Acute myeloid leukemia (AML) is a disease that affects adults aged 65 years and above, and survival in this population is poor. Allogeneic hematopoietic cell transplantation  is a potentially curative therapy for these patients but is underutilized due to frequent comorbidities and perceived higher risk of treatment-related mortality and non-relapse mortality. Increasing data supports the utility of allo-HCT in fit older patients after intensive chemotherapy resulting in improvement of outcomes. With the development of reduced intensity and non-myeloablative conditioning regimens that are associated with lower rates of treatment-related toxicity and mortality, this has allowed more older patients with AML to receive allo-HCT. In this review, we provide some guidance on appropriate selection of older patients as transplant candidates, benefits and risks associated with allo-HCT, conditioning regimen choice, and stem cell transplant sources as they relate to the conduct of stem cell transplantation in older patients. Acute myeloid leukemia (AML) is a disease that primarily affects adults aged 65 years and above; the median age of patients at diagnosis is 68 years . The estMyeloablative conditioning regimens are frequently used in allo-HCT, but they are sometimes associated with an unacceptable rate of treatment-related mortality in older adults. The development of reduced intensity and non-myeloablative conditioning regimens that are associated with lower rates of treatment-related toxicity and mortality, in place of myeloablative conditioning regimens, has allowed a higher number of older patients with AML to receive allo-HCT . In addip = 0.23). Four-year non-relapse mortality rate was 36% and 39% (p = 0.39), respectively [According to the Center for International Blood Marrow Transplant Research (CIBMTR) database, the number of patients with AML aged 70 years and over who received allo-HCT increased from 0.1% in 2000 to 3.9% in 2013 . This paHistorically, older patients with AML were excluded from consideration of hematopoietic stem cell transplantation solely based on chronological age. However, age alone is not a reliable predictor of a patient’s ability to tolerate intensive chemotherapy or allo-HCT. Instead, other factors such as comorbidities, functional status, and psychosocial support, in addition to disease characteristics need to be taken into account when considering treatment tolerance and outcomes ,15,16. FTo improve the selection of candidates for allo-HCT, it is important to assess the physiological age and not rely on chronological age alone. The use of available tools such as the HCT-CI and geriatric assessment can help inform the risk of treatment-related mortality and overall survival . A multiThe choice of a conditioning regimen is an integral part of allo-HCT with influence on disease control and transplant-related toxicities. The CIBMTR classifies the conditioning regimens into myeloablative, reduced-intensity, and non-myeloablative categories ,26. Genep < 0.01) [In older patients with AML, treatment with a myeloablative regimen for allo-HCT is associated with higher treatment-related mortality rates compared to those who did not undergo transplant . Table 1 < 0.01) . This ri < 0.01) ,31,34. p < 0.01) and overall survival  at 18 months. Treatment-related mortality at 18 months was higher in the myeloablative group compared to the reduced-intensity group . Although treatment-related mortality was lower in the reduced-intensity group, this difference seems to have been offset by an increase in relapse rate and therefore a lower overall survival rate. Whether these results would be similar in studies examining only older recipients has not been explored in depth. In the BMT CTN 0901 study, the HRs for overall survival for myeloablative conditioning versus reduced-intensity conditioning did not appear to be different by age subgroups .One concern, however, is the higher relapse rate associated with reduced-intensity regimens compared to myeloablative conditioning regimens . It was p-value comparing both myeloablative regimens versus both reduced-intensity and non-myeloablative group was <0.01), respectively. Relapse rates were 28%, 22%, 29%, and 49% (p = 0.20), and overall survivals were 21%, 41%, 56%, and 27% , respectively. On multivariate analyses, older age (>50 versus ≤50 years) was significantly associated with a higher non-relapse mortality  and lower overall survival , but not relapse. As opposed to the BMT CTN 0901 study, this large retrospective study suggests potential lower non-relapse mortality, comparable relapse rate, and higher overall survival with reduced-intensity compared to conventional myeloablative conditioning regimens in older patients. Therefore, whether reduced-intensity versus myeloablative or non-ablative regimens lead to better survival in older patients with AML remains uncertain, and it is unlikely a randomized trial in older patients will be accomplished to answer this given the concern about high mortality rates with ablative regimens. Finally, a meta-analysis of eight studies included 6,464 AML/MDS patients who received myeloablative and reduced-intensity regimens. Of note, the BMT CTN 0901 was not included in this meta-analysis [Another large multicenter, retrospective study from the EBMT registry included 878 patients with AML or MDS who received allo-HCT utilizing myeloablative, reduced-intensity, or non-myeloablative conditioning regimens from 1998 to 2004 . The myeanalysis . There wTaken together, the BMT CTN 0901 study suggests that myeloablative conditioning regimens should be the standard of care for patients who are considered fit enough to tolerate this degree of intensity. For those who are perceived to be unfit for myeloablative regimens, reduced-intensity or non-myeloablative regimens may be considered. Alternatively, clinical trials or systemic agents such as chemotherapy without a transplant are reasonable in an unfit population. This population typically has a higher burden of comorbidities and decreased functional and performance status. Matched-related sibling donors are the main donor source for allo-HCT. However, the sibling match probability is decreased in older adults (28% in 65–74 year olds versus 39% in 45–64 year olds) . SimilarStudies comparing patients who received allo-HCT using matched-related donors versus matched-unrelated donors demonstrated comparable outcomes, although compared to young adults, older patients may have worse outcomes ,46. In aThe effect of donor age on transplant outcomes is an area of investigation. Some studies suggest a possible survival advantage when younger sibling donors were used as compared to older donors , while oA haploidentical transplantation is a technique that was initially limited by high transplant-related morbidity and mortality and engraftment failures ,53. Withp = 0.05), but no different than the 7/8 matched-unrelated donor group  [p < 0.01), and comparable to the 7/8 matched-unrelated donor group . Umbilical cord blood transplantation is another reasonable alternative to matched-related and unrelated donor transplantation in the absence of available donors. Some of the benefits of cord blood transplantation include rapid availability and greater tolerance of HLA disparity ,60. Howe = 0.30) . Three-yGraft-versus-host disease (GVHD) is the most common transplant-related complication that affects patients who have undergone hematopoietic stem cell transplantation. GvHD occurs when the donor T-cells attack recipient tissues, affecting organs such as the skin, mouth, eyes, joints, gastrointestinal tract, liver, and lung. Acute GVHD generally occurs shortly after transplantation (within 100 days), whereas chronic GVHD typically occurs beyond 100 days of transplantation . HoweverCompared to reduced-intensity or non-myeloablative regimens, myeloablative regimens have a higher incidence of acute and chronic GVHD, which is an important factor contributing to its high treatment-related morbidity and mortality rates ,75. In tHigh-dose steroids are typically the first-line of treatment for both acute and chronic GVHD. Steroids are associated with a myriad of side-effects such as hypertension, hyperglycemia, confusion/delirium, infections, bone loss, and easy bruising that can be problematic in older adults. Therefore, there is a need to balance the efficacy of steroids for controlling GVHD and the risks of steroids in this population. Steroid sparing agents can be utilized, but these may also be poorly tolerated in an older population due to immune suppression effects. Newer oral agents with activity in GVHD may be better tolerated in older patients , but these have not been systematically studied in older patients ,84,85. There are several strategies used in the post-transplant setting to prevent relapse of AML. This is especially important in older patients with AML given high rates of relapse. The first approach is typically reducing the doses of immunosuppressive agents to enhance graft versus leukemia effect. However, this can be difficult in patients with ongoing GVHD. Donor lymphocyte infusion is another strategy that can be given when there is increasing mixed-chimerism or in the setting of relapsed AML. DLI may be combined with lymphodepleting agents or systemic chemotherapy such as hypomethylating agents ,87. OnceMany of these regimens have not been specifically examined in an older population, but they represent a spectrum of what has been used for prevention or treatment of relapse in older individuals. Second transplant or intensive chemotherapy is rarely used in older adults to treat post-transplant relapse. Immunomodulatory drugs have been examined but are thought to be associated with increased risk of graft-versus-host disease in patients with acute myeloid leukemia.There are many gaps in our knowledge in the field of allo-HCT for older patients with AML. To better guide the selection of older patients for allo-HCT, prospective trials need to incorporate patient-factors  and disease-factors . There are also limited phase 3 randomized controlled trialss that compare the various conditioning regimens and alternative donor sources in older patients with AML. Multiple studies are ongoing that investigate various post-transplant maintenance strategies such as midostaurin (NCT02723435) or crenolanib (NCT01522469) in older patients with FLT3 activating mutations (NCT02723435). Although not limited to older patients, the BMT CTN 1506 study (NCT02997202) is currently investigating the use of gilteritinib as a maintenance therapy in patients with FLT3-internal tandem duplication AML. How best to treat GVHD in older transplant recipients has not been systemically studied and these studies have importance as GVHD may have greater impact on physical function in older transplant recipients . ResearcSelected older patients with AML can benefit from allo-HCT, which provides the best chance for durable remission. Advances in the techniques and procedures of hematopoietic stem cell transplantation including alternate donor sources, reduced intensity conditioning regimens, and advanced strategies for preventing post-transplant relapse, have increased the availability and appropriateness of transplant for older adults with AML. Despite these advances, the number of older patients with AML who receive allo-HCT remains low. Further research is needed to improve candidate selection and access to donors, to optimize existing conditioning regimens, and to develop effective post-transplant maintenance strategies and treatment of relapsed disease.


PR-born Hispanics/Latinos were more likely to be prescribed antiretroviral therapy (ART) (94%) and retained in care (94%) than mainland-US-born  and non-US-born  Hispanics/Latinos. PR-born Hispanics/Latinos were more likely to have sustained viral suppression (75%) than mainland-US-born Hispanics/Latinos (57%). Non-US-born Hispanics/Latinos were more likely to be prescribed ART (91% vs. 79%), retained in care (87% vs. 77%), and have sustained viral suppression (74% vs. 57%) than mainland-US-born Hispanics/Latinos. Greater Ryan White HIV/AIDS-funded facility usage among PR-born, better mental health among non-US-born, and less drug use among PR-born and non-US-born Hispanics/Latinos may have contributed to better HIV outcomes. Expanding programs with comprehensive HIV/AIDS services, including for mental health and substance use, may reduce HIV outcome disparities among Hispanics/Latinos.Relocation from one’s birthplace may affect human immunodeficiency virus (HIV) outcomes, but national estimates of HIV outcomes among Hispanics/Latinos by place of birth are limited. We analyzed Medical Monitoring Project data collected in 2015–2018 from 2564 HIV-positive Hispanic/Latino adults and compared clinical outcomes between mainland US-born (referent group), Puerto Rican (PR-born), and those born outside the United States (non-US-born). We reported weighted percentages of characteristics and used logistic regression with predicted marginal means to examine differences between groups ( Human immunodeficiency virus (HIV) continues to be a serious threat to the health of Hispanic/Latino communities. Hispanics/Latinos represented 18% of the US population in 2015 but accounted for 27% of new HIV diagnoses in 2016 ,4. ImproHispanics/Latinos born outside of the mainland United States comprised 61% of Hispanics/Latinos with diagnosed HIV in the United States in 2003–2006 . AnalyseNon-US-born persons with diagnosed HIV were more likely to be prescribed antiretroviral therapy (ART), retained in care, and virally suppressed, compared with US-born persons . HoweverThe Medical Monitoring Project (MMP) is an annual cross-sectional survey designed to produce nationally representative estimates of behavioral and clinical characteristics of adults with diagnosed HIV in the United States. MMP data collection is a part of routine public health surveillance, and thus, determined to be nonresearch . ParticiMMP uses a two-stage sampling method in which, during the first stage, 23 project areas were sampled from all US states, the District of Columbia, and Puerto Rico . During All sampled states and Puerto Rico participated in MMP. Participating areas included California, Delaware, Florida, Georgia, Illinois, Indiana, Michigan, Mississippi, New Jersey, New York, North Carolina, Oregon, Pennsylvania, Puerto Rico, Texas, Virginia, and Washington. Separately funded cities or jurisdictions include Los Angeles County, San Francisco, Chicago, New York City, Philadelphia, and Houston. For this analysis, we combined three cycle years of MMP data: 2015, 2016, and 2017. Data collection began on June 1 of the cycle year and ended on May 31 of the following calendar year. For each cycle, the sampling frame was adults with diagnosed HIV reported to NHSS as of December 31 of the prior year. The response rate for adults with diagnosed HIV was 40%, 44%, and 46% for the 2015, 2016, and 2017 MMP cycles, respectively. Data were weighted on the basis of known probabilities of selection at state or territory and person levels . Furthermainland-US-born, those born in Puerto Rico were classified as PR-born, and those born elsewhere were classified as non-US-born. Hispanics/Latinos born in US territories other than Puerto Rico were excluded from this analysis due to small cell size. We also categorized PR-born Hispanics/Latinos as currently residing in Puerto Rico or the US mainland. Data were collected via telephone or face-to-face interviews and medical record abstractions from June 2015 to May 2018. Interviews were conducted in English or Spanish. All measures were assessed over the 12 months before the date of the interview unless otherwise noted. Medical records were abstracted at the health care facility the participant identified as their most frequent source of HIV care. Abstracted information included documented prescription of ART, laboratory results, and health care use. Persons born in the mainland US (50 States and Washington DC) were classified as For non-US-born Hispanics/Latinos, age at the time of immigration to the United States was categorized as younger than 18 years old and 18 years or older. The date of diagnosis relative to immigration was calculated by comparing the reported date the person immigrated to the United States with their first HIV diagnosis date. Transgender Hispanics/Latinos were not included in the gender category because of small cell sizes. Binge drinking was defined as drinking five or more alcoholic beverages in a single sitting for men and four or more alcoholic beverages in a single sitting for women in the 30 days prior to the interview. Depression in the past two weeks was assessed using the eight-item Patient Health Questionnaire Depression Scale (PHQ-8) , and anxPneumocystis jiroveci pneumonia prophylaxis, or Mycobacterium avium complex prophylaxis. Viral suppression was defined as an HIV RNA level that was undetectable or < 200 copies/mL. Recent viral suppression was defined as virally suppressed at the most recent test, and sustained viral suppression was defined as virally suppressed at all tests in the past 12 months. Adherence to ART doses was assessed using a 3-item scale [Documentation in the medical record of ART prescription in the 12 months before interview was assessed. Retention in care was defined as documentation of two elements of outpatient HIV care at least 90 days apart in the past 12 months. Outpatient HIV care was defined as documentation in the medical record of any of the following: an encounter with an HIV care provider , viral load test result, CD4 test result, HIV resistance test or tropism assay, ART prescription, em scale . ParticiThe analytic dataset included 2564 adults with diagnosed HIV that self-identified as Hispanic/Latino, including 944 born in the United States mainland, 634 born in Puerto Rico (of whom 435 currently reside in Puerto Rico and 199 reside in the mainland United States), and 986 born outside the United States. We calculated weighted prevalences with 95% confidence intervals (CI) for demographic, behavioral, and clinical characteristics. Estimates with coefficients of variation ≥0.3 were considered unreliable and were not reported. p-value of < 0.05 were considered statistically significant.For the analysis, we first reported characteristics of Hispanic/Latino adults with diagnosed HIV by place of birth. Next, we examined differences in selected characteristics and HIV care outcomes by place of birth. We used logistic regression with predicted marginal means to estimate unadjusted prevalence ratios and corresponding 95% CIs using the mainland-US-born as the reference group. Finally, we assessed differences in HIV clinical outcomes by place of residence among PR-born persons using Rao–Scott chi-square tests. For all analyses, associations with a Among Hispanic/Latino adults with diagnosed HIV, an estimated 40% were born in the mainland United States, 22% were born in Puerto Rico, and 38% were born outside of the United States . Most HiA lower proportion of PR-born compared with mainland-US-born and non-US-born Hispanics/Latinos were men . PR-bornNon-US-born Hispanics/Latinos were less likely to binge drink, use non-injection drugs, and report symptoms of depression and anxiety compared with mainland-US-born Hispanics/Latinos . PR-bornPR-born Hispanics/Latinos were more likely to have been prescribed ART (94%), retained in care (94%), and virally suppressed at their most recent viral load test (85%) compared with mainland-US-born  Hispanics/Latinos . Non-US-PR-born Hispanics/Latinos who resided in Puerto Rico were more likely to have been prescribed ART (96%), been retained in care (97%), and had sustained viral suppression (78%) compared with those who resided in the US mainland at the time of sampling  .Our findings demonstrate disparities in HIV care outcomes among Hispanics/Latinos with diagnosed HIV by place of birth. Although Hispanics/Latinos born outside of the mainland US had a higher prevalence of AIDS, they were more likely to be on ART, be engaged in care, and virally suppressed compared with mainland-US-born Hispanics/Latinos. Similarly, previous studies reported a higher proportion of non-US-born blacks compared with US-born blacks were retained in HIV medical care and virally suppressed . Sheena One possible explanation for these outcome disparities may be that more advanced disease among PR-born and non-US-born groups may have resulted in closer medical follow-up that may have led to better HIV care outcomes, such as retention in care. Similarly, a study of patients at two academic medical centers in Massachusetts found that non-US-born persons with HIV more often presented with late-stage disease but were more likely to be linked to care compared with US-born counterparts . Another possible reason for poorer HIV outcomes among Hispanics/Latinos born in the US mainland may be differences in the utilization of RWHAP and receipt of care at RWHAP-funded facilities. A lower percentage of mainland-US-born than PR-born and non-US born Hispanics/Latinos received care at RWHAP- funded facilities, which may have contributed to the disparity in HIV care outcomes observed by place of birth. The RWHAP provides funds to HIV clinics to increase access to high-quality HIV care and treatment, including financial assistance for HIV medications and access to supportive services for low-income, uninsured, and underinsured individuals and families affected by HIV . The RWHDifferences in mental health and substance use are another possible explanation for HIV outcome disparities found between the examined groups. Mainland-US-born Hispanics/Latinos were more likely than PR-born and non-US-born Hispanics/Latinos to report the use of drugs and were more likely than non-US-born Hispanics/Latinos to report symptoms of anxiety and depression. Psychiatric illnesses combined with substance use are associated with poor HIV outcomes ,23. PersWe further stratified PR-born Hispanics/Latinos with diagnosed HIV by their current residence and found that PR-born Hispanic/Latinos who resided in Puerto Rico were more likely to be prescribed ART, retained in care, and sustainably virally suppressed compared with those who resided in the mainland US. PR-born Hispanics/Latinos who live on the island were the only groups that reached the national HIV prevention goal of 90% retention in care among persons with HIV . AvailabOur analysis is subject to limitations. First, MMP’s design is cross-sectional, and thus, causal relationships between sociodemographic, behavioral, and clinical characteristics and HIV outcomes cannot be inferred. Second, MMP’s person-level response rate was low; however, the data were adjusted for nonresponse, which should reduce bias. Third, medical records were abstracted from the facility where the person received the most HIV care, not from all facilities that provided care. Thus, our findings may not be inclusive of all possible medical services the person received.Disparities in HIV care outcomes exist among Hispanics/Latinos with diagnosed HIV by place of birth. Factors contributing to favorable HIV care outcomes may include the utilization of RWHAP-funded facilities among PR-born persons and better mental health and less drug use among non-US-born persons. Expanding access and reducing barriers to the use of comprehensive HIV/AIDS programs that provide care to the whole person, including treating mental health and substance use issues, may reduce HIV care outcome disparities and support ending the HIV epidemic in Hispanic/Latino communities.


The compounds tested for ability to scavenge ABTS radical cations was in the order of ferulic acid > coniferyl aldehyde ≈ iso-ferulic acid > ethyl ferulate ≈ methyl ferulate. The results of the FRAP assay for ferulic acid, iso-ferulic acid, and coniferyl aldehyde were similar to and higher than those of methyl ferulate and ethyl ferulate. In the lipid system, iso-ferulic acid showed weak antioxidant activity. The other ferulates exhibited much stronger, yet similar, activities.The antioxidant activity of ferulic acid ( RRm represents the ratio of Rm to RA, i.e., RRm = Rm/RA.Antioxidant efficiency, induction period, protection factor (PF), inhibition degree (ID), and antioxidant capacity were calculated for the ferulates . Antioxip < 0.05 to evaluate the significance of differences among mean values.All experiments and chemical determinations in this study were performed in triplicate. Results are reported as mean and SD values. Analyses of variance and Duncan’s test were performed at the level of Ferulic acid exhibited the strongest antioxidant activity investigated using ABTS and FRAP assays.iso-ferulic acid, and coniferyl aldehyde.Methyl and ethyl ferulates showed lower results of ABTA and FRAP assays than those of ferulic acid, iso-Ferulic acid showed weak antioxidant activity in this system. The other ferulates exhibited much stronger, yet similar, activities.This is the first work to compare five ferulates in terms of their antioxidant activity in the lipid system (TGSO autoxidation).


Background: Immune checkpoint inhibitors (ICIs) have evolved for the treatment of solid tumors. In addition to the efficacy of ICIs for cancer, the adverse events (AEs) of ICIs are also noteworthy for gradually more extensive clinical use.Objective: To conduct a systematic review and network meta-analysis to evaluate the treatment-related AEs that occurred in clinical trials using different kinds of ICIs, to explore the differences in AEs among ICIs for treating non–small cell lung cancer (NSCLC) and melanoma, and to compare select immune-related AEs.Methods: PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and other available sources were systematically searched for published reports up to January 1, 2019. Two reviewers independently selected reports about phase II/III randomized controlled trials to compare among ICIs and between ICIs and chemotherapy. After the bias assessment of all included trials, a Bayesian network meta-analysis was performed. The primary outcomes were any-grade and high-grade treatment-related AEs from all ICIs. The secondary outcomes were AEs in patients with NSCLC and melanoma and the presence of the select AEs pneumonitis/pneumonia and colitis.Results: Eighteen randomized controlled trials containing 11,223 patients with NSCLC or melanoma were included. A total network meta-analysis was conducted. The meta-analysis showed that atezolizumab 1,200 mg and pembrolizumab 2 mg/kg every 3 weeks were generally more tolerable than other ICIs. ICI combined with chemotherapy might suggest a higher risk of treatment-related AEs than monotherapy with a single ICI, except durvalumab and ipilimumab. In the NSCLC subgroup, pembrolizumab was associated with a higher risk of high-grade AEs than nivolumab. In addition, ICIs  led to a lower risk of any/high-grade treatment-related AEs than traditional chemotherapy and ICI combination chemotherapy. However, ICIs did not present preferable safety and tolerability compared to chemotherapy in treating melanoma. Compared with chemotherapy, nivolumab, durvalumab, two ICIs, and ICI combined chemotherapy led to more pneumonitis/pneumonia. However, when treating NSCLC, different types of ICIs did not differ significantly regarding the incidence of pneumonitis/pneumonia. A combination of nivolumab and ipilimumab had the highest risk for colitis, while pembrolizumab and atezolizumab had a lower possibility than the other ICIs.Conclusion: Atezolizumab 1,200 mg and pembrolizumab 2 mg/kg every 3 weeks were ordinarily safer than other ICIs. When treating NSCLC, nivolumab had the lowest risk; when treating melanoma, pembrolizumab had the lowest toxicity. Since ipilimumab, an anti–cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) therapy, was approved by the Food and Drug Administration (FDA) in 2011, remarkable progress has been made in immunotherapy. As the first approved checkpoint inhibitor, ipilimumab is indicated only for melanoma. Another checkpoint inhibitor against the programmed death 1(PD-1)/programmed death ligand 1 (PD-L1) has also shown prominent success for patients with advanced solid tumors. In the National Comprehensive Cancer Network guidelines for non–small cell lung cancer (NSCLC) , an updaCompared with standard chemotherapy, immune checkpoint inhibitors (ICIs) showed great clinical benefits in prolonging the overall survival and progression-free survival for patients with solid tumors . This reAcknowledging the AEs caused by ICIs is necessary for better clinical management. In a study by The purpose of this study was to systematically review and conduct a network meta-analysis on the safety and toxicity of different ICIs in treating NSCLC and melanoma. The risks for select specific treatment-related AEs (colitis and pneumonitis/pneumonia) were also compared among these different treatment patterns.The present report was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the PRISMA extension statement for network meta-analysis . Two autOnly randomized controlled clinical trials were included. Articles that met the following criteria were included: (a) phase II or phase III clinical trials on patients with NSCLC or melanoma; (b) studies with outcomes reporting of the rates of any all-grade and high-grade (3–4) AEs or treatment-related AEs that led to discontinuation or treatment-related death; and (c) at least one ICI as the intervention. It has been proven that autoimmune AEs occur, such as colitis, pneumonitis, skin AEs, endocrine dysfunction, and hepatitis . It was Two researchers (Q-QC and J-YD) independently conducted the data extraction. The following data were summarized: first author, title, year of publication, study ID, tumor site, trial phase, treatments, median follow-up time, version of the Common Terminology Criteria for Adverse Events, any AEs, treatment-related AEs, specific AEs, specific treatment-related AEs, treatment-related AEs leading to discontinuation, and treatment-related deaths.The qualities of the trials were ranked by the Jadad scale based on the original article, updated references and P < 0.05).The primary objective of this article was to compare the toxicity and AEs among all ICIs and standard chemotherapy. Additionally, the differences in AEs between patients with NSCLC and melanoma were studied. Pairwise meta-analysis (PWMA) was applied for direct evidence that was pooled in random-effects models if heterogeneity existed (I2 index (P > 0.05), pooled odds ratios/RRs and their 95% confidence intervals were reported in a fixed-effects model; otherwise, a random-effects model was applied.A total network was built containing all the included trials, and both direct and indirect comparisons were conducted. The consistency between the direct and indirect evidence was statistically confirmed by node-splitting analyses. The incidence of specific treatment-related toxicity, relative risk (RR) for any AEs, and odds ratio for high-grade AEs were calculated with 95% confidence intervals. When treatment-related AEs were not observed in the original studies, a relative index of any AEs that occurred during treatment was taken as a replacement. Heterogeneity among the trials was verified by the Cochrane Q statistic and quantified with the 2 index . When emSubgroups were created based on the cancer site, specific treatment-related AEs, and different ICIs. All analyses involved the use of the packages “gemtc” and “pcnetmeta” in R v3.5.1, and PWMA was conducted in Review Manager v5.3.The selection and exclusion criteria of the study are presented in Detailed characteristics of the included trials are shown in All relative outcomes of any-grade or high-grade treatment-related AEs in the NMA are presented in The patients were divided into NSCLC and melanoma subgroups. Group NSCLC involved 11 original studies with 7,033 patients, while the melanoma group involved 4,190 patients from seven articles. In the selected AE analyses, indirect comparisons were conducted on pneumonitis/pneumonia and colitis. The results suggested that nivolumab, durvalumab, two ICIs, and ICI combination chemotherapy would remarkably increase the risk of any-grade pneumonitis/pneumonia compared with chemotherapy. Avelumab was the only ICI that might be ranked higher (lower risk) than chemotherapy. However, the risks did not vary in the NSCLC subgroup among different ICIs.In the colitis analysis, ipilimumab and two ICIs (nivolumab + ipilimumab) had the highest risk of occurrence. In a sensitive analysis that ignored durvalumab and did not report the risk of colitis, we found that nivolumab combined with ipilimumab could cause more colitis than other ICIs. In general, pembrolizumab and atezolizumab had a lower possibility of leading colitis than other ICIs. All the outcomes are shown in I2 > 50%, P < 0.05). For the one direct comparison, obvious inconsistency existed between the network meta-analysis and direct comparison for durvalumab, which presented a drastically higher risk than chemotherapy for any- and high-grade treatment-related AEs in the PWMA.The node-splitting analysis indicated no significant inconsistencies except for the comparison between nivolumab and two ICIs Table 2.As the number of FDA approvals for ICIs increases, the indications for different ICIs have also expanded. However, different ICIs have distinct immunologic mechanisms and should not be taken as a whole category; even ICIs that belong to the same mechanism might lead to unlikely treatment effects and tolerability in different diseases . This reSeveral meta-analyses and network meta-analyses concerning the safety and tolerability of ICIs have been reported . These pIn our analysis, most clinical trials used chemotherapy as a controlled arm, and we performed direct and indirect analyses to compare all types of ICIs, not only head-to-head trials. This process was different from that of a previous meta-analysis, which only contained direct comparisons. More importantly, pneumonia and colitis (two specific AEs related to ICI treatment) were analyzed among different ICIs. This study indicated that ICI leads to more pneumonitis/pneumonia and colitis than chemotherapy. Avelumab has the lowest risk for pneumonitis/pneumonia among all comparators, including chemotherapy. Compared with pembrolizumab and avelumab, the combination of two ICIs (nivolumab + ipilimumab) might lead to a higher risk of any-grade pneumonitis/pneumonia  were reported in this review to identify the different immune-related effects.Limitations also exist in this analysis. Due to the nature of network meta-analyses, missing values always exist in published articles. In the current analysis, we conducted a comprehensive assessment of the evidence we collected and excluded low-quality evidence to improve the quality of this review. Second, some treatments  were adopted in only one clinical trial, which might lead to a biased evaluation without enough head-to-head evidence. Third, as the reported AE types were different among the original trials, the specific treatment-related AEs could not be completely evaluated. Thus, we focused on any-grade and high-grade treatment-related AEs as the primary outcome, which could suggest the overall safety and tolerability. Additionally, specific AEs related to ICIs for NSCLC and melanoma were selected to distinguish the differences between tumor types. Third, the incidences of immune-related AEs (including pneumonitis/pneumonia and colitis) were not high, especially those of serious lung toxicities and colitis . The lowIn summary, atezolizumab 1,200 mg and pembrolizumab 2 mg/kg every 3 weeks were generally safer than other ICIs. Nivolumab and pembrolizumab were safer for NSCLC and melanoma than other ICIs, respectively.Q-QC is the first author of this NMA, and she is responsible for the modification of this paper. J-YD is the second author. JZ is the third author. BW is the corresponding author, and he takes responsibility for the authenticity of the paper and also the modification.This work was sponsored by unrestricted grants from the National Natural Science Foundation of China (NO. 7172810).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The study on the impact of video lecturing on clicker-assisted English flipped class was necessary because it has seldom been explored.This study studied the impact of video lecturing on student satisfaction and English proficiency, plus correlations between student satisfaction levels and English proficiency.Randomly recruited Chinese participants  from a university in China received both pre and post College English Test Band 4 and satisfaction measurements, together with a semi-structured interview.p < .001, Partialη2 = .216); there were significant differences between video- and non-video-assisted cohorts for post interaction , post efficacy , and post regulation ; there were strong, positive relationships between post English proficiency and post student interaction , self-efficacy  and self-regulation  levels in both cohorts at the .05 level. However, no strong, positive correlations were found in both cohorts at the .05 level between pre English proficiency and pre student interaction , self-efficacy  and self-regulation  levels. Future research into video-assisted English flipped class may need interdisciplinary cooperation.We concluded that the video-assisted class could cause significantly higher English proficiency than the non-video-assisted class (F = 23.17,  The flipped or flipped pedagogical approach is a method which flips the teaching and learning process–2. ThrouClicker system, also referred to as classroom response system, is a popular information technology mainly composed of remote controllers, hand-held emitters, receivers, computers, multimedia projectors, screens and software. Using this system, students can anonymously poll and join learning activities involving peer discussion and problem solving, by which learning efficiency can be improved and learAssisted with video lecturing designed and provided by teachers, the concepts hard to be perceived through texts, and graphics or PowerPoint slides may be easily understood. Before Considering the contradictory results, it is therefore important to determine the effectiveness of teaching tools, e.g. videos, slides, blackboard, multimedia projector, and online communicative technologies in the cVideo-assisted learning was endowed with powerful features to constitute an effective pedagogical approach to improve academic achievements and student satisfaction. With raVideos provided students with convenience in English listening and speaking practice, together with easiness of relearning contents. Videos-Video lecturing also enabled students to understand previous lectures before they attended the physical or virtual class, facilitating their understanding and improving academic activities. Video lFurthermore, in the context of online learning, video lecturing through images, sound, and other multiple inputs might enlarge capacity of working memory than the traditional blackboard and chalks-aided teaching. They miTeachers and students were more interested in classes assisted with videos than in those without aid of videos. The vidBesides watching video lecturing, students could also discuss and finish the academic tasks assigned by teachers in the flipped classroom that involved blended learning. This isThe appropriate selection of pedagogy plays an important role in the asynchronous learning assisted with video lecturing. The video assisted pedagogy was beneficial to students’ academic activities. StudentAs a popular teaching style, the flipped class integrated the asynchronous video lecturing into assignment, and cohort-based learning activities. As a poFurthermore, video lecturing-based pedagogical approach enjoyed students, reduced their anxiety and lessened their workload. Video-aIn the flipped pedagogical approach, student participation in learning activities was encouraged and student satisfaction was also enhanced. The vidHowever, video lecturing did not prove the best medium of instruction for introductory political science course. In the non-video-assisted course, the teacher and the course were more highly evaluated and students scored higher on exams than the video-assisted course, and theDespite that use of videos has been widely studied in the flipped class, the results were inconsistent and the effect of videos on clicker-assisted flipped English class has seldom been explored. Considering the research status quo, research questions are thus raised as: (1) Could the video-clicker-assisted flipped English class cause significantly better academic achievements than the non-video-clicker-assisted flipped English class? (2) Could the video-clicker-assisted flipped English class cause significantly higher student interaction, self-efficacy and self-regulation levels than the non-video-clicker-assisted flipped English one? (3) Are the post interaction, self-efficacy and self-regulation levels positively correlated with the post English proficiency in both pedagogical approaches? In order to answer this question, the pre interaction, self-efficacy and self-regulation levels (pretests) should be equivalent in both cohorts, and so should the pre-CET 4 results (pretests).Most literature supported the effectiveness of videos in flipped classes in terms of academic achievements and satisfaction. It has also been largely demonstrated that there is a positive relationship between academic achievements and satisfaction. Based on previous findings, three null hypotheses are raised as follows:H1: The video-clicker-assisted flipped English class could not lead to significantly higher English proficiency than the non-video-clicker-assisted flipped English class.H2: The video-clicker-assisted flipped English class could not cause significantly higher student interaction, self-efficacy and self-regulation levels than the non-video-clicker-assisted flipped English class.H3: The post interaction, self-efficacy and self-regulation levels are not positively correlated with the post English proficiency in both pedagogical approaches. We assume that the pre interaction, self-efficacy and self-regulation levels are positively correlated with the pre-English proficiency in both pedagogical approaches.The research lacks consent because the data were analyzed anonymously. The research has been approved by the authors’ institutional review board-School of Foreign Languages of Hohai University, which waived the need for written informed consent from the participants. All experiments conform to the relevant regulatory standards.http://dx.doi.org/10.17504/protocols.io.7sjhncnThe DOI link: This research attempts to integrate quantitative into qualitative research methods using several scales to measure English proficiency and satisfaction levels, together with a semi-structured interview to collect qualitative data. English was the linguistic medium of administration of questionnaires and interviews.Randomly selected 87 Chinese undergraduates  from a public university in China were willing to join the research, whose formal English education endured for approximately eight to nine years. They were normally literate and were in a normal psychological state based on their self-reports. They ranged from 19 to 22 in age . They were assigned to two cohorts on a random basis, who received English teaching in the video-clicker-assisted flipped English class (N = 41) and the non-video-clicker-assisted flipped English class (N = 46) respectively. Both cohorts, under the instruction of the same teacher, had similar English proficiency identified through College English Test Band Four (CET 4). Both cohorts were assumed to be equivalent to each other in terms of pre-interaction, self-efficacy and self-regulation levels because they were randomly divided into two groups from the same population who shared the same educational and social backgrounds. This assumed similar English proficiency and interaction, self-efficacy and self-regulation levels established a basis for comparison.Pre English proficiency and pre interaction, self-efficacy and self-regulation levels of the randomly selected participants were then determined via CET 4  and the interaction, self-efficacy and self-regulation scales after they were randomly assigned to either intervention or control cohorts.The teacher was awarded a Ph.D. degree in English language. Before the study commenced, he also received specialized training regarding both video-assisted and non-video-assisted pedagogical approaches.Participants in the non-video-assisted cohort were asked to read textbooks before class without access to videos, while those in the video-assisted cohort had access to videos plus textbooks when preparing for class. The video-assisted cohort was required to complete all of the tasks that the non-video-assisted cohort completed and vice versa. Both cohorts of participants were instructed via clickers. The only difference was whether students could learn English assisted with videos. In the video-clicker-assisted flipped English class, students learned English aided with videos, while in the non-video-clicker-assisted flipped English class, they learned English without aid of videos.Four scales, including a CET 4 to determine English proficiency and three scales to identify interaction feasibility, self-efficacy and self-regulation levels, were used as research instruments in both the video-clicker-assisted flipped English class and the non-video-clicker-assisted flipped English class.CET 4 in June, 2012, designed under the guideline of Ministry of Education of China, was used to identify English proficiency. CET4 was internally reliable and externally valid. Its identification of English proficiency has been generally accepted since it came into being decades ago. Test itAs shown in I strongly disagree, I disagree, neutral, I agree, I strongly agree, were used to identify interaction feasibility, self-efficacy and self-regulation respectively  Clickers-assisted English class provides a discussion platform for interaction; (2) Clickers-assisted English class presents an easy access to frequently asked questions; (3) Clickers-assisted English class provides a place to discuss questions.Cronbach’s alpha is a method to examine reliability, which was proposed by Lee Cronbach in 1951. It overcomes the shortcomings of partial halving method and is the most commonly used reliability analysis method in social science research. In general exploratory studies, the Cranbach’s alpha coefficient is above 0.6, and the benchmark study is above 0.8.The internal consistency was demonstrated by Cronbach’s alphas see . Three sA semi-structured interview, designed by professors in English language teaching, was designed in order to collect qualitative data. Researchers informed participants that all the information in the interview would remain confidential and would merely be used in the research. All the interviewees would be properly rewarded for their cooperation after the interview.The interview is made of three sections involving demographic information, interview questions and acknowledgment. Section 1 focuses on interviewees’ demographic information including names, ages, genders, educational backgrounds, working experiences, literacy and psychology. Section 2 is mainly concerned with interview questions. For the interaction feasibility, we selected 2 to 3 questions for interviewees to answer. For the scale of self-efficacy, 3 to 4 questions were selected. For the scale of self-regulation, we selected 2 to 3 questions See . We alsoLearning tasks of participants were to improve their English proficiency through an intensive English reading course for two semesters. Both cohorts learned English assisted with Clicker system.The teaching progress assisted with Clicker system is visualized in As shown in The teaching progress was decided based on the answers of students. If most of students (>80%) answered correctly, the teacher would move on after correcting the wrong answers. If nearly half students answered correctly, the teacher would stop to explain the question in details and continue the teaching progress after they understood them. If most of the students answered wrongly, the teacher would repeat the teaching progress after most of them learned the knowledge, understood the questions and provided correct answers.The intervention cohort was instructed through the video-clicker-assisted flipped English class, while the control cohort was taught via the non-video-clicker-assisted flipped English class instruction.The video was used to both present the image of the teacher and show educational materials. The intervention cohort was provided with teaching videos through the communicative platform. They were required to download videos from the online space. The activities were automatically recorded by the platform. In both the physical and virtual classes, the teacher designed quizzes or tests in the content of the videos in order to encourage students to view and understand videos. Task and key knowledge were included in the videos. Students could not successfully perceive the knowledge and complete the task without watching videos, which ensured that the intervention cohort truly made use of the videos.After two academic semesters, both cohorts were tested in terms of English proficiency and interaction, self-efficacy and self-regulation levels. The pre and post test results were entered into a computer for further analysis and discussion. The only difference between the intervention cohort and the control cohort was that the former was instructed assisted with videos, while the latter was not instructed with the aid of videos. Consequently, differences in student interaction, self-efficacy and self-regulation levels and English proficiency were due to whether video lecturing was used. The effect of videos on clicker-assisted flipped English class would thus be revealed.The videos, enduring 10 to 50 minutes, were all designed by the teacher, who aimed to inspire and encourage students to improve their listening, speaking, reading, writing and translating skills. Cultural awareness and linguistics-related knowledge would also be integrated into language teaching via the videos.This section includes the results of the assumption and hypotheses, together with those from the semi-structured interview.In order to test the hypotheses using an appropriate statistical test, the pre interaction, self-efficacy and self-regulation levels and pre English proficiency were assumed equivalent in both cohorts.F = .739, p = .392), self-efficacy  and self-regulation levels  and pre English proficiency  at the .05 significance level for video or non-video assisted conditions. Taken together, pre interaction, self-efficacy and self-regulation levels and pre English proficiency are not significantly different in video or non-video assisted conditions. Our results suggest that the pre interaction, self-efficacy and self-regulation levels and pre English proficiency are equivalent in both cohorts.A one-way between-subjects ANOVA was conducted to compare the effect of video or non-video assisted conditions on pre interaction, self-efficacy and self-regulation levels and pre English proficiency. There was insignificant effect of pre interaction  between video and non-video lecturing-assisted cohorts. Post hoc tests showed there was a significant difference between video lecture and non-video lecture assisted cohorts (p<0.001). Comparing the estimated marginal means showed that the video lecturing-assisted cohort (M = 5.058) obtained significantly higher English proficiency than the non-video lecturing-assisted cohort (M = 5.009). Therefore, we rejected the null hypotheses “the video-clicker-assisted inverted English class could not lead to significantly higher English proficiency than the non-video-clicker-assisted inverted English class”.As shown in To test Hypothesis 2, we included video or non-video lecturing condition as a fixed factor, and post satisfaction levels  as dependent variables see .Pillai’s Trace = .169, F = 5.41, df = 3, p = .002, indicating a significant difference in the satisfaction levels of student use of video lecturing between both cohorts. The univariate F tests showed there were significant differences between video lecturing-assisted and non-video lecturing-assisted cohorts for post interaction , post efficacy , and post regulation  with respect to satisfaction levels. Therefore, we rejected the null hypotheses “the video-clicker-assisted inverted English class could not cause significantly higher student satisfaction than the non-video-clicker-assisted inverted English class”.As shown in In order to test the relationship between English proficiency and student interaction, self-efficacy and self-regulation levels, data collected from the corresponding scales were entered into WarpPLS 6.0 for analysis since WarpPLS is especially reliable for small samples. A WarpPWhen assessing the model fit with the data, several criteria need to be recommended. In this study, average path coefficient (APC) is 0.466, p < 0.001; the average R-squared (ARS) is 0.323, P < 0.001; average adjusted R-squared (AARS) is 0.315, P < 0.001. The model fit is thus recommended since the P values for the APC, ARS and AARS are all equal to or lower than 0.05. FurtherBoth pre and post analyses were conducted simultaneously through the correlational analysis of WarpPLS model See .R2= .70; β = .84; p < .01), self-efficacy  and self-regulation  levels under both the video-clicker-assisted and non-video-clicker-assisted inverted English class models at the .05 level. However, no strong, positive correlations between pre English proficiency and pre student interaction , self-efficacy  and self-regulation  levels were found in both video- and non-video-clicker-assisted cohorts at the .05 level. As a result, we rejected the null hypothesis “the post interaction, self-efficacy and self-regulation levels are not positively correlated with the post English proficiency in both pedagogical approaches”, and the assumption “the pre interaction, self-efficacy and self-regulation levels are positively correlated with the pre English proficiency in both pedagogical approaches” was violated.It can be found from To enhance the reliability of the correlational analysis, a bivariate correlation program was conducted. The results are shown in r = .021, p = .845), self-efficacy  and self-regulation  levels, while there was a strong, positive correlation between the post English proficiency and the post student interaction , self-efficacy  and self-regulation  levels. The results are consistent with those obtained from the WarpPLS model and therefore enhance the reliabilities of rejecting the third null hypothesis and the assumption.Pearson correlation coefficients were computed to assess the relationship between student interaction, self-efficacy and self-regulation levels and English proficiency. As shown in The interview was recorded and the recording was then transcribed for further analysis. The results are generally consistent with the quantitative research findings based on CET 4 and satisfaction scales. Specifically, the results were divided into two sections: opinions of interviewees and the information revealed.We randomly selected 35 interviewees on a voluntary basis. Most of them felt that the video-clicker-assisted flipped English class could help them reach a higher English proficiency level than the non-video-clicker-assisted flipped English class. They reported that the video-clicker-assisted flipped English class was more satisfactory than the non-video-clicker-assisted flipped English class. It was believed that the post satisfaction might exert an important influence on the post English proficiency in either video or non-video assisted approach. They assumed that their pre satisfaction levels were similar and their satisfaction levels with the video and non-video assisted approaches were not significantly different before they joined the research.Many participants thought that videos could expedite the pedagogical process since teachers do not need to painstakingly write with chalks on the blackboard. Instead, they could deliver knowledge assisted with educational technologies such as online recording, typing, and presenting. Participants said, “Videos light us up; They are time-saving; They energize us.” They could also share resources among students asynchronously. Videos including large quantities of contents could undoubtedly increase learning efficiency. Videos could also act as a tutor guiding students through the learning process. Many participants said, “Videos are highly efficient; Videos share information quickly and widely; Videos carry a large amount of information.”It was reported by most interviewees that video lecturing provided them with flexibility, accessibility, and diversity when they achieved academic achievements by meeting various individual learning needs via pieces of knowledge and by accommodating individual needs via rich resources. Video lecturing was also available to students day and night, and students were able to watch video lectures from any internet-connected, video-play device such as smart phones and laptops. Interviewees thus believed that their learning styles were flexible with regard to their timetables, with which students with different learning styles were satisfied since they could flexibly choose the time and venue to watch or review lectures. Many interviewees thought that they could apply and appreciate the videos that enabled them to pause, rewind or replay at their will.Note taking and note reviewing were essential learning activities, which was demonstrated by a tremendous number of studies. InterviNevertheless, interviewees also showed their worry about the possibility of increasing teachers’ cognitive load in that teachers had to spend a huge amount of time and energy in recording and designing the videos. Furthermore, the benefits of video lecturing failed to be demonstrated as better results in English intensive reading courses. They complained that they preferred to read the static books rather than read books when walking. They also sometimes considered video lecturing a way to distract them from reading due to the noise along with the video play. When forced to read the mobile materials, they tended to suffer from eye strain, which discouraged them from continuously watching the videos.The qualitative accounts provided by the participants also revealed some important information. A phenomenon worth attention is participants’ report on their feelings about use of videos. For example, numerous students gave detailed accounts of experiencing pleasure and enjoyment about video viewing. They said, “I like watching videos; I enjoy watching videos; Learning through the video is interesting.” They also expressed their negative feelings about the lecturing without videos, e.g., “I hate reading the boring texts; I don’t like following the teacher; Listening to the teacher is sometimes boring.”Besides, participants detailed their positive feelings about English learning with the assistance of videos. Many of them expressed similar feelings. Examples are “watching videos can improve my English listening skills; I can improve my sense of English language through viewing videos; Videos can improve my English pronunciation; Watching videos can improve my English skills.” By contrast, they disliked the English learning style without aid of videos. They said, “Learning without videos disgusts me; No lively pictures can be seen without videos; No videos, no English.”This study arrived at the conclusion that the video-clicker-assisted flipped English class could lead to significantly higher levels of English proficiency and student interaction, self-efficacy and self-regulation than the non-video-clicker-assisted flipped English class; the post interaction, self-efficacy and self-regulation levels are positively correlated with the post English proficiency in the video or non video-assisted pedagogical approach; the pre interaction, self-efficacy and self-regulation levels are not significantly correlated with the pre English proficiency in both pedagogical approaches. The findings of this study are generally consistent with previous works, 42, 15.Assisted with videos, students could freely learn the difficult contents they feel necessary. They may speed up, rewind or pause to meet their own needs. Videos made of interesting stories, vivid sounds and colorful pictures could have attracted student attention, due to which students might concentrate on the learning contents. In this way, their English proficiency could doubtlessly be improved. Pieces of knowledge in the videos could also be helpful for students to construct organized and systematic schema. It is therefore reasonable to find that video-assisted academic achievements are significantly higher than those without videos.Interaction, self-efficacy and self-regulation constitute the elements that play key roles in student satisfaction. To deteThe positive correlation between post English proficiency and post interaction, self-efficacy and self-regulation levels indicates that the higher English proficiency is, the more satisfied students will feel and vice versa. In the clicker-assisted flipped English class, student interaction, self-efficacy and self-regulation levels are important factors influencing post English proficiency. To improve student interaction, self-efficacy and self-regulation levels may be a decisive strategy to raise the English proficiency level in the clicker-assisted flipped English class whether or not videos are in use. Interaction, self-efficacy and self-regulation play important roles in student satisfaction. English proficiency is closely related with self-efficacy, self-regulation, peer interaction, and student-content interaction. Thus interaction, self-efficacy, and self-regulation are strongly correlated with English proficiency.This part aims to summarize the research in terms of advantages, disadvantages and future research directions.Despite this study finds that video lecturing is positively correlated with student interaction, self-efficacy and self-regulation levels and academic achievements, no evidence of this finding has been found in previous empirical studies, 44. FinAlthough extensively explored, satisfaction is still an elusive variable that can hardly be fully measured. Measurement of satisfaction may need highly advanced and precise technologies. Questionnaires may never be perfect scales to identify satisfaction. The elements of satisfaction may not be limited to interaction, self-efficacy and self-regulation. Other elements may also be important factors related to satisfaction. Additionally, features of videos may vary from one to another. Features of video lecturing may be an inescapable factor in this study.Many video lectures are simply videos of the face-to-face lecture and therefore, many of the advantages may not be applicable. There may be no rationale for the video lecturing design if interesting pictures and other engaging techniques can’t be presented in the classroom. Video lectures can be rewound or sped up, but they may fail to offer the possibility of clarification that can be realized through face-to-face pedagogy.The double blind approach was not used since it was impossible that the researchers who interacted with the participants did not know which cohort was the intervention group and which was the control group.Students with various economic statuses may perform differently on the video lecturing-assisted teaching. Those who are better-off may have more convenient access to technologies and have better skills than those who are economically lower. The economic status may be considered an important factor in the research of educational technologies.The Type of videos is also a topic worth exploring. As mentioned, rich moving pictures, vivid voice, connected plots, and background music may help students perceive the main contents and command the linguistic knowledge. Future research may thus focus on the effect of videos carrying different information in the flipped pedagogy. Measurement of psychology may be in need of advanced technologies and interdisciplinary cooperation. Interdisciplinary research involving psychology, education, statistics, linguistics and mathematics may be necessary in the future research.S1 Dataset file(RAR)Click here for additional data file.


Individuals who lack a sense of control over cognitive aging (SOC-CA) believe little can be done to optimize their cognitive functioning. While prior research indicates that higher SOC-CA is a protective factor against age-related cognitive decline, few studies have examined predictors of change in SOC-CA. To address this gap, we used data from the Midlife in the United States (MIDUS) study. Guided by prior research on linkages between socioeconomic status (SES) and control beliefs, we examined childhood SES as an early life course influence on changes in SOC-CA. The analytic sample consisted of 663 White participants, ages 34 to 81, who were interviewed in 2004 and approximately nine years later. SOC-CA was measured by using three items from the Personality in Aging Context scale, and childhood SES encompassed retrospective reports of parental education and occupational status. A hierarchical linear model was estimated, which modeled SOC-CA at baseline, as well as change over the study period, controlling for gender, age, ancestry, and adult SES. While childhood SES was not associated with SOC-CA at baseline nor over time, a statistically significant gene-environment interaction was found over the 9-year study period. Specifically, participants who scored high on a polygenetic measure for cognitive ability and reported high childhood SES demonstrated a faster rate of decline in SOC-CA. These findings indicate that inter-individual differences stemming from early life influence people’s SOC-CA as they age. Overall, results suggest the importance of subgroup differences within efforts to engage individuals in preventive measures to optimize healthy brain aging.


Esophageal, esophago-gastric, and gastric cancers are major causes of cancer morbidity and cancer death. For patients with potentially resectable disease, multimodality treatment is recommended as it provides the best chance of survival. However, quality of life may be adversely affected by therapy, and with a wide variation in outcome despite multi-modality therapy, there is a clear need to improve patient stratification. Radiomic approaches provide an opportunity to improve tumor phenotyping. In this review we assess the evidence to date and discuss how these approaches could improve outcome in esophageal, esophago-gastric, and gastric cancer. Esophageal or esophago-gastric cancer  and gastric cancer  are leading causes of cancer deaths worldwide . Above 5As an example, data from the OEO2 and MAGIC trials for esophageal and esophago-gastric cancer have shown a 6%  and 13% p < 0.01) [A recent systematic review and meta-analysis of neoadjuvant chemotherapy in patients with gastric cancer has also found improved 3-year survival rates  remains the most commonly performed first step in staging due to the high prevalence of metastatic disease at presentation –16. For For gastric cancer, initial staging is again by contrast-enhanced CT. If curative treatment is being considered, the use of endoscopic ultrasound (EUS) is helpful in determining the proximal and distal extent of the tumor, whereas 18F-FDG PET/CT has been shown to improve staging by detecting involved lymph nodes and metastatic disease, although it can be less accurate in mucinous and diffuse tumors .In esophageal cancer, PET has the potential to change management in up to a third of patients , 22, andMagnetic resonance imaging (MRI) is currently not recommended for the routine imaging of esophageal or gastric cancer. However, with the recent advent of hybrid PET/MRI systems in clinical practice, there has been growing interest in MRI’s ability as an assessment tool. MRI provides excellent soft-tissue contrast, and may demonstrate the esophageal wall layers and adjacent nodes. Physiological sequences  may also be included as part of the protocol. An initial staging 18F-FDG PET/MRI study with a pathology gold standard has been promising for nodal assessment with reported accuracy of 83% compared to 75% and 50% for EUS and CT, respectively .Radiomic approaches are showing promise for patient stratification. Radiomics exploit the data performed as part of the clinical management pathway. In terms of imaging, a number of parameters may be extracted and combined including standard descriptors  stage); qualitative, semi-quantitative, or quantitative physiological parameters ; and additional agnostic features which are otherwise ‘invisible’, with bioinformatic approaches. Of these, texture-based features have been investigated most commonly to date. Radiomic signatures provide additional information predictive of underlying tumor biology and behavior. These signatures can be used alone or with other patient-related data  to improve tumor phenotyping, treatment response prediction and prognosis. Radiomic signatures may be obtained for all cross-sectional imaging modalities, including CT, PET, and MRI. Nine 18F-FDG PET studies have been performed in esophageal and esophago-gastric cancer and are summarized in n = 2); prognosis alone (n = 1) and the prediction of response to therapy and prognosis (n = 2) from pre-therapy imaging. One of the earliest studies by Tixier et al. showed in 41 patients that gray-level co-occurrence matrix (GLCM) homogeneity, GLCM entropy, gray-level size-zone matrix (GLSZM) size-zone variability and run length matrix (RLM) intensity variability differentiated non-responders, partial-responders, and complete-responders with sensitivities of 76%–92% [max) in predicting therapy response [In greater detail, five studies have investigated the prediction of response to therapy alone  and total lesion glycolysis (TLG), were predictors of tumor response but not of progression free or overall-survival . Non-resmean parameters, SUVmean decline and SUVmean skewness, and 3 texture features GLCM inertia, GLCM correlation, and GLCM cluster prominence, were significant predictors of complete response with an AUROC of 0.76 [18F-FDG PET orderliness provided high discriminatory accuracy in predicting pathologic complete response compared to clinical variables or SUVmax alone [Four studies have assessed pre- and post-therapy 18F-FDG PET imaging. An initial study by Tan et al. found in 20 patients that 2 SUV of 0.76 . In 217  of 0.76 . Yip et  of 0.76 . More reax alone .Nine studies have investigated the ability of CT-derived heterogeneity parameters for classification, prediction of response and overall-survival in patients with esophageal or gastric cancer. Three studies have been performed for esophageal cancer in terms of prediction of response or prognosis . These hThe largest study in 49 patients found that histogram skewness, histogram kurtosis, GLSZM long-zone emphasis, and 2 Gabor transformed parameters MSA-54 and MSE-54, discriminated non-responders from responders using an artificial neural network-derived prediction model . The twoFor gastric cancer , three sTo date there have been little data for MRI in this tumor group as MRI is not performed routinely in the clinical pathway. There have been some exploratory data of pre-therapeutic ADC-maps of gastric cancer . Liu et To date 22 imaging studies have been published investigating radiomic approaches in esophageal, esophagogastric, and gastric cancer, predominantly focused on texture analysis. Preliminary data for esophageal and esophago-gastric cancer suggest that there is potential for radiomic approaches in improving patient stratification for therapy. Eight 18F-FDG PET studies investigated the feasibility of heterogeneity analysis for response prediction (four studies with pre-therapy imaging only). Among the most often reported significant feature was GLCM entropy, reflecting the local randomness (irregularity) within the image, and where low GLCM entropy represents a more homogeneous texture. The reported accuracy for successful classification of therapy response ranged from 0.7 to 1.0 (AUC).max, total lesion glycolysis and metabolic tumor volume into predictive models. In general radiomic parameters contributed to predictive models and provided additional information to standard parameters. Three CT studies of esophageal cancer have also suggested that greater tumoral heterogeneity is associated with poor response and outcome.Nearly all published studies incorporated “classical” PET parameters e.g., SUVPET-studies investigating texture features as a prognosticator were more mixed. Only two studies found associations with overall-survival. The CT and MRI data for gastric cancer were also varied. Two studies found several features to be associated with survival time, however, for some parameters, e.g., histogram entropy and energy, it was surprising to find both parameters to be associated in the same direction given what they represent mathematically.A challenge for interpretation of studies to date is the use of retrospective datasets with different imaging techniques across different scanners and/or institutions; different methodologies for feature selection; the focus on different feature sets; the lack of transparency in methodology with the use of different in-house software; as well as varying statistical and bioinformatics approaches for data analysis and interpretation. This has been highlighted by researchers in the field .Moving forward in the context of esophageal and esophago-gastric cancer, it is important to improve our data quality. Planned prospective studies incorporating quality control is a step in the right direction to improving data curation and ensuring prediction models are fit for purpose and fulfill the promise of radiomics for improving patient stratification.


Glossina, spp. detection of bacterial symbionts such as Wolbachia is challenging since their prevalence and distribution are patchy, and natural symbiont titers can range at levels far below detection limit of standard molecular techniques. Reliable estimation of symbiont infection frequency, especially with regard to interrelations between symbionts and their potential impact on host biology, is of pivotal interest in the context of future applications for the control and eradication of Glossina-vectored African trypanosomosis. The presence or absence of symbionts is routinely screened with endpoint polymerase chain reaction (PCR), which has numerous advantages, but reaches its limits, when detecting infections at natural low titer. To not only determine presence of native tsetse symbionts but also to localize them to specific host tissues, fluorescence in situ hybridization (FISH) can be applied. However, classic FISH assays may not detect low-titer infections due to limitations in sensitivity.In African tsetse flies Wolbachia in the morsitans and palpalis groups while classic endpoint PCR does not. In order to localize Wolbachia in situ in high and low-titer Glossina species, we applied high-end Stellaris® rRNA-FISH. We show that with this high sensitivity method, even low amounts of Wolbachia can be traced in specific tissues. Furthermore, we highlight that more tissues and organs than previously recorded are infested with Wolbachia in subspecies of the morsitans and palpalis groups.We have compared classic endpoint PCR with high-sensitivity blot-PCR. We demonstrate that the latter technique allows for clear detection of low-titer Our results demonstrate that overall symbiont infection frequencies as well as the presence in specific host tissues may be underestimated when using low-sensitivity methods. To better understand the complex interrelation of tsetse flies and their native symbionts plus the pathogenic trypanosomes, it is important to consider application of a broader range of high-sensitivity detection tools.The online version of this article (10.1186/s12866-018-1291-8) contains supplementary material, which is available to authorized users. Glossina spp., Diptera: Glossinidae), detection of bacterial symbionts such as Wolbachia is challenging since their prevalence and distribution are patchy [16S rRNA oligo probes is the method of choice for following tissue tropism. However, sensitivity may be too low for symbiont detection in biologically relevant host organs like testes but also for the in situ detection of generally low-titer infections such as the ones of G. p. gambiensis. In the presented study, we have compared the feasibility of classic PCR and blot-PCR for low-titer Wolbachia in species and subspecies of the genus Glossina. Furthermore, we took advantage of the novel Stellaris® technology to trace such low-titer Wolbachia in situ. As known from recent studies, not only high-titer infections, but also Wolbachia low-titer infections impact host biology [In the African tsetse fly  with Glossina subspecies from the palpalis and morsitans groups  and G. m. centralis (Gmc), but G. swynnertoni (Gsw) and G. p. gambiensis (Gpg) seem uninfected. We did also not detect Wolbachia in the two subspecies G. p. palpalis (Gpp) and G. f. fuscipes (Gfu), which were previously reported Wolbachia-negative  [wsp-PCR, the more sensitive multicopy specific ARM-PCR easily detects high-titer Wolbachia of Gmm and Gmc. In addition, it traces the earlier described low-titer infection in Gsw [ARM-PCR successfully amplifies a smaller fragment in Gfu males but not females,   to the sn in Gsw . Intereswsp and ARM markers are efficient tools to screen for Wolbachia infection status when symbiont titers are at high or medium levels. In order to further increase the detection limit of our assay, we employed a combined PCR-hybridization (blot-PCR) assay [Wolbachia, which were undetected in standard PCR assays such as the wsp-based PCR [Wolbachia-specific wsp-probe allows more Wolbachia to be traced than in the wsp-PCR assay shown in Fig. wsp-PCR, blot-PCR detects high-titer Wolbachia of Gmm and Gmc  assay , 6. Thisased PCR , 5, 6. Aeviously , seems tWolbachia in situ, we tested various Glossina species via fluorescence in situ hybridization (FISH). As standard FISH is not sensitive enough to detect low-titer Wolbachia  we employed high-end Stellaris® rRNA-FISH. This method uses a set of up to 48 oligonucleotides, which collectively bind along the same target transcript (see Methods section for probe design). First, we tested in situ localization of high-titer Wolbachia in Gmm and Gmc  [rRNA-FISH, however, we clearly detected the symbiont in the testes of both Gmm and Gmc. Most interestingly, we did not observe overall infection of the reproductive organ, but a strong restriction to certain stages of spermatogenesis  , 8. By usis Fig. . We detells Fig. . Furtherids Fig. .Fig. 4StWolbachia in the low-titer species G. p. gambiensis (Gpg), and could clearly detect the symbiont in ovaries  with an improved multicopy locus assay (ARM). The standard Wolbachia outer surface protein gene (wsp) PCR is commonly used to detect and type Wolbachia in various host species, but has the disadvantage of low detection limit when it comes to low-titer infections. For the tsetse fly samples where standard wsp-PCR was not sufficient to detect Wolbachia, the more sensitive ARM-marker, however, enhanced the detection sensitivity and thus detected low-titer Wolbachia infection in Gsw. This finding is a confirmation of previous results on the feasibility of ARM for low-titer Wolbachia infections [Wolbachia of Gpg, Gpp and Gpal could not be traced with ARM in laboratory-reared flies, although the presence of Wolbachia in these species was reported previously in field collected samples [ARM motif from the genomes of these Wolbachia strains. Gpg falls into a different species group than Gpal, Gmm and Gmc, which could account for differences in the associated Wolbachia strains, such as presence or absence of a repeat motif. Alternatively, the Wolbachia titer could simply be below the detection limit of ARM-PCR in these species. Finally, we could not detect any Wolbachia in Gfu and Gpp using ARM-PCR, which agrees with a previous study that reported those species uninfected  but higher sensitivity, at least for Drosophila specimens [ARM multicopy target variant seems to be restricted to A-supergroup Wolbachia strains and absent in the others [Drosophila, we report on various Glossina subspecies in the present study, and for the tested Glossina specimens, ARM does not have an advantage over blot-PCR. In contrast, the blot technique confirms an earlier study, which claims an increased sensitivity for Wolbachia by up to 1000-fold [ARM motif from Wolbachia in certain subgroups within the genus Glossina.We recently reported on the advantage of the multicopy pecimens . Furthere others . However000-fold . As mentWolbachia signal in Gfu females via blot-PCR. This is interesting as this subgroup was reported uninfected previously [Wolbachia is indeed present in Gfu, but in ‘ultra-low’ amounts and is hence very difficult to detect or as a translocated chromosomal copy. The latter event is not unlikely since the presence of multiple extensive chromosomal insertions of Wolbachia into the host genome (chrWol) was reported in Gmm [Wolbachia infection frequencies between populations of Gfu. Hence, larger numbers of individuals, preferentially from lab colonies as well as from different field collections, need to be tested in order to confirm the presence or absence of low-titer Wolbachia.Most unexpectedly, we detected a weak eviously . Howeverd in Gmm , 9, 10. Glossina subspecies, we employed high-end Stellaris® RNA-FISH. As anticipated we detected massive Wolbachia infestation in gonads of high-titer Gmm and Gmc females. However, we also found Wolbachia in lumen and secretory cells of the milk gland of Gmm, along with the primary tsetse fly symbiont Wigglesworthia . SiWolbachia-uninfected is the fat body, mainly composed of adipocyte cells [Wolbachia in these cells by using Stellaris® rRNA-FISH. Adipocytes play an important role in insect metabolism as they store and release energy in response to the energy demands of the insect [Wolbachia found a way to exploit this host-provided energy source for their own purpose. However, this and their milk gland tropism have to be further elucidated in more detailed studies.Another tissue that was previously reported te cells . In conte insect . Hence, Wolbachia are transmitted maternally, the presence of the symbionts in male tsetse flies has not been tested and/or reported so far. However, a recent study demonstrated that Sodalis, the second maternally transmitted facultative symbiont of Glossina, are transmitted paternally too [Wolbachia in Gmm and Gmc males via FISH is particularly interesting. It pinpoints that Wolbachia not only persist in male tsetse flies, but are obviously restricted to certain stages of spermatogenesis in the testis. The importance of such host-derived restriction of the symbiont was recently reported in other systems and tissues [Wolbachia in the male reproductive organ is important in relation to the capacity of Wolbachia strains to CI. This is in accordance with recent reports on the ability of Wolbachia from Gmc and Gmm to trigger CI [As ally too . In the  tissues –13. Moreigger CI , 8.Wolbachia in Glossina subspecies (data not shown). However, with the help of Stellaris® rRNA-FISH technique, we could show that Wolbachia are present in the reproductive tissues of Gpg. This finding confirms our data from blot-PCR, where we could also detect Wolbachia in Gpg. The presence of Wolbachia in the uterus has not been reported previously [Classic FISH is not sufficient to detect low-titer eviously  and it rWolbachia to tissues that were previously characterized as uninfected. We also highlight how feasible this method is to trace low-titer Wolbachia in two Glossina subspecies.Here we demonstrate that detection of symbionts inside the host requires various tools. Low-titer infections can only be detected with high-sensitivity methods such as combined PCR and hybridization. Furthermore, we show that high-end Stellaris® technology helps to uncover the localization of Glossina species, their native symbionts and the pathogenic trypanosomes, we should not underestimate their actual infection frequencies and infection localization through applying only low sensitivity detection tools.Taken together these results demonstrate that choosing a sensitive detection tool for determining symbiont infection status is very important. Gaining deeper insight into the biological and functional interactions between Glossina species from the palpalis group , the morsitans group , and from the fusca group . The Wolbachia-uninfected strain Drosophila simulans, NouméaTC [Wolbachia-positive control was D. willistoni, Panama98 (P98), carrying native high-titer Wolbachia . StrainDrosophila or a single adult tsetse fly. Individuals were disrupted with a TissueLyser TL bead mill, and DNA was consequently extracted using Puregene chemistry . Extracts were stored at − 20 °C until used for experiments. For classic endpoint-PCR, the Wolbachia-specific outer surface protein gene (wsp) was used to determine infection status. Diagnostic wsp-PCR reactions were performed as described in [wsp marker, the multi copy ARM locus (Wolbachia A-supergroup Repeat Motif) was used to screen for Wolbachia infection [Wolbachia-specific wsp-PCR was run on genomic DNA samples from all three species groups followed by gel electrophoresis on a 1% agarose gel. Amplicons were then transferred on a positively charged nylon membrane via capillary blotting, cross-linked and finally hybridized overnight with a digoxygenin-labeled internal wsp-probe. Detection was performed using sheep anti-DIG-conjugate .DNA was extracted from pools of 5–15 nfection . Endpoinnfection . BrieflyWolbachia 16S–23S ribosomal RNA transcripts were designed using the Stellaris® FISH probe designer Additional file 2:Figure S1. Control FISH on Glossina spp. (a) G. m. morsitans ovary hybridized with Wolbachia (red), and Wigglesworthia (green) probes in parallel. Wigglesworthia probe does not cross-react with Wolbachia. (b) Milk gland of Wolbachia-uninfected G. p. palpalis hybridized with Wigglesworthia (green) and Wolbachia (red) probes. While Wigglesworthia is recognized in the lumen of the gland, Wolbachia probe does not give any signal. (c) Triple staining  on tetracyline-treated G. m. morsitans female. None of three probes give a signal in the ovary. Fluorophore labels of 16-23S ribosomal RNA probes are FITC (Wigglesworthia), CAL Fluor Red 590 (Wolbachia), and Quasar 670 . Glossina DNA is stained in blue . (PDF 31389 kb)


The burden of non-communicable diseases has increased rapidly in low- and middle-income countries. Past studies have reported an association between socioeconomic status (SES) and cardio-metabolic risk factors, but most have focused on upper income countries. The purpose of this study is to examine the association between SES over the life-course and the burden of cardio-metabolic risk factors in middle-income countries.A total of 38 297 adults from China, Mexico, India, South Africa and Russia were included in this cross-sectional study. Life-course SES was defined based on maternal and participant education, and data on blood pressure, body mass index (BMI), self-reported diabetes and hypertension were obtained by trained interviewers. Descriptive, age standardized and multivariable adjusted analyses were conducted using survey weighted statistical procedures in SAS 9.4 .Although 14% of men and 12% of women had current hypertension based on blood pressure measurements, only 2% of men and 4% of women were aware of their hypertensive status. Men with stable high life-course SES had higher odds of being overweight/obese  = 1.30-3.10), diabetic  and hypertensive based on self-report  compared to men of low life-course SES. Among women, the odds of being overweight/obese were significantly higher among women with high life-course SES .Higher life-course SES for both men and women was associated with increased odds of overweight/ obesity, and additionally diabetes and hypertension for men in middle income countries. Cardio-metabolic risk factors such as hypertension, obesity and diabetes are associated with increasing burden of morbidity and mortality globally ,2. ChronSocioeconomic status (SES) at both individual , parentahttp://www.who.int/healthinfo/sage/cohorts/en/). The current analysis focused on one country from each continent represented in SAGE and included 38 297 participants ages 18 and older from the nationally representative samples of five middle-income countries – China, India, Mexico, Russia and South Africa.The data used for this analysis was obtained from wave one of the World Health Organization (WHO) Study on Global Ageing and Adult Health (SAGE) conducted between 2007 and 2010. The SAGE study was designed as a longitudinal study aimed to assess well-being, quality of life, and access to health care for individuals in developing countries, and obtained data across populations in six different countries; China, Ghana, India, Mexico, South Africa and Russia. A multistage cluster sampling study design was utilized to create nationally representative cohorts from each country. Survey instruments were adapted and modified from the World Health Survey (WHS) and used for individual and household interviews. Trained field staff obtained measurements of blood pressure, height and weight of participants, and a detailed questionnaire translated to the local languages were administered. More information on the SAGE study can be obtained through the WHO SAGE website: (2) and overweight/obese (BMI≥25.0 kg/m2). Current hypertension was based on the average of 3 blood pressure readings obtained by trained field personnel, and classified as present if average blood pressure reading was ≥140/90 mm Hg. History of hypertension was defined based on self-reported ever diagnosed of hypertension, use of anti-hypertensive medications or diet modification to control hypertension. History of diabetes was defined based on self-reported ever diagnosed of diabetes and the use of anti-diabetes medication or dietary control of diabetes.Cardio-metabolic risk factors assessed included body mass index (BMI), current hypertension, history of hypertension, and history of diabetes. BMI was calculated based on measurement of height and weight and categorized into normal weight  (P < 0.001), systolic blood pressure (SBP) (P < 0.001), and BMI (P < 0.001) than participants with complete data but there was no difference in type 2 diabetes status (P = 0.763). All statistical analyses were conducted in SAS 9.4  using survey weights, strata and cluster variables provided with the SAGE data set, thus enabling study results to be generalizable to the entire population of included countries.Survey-weighted frequencies and percentages and χata Base , using sA total of 38 297 participants were included in this analysis: 16 014 men and 22 283 women ages 18 years and older  = 1.30-3.10) or declining SES  had higher odds of overweight/obesity compared with men in stable low SES, while women with stable high , increasing  or declining  life-course SES had higher odds of overweight/obesity compared with women with stable low SES , we observed that the population distribution of stable high life-course SES ranged from 18% in China to over 80% in Russia. In addition, the highest age-standardized rates of overweight/obesity, history of hypertension, and diabetes were observed in Mexico, South Africa, Russia, respectively. Across the included countries, men with stable high life-course SES had two to four times higher odds of being overweight/obese, diabetic and hypertensive compared with men of stable low life-course SES. While women with stable high, declining and increasing life-course SES had up to a 2-fold increased odds of overweight/obesity compared with stable low life-course SES. We also observed that a significant proportion (13%) of participants were hypertensive based on blood pressure measurements obtained during in-person interviews, but 76% them had no prior knowledge of having hypertension. The largest disparity between self-reported history of hypertension and current hypertension was observed in South Africa where only 6% of men with hypertension were aware that they had hypertension or high blood pressure, whereas 38% had hypertension based on blood pressure measures.The associations observed in this study are consistent with existing studies showing that in lower and middle income countries, higher SES individuals have a higher prevalence of obesity, diabetes and hypertension compared with lower SES individuals, while in high-income countries, the association is typically inverse -22. Few The potential mechanisms explaining the association between SES and cardio-metabolic risk factors in the studied countries may include socially patterned behavioral risk factors such as alcohol use, dietary quality and physical activity . AlcoholCardio-metabolic risk factors are implicated in the etiology of multiple non-communicable diseases such as cardiovascular diseases and cancer, with increasing prevalence of those conditions in LMICs, and accounting for increasing majority of deaths worldwide . FindingThis study evaluated data on a large sample of adult representative of five middle-income countries, therefore enhancing the generalizability of these results. In-person interviews and biometric measures were obtained directly by well-trained WHO field staff, enhancing the quality and internal validity of our study variables. Life-course SES was measured consistently with other studies, and the current analysis focused on maternal and individual education since these variables have been observed to be highly correlated with health behaviors in prior studies .Data on SES and certain risk factors were based on self-reported information which may be vulnerable to recall bias. Classification of participants on the risk factor measurements might underestimate the number of those with the risk factors or participants with ongoing treatment, which may bias the result towards the null. In addition, we used BMI to assess overweight/obesity although studies suggest that central obesity may be a more important measure of adiposity in certain population groups.Stable high and declining life-course SES was associated with increased odds of overweight/obesity, diabetes and hypertension among men in the middle-income countries examined. Among women, stable high, increasing and declining life-course SES was also associated with increased odds of overweight/obesity. These patterns suggest that the influence of SES on adult health for men may operate during critical periods in early life, while for women, it may be accumulative over the life-course. The majority of adults who were hypertensive based on blood pressure measurements by trained interviewers were unaware of their condition, indicating an urgent need for increased awareness, primary prevention and treatment.