explored. In this systematic review and meta-analysis, the articles published from January 2000 to November 2022 were searched using the PubMed, Springer, Embase, Cochrane Library, and Web of Science databases to assess the effects of cesarean section on the risk of pediatric allergic rhinitis. The use of keywords associated with medical subject terms (MeSH) cesarean section and allergic rhinitis was consistent with the preferred reporting items for systematic reviews and meta-analyses . Specifi2.2.The inclusion criteria were as follows: (1) trials of allergic rhinitis in children and diagnosis of allergic rhinitis in accordance with international guidelines; (2) children aged 0–18 years and the availability of detailed statistics of types of childbirth and delivery methods; (3) cross-sectional, cohort, and case–control studies; (4) data that could be used to calculate 95% confidence intervals (CIs) for the effects of air pollutants on allergic rhinitis; and (5) trials published in the English language only, without the need of contacting the authors.2.2.1.The exclusion criteria included incomplete data and data not accessible from the original author.2.3.Data were initially extracted from the included studies. Then, two reviewers (XH and JW) independently extracted data from those studies, including the first author's name, year of publication, study duration, study type, sample size, diagnostic criteria, outcome evaluation criteria, and study results . Discrepancies in the extracted data were resolved after a discussion with a third reviewer (SZ). Furthermore, the data were categorized by region  and whether confounders could be adjusted for subsequent subgroup analysis.2.4.The quality scores used in the meta-analysis were found controversial. Thus, the quality of the included studies and the risk of bias were analyzed. Different assessment scales were used due to the different types of studies included. The included cohort and case–control studies were assessed using the Newcastle–Ottawa Scale (NOS), with a score of 14. Two reviewers (XH and JW) independently assessed the quality of the included cross-sectional studies using the Agency for Healthcare Research and Quality (AHRQ) scaling system , with sc2.5.Q test and Higgins I2 statistics were used to assess the level of heterogeneity between outcomes. The Q test and I2 statistics were utilized to examine heterogeneity, in which I2 > 50% indicated a significant heterogeneity. A fixed-effects or random-effects model indicated a significant difference in effect size (P < 0.05). The sensitivity analysis of the results and publication bias were evaluated using the leave-one-out and funnel plot techniques, respectively. A two-tailed P < 0.05 was considered statistically significant.The statistical analysis was performed using Review Manager (RevMan) 5.2 software . The OR value of 95% CI was calculated as the effect size. The Cochran 3.3.1.3.1.1.The results of subgroup analysis by region  showed that the risk of allergic rhinitis in children delivered by cesarean section was most increased in South America , 14 OR:–19 OR: , 20–23 , 24–29  did not significantly differ from the overall OR of studies that adjusted for confounding factors for family history of allergy , as shown in 3.2.We analyzed the publication bias of 19 studies on the relationship between cesarean section and AR risk in children using a funnel plot . The res4.Allergic rhinitis is a respiratory disease that can be affected by several factors. This meta-analysis examined the relationship between cesarean section and the risk of pediatric allergic rhinitis. As a result, the disorder of physiological bacterial colonization in children, especially in the gastrointestinal tract, affects the immune system , hindersThe present study analyzed the association between cesarean section delivery patterns and the risk of pediatric allergic rhinitis after adjusting for confounding factors, such as age, gender, birth weight, passive smoking, feeding patterns in the first 6 months, maternal educational level, household income, and antibiotic exposure. However, due to lacking raw data, adjusting for confounding factors for maternal diseases during pregnancy and family allergy was infeasible. Mitselou et al.  categoriIn the present study, subgroup analysis was performed on data stratified by region. For this purpose, four subgroups of Asia, Europe, South America, and North America were considered. The results of subgroup analysis revealed that in Asia , Europe , South America , and North America , both cesarean delivery methods increased the risk of pediatric allergic rhinitis, while OR indicated a different level of risk. The results showed that the risk of pediatric allergic rhinitis was the highest in South America and the lowest in Europe. ECRHS reports have also shown that the risk of nasal allergies varies by geographical region , which mEurope is located in the northeastern hemisphere and has rich fishery resources, and fish has become a very important part of the daily diet. South America is located in the western and southern hemispheres, and due to the climatic and environmental conditions, its animal husbandry is more developed, and the local people mainly consume beef products. Fish has a richer vitamin D content than beef. Previous studies have shown that allergic rhinitis is associated with a reduced vitamin D level , 40–42, South America is located almost between the equator and the Tropic of Capricorn, and its climate is mainly tropical rainforest. Compared with the climate of Europe, the climate of South America is characterized by high temperature, high humidity, and heavy rainfall. Such climatic characteristics have led to differences in mite species and concentrations in different regions, especially in the Andes of Colombia, Peru, and Venezuela, where the prevalence of mites is high , 44, andThe risk of pediatric allergic rhinitis from cesarean section is also associated with the degree of industrialization and development of the region. Chou et al.  assessedThe high level of industry in Europe, combined with robust healthcare, a great climate, and a healthy diet containing vitamin D, may explain why cesarean section in Europe is associated with a lower risk of pediatric allergic rhinitis compared with that in other regions.5.To our knowledge, this study is one of the few recent meta-analyses that have studied the relationship between cesarean section and the risk of pediatric allergic rhinitis, and the results were meaningful for both the prevention and selection of delivery methods for pediatric allergic rhinitis. However, the results indicate the necessity of conducting further relevant research. It is noteworthy that the number of relevant studies was limited; thus, additional studies should be performed to clarify the differences in the risk of pediatric allergic rhinitis stratified by region. Moreover, the number of research subjects in the included studies remarkably varied. In the present meta-analysis, the majority of the included studies were cross-sectional studies, and patients had recall biases in their memories, demonstrating the necessity of more cohort studies to supplement the findings. At the same time, it is well known that prophylactic antibiotics are usually used to avoid infection after cesarean section, and antibiotic use also exists after some vaginal births. We found that this detail was not documented in the present study, so this factor may influence our analysis results. We need to conduct a long-term cohort study in the future to observe whether using antibiotics after delivery has a certain influence on the early development and health of children.6.In summary, the results of the present meta-analysis suggested that the mode of delivery via cesarean section increased the risk of pediatric allergic rhinitis after adjusting for confounding factors. The results of the subgroup analysis showed that children in high-risk areas were more affected by cesarean section. In contrast, our experimental results did not support the assumption that family history of allergy increased the risk of pediatric allergic rhinitis. The results of this study provide some reference value for pregnant women in choosing their delivery method, especially in high-risk areas. However, the final choice of pregnant women is influenced by many factors, and the final mode of delivery should be combined with individual specific circumstances. Further evidence is required to clarify the relationship between family history of allergy and the risk of pediatric allergic rhinitis. However, the sample size of the present study was not large enough, it was a retrospective study, and the adjustment of confounding factors was insufficient. Thus, additional studies are required to verify the conclusions.


This study investigated the associations between heatwaves and daily hospital admissions for cardiovascular and respiratory diseases in two provinces in Viet Nam known to be vulnerable to droughts during 2010–2018. This study applied a time series analysis with data extracted from the electronic database of provincial hospitals and meteorological stations from the corresponding province. To eliminate over-dispersion, this time series analysis used Quasi-Poisson regression. The models were controlled for the day of the week, holiday, time trend, and relative humidity. Heatwaves were defined as the maximum temperature exceeding P90th over the period from 2010 to 2018 during at least three consecutive days. Data from 31,191 hospital admissions for respiratory diseases and 29,056 hospitalizations for cardiovascular diseases were investigated in the two provinces. Associations between hospital admissions for respiratory diseases and heatwaves in Ninh Thuan were observed at lag 2, with excess risk . However, heatwaves were negatively associated with cardiovascular diseases in Ca Mau, which was determined amongst the elderly (age above 60), ER = −7.28%, 95%CI: −13.97–−0.08%. Heatwaves can be a risk factor for hospital admission due to respiratory diseases in Vietnam. Further studies need to be conducted to assert the link between heat waves and cardiovascular diseases. Cardiovascular disease (CVD) was ranked as the greatest single contributor to the overall disease burden in the world. In 2017, CVDs were responsible for 17.79 million deaths globally and 201.14 thousand deaths in Vietnam .Heatwave is defined as a period when the weather is hotter than usual ,5, and aThe Global Climate Risk Index 2020 ranked Vietnam, a tropical developing country in Southeast Asia, as the sixth country in the world most affected by climate variability and extreme weather events over the period 1999–2018 . Over thPrevious studies evaluated the relationship between heatwaves and hospitalizations in multiple provinces across Vietnam, except Ninh Thuan. The findings in Ca Mau indicated negative associations between heatwaves and admissions for respiratory diseases and CVDs in this province. Ninh Thuan and Ca Mau provinces experienced severe droughts during 2015–2016 and the Vietnam authorities announced an emergency in the region. As such, we conducted a time-series study to investigate the association between heatwaves and hospitalization due to respiratory diseases and CVDs in two provinces, Ninh Thuan in Central Vietnam (a province that frequently experiences heatwaves) and Ca Mau in Southern Vietnam. The results of this study provide insight into developing appropriate responses to heatwaves in these two provinces as well as in similar settings in other countries to help reduce the burden of RDs and CVDs. The study received approval from the Ethical Review Board of Hanoi University of Public Health (Decision No. 371/2018/YTCC-HD38).2 and 607,000 inhabitants in 2017 [2. Ca Mau has a subtropical monsoon climate with a short dry season from January to March. The average temperature in Ca Mau was about 27.2 °C from 1979 to 2017. The highest temperature in Ca Mau was recorded at 38.3 °C in 1983.Ninh Thuan is a coastal area of South-Central Vietnam with a total area of 3355 km in 2017 . CompareDaily hospital admissions were obtained from the electronic database of two provincial hospitals from 1 January 2010 to 31 December 2017 in Ninh Thuan and 31 May 2013 to 31 July 2018 in Ca Mau . The provided data period depended on what was available in the available electronic database. Individual data collected included residential locations of the patients, age (or year of birth), gender, primary and discharge diagnoses , and admission and discharge dates. While the location or address of the patients in the electronic database were self-reported information, the diagnosis and the ICD code were provided by the physicians. In this analysis, we only examined data from patients living in Ninh Thuan or Ca Mau when they were hospitalized.We calculated the daily counts of hospital admissions for two outcomes: CVDs and RDs. In this analysis, patients with ICD codes J00–J99, excluding J60–J70 , were coded as hospital admissions for respiratory diseases. Patients with ICD10 codes from I00 to I99, excluding I00 to I02 (acute rheumatic fever) and J05 to I09 (chronic rheumatic heart diseases), were coded as hospital admissions for CVDs. The codes used in this definition were primary codes at admission. Since daily means of hospital admissions for CVDs in Ninh Thuan were quite low (fewer than one case per day), the analysis for CVD in Ninh Thuan was not conducted.The meteorological data were provided by the corresponding provincial hydrometeorological stations, Phan Rang and Ca Mau. Daily data variables include the mean, minimum, maximum temperature (Celsius degree—°C), the daily mean relative humidity (%), the daily amount of sunshine (hour), and rainfall level (mm). Due to various existing heatwave definitions , we defiGeneralized additive Quasi-Poisson log-linear models were used to assess the increased risk of hospitalization during heatwave days compared to non-heatwave days, controlling for long-term trends and seasonality. The associations in each province were investigated separately. The core model—a model with only a time trend—was built at first. We used Partial autocorrelation function plots (PACF) of the residuals to determine the degrees of freedom of the spline function to minimize the residual serial correlation . We usedp-value smaller than 0.05. All statistical analyses were conducted using R , using the “mgcv”, “spline” and “gam” packages.To investigate the delayed acute effects, the associations between heatwaves and hospital admissions for lag 0–lag 4 were reported. Sensitivity analyses were conducted with a variety of degrees of freedom for the long-term trend, df = 3, 4, 5, 6, 7, and restricted the data to warm seasons (from April to September). The risks were presented in the percentage change (excess risk—ER % = (Risk Ratio-1) × 100%) in the number of hospitalizations for respiratory diseases or CVDs two days after the heatwave occurred. Statistical significance was defined as a two-tailed The number of admissions during heatwaves in two provinces is presented in In Ca Mau, on the other hand, there were 18 heatwaves between 2013 and 2018. However, the duration of each heatwave was longer than Ninh Thuan, with a mean of 7.8 days. Indeed, a heatwave occurring in 2015 extended for a month (18 April to 22 May), and another in 2016 extended for more than a month (9 April to 15 May). As with Ninh Thuan, relative humidity and rain level during heatwave periods were significantly lower than the entire study period.Hospital admissions for respiratory diseases in Ninh Thuan were associated with heatwaves at lag 2, ER = 8.31% (95% CI: 0.64–16.55) . HoweverThis research assessed the relationship between heatwaves and the two heat-related health outcomes—cardiovascular and respiratory diseases. This study also fills the gap and updates the previous study on the effect of heatwaves in Vietnam. Hence, they provide scientific evidence to understand the effects of heatwaves or high temperatures on human health in Vietnam.In this research, we found the association between respiratory admissions and heatwaves at lag 2  in the Ninh Thuan province. This finding reinforces existing evidence that the number of admissions for respiratory diseases increased during heatwave periods ,21,22,23p = 0.61) [The results illustrated a negative association between heatwave exposure and the risk of CVD hospitalization in Ca Mau. However, the association was only statistically significant for the elderly group (age above 60) . In this case, heatwave appears to be a protective factor for CVD morbidity. In the literature, the relationships between heatwaves and CVDs are mixed, and the effects of heatwaves on cardiovascular and respiratory morbidity are still unclear. A systematic review and meta-analysis pooling data from 18 studies globally has shown a statistically insignificant relationship between heatwaves and cardiovascular morbidity ( = 0.61) . For exa = 0.61)  reported = 0.61)  demonstrOur study defines heatwave periods of at least three consecutive days when the maximum temperature exceeded the 90th percentile. In the literature, a heatwave is defined many ways including temperature indicators, intensity, and duration . The autAlthough this study reported certain important results, some methodological limitations of this study should be acknowledged. Firstly, the study did not examine socioeconomic or air pollution factors on the association between heatwave and hospitalization data. In particular, we could not control our analysis for lifestyle (use air conditioning or not) and level of living standards (the poor or not), and comorbidities which might influence the estimation as seen in previous studies ,33. SecoAssociations between hospital admissions for RDs and heatwaves in Ninh Thuan were observed at lag 2, with excess risk . However, the heatwave was negatively associated with CVDs in Ca Mau, which was determined amongst the elderly (aged above 60), ER = −7.28%, 95%CI: −13.97–−0.08%. Heatwaves can be considered a risk of hospital admission for RDs in Vietnam. Further studies are needed to assert the link between heatwaves and not only on CVDs, but other public health outcomes, particularly in terms of mortality, to identify recommendations to mitigate the negative health impacts. To mitigate health impact, Vietnam should implement urgent actions such as developing an alert and warning system or community prevention strategies.


Metabolic-associated fatty liver disease (MAFLD) is closely associated with omentin, a novel adipokine that plays a vital role in metabolic balance. The literature about the relationship between circulating omentin and MAFLD is conflicting. Therefore, this meta-analysis evaluated circulating omentin levels in patients with MAFLD compared with healthy controls to explore the role of omentin in MAFLD.SMD) and 95% confidence interval (CI).The literature search was performed up to April 8, 2022, using PubMed, Cochrane Library, EMBASE, CNKI, Wanfang, CBM, Clinical Trials Database and Grey Literature Database. This meta-analysis pooled the statistics in Stata and presented the overall results using the standardized mean difference . Subgroup analysis and meta-regression demonstrated that fasting blood glucose (FBG) might be the source of heterogeneity and was inversely associated with omentin levels . No significant publication bias existed (P>0.05), and outcomes were robust in the sensitivity analysis.Twelve studies with 1624 individuals (927 cases and 697 controls) were included, and all of them were case-control studies. In addition, ten of twelve included studies were conducted on Asian participants. Patients with MAFLD had significantly lower circulating omentin levels than healthy controls (Lower circulating omentin levels were associated with MAFLD, and FBG might be the source of heterogeneity. Since Asian studies accounted for a significant portion of the meta-analysis, the conclusion might be more applicable to the Asian population. By investigating the relationship between omentin and MAFLD, this meta-analysis laid the foundation for the development of diagnostic biomarkers and treatment targets.https://www.crd.york.ac.uk/prospero/, identifier CRD42022316369. Nonalcoholic fatty liver disease (NAFLD) is becoming more prevalent, alongside an increasing prevalence of obesity and diabetes mellitus, with a global incidence of 29.84% . RealiziOmentin, a secreted protein consisting of 313 amino acids, was first identified from an omental fat cDNA library in 2006 by Yang et al.. It was found to be potentially associated with insulin resistance . OmentinRecently, further research has proposed that omentin might be one of the salient adipokines intervening in the occurrence and progression of MAFLD, but the relationship between MAFLD and circulating omentin levels was inconsistent in different studies. Therefore, this study performed an integrative analysis of the circulating omentin levels in patients with MAFLD compared with healthy controls to reveal the association between omentin levels and MAFLD. This may lay the foundation for understanding the effects of omentin in MAFLD and provide new approaches for early diagnosis and identification of therapeutic targets of MAFLD.clinicaltrials.gov) and the Grey Literature Database (opengrey.eu) was also performed. The search was not limited by language and included publications up to April 8, 2022. Using the combination of subject terms and free-text words, the search query was formed as follows:  OR “NAFLD” OR “Nonalcoholic Steatohepatitis” OR “NASH” OR “Metabolic Associated Fatty Liver Disease” OR “MAFLD” OR “metabolic associated steatohepatitis” OR “MASH”) AND  OR “omentin” OR “intestinal lactoferrin receptor” OR “hIntL protein”). This query was slightly modified according to the different databases. A specific strategy is provided in via email for relevant information.This study was performed following the protocol published in PROSPERO (registration ID: CRD42022316369) and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria (via discussion with a third reviewer (YNK). Studies were included if (1) patients were diagnosed with MAFLD, based on radiologically- proven hepatic steatosis and one of the three following conditions: overweight/obesity, diabetes mellitus, or metabolic dysregulation ; (2) the control group comprised healthy participants without MAFLD; (3) both groups included adults (age ≥18 years); and (4) outcomes included circulating serum or plasma omentin levels. Observational research cohort and case-control studies were included.Two reviewers (QZ and SHC) independently assessed the eligibility of all studies, and any contradiction was resolved Studies were excluded if (1) patients had other causes of liver disease  or severe disease; (2) omentin levels were not detected or were not derived from serum or plasma; (3) there were patient overlaps ; or (4) full-text or critical data of the articles was not obtained. Reviews, editorials, case reports, letters to the editor, hypotheses, studies on animals or cell lines, and abstracts from conferences were excluded.Two reviewers (QZ and SHC) independently extracted the relevant data and evaluated the quality of the included literature. If conflicts arose during the process, a third reviewer (YNK) adjudicated the disagreement between the two reviewers. The following data were extracted from the included studies: (1) basic characteristics of the studies , (2) criteria applied to diagnose and classify MAFLD, (3) methods used to detect circulating omentin levels, (4) characteristics of patient/control cohort , (5) circulating omentin levels in serum or plasma, (6) biochemical measurements , and (7) calculation of homeostasis model assessment of insulin resistance [HOMA-IR].https://gdt.gradepro.org).The Newcastle–Ottawa Scale (NOS) is a useful tool for performing a semi-quantitative assessment of the quality of observational studies in a meta-analysis. The NOS contains eight items based on three dimensions: selection of cases, comparability of groups, and evaluation of exposures. Each item corresponds to one score, except that the item related to comparability corresponds to two scores. The quality of the studies is rated from 0 (very poor) to 9 (high) . The Gramean ± standard deviation (SD). For omentin levels expressed as the median , the mean and SD were calculated using standardized formulas (SMD) was used to calculate the effect size in all studies. Heterogeneity among different studies was examined using the 2I test, Cochran’s Q-test, and Galbraith’s test. A fixed-effects model was used for low heterogeneity (P≥0.1) and a random-effects model for high heterogeneity (P<0.1)  in the univariate analysis were entered into the multivariate meta-regression analysis. Additionally, a sensitivity analysis was conducted to assess the stability of the outcomes by sequentially excluding studies. Egger’s test and funnel plots were used to examine publication bias . Omentin levels across each group were calculated as the formulas , 25. The (P<0.1) . Subgrouion bias .2 in MAFLD cases and 21.35 to 27.4 kg/m2 in healthy controls. Supplementary specific information regarding the characteristics of the included studies can be found in The entire literature search and selection process are presented in a PRISMA flow diagram Figure 1Waluga et al. also did not include community controls and failed to meet the standard of representativeness (https://gdt.gradepro.org), the certainty of the present meta-analysis was very low . The random-effects model was applied because of its high heterogeneity . Obvious heterogeneity according to Galbraith’s test is also vividly exhibited in This meta-analysis examined 12 studies consisting of 14 comparisons of omentin levels between MAFLD and control groups Figure 2SMD of -1.69 . In contrast, in the Middle East subgroup, patients with MAFLD had significantly higher omentin levels than healthy individuals with an SMD of 0.30 . There was no significant difference in omentin levels between patients with MAFLD and controls in the European subgroup, with an SMD of 0.78 . It is worth noting that the heterogeneity in the East Asian and European groups were still high (P<0.001), and only that in the Middle East group decreased (P=0.327).Subgroup analysis was implemented by region, sex, age, BMI and FBG Figure 42 had significantly lower omentin levels than controls , whereas MAFLD patients with BMI ≥27.5 kg/m2 showed no significant difference compared with controls . Furthermore, patients with BMI between 23 and 27.5 kg/m2 had relatively lower omentin levels than those with BMI ≥27.5 kg/m2.Regarding subgroup analysis by BMI. MAFLD patients with BMI between 23 and 27.5 kg/mSMD=0.04 ). However, patients with FBG of 5.6-6.9 mmol/L or ≥7 mmol/L had significantly lower omentin levels than healthy controls . Intragroup heterogeneity was also reduced . Other results of subgroup analysis by sex and age are listed in In addition, we performed subgroup analysis based on FBG. The cutoff values were based on Standards of Medical Care in Diabetes  . Region and FBG levels were then included in the multivariate meta-regression. The results showed that FBG level could better explain the heterogeneity, along with an inverse association with the SMD of circulating omentin levels   were included in the univariate meta-regression. The results demonstrated that both region and FBG level exerted significant effects on the outcome. Region and FBG levels accounted for 39.22% and 78.47% of the between-study variance, respectively. Moreover, patients in Europe and the Middle East had higher omentin levels than those in East Asia. Patients with higher FBG levels had lower circulating omentin levels  Table 4.P=0.919). No obvious asymmetry was observed in the funnel plot, suggesting a low possibility of publication bias  from China, Germany, Turkey, Poland, and Iran. The pooled outcomes showed that circulating omentin levels were significantly lower in patients with MAFLD than in the healthy controls. The sensitivity analysis exhibited robustness of the results, and no significant publication bias was observed based on the Egger’s test and funnel plot. As heterogeneity was obvious between these studies, further subgroup analysis and meta-regression were necessary. In the subgroup analysis, studies in the Middle East and subgroups with FBG of 5.6-6.9 mmol/L showed no heterogeneity, whereas other subgroups divided by gender, age, and BMI showed high heterogeneity. Thus, the meta-regression analyzed more influential factors (including factors dividing the subgroups) to further explore the source of heterogeneity. Region and FBG both significantly affected the Regarding different regions, subgroup analysis showed that patients with MAFLD from East Asia had significantly lower circulating omentin levels, whereas patients with MAFLD in the Middle East showed significantly higher omentin levels than healthy controls. In contrast, there were no significant differences in omentin levels between patients with MAFLD and controls among European patients. Additionally, univariate meta-regression showed that patients from the Middle East and Europe exhibited higher omentin levels than those from East Asia. Given that high heterogeneity existed within the subgroups of different regions and insufficient studies were included in each region, future research is needed to verify the impact of region on circulating omentin levels.SMD of circulating omentin levels. To fully understand this relationship, we should bear in mind that FBG, insulin resistance, and MAFLD are closely associated. Insulin resistance, particularly hepatic insulin resistance, has been detected in subjects with impaired fasting glucose  as the basis for dividing subgroups  were not included in the meta-regression due to an insufficient number of studies that reported those indicators. Some of those indicators were essential to the association between omentin and MAFLD. Therefore, we hope that relevant articles in the future will pay more attention to multiple serum biomarkers. Furthermore, in order to fully identify the source of heterogeneity, different severities of MAFLD are another important factor to be considered. Since classification of the severity of MAFLD was rarely seen in the included studies, we could not perform a subgroup analysis based on disease severity.This meta-analysis had certain limitations. First, the number of included studies and participants was small. Omentin is a novel adipokine that was identified in 2006, and relevant studies have been limited so far. Further studies are encouraged to investigate the association between omentin levels and patients with MAFLD, and an updated meta-analysis should be performed in the future. Second, the absolute value of omentin varied significantly from 2.85 to 460 ng/mL, although the units were uniform. Therefore, In conclusion, this meta-analysis demonstrated that circulating omentin levels were significantly lower in patients with MAFLD than in healthy controls. The FBG level, which had a significantly inverse relationship with circulating omentin levels, might be the source of heterogeneity. It should be noted that this conclusion might be more suitable for the Asian population, because Asian studies accounted for a large part of the meta-analysis. This meta-analysis might be conducive to clinical advances. Investigation of the association between circulating omentin and MAFLD could provide new insights into developing more convenient diagnostic biomarkers and effective treatment targets. Further research on omentin and MAFLD is necessary to confirm our conclusions.The original contributions presented in the study are included in the article/JH and SL: study design, quality assessment of the included studies and revision of the article. QZ and SC: data collection, performing the analysis and drafting the article. YK: quality assessment of the included studies and revision of the article. QL, CS, KW and YR: data collection and quality assessment of the included studies. All authors contributed to the article and approved the submitted version.


Genetics researchers increasingly combine data across many sources to increase power and to conduct analyses that cross multiple individual studies. However, there is often a lack of alignment on outcome measures when the same constructs are examined across studies. This inhibits comparison across individual studies and may impact the findings from meta-analysis. Using a well-characterized genotypic (brain-derived neurotrophic factor: BDNF) and phenotypic constructs (working memory and reading comprehension), we employ an approach called Rosetta, which allows for the simultaneous examination of primary studies that employ related but incompletely overlapping data. We examined four studies of BDNF, working memory, and reading comprehension with a combined sample size of 1711 participants. Although the correlation between working memory and reading comprehension over all participants was high, as expected ( Comparisons of primary data across studies, as well as meta-analysis, have difficulty effectively managing the variability measurement that naturally occurs across primary studies ,2,3. ThiFor example, brain-derived neurotrophic factor (BDNF) has drawn particular attention in the literature for its wide-ranging effects on the central nervous system, including significant associations with schizophrenia ,6,7, depThough highly useful and informative, meta-analysis has some limitations. First, meta-analysis does not directly assess person-level variability, instead examining variability across the selected studies. More fundamentally, meta-analysis, as well as most comparisons of primary data across studies, has difficulty effectively managing the variability measurement that naturally occurs across primary studies ,2,3. ThiIn the case of BDNF, meta-analysis limitations impinge on clinical studies, especially given that the relationships among BDNF and complex human traits appear to be moderated effects as opposed to main effects. This is true for all meta-analyses that compare the impact of gene variants across multiple studies. This is especially true when allelic or genotypic frequencies are uncommon or rare. Single studies often have reduced power to study uncommon and rare variants. When a variant is observed by independent research groups, a method that best combines data across those groups is desirable.rosettaR package v 0.1 for the R programming language (https://github.com/cwbartlett/rosettaR (accessed on 23 June 2023)). We apply this method to four datasets that had genotype data and our cognitive phenotypes of interest to assess the effects of BDNF on complex cognition. Second, we compare the results of meta-analysis to Rosetta and highlight the difference between the two approaches for combining data. Overall, the current analysis examines five independent studies to further define the relationships among BDNF, memory, and reading comprehension. This study demonstrates the usefulness of the Rosetta approach, which not only provides a powerful tool for examining genetic effects across different studies and multiple measurement domains but is also applicable to nongenetic studies. This study also tests a hypothesis that is important to the language genetics literature. Namely, we hypothesize that language and reading measures are correlated within the Val/Val and the Val/Met BDNF groups but not within the Met/Met group.The present study addresses two goals. First, we employ a novel analytical approach that uses a flexible platform to examine the relationships among gene variants and phenotypes across multiple studies using primary data. This method is called Rosetta  and it iTo combine data, we used a latent trait approach, which refers to a method that analyzes an unobserved (latent) trait based on observable or measured behavioral responses. This approach was used to create a set of analyzable traits that represent each underlying phenotypic construct, where each latent trait is on the same scale within the construct and across datasets. This approach, called Rosetta, allows for a joint analysis across all datasets, often called a mega-analysis. While our focus is on psychiatric genetics and the example dataset focuses within this domain , we only used those data as a real-world example of how Rosetta can be applied to genetic datasets with varied phenotypes across datasets. The use of latent factor modeling has the advantage of (1) generating a common metric for the analysis of each construct that we then used for a single mega-analysis and (2) reducing measurement error through the combination of multiple measures of each construct. Each study was also analyzed separately to assess patterns across the datasets.Overview of the Rosetta method : RosettaBDNF. To combine data, we used Rosetta to create a set of latent traits for each underlying construct . Each latent trait is on the same scale across datasets. Within each study, working memory and reading comprehension were assessed with  nonoverlapping measures . A permutation test was implemented to assess if the observed pattern of correlations was significant.As an overview of the study methods, we combined data from four independent studies including measures for the behavioral constructs of working memory and reading comprehension along with genetic data for measures . The useBDNF. Within each study, working memory and reading comprehension were assessed with  nonoverlapping measures  is an ongoing longitudinal twin study consisting of a community-based sample of both monozygotic and same/opposite sex dizygotic twins followed for over 10 years beginning at age 5 [at age 5 ,29.The New Jersey Language-Autism Genetic Study (NJLAGS) is a collection of nuclear and extended families that segregate both autism and specific language impairment in each pedigree [pedigree ,31.The Biology of Language Study (BLS) is an ongoing study of the genetics of specific language impairment conducted in 31 nuclear and extended pedigrees ascertained for multiple family members with language impairment [pairment ,33.The Colorado Learning Disabilities Research Center (CLDRC) is an ongoing collection of monozygotic and dizygotic twins ascertained for reading disability, attention-deficit/hyperactivity disorder, and other learning disabilities [bilities . Study n2 test implemented in HardyWeinberg package v1.7.2 [2 test. To test the main effects of BDNF SNP rs6265, we conducted linear regression analysis assuming an additive allelic effect. Since persons in the same family are correlated observations, to account for familial relationships, we implemented a repeated sampling across family units to maintain independence of observations while also adjusting for error in estimates.We conducted all statistical analysis with the R statistical language v4.2.1  in the Re v1.7.2 . Assessioptim function from the standard R stats package.To combine datasets, we used the Rosetta method  to creatRosetta allows the input of a preferred factor structure, if such information is known from the literature. In Within each dataset, we analyzed correlations between the Rosetta output factors for memory and reading comprehension stratified by genotype using the standard Pearson’s product-moment correlation by genotype.BDNF-genotype subsets have the same correlation as when all three genotypes are analyzed jointly, we performed a parametric bootstrap analysis by dataset. Using the observed working memory and reading comprehension data, we randomly selected subjects without replacement to subgroups of size equal to the original BDNF-genotype subsets. Correlations were calculated by subgroup for each bootstrap replicate . The value of the correlation by subgroup was collated into a file for further analysis in the next step, for a total of 10,000 bootstraps . Next, we calculated the standard deviation of the three correlations per replicate to assess the distribution of deviations assuming no effect of the genotype. The permutation subgroups were chosen randomly without regard to any genetic information, which necessarily assumes the correlation is constant between the subgroups. This empirical distribution can be used as the basis for null hypothesis testing by comparing the observed difference in correlations across genotypes with the distribution derived from the bootstraps. In this case, the p-value represents how often a deviation equal to, or larger than, the observed deviation is expected by chance if BDNF had no effect on the correlation between memory and reading. We used p < 0.05 as the cut-off for significance.To assess the null hypothesis that all three BDNF rs6265 genotypes (p > 0.05). No regressions of either working memory or reading comprehension on rs6265 were significant either by dataset or in the mega-analysis of all datasets.To examine the relationship between BDNF and assessments of working memory and reading comprehension across the WRRMP, NJLAGS, BLS, and CLDRC studies, we analyzed the genotype at SNP rs6256. To test if BDNF had a main effect on working memory and/or reading comprehension, the Rosetta output for working memory and reading comprehension factors were regressed onto enotypes . GenotypNext, to test whether our initial observation of a weak or absent correlation between reading comprehension and working memory for BDNF Met/Met carriers in Canadian families of Celtic ancestry could be replicated, we examined correlations between the four studies. In all datasets, the individuals with the rs6265 genotype leading to homozygous Met/Met lack a significant correlation between the reading comprehension and working memory measures, while those measures are significantly correlated in individuals with the other genotypes . The results also hold for all samples in the analysis  and even with Bonferroni correction (p < 0.01), all four studies are significant. When assessing all samples combined, the permutation test was likewise significant (p < 4 × 10−4).Assuming no effect of rs6265 on the correlation of reading comprehension and working memory, a permutation procedure can be used to derive an empirical null distribution. Random subsets of subjects are expected to have the same correlation on average as the dataset from which they were randomly selected. This assertion can be used to derive the counterfactual for this study. If we assume that the rs6265 T/T genotype (corresponding to Met/Met) has the same correlation as the other two genotypically defined groups, we can calculate the probability that only one genotype out of the three would randomly have a reduced correlation through parametric bootstrapping  A sBDNF, genotypes underlying Val/Val and Val/Met groups show correlations between working memory and reading comprehension, but we found no evidence for correlation in individuals with Met/Met variants in any single dataset, nor in the combined dataset. Variants that mediate the correlation between gene transcription traits have been observed previously [With respect to eviously  (often ceviously ), but fiTaken together, the conservative interpretation of our findings is that BDNF Met/Met attenuates the correlation between reading comprehension and memory such that a correlation was not detectable in our study, if indeed the correlation is greater than zero. Larger studies using Rosetta to combine datasets, and possibly meta-analyses when the primary data are not available, will be required to estimate BDNF Met/Met attenuation with greater precision, or to conclude that the correlation is truly negligible (or zero). Our research suggests that Met/Met carriers are a unique and robustly defined subgroup in terms of memory and comprehending written language. Further studies of this subgroup will elucidate the role of BNDF-associated memory in oral and written language learning. Though more research will be needed to explain how BDNF-associated memory resolves between reading comprehension and working memory, this study provides further evidence for the existence of BDNF-dependent memory processes in human cognition, a topic that may rapidly develop since animal models are already available.This study demonstrates the versatile capabilities of Rosetta in assessing relationships between gene variants and cognitive phenotypes across multiple studies, offering an innovative approach to consolidating disparate datasets. Despite the complexities presented by varying measurement strategies, Rosetta proves adept in handling these numerical complications, allowing for the integration of all study components into one graph for enhanced interpretation and one model for modeling flexibility. Given the appropriate sample size and correlation conditions, Rosetta could serve as an alternative model to traditional meta-analysis, enhancing the scope of genetic studies and facilitating the exploration of nuanced trait correlations .


Background: Non-Small Cell Lung Cancer (NSCLC), the leading cause of cancer-related death in the United States, is the most diagnosed form of lung cancer. While lung cancer incidence has steadily declined over the last decade, disparities in incidence and mortality rates persist among African American (AA), Caucasian American (CA), and Hispanic American (HA) populations. Researchers continue to explore how genetic ancestry may influence differential outcomes in lung cancer risk and development. The purpose of this evaluation is to highlight experimental research that investigates the differential impact of genetic mutations and ancestry on NSCLC incidence.Methods: This systematic review was conducted using PubMed and Google Scholar search engines. The following key search terms were used to select articles published between 2011 and 2022: “African/European/Latin American Ancestry NSCLC”; “Racial Disparities NSCLC”; “Genetic Mutations NSCLC”; “NSCLC Biomarkers”; “African Americans/Hispanic Americans/Caucasian Americans NSCLC incidence.” Systematic reviews, meta-analyses, and studies outside of the US were excluded. A total of 195 articles were initially identified and after excluding 156 which did not meet eligibility criteria, 38 were included in this investigation.Results: Studies included in this analysis focused on racial/ethnic disparities in the following common genetic mutations observed in NSCLC: KRAS, EGFR, TP53, PIK3CA, ALK Translocations, ROS-1 Rearrangements, STK11, MET, and BRAF. Results across studies varied with respect to absolute differential expression. No significant differences in frequencies of specific genetic mutational profiles were noted between racial/ethnic groups. However, for HAs, lower mutational frequencies in KRAS and STK11 genes were observed. In genetic ancestry level analyses, multiple studies suggest that African ancestry is associated with a higher frequency of EGFR mutations. Conversely, Latin ancestry is associated with TP53 mutations. At the genomic level, several novel predisposing variants associated with African ancestry and increased risk of NSCLC were discovered. Family history among all racial/ethnic groups was also considered a risk factor for NSCLC.Conclusion: Results from racially and ethnically diverse studies can elucidate driving factors that may increase susceptibility and subsequent lung cancer risk across different racial/ethnic groups. Identification of biomarkers that can be used as diagnostic, prognostic, and therapeutic tools may help improve lung cancer survival among high-risk populations. Lung cancer is the second most diagnosed cancer and leading cause of cancer related death in the United States, with the Non-Small Cell Lung Cancer (NSCLC) subtype constituting 85% of all lung cancer cases . There aKRAS, EGFR, TP53, PI3KCA, MET, BRAF, ALK Translocations, and STK11/LTKB-1  are directly correlated to certain mutations . AnotherSeveral studies have also shown that having a family history of lung cancer increases an individual’s risk of developing the disease, with the highest risk being associated with having a first degree relative who was diagnosed with lung cancer . This faThe literature search for this review was conducted using the PubMed Central database and Google Scholar search engines. Initial key terms used in both search engines included: “African American Ancestry NSCLC,” “European American Ancestry NSCLC,” “Latin American Ancestry NSCLC,” “Racial Disparities NSCLC,” “Genetic Mutations NSCLC,” “NSCLC Biomarkers,” “African American NSCLC Incidence,” “Hispanic American NSCLC Incidence,” and “Caucasian American NSCLC Incidence”. A total of 195 articles were initially identified and subsequently screened to assess whether criteria for inclusion were met. After excluding 156 which did not meet the eligibility criteria, 39 articles were included in this review.During the initial search, a filter was applied to exclude articles published prior to 2011. Afterward, any article that included one or more of the key search terms listed previously were selected for screening. This included clinical trials, comparative analyses, systematic reviews, meta-analyses, US-based cohort studies, and international-based cohort studies that incorporated race, ethnicity, sex, and age relative to NSCLC. This search yielded a total of 195 articles.Moving forward, we identified primary literature, excluding all systematic reviews and other secondary studies. 32 systematic reviews and 17 meta-analyses (N = 49) were excluded. Afterward, we screened the abstracts of the remaining 146 articles to ensure that the paper was focused on NSCLC or one or more of its associated subtypes, leading to the exclusion of 43 articles that did not meet these criteria. Of the remaining 103 articles, 65 articles were further excluded for not meeting the remaining eligibility criteria detailed below.Publications for this systematic review were considered for inclusion based on cohort size, demographic characteristics of each cohort , geographic location, ancestral background, mutation analysis, and specific focus on NSCLC and/or associated histological subtypes: Lung Adenocarcinoma (LUAD), Squamous Cell Carcinoma (SCC), and Large Cell Carcinoma (LCC)-N = 47 articles. Publications that mentioned biomarkers, mutation prevalence, and therapeutic methods targeting specific mutations were also included in the discussion section. A PRISMA schematic of the literature screening process can be found in There are limited number of NSCLC reports in the literature that include a significant number of AAs, Cas, HAs, and LAs. As a result, no criteria specifying the minimum or maximum number of study subjects in a cohort were imposed when assessing eligibility. Instead, emphasis was placed on general racial/ethnic representation in a cohort, resulting in a varying range of cohort sizes observed in different studies , 3.During the screening phase, relevant articles with study cohorts that incorporated one or more racial/ethnic groups of interest  were included in this systematic review. In the context of this review, Latin Americans and Hispanic Americans are considered two distinct ethnic groups. This was to ensure that sufficient evidence for each racial and ethnic group was included, even if all 4 groups were not mentioned or incorporated into a given study. For studies focused on genetic ancestry, this criterion was also used for ancestral groups of interest . Furthermore, studies that examined age, sex, and smoking history: Current Smoker (CS), Former Smoker (FS), and Never Smoker (NS) as covariates were also included to assess potential relationships between each covariate and genetic factors highlighted in this review.This review article focuses specifically on AA, HA, LA, and CA populations. Studies conducted anywhere other than the US or that included individuals outside of the US in addition to a US based cohort were excluded. All genomic analyses and genetic ancestry studies were conducted in US-based cohorts; patients currently living in the United States. There were no specific criteria for regions in the United States. There are two general types of lung cancer: Small Cell Lung Cancer and Non-Small Cell Lung Cancer. This review article focuses on NSCLC since it is the most diagnosed subtype of lung cancer in the United States. Articles were excluded if the type of lung cancer was not specified. Additionally, NSCLC is further categorized into 3 subtypes: Lung Adenocarcinoma (LUAD), Squamous Cell Carcinoma (SCC), and Large Cell Carcinoma (LCC). Studies were included regardless of whether their analyses focused on NSCLC in general, or were subtype specific. Articles were also included if genomic analyses were focused specifically on one or more subtypes of NSCLC , 2.KRAS, EGFR, TP53, PIK3CA, MET, BRAF, ALK Translocations, and STK11. Studies that investigated one or more of these genes relative to NSCLC at the racial and ethnic level were included in this review. This review simply highlights genes that were frequently mentioned and were the subject of genomic analyses and is not an exhaustive list of each type of mutation discovered in NSCLC. Other genes mentioned in the results also included ERBB2, NRAS, MAP2K1/MEK1, and AKT. However, these were not considered common mutations associated with NSCLC. Importantly, articles that also discussed potential diagnostic and prognostic biomarkers and those using mutational profiling to enhance existing treatment methods were also incorporated in the Discussion section.After conducting a preliminary search on PubMed, the most prominent genetic mutations that were associated with and implicated in NSCLC were identified as the following: The studies reviewed in this investigation were organized into one of the following categories: gene mutations in NSCLC, genetic Ancestry and family history of NSCLC, and genomic landscape of NSCLC in African, Hispanic, and Caucasian Americans.Studies that compared somatic mutations among one or more racial/ethnic groups or examined the mutational frequencies of somatic mutations in NSCLC in AA, HA, LA, and CA individuals were selected to investigate whether significant differences exist in mutational profiles of oncogenic drivers associated with NSCLC among different racial/ethnic populations. Since most studies examined the mutational profile of more than one gene, this section groups the results of each study associated with each gene , 2.KRAS is the most common oncogenic driver associated with NSCLC incidence, and a frequent gene of interest that is often selected for genotyping analyses. KRAS is a signaling transducer protein that is activated in numerous cell signaling pathways which function to regulate cell growth, cell proliferation, and apoptosis; inclusive of the MAPK pathway . Geneticp = 0.04). Mutational frequency was higher in CAs (26%) compared to AAs (17%). In addition, In addition to observing the mutational profile of KRAS in CAs and AAs, Araujo et al. also used histology, age, and gender as covariates alongside mutational frequency to determine if there was any correlation between each covariate and overall survival in AAs and CAs. No significant differences in the mutational frequency of KRAS between CAs (18.0%) and AAs (15.4%) were observed. In addition, none of the covariates  correlated with overall survival. Despite these findings, this study did observe that KRAS mutations were found more frequently in Lung Adenocarcinoma (LUAD), a common histological form of NSCLC, and were more common in current and former smokers . Steuer p < 0.01) (Studies by researchers  < 0.01) . However < 0.01) . Another < 0.01) . Additio < 0.01) .EGFR) is another oncogenic driver found in NSCLC cases. In addition, a growth factor receptor which regulates cell growth in various cell-signaling pathways, including the MAPK signaling pathway, was also noted , a therapeutic agent used to treat patients harboring EGFR mutations. Harboring this mutation results in low sensitivity and diminished response to TKIs treatment  and the overall mutational frequency (p = 0.53) in AAs and CAs ( and CAs . Multipl and CAs .p = 0.067)  . However= 0.067) .TP53) gene is responsible for cell cycle regulation, mediating cell proliferation, and inducing apoptosis in damaged cells that are not successfully recovered via cell repair mechanisms. Characterized as a tumor suppressor gene, TP53 is critical for inhibition of tumor growth. TP53 transitions from a proto-oncogene to an oncogenic driver when a mutation causing either reduced function or complete silencing of the gene occurs, leading to the loss of a crucial cell control mechanism, ultimately promoting tumorigenesis   .ALK rearrangements, ROS-1 Rearrangements, ERBB2, BRAF (BRAF V600E) , MET  , STK11 (B1), MET , and PIKand TP53 . Howeverand TP53 .ALK rearrangements in HA. However, a total of nine HA patients were included in this study cohort and ALK rearrangements were only identified in three of these individuals (p = 0.005)  . These fALK rearrangements at the racial/ethnic level. However, several studies suggest that the frequency of ALK rearrangements is higher in never-smokers. In one study, although findings did not reflect any racial/ethnic differences, 61% of ALK rearrangements were found in never-smokers , and other variants at the population-level, in addition to examining the frequency of these variants and their associations with NSCLC incidence, mortality, and overall survival outcome were selected to investigate whether ancestral background  plays a role in observed genetic differences among racial/ethnic populations and as a result, contribute to the socioeconomic and environmental effects that are associated with individuals at high risk for NSCLC incidence and larger NSCLC tumor burden. Few studies also considered population admixture, as many individuals are known to have more than one ancestral background. Genetic ancestry and family history of NSCLC may have a profound influence on potential risk variants that are present in different populations and individuals .Genetic ancestry level analyses conducted in Genome-Wide Association Studies (GWAS) have successfully identified differences in NSCLC risk, incidence, and survival across ancestral groups . Sinha eBRCA2 and SCC incidence  (HNF1B gene in chromosome 5q14.3) associated with increased lung risk, rs7186207 (DHODH gene in chromosome 16q22.2) significantly associated with lower lung cancer risk, and rs11658063 (HAPLN1 gene in chromosome 17q12) associated with lower NSCLC risk  . A few oCLC risk .CHRNA5 gene in chromosome 15q25.1) and rs2853677 (TERT in chromosome 5p15.33) that was specifically associated with susceptibility for LUAD histology. There was no evidence of associations between any of these novel gene variants and prognosis/overall survival outcome in NSCLC. Overall, findings suggest that genetic ancestry alone is not a significant predictor of lung cancer risk, incidence, nor survival . Another study identified a predisposing fusion gene known as KANSARL associated with lung cancer and has only been characterized in European ancestry studies. Gene fusions may also occur during tumorigenesis, and genetic ancestry studies have also examined how this specific genetic alteration impacts risk and mortality in European ancestry groups (p < 3.5 × 10−7)  .p < 0.001) (p = 0.002), STK11  and TP53 , although none of these differences were significant. Moreover, the results from this study suggested that Hispanic/Latin American ancestry is potentially associated with the rate of TP53 mutations (p = 0.009) and may also be associated with the rate of EGFR, KRAS, and STK11 mutational frequencies  . This stquencies . Additioquencies   was designed to investigate any correlation between behavioral patterns and onset of disease across 5 racial/ethnic groups in Hawaii and California, including AAs, LAs, and Whites . Stram eFurther investigations are needed to explore the mechanism of smoking and contribution to NSCLC incidence differences in different histological subtypes, as well as its potential effects on racial and ethnic populations. Despite the dominant role of smoking in NSCLC incidence, smoking as a risk factor is not actively studied in never-smokers. As such, the causal factors of NSCLC incidence in never-smokers has not been fully characterized. Incorporating never-smokers into cohort studies at the racial ethnic level is critical because the overall incidence, mortality, and survival outcome rates of each group are comprised in part by never-smokers .Racial disparities potentially have differential effects on AAs, CAs, and HAs when looking at each racial and ethnic population at a specific geographic location . PreviouComorbidities are another lifestyle factor that may influence NSCLC risk, incidence, and adverse health outcomes in NSCLC patients. Several comorbidities associated with worse survival outcomes in NSCLC patients include myocardial infarction, congestive heart failure, diabetes with and without complications, and chronic pulmonary disease . In a stOut of the 19 chronic diseases, the most prevalent comorbidities observed in NSCLC included chronic obstructive pulmonary disease (COPD), coronary artery disease, diabetes, a prior lung cancer tumor, chronic heart failure, peripheral vascular failure, and cerebrovascular diseases respectively. The findings suggested that patients diagnosed with specific NSCLC tumor histological subtypes were also associated concurrently with having one or more comorbidities. Generally, squamous cell carcinoma tumor subtypes were associated with being males, older age, and at earlier stage at diagnosis (Stage I and II). Furthermore, patients without comorbidities had a significantly higher diagnosis rate at earlier stages of NSCLC in comparison to patients with comorbidities, suggesting that comorbidities also contribute to survival outcomes of NSCLC in patients and potentially exacerbate disease burden leading to higher rates of mortality . AnotherHIV was also highlighted as an independent risk factor for incident lung cancer, as it is considered the most common cancer diagnosed among patients that also have HIV . The stuFuture studies should also investigate the lower incidence rates of respiratory diseases in AA patients, as this can help determine which comorbidities are likely associated with increased risk and burden of NSCLC in AA patients, as well as other racial and ethnic groups. Taken together, this suggests that comorbidities are also potentially an influential factor to consider in NSCLC incidence and mortality and should be another parameter considered when measuring NSCLC risk and screening for lung cancer in diverse patient populations.TP53, RB1, ARID1A, CDKN2A, PIK3CA, and NFL. Of these gene, TP53, CDKN2A, and PIK3CA were found significantly in SCC tumor subtypes (p < 0.01). Additionally, gene mutations that were detected significantly in other cancer types including colorectal cancer (CRC) and glioblastoma (GBM) were also found at significant rates in LUAD  that influence NSCLC risk and incidence, and ultimately reduce mortality rates, address healthcare disparities, and improve overall survival outcomes in high-risk populations.


A significant difference in BOT incidence was observed among infertile women and nulliparous women who were treated with or without infertility drugs. In conclusion, the use of infertility drugs may increase the risk of BOTs, but a dose-dependent relationship was not observed between the number of assisted reproduction technology cycles and the risk of BOTs, and infertile women who successfully became pregnant might have a reduced risk. Registration: PROSPERO, CRD42022330775.Whether infertility drug exposure increases the risk of borderline ovarian tumors (BOTs) remains controversial. The present study was conducted with a comprehensive search for studies published from January 1990 to December 2021 in the online databases Cochrane Library, PubMed, Web of Science and EMBASE. We considered the first diagnosis of a BOT as the primary outcome. The odds ratio (OR) was calculated with corresponding 95% confidence intervals (CIs) for the risk of BOTs in patients who were treated with infertility drugs. Ten studies, a total of 2,779,511 women, qualified for inclusion in this meta-analysis. The pooled OR of 1.56 (95% CI: 1.09–2.22) revealed a significant positive association between infertility drugs and an increased risk for BOTs, but for specific drugs, only CC plus Gn had statistical significance. No publication bias was detected using the Egger and Begg tests ( The global incidence of infertility is increasing annually due to environmental pollution, mental and psychological pressure, delayed childbearing and other factors ,2,3. A vExposure to these hormones raises concerns about the long-term safety of ovarian stimulation, such as ovarian malignancies ,6,7. TheHowever, for borderline ovarian tumors (BOTs), the results are more controversial. BOTs, also known as low malignant potential tumors, account for 15–20% of epithelial ovarian tumors. The pathological characteristic of BOTs is the dysplasia of ovarian epithelial cells without frank invasion by the tumor nodules microscopically. BOTs have been proposed to be separate entities with a different etiology from ovarian cancer . The assThis review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . The proThis systematic review and meta-analysis assessed the use of infertility drugs during ART on the risks of BOTs. All studies (case–control studies and cohort studies) written in English reporting the incidence of BOTs in both the treatment group (infertility drugs) and the control group were eligible for inclusion. Some studies pooled the patients exposed to ART, and these were screened and included if data on infertility drug use were available in the article.Duplicates were removed. Reviews were excluded. Studies that did not report separate data for BOTs were excluded. Studies that only reported combined data for all types of ART were excluded.Two authors independently screened all the studies and extracted data. Disputes were resolved through discussion. If no consensus was reached, the third senior author helped make a final decision. The study quality of the cohort and case–control studies was assessed using the Newcastle–Ottawa Scale (NOS) scores based on the quality of the selection, comparability, and outcome/exposure  . High-qu2), in which proportions of 25%, 50%, and 75% indicated low, moderate, and high heterogeneity, respectively [2 was more than 50%), a random-effects model. When the effect models were contradicting in the different subgroup analysis, the random-effects model was usually chosen to be combined to obtain a more reliable result. Forest plots were created to visualize ORs. Publication bias was evaluated by constructing funnel plots, and a sensitivity analysis was performed to assess the effect (leverage) of each study on the results. A p value less than 0.05 was considered statistically significant.The meta-analysis was performed using Stata software version 12.0. Study results were compared by calculating ORs with corresponding 95% confidence intervals (CIs). Heterogeneity between studies was evaluated using the Cochran’s Q and I-squared statistic ; thus, the random effects model was used. The pooled OR was 1.56 (95% CI: 1.09–2.22). Overall, a significant difference in the incidence of BOTs was observed, indicating that patients exposed to any infertility drugs had an increased risk of BOTs. As for the specific drug used, the results were as follows , I2 = 82%; and CC + Gn: OR, 3.74 (95% CI: 1.76–7.96), I2 = 0. Data from women treated with CC combined with Gn were statistically significant, while the use of CC or Gn alone was not associated with a significant difference in BOT incidence between women with or without infertility drug use. The detailed counts for exposure and controls are shown in An analysis was conducted using the available information from the 10 studies to investigate the risk of BOTs in patients who were treated with infertility drugs. As shown in  follows b: CC: ORp = 0.669). The sensitivity analysis revealed that the removal of each study did not alter the final result, indicating that the main result was reliable , compared to infertile women not treated .Regarding the effect of parity on the risk of BOTs, we stratified the population into parous women and nulliparous women. As shown in 2, and hCG might even significantly inhibit the proliferation of BOT cells. Facing the two contradictory views mentioned above, this study aimed to systematically elucidate the association between ovulation-stimulating drugs and the risk of BOTs.Recently, the relationship between the use of infertility drugs and the risk of BOTs has attracted increasing attention as the application of ART has become more prevalent. One view is that ovulation-stimulating drugs may increase the potential risk of BOTs because repeated ovulation and oocyte retrieval may increase the mechanical trauma and microenvironment with supraphysiological doses of estrogen levels, which produce excessive proliferation and a higher risk of malignant transformation of ovarian epithelial cells. Another view is the opposite, which is based on epidemiological data suggesting no significant correlation between ovulation-stimulating drugs and the occurrence of BOTs. By performing in vitro cell experiments, some scholars also found that BOT cells do not exhibit an obvious proliferative response in the superovulation environment stimulated by FSH and EOverall, this meta-analysis included 10 studies that assessed 2,779,511 patients, and the results suggest that treatment with any infertility drugs was associated with a significantly increased risk of BOTs, OR, 1.56 (95% CI: 1.09–2.22), compared to women who did not use infertility drugs. After examining drug-specific outcomes, CC + Gn exposure  was significantly associated with a higher incidence of BOTs. Conversely, the remaining associations between individual infertility drugs (CC and Gn) and BOT incidence were not statistically significant. No publication bias was observed in this study, and a sensitivity analysis was performed and showed no difference in the final result after removing each study. The subgroup analysis showed a higher pooled OR of 1.59 (95% CI: 1.26–2.00) among infertile women. In addition, infertility drugs were associated with a significantly higher BOT incidence among nulliparous women, OR, 1.79 (95% CI: 1.25–2.56), while among parous women, the difference was not statistically significant.BOTs are rare tumors with an incidence of 4.5/100,000 cases . In contEarlier studies reported a greater risk of BOTs due to CC exposure ,31. HoweThe parity status is also an important risk factor for BOTs. Similar to other researchers ,24, we oBOTs are mainly classified as serous, mucinous, and other rare types. Serous BOTs are the most common subtype, accounting for 50–60% of BOTs . A recenIn addition, we concluded the association of the dose and IVF cycles with the risk of BOTs . The preIn this meta-analysis, substantial heterogeneity was observed among these studies. The possible explanations may be the long-time span of the included studies and differences in the sample size and data sources among the studies. Few studies contained and controlled for the infertility diagnosis, family history of ovarian cancer, and additional comorbidities such as endometriosis. The lack of a follow up varied greatly between studies. Given an earlier presentation age, more cases of BOTs than invasive ovarian cancer would likely be detected within a relatively short follow up. In addition, a greater chance of detecting BOTs in infertile women receiving medical monitoring and treatment has been noted. Previous studies had methodological limitations, including selection bias, a small sample size, a short follow up, and a lack of consideration of potentially important confounders such as infertility and the parity status, the underlying causes of infertility, and various types and cycles of infertility drugs. Therefore, the conclusions listed above must be verified by more high-quality and large-scale clinical studies.In summary, the present study showed that the use of infertility drugs appeared to be positively associated with an increased risk of BOTs , and the separate analysis of specific drugs showed only CC plus Gn revealed a significant association . However, this finding must be verified because a dose-dependent relationship was not observed. Meanwhile, previous studies with methodological limitations and a lack of adjustment for important confounding factors made the results further debatable. In addition, as pointed out in many previous studies, the small number of cases makes it difficult to determine whether it is the diagnosis of infertility or the treatment of infertility drugs that results in the increase; thus, the association does not imply causation. Additionally, parity might further reduce this risk. The information from this meta-analysis might be valuable to both clinicians and patients in their decision making. Certainly, further large-scale studies that consider other confounding factors, such as parity, genetic factors, and the etiology of infertility, and include longer follow-up times are needed.