Background: This study aimed to examine trends in smoking-related cancer mortality rates and to investigate the effect birth cohort on smoking-related cancer mortality in Korean men. Methods: The number of smoking-related cancer deaths and corresponding population numbers were obtained from Statistics Korea for the period 1984–2013. Joinpoint regression analysis was used to detect changes in trends in age-standardized mortality rates. Birth-cohort specific mortality rates were illustrated by 5 year age groups. Results: The age-standardized mortality rates for oropharyngeal decreased from 2003 to 2013 : −3.1 ) and lung cancers decreased from 2002 to 2013 (APC −2.4 (95% CI −2.7 to −2.2)). The mortality rates for esophageal declined from 1994 to 2002 (APC −2.5 (95% CI −4.1 to −0.8)) and from 2002 to 2013 (APC −5.2 (95% CI −5.7 to −4.7)) and laryngeal cancer declined from 1995 to 2013 : −3.3 (95% CI −4.7 to −1.8)). By the age group, the trends for the smoking-related cancer mortality except for oropharyngeal cancer have changed earlier to decrease in the younger age group. The birth-cohort specific mortality rates and age-period-cohort analysis consistently showed that all birth cohorts born after 1930 showed reduced mortality of smoking-related cancers. Conclusions: In Korean men, smoking-related cancer mortality rates have decreased. Our findings also indicate that current decreases in smoking-related cancer mortality rates have mainly been due to a decrease in the birth cohort effect, which suggest that decrease in smoking rates. Cigarette smoking is the most important health problem worldwide, accounting for an estimated six million deaths annually—both from cancer and other diseases . In Korepast smoking rates—9–40 years prior to these outcomes occurring [Conversely, the disease burden from smoking-related cancers in Korean women was estimated to have increased from 351.8 disability-adjusted life years (DALY) in 2001 to 732.2 DALYs in 2008. Korean men have followed a similar pattern, with a DALY of 1930.1 in 2001 increasing to 2038.9 in 2008 [Age-period-cohort modeling enables the separation of the effects of age, period, and cohort. Additionally, it allows description of their simultaneous effects on disease trends . The cohThe aim of this study was to examine the secular trends in smoking-related cancer mortality rate and to investigate the birth cohort effect on smoking-related cancer mortality in Korean men.We restricted our study to Korean men only because men have much higher smoking rates compared to women. Indeed, smoking rate in women is relatively low and stable compared to men in Korea . Accordihttp://kosis.kr/) [We thus postulated that trends in cancer mortality in men would better reflect the effects of smoking. We defined smoking-related cancer as oropharyngeal, esophageal, laryngeal, and lung cancer ,6,15. Thsis.kr/) . Oropharsis.kr/) .To examine the time trends in age-standardized mortality rates for oropharyngeal, esophageal, laryngeal and lung cancer, we conducted Joinpoint regression analysis for mortality rates of oropharyngeal, esophageal, laryngeal and lung cancer.After estimating the time trends in age-standardized mortality rates, study participants were restricted to men aged ≥40 years old, because the mortality rate among men aged <40 years old was very low. To investigate the birth cohort effects on smoking-related cancer mortality, the mortality data were divided into six periods of five years each (1984–1988 to 2009–2013) and nine age groups of five years each (40–44 to ≥80 years). The consecutive fourteen birth cohort groups were calculated by subtracting age from the period (birth cohort = period − age). Ethics approval for the research protocol was granted by the institutional review board (IRB) of the National Cancer Center .Age-standardized mortality rates (ASMRs) for oropharyngeal, esophageal, laryngeal, and lung cancer were calculated by using Segi’s World Standard population as the standard population. Joinpoint regression modelling was used to test trends in ASMRs for oropharyngeal, esophageal, laryngeal and lung cancers and to establish significant changes over time to fit a better multi-segmented model compared with a simple linear model . The treTo evaluate the birth cohort effect on smoking-related cancer mortality, age was categorized into five-year age groups (from 40–44 years to ≥80 years of age). The birth cohort specific cancer mortality rate were stratified by age group to evaluate the cohort effects. To evaluate birth cohort effects after adjusting for age and period effects, a log-linear model using the intrinsic estimator (IE) method was performed, based on the assumption that the number of deaths in each age group followed a Poisson distribution ,19. The p-values less than 0.05 were considered statistically significant. The statistical analysis was performed using SAS software version 9.3 , Stata Statistical Software Release 12  and Joinpoint Regression Program software version 4.1.1 .The final model was selected by goodness of fit test using Akaike information criterion (AIC) and likelihood ratio test . p-valueBetween 1984 and 2013, the total number of deaths for all cancer sites combined among Korean men was 1,024,976 . Of thesRecent trends show that the ASMRs from these smoking-related cancers have begun to decrease. The mortality rate for oropharyngeal cancer has decreased from 2003 to 2013 ), as shown in The annual percentage increase of lung cancer has slowed, from an increase of 9.4%  between 1984 and 1994, to an increase of 1.5%  between 1994 and 2002. After 2002, the mortality rate of lung cancer has reduced , shown in According to the age group, the mortality rates for oropharyngeal cancer, esophageal cancer and laryngeal cancer showed the highest mortality rate for the period of 1999–2003, and then leveled off for the period of 2004–2008 and 2009–2013 among ≥80 years old age group A–C. On tOur study showed that mortality from various smoking-related cancers has decreased since 1995 or 2003. Although there were cancer-specific differences in when mortality rate (of the four smoking-related cancers) decreases started, the pattern was very similar. The age-standardized mortality rates for smoking-related cancers have decreased later as age increases. This study also shows that birth cohorts born in the 1920–1930s had the highest smoking-related cancer mortality rate. The birth cohort effects subsequently leveled off, and then began to decrease in younger generations.In our study, the decrease in the smoking-related cancer mortality rate began at a similar point in time for oropharyngeal and lung cancer, and for esophageal and laryngeal cancer. Although well known that these four cancer types are especially related to smoking, the different time points at which their mortality rates began to decrease were likely due to the different period effects, reflecting advances in treatment. Indeed, the starting points and patterns of mortality decrease given birth cohort effects for these smoking-related cancers were similar. The decreasing birth cohort pattern for lung cancer mortality parallels the age-period-cohort analyses in Spain , the UniIn our study, the mortality rates of esophageal and laryngeal cancer decreased from 1996. Although it was difficult to establish smoking rates in Korea, the smoking rate seemed to reach its peak (79.3% among Korean men), in the 1980s and then to have leveled off . The KorAlthough we could not show the change of trends in mortality rate for cardiovascular disease or chronic obstructive lung disease, it is obvious that many people also died from smoking related cardiovascular disease or respiratory disease in Korea. The nationwide representative study showed that about 35% of Korean men aged >45 years old with 20 pack-years of smoking had chronic obstructive pulmonary disease . In addiOur findings have some limitations. Firstly, it is impossible to investigate a causal relationship or to calculate an attributable fraction, because our study was not an individual-based study. Secondly, the accuracy and completeness of the mortality data in Korea has gradually improved, but may have inaccuracies. Therefore, it could bias the estimates of either changes in mortality trends or birth cohort effects. Although smoking is the most important single factor which accounts for >50% of smoking-related cancer risk in our study, changes another risk factors for smoking-related cancer could be included in the cohort effects. Therefore, the interpretation of changes in birth cohort effects of smoking-related cancer mortality should be caution, because historical differences, history of infection epidemics, and changes of life style except smoking habit were involved in birth-cohort effects. In addition, it was impossible to analyze the age-period-cohort effects for incidence rate of smoking-related cancer, because the time period for cancer incidence was relatively short. Despite these limitations, our findings are useful to examine the secular trends in smoking-related cancer mortality. This study demonstrates that smoking-related cancer mortality follows similar birth cohort effects, suggesting that this reduction was mainly due to decreases in smoking rates.In summary, oropharyngeal, esophageal, laryngeal, and lung cancer followed similar birth cohort effects, although the time points at which the mortality rate decreases began were slightly different slightly for each particular cancer. The similar cohort patterns for four types of smoking-related cancers suggest that the reduction in smoking rate led to a decrease in the cohort effect on smoking-related cancer mortality.


Doppler ultrasonography can be used to assess neoangiogenesis, a characteristic feature of postmolar gestational trophoblastic neoplasia. However, there is limited information on whether uterine artery Doppler flow velocimetry parameters can predict gestational trophoblastic neoplasia following a complete hydatidiform mole. The purpose of this study was as follows: 1) to compare uterine blood flow before and after complete mole evacuation between women who developed postmolar gestational trophoblastic neoplasia and those who achieved spontaneous remission, 2) to assess the usefulness of uterine Doppler parameters as predictors of postmolar gestational trophoblastic neoplasia and to determine the best parameters and cutoff values for predicting postmolar gestational trophoblastic neoplasia.This prospective cohort study included 246 patients with a complete mole who were treated at three different trophoblastic diseases centers between 2013 and 2014. The pulsatility index, resistivity index, and systolic/diastolic ratio were measured by Doppler flow velocimetry before and 4-6 weeks after molar evacuation. Statistical analysis was performed using Wilcoxon’s test, logistic regression, and ROC analysis.No differences in pre- and post-evacuation Doppler measurements were observed in patients who developed postmolar gestational trophoblastic neoplasia. In those with spontaneous remission, the pulsatility index and systolic/diastolic ratio were increased after evacuation. The pre- and post-evacuation pulsatility indices were significantly lower in patients with gestational trophoblastic neoplasia (odds ratio of 13.9-30.5). A pre-evacuation pulsatility index ≤1.38 (77% sensitivity and 82% specificity) and post-evacuation pulsatility index ≤1.77 (79% sensitivity and 86% specificity) were significantly predictive of gestational trophoblastic neoplasia.Uterine Doppler flow velocimetry measurements, particularly pre- and post-molar evacuation pulsatility indices, can be useful for predicting postmolar gestational trophoblastic neoplasia. A complete hydatidiform mole (CHM), which is characterized by increased hyperplasia, progresses to gestational trophoblastic neoplasia (GTN) in 9-20% of cases Predicting CHM malignancy potential is of the utmost importance because it allows for the prompt treatment of post-molar GTN, limiting the exposure of most patients to combination chemotherapy Clinical factors, such as age, ovarian enlargement, a large-for-date uterus, previous history of molar pregnancy, hCG level Transvaginal ultrasound with power Doppler can predict delayed response to chemotherapy and drug resistance in low-risk trophoblastic neoplasia The purpose of this study was two-fold and is summarized as follows: 1) to compare uterine blood flow before and after CHM evacuation between women with post-molar GTN and those with spontaneous remission 2) to assess the usefulness of uterine DFV parameters as predictors of post-CHM GTN and determine the best prediction parameters and cutoffs.This prospective cohort study included women with CHM who were treated at three different trophoblastic diseases centers between 2013 and 2014. CHM was diagnosed based on ultrasound findings confirmed by histopathological analysis and p57 immunohistochemistry. All patients were initially treated with suction D&C, and they underwent uterine artery Doppler flow velocimetry (DFV) at admission and after CHM evacuation. Women were excluded from the study if they did not undergo post-evacuation DFV or were lost to follow-up after this procedure. The study was approved by the Institutional Committee of Research Ethics , and it was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients.Assuming that GTN follows CHM in 15% of cases, the minimum sample size was estimated to be 175 patients (type 1 error = 0.05 and type 2 error = 0.20) to achieve a statistical power of 0.8 (80%) in all tests.Data collected at admission included age, number of pregnancies, parity, gestational age at diagnosis, uterine size, presence of theca lutein cysts >6 cm , and pre-evacuation hCG level. An excessive uterine size was considered present if the uterus was at least 4 weeks greater in size than expected for the gestational age on clinical examination ®, New York, NY, USA) with a 5.0-MHz convex transducer. For the transvaginal scan, women were asked to empty their bladders and were placed in the dorsal lithotomy position. The ultrasound probe was then inserted into the vagina and placed in the lateral fornix, and the uterine artery was identified using color Doppler at the level of the internal cervical os. The ascending branch of the uterine artery at both its paracervical portion and at the point closest to the internal os was identified, and pulsed wave Doppler was applied with the sampling gate set at 2 mm at an angle of insonation <30°. After four consecutive similar waveforms were obtained, the pulsatility index (PI), resistivity index (RI), and systolic/diastolic ratio (S/D) were automatically calculated by the scanner software. The PI, RI and S/D were defined by the following formulas:Transabdominal sonography was performed for global evaluation of the pelvis, and transvaginal imaging was performed for a more detailed evaluation of the uterus, endometrial cavity and adnexae. Because the site of molar implantation in the uterus was unknown, the DFV of both uterine arteries was performed at admission (up to 2 hours pre-evacuation) and 4-6 weeks after CHM evacuation. Doppler assessments were performed using a Colored Doppler Ultrasound  An hCG level plateau of four values ±10% recorded over a 3-week duration .An hCG level increase of more than 10% of three values recorded over a 2-week duration .Remission was declared after undetectable hCG levels were achieved for 3 consecutive weeks and then at monthly intervals for 1 year.p<0.05.Statistical analyses were performed using SPSS v 21.0. The non-parametric Wilcoxon test was used to compare pre- and post- CHM evacuation DFV parameters between women who developed post-molar GTN and those who achieved spontaneous remission. The usefulness of uterine DFV parameters as predictors of post-CHM GTN was assessed using multiple logistic regression adjusted for age, gestational age, enlarged uterus for gestational age, theca lutein cysts, and pre-evacuation hCG level. The best DFV parameters and cutoff values for predicting post-CHM GTN were determined by receiver operating characteristic (ROC) analysis, including calculation of the areas under the curves. Statistical significance was set at Of 276 women diagnosed with CHM, 246 were included in the analysis. Of the 30 remaining women, 17 did not undergo post-evacuation DFV, and 13 were lost to follow-up after post-evacuation DFV; therefore, they were excluded from the study. The median patient age was 24 years (13-47 years), and the median gestational age was 8 weeks (4-16 weeks). No significant differences were observed between pre- and post-evacuation or right and left uterine artery DFV measurements. Development into GTN occurred in 20% of the cases .PI was the Doppler parameter that was most strongly associated with risk of post-CHM GTN both pre-and post-evacuation, i.e., women showing lower PI values were more likely to develop GTN following CHM  . The besNeoangiogenesis is a critical feature of malignancy. It is a key component of tumorigenesis, tumor growth and metastatic spread, and it is associated with drug resistance and poor prognosis in several solid tumors Doppler flow velocimetry (DFV) offers a noninvasive technique for neoangiogenesis quantification by assessing the vascularity and circulatory resistance of blood flow through the uterine arteries. In the early diagnosis of invasive GTD, DFV clearly shows an advantage over classical hCG measurements because it can detect the presence of post-evacuation invasive GTD weeks before an hCG rise or plateau occurs Our results show that most women participating in this study were young (13-47 years) and were diagnosed in the early first trimester of pregnancy. The development of post-CHM GTN occurred in 20% of the cases; this rate is similar to those found in studies that include patients diagnosed later in the first trimester or even in the second trimester of pregnancy Compared to pre-evacuation measurements, the PI and S/D significantly increased (in both arteries) after evacuation in participants with spontaneous remission (n=197). In those who developed GTN, the pre- and post-evacuation DFV measurements remained (n=49) significantly lower. Similar findings In this study, PI was the Doppler parameter that was most strongly associated with the risk of post-CHM GTN pre-and post-evacuation. The best cutoff PI values for predicting GTN were ≤1.3 pre-evacuation  and ≤1.7 post-evacuation . These values are similar to those reported by Maymon et al. Previous studies assessing the role of Doppler indices in predicting the development of trophoblastic tumors have yielded conflicting findings, which is probably because of the small number of patients. The results of this larger prospective study show that uterine DFV measurements, particularly pre- and post-molar evacuation PI, can be useful for predicting GTN following CHM in a much larger population. Indeed, participants with lower PI values were more likely to develop GTN following CHM. However, although the Doppler angle of insonation was kept as low as possible, small deviations and inaccuracies in drawing the contour of the waves may have occurred due to the small diameter and tortuosity seen in the uterine vessels. Nonetheless, the uterine artery PI has been considered an objective measure of vascularity that is not based on the subjective selection of regions of interest, and it has been reported as a useful noninvasive marker of tumor vascularity in previous studies Predicting a high chance for developing GTN has become highly important as the early detection of molar pregnancy with ultrasound no longer allows for observation of some clinical features, such as theca lutein cysts and large-for-age uterine size, which are only encountered at a more advanced gestational age It is noteworthy, however, that, according to Kohorn In brief, this study demonstrated the following: 1) post-evacuation DFV parameters were significantly increased (in both arteries) in women with spontaneous remission, 2) lower PI values were associated with a higher risk of developing GTN following CHM, and 3) PI was the Doppler parameter most strongly associated with risk of post-CHM GTN with cutoffs of ≤1.3 pre-evacuation and ≤1.7 post-evacuation. These results, which were prospectively obtained in a large population, validate the usefulness of the uterine artery PI as a marker of GTN development following CHM.Asmar FT conducted the research and wrote the manuscript. Braga-Neto AR helped selecting patients, performed data collection and critically revised the manuscript. Rezende-Filho J critically revised the manuscript. Villas-Boas JM designed the analytic strategy. Charry RC critically revised the manuscript. Maesta I conceived, designed and supervised the project.


BMC Medicine, “Spotlight on landmark oncology trials”, features articles from invited experts on recent clinical practice-changing trials.The era of precision oncology is marked with prominent successes in the therapy of advanced soft tissue sarcomas, breast cancer, ovarian cancer and haematological neoplasms, among others. Moreover, recent trials of immune checkpoint inhibitors in melanoma, non-small cell lung carcinoma, and head and neck cancers have significantly influenced the therapeutic landscape by providing promising evidence for immunotherapy efficacy in the adjuvant setting in high-risk locoregional disease. To speed up the introduction of targeted therapy for cancer patients, novel phase II trials are being designed, and may likely form the basis for the ‘landmark trials’ of the future. A special article collection in  The era of precision medicine has led to significant developments in the therapy of advanced soft tissue sarcomas (STS), breast cancer, ovarian cancer and haematological neoplasms, among others. However, cancer research also faces challenges in the effective development and assessment of targeted therapeutics , includiBMC Medicine, which focuses on the core clinical trials of selected solid tumours . We alsThe first articles in the special article collection focus on landmark clinical trials in selected advanced solid tumours, with special attention on the most studied tumours with regards to immunotherapy development, namely melanoma , 4, NSCLBRAF-mutated cases.The current results of anti-PD-1 therapy with pembrolizumab or nivolumab monotherapy in melanoma indicated a median overall survival (OS) of approximately 2 years, but the combination of anti-PD-1 and anti-CTLA-4 (nivolumab with ipilimumab) was shown to be superior in terms of progression-free survival (PFS) and OS . A more recent niraparib study had similar results [BRCA cohort; 12.9 vs. 3.8 months in the non-gBRCA cohort for patients who had tumours with homologous recombination deficiency; and 9.3 vs. 3.9 months in the overall non-gBRCA cohort; P < 0.001). Both trials demonstrated significant benefit for maintenance PARP inhibitors in all subgroups of platinum-sensitive relapsed high-grade serous ovarian cancer.The landmark phase III trials in high-grade serous ovarian cancer are testing PARP inhibitors as maintenance therapy after response to platinum-based therapy in relapsed disease. Study 19 , 29 used results , where pWith the advent of novel oral agents that are well tolerated and highly efficacious, the therapeutic landscape of CLL underwent radical changes . In phasIn conclusion, the RESONATE-2 trial demonstrates that ibrutinib is a new important player in the treatment of elderly unfit patients and in those with high-risk disease. A potential shortcoming with the upfront use of ibrutinib includes cost and indefinite treatment course . FinallyBMC Medicine series “Spotlight on landmark oncology trials” and this editorial are recent trials that have produced practice-changing results for patients. These trials represent the end of the long process of translating scientific innovation and drug discovery, through first-in-man studies, followed by phase II trials and finally by randomised phase III trials as required for licensing of new treatments. Novel trial designs could potentially lead to a different type of landmark trial that would accelerate the process and allow cancer patients to access new treatments faster. In the phase I setting, there is a pressing need to develop better trial methodologies for novel combinations, often of a standard chemotherapy with a novel targeted agent. Di Veroli et al. [The landmark oncology trials highlighted in the i et al.  publishei et al. .In the era of precision cancer medicine, innovative trial designs will also require the matching of novel drugs with putative targets. Indeed, BATTLE, a landmark phase II trial using an adaptive randomised design, tested four novel drugs and biomarker pairings in NSCLC . This wa


Few studies have focused on exploring the association of self-efficacy and suicidal behaviour. In this study, we aim to investigate the association between health-related self-efficacy and suicidality outcomes, including lifetime/recent suicidal ideation, suicidal attempts and future intent of suicide.A computer-assisted telephone interview (CATI) system was used to draw potential respondents aged over 15 in Taiwan via telephone numbers, which were selected by a stratified proportional randomization method according to the distribution of population size in different geographic areas of Taiwan. We obtained available information on suicide behaviours for the analysis of 2110 participants. Logistic regression was applied to investigate the independent effect of health-related self-efficacy on life-time suicidal thoughts and attempts.Suicidality measured as suicide ideation and attempted suicide was reported as 12.6 and 2.7% respectively in the sample. Among those with suicide ideation, 9.8% had thoughts of future suicide intent. Female gender, low education, people living alone or separated, history of psychiatric disorders, substance abuse, poor self-rated mental health and physical health were associated with suicidality factors. Low health-related self-efficacy was associated with lifetime suicide ideation, prior suicide attempt and future suicidal intent. Among those with recent suicidal ideation, low health self-efficacy was independently associated with future suicide intent after adjustment of gender, age, education, marital status, substance abuse, psychological distress, poor mental and physical health.Health-related self-efficacy was associated with suicide risks across different time points from prior ideation to future intention. Evaluation of the progress of self-efficacy in health may be long-term targets of intervention in suicide prevention strategies. The suicide rate in Taiwan has been decreasing since 2010 from a high rate of 16.8 to 15.7 per 100,000 in 2015 according to national statistical data. Suicide poses a significant social and economic burden . PsychiaSuicidality is a complex multifactorial process. It is not known whether self-efficacy impacts on suicide behaviours in the cultural context of Taiwan. Health confidence and health-related self-efficacy are adaptive cognitive factors that have been shown to improve health behaviours . A higheOnly a few studies have globally focused on the association of self-efficacy and suicidal behaviour . A commuPopulation study sampling was performed via the project administrator of Taiwan Suicide Prevention Centre (TSPC). Specifically, participants were contacted upon sampling via a telephone survey on population mental health, knowledge and behaviour of suicide prevention carried out by the Centre. The ethical approval was acquired from the general hospital the corresponding author affiliates (reference number 201204034RIC). The survey recruited a representative random sample of the general population aged over 15 in Taiwan. Data were collected between July 14th and 23th in 2015 by personnel with specific training for this survey. A computer-assisted telephone interview (CATI) system was used to draw potential respondents via telephone numbers selected by a stratified proportional randomization method according to the distribution of population size, gender and age in different geographic areas of Taiwan. In total, initially, 21,384 subjects landline phone numbers were randomly selected, and 5430 respondents aged 15 years or older were contacted, with 2110 respondents agreed to take part in the survey anonymously over the phone and accomplished the interview .The questionnaire used in the interview included demographics  and health-related bio-behavioural measures , and suicide risk factors . Definition and assessment for these key variables are listed below.Suicide ideation/intention to suicide: We evaluated whether the respondents had had previous suicide ideation across different time points; lifetime and in the past week. We also assessed whether they may have future suicide intent through the question, “Is it likely that you may attempt suicide in the future?”Suicide attempts: The respondents were asked whether they had engaged in a suicide attempt and when this occurred. We determined if this attempt ever happened in their lifetime (classified as a previous attempt).Health-related measures: A single item question was used to assess health-related self-efficacy based on standard methodology for measuring self-efficacy beliefs . The parPsychopathology assessment: We used the Brief Symptom Rating Scale to measure the level of psychological distress in the past week of the respondents . It is aSubstance abuse: A single question was used to assess whether a previous substance misuse leading to life impairments had occurred due to any illicit drug, prescription medication, or alcohol. Substance abuse during any period of lifetime was recorded as a binary response of yes or no based on self-report.p < 0.05.Descriptive statistics of demographic variables are presented. The following tests were used for data analyses. Univariate and bivariate tabulation was conducted as a prerequisite for multivariate analyses. Associations between independent variables and lifetime suicidal ideation, suicide attempt and future suicide intent were performed using chi-square tests and then were presented as odds ratios (ORs) with 95% confidence intervals (CIs). Self-efficacy score was significantly skewed, therefore the score was log-transformed for further analysis. In order to identify low health-related self-efficacy, a tertile spit of the self-efficacy scale was conducted. The participants in the lower tertile (represented a score of below 80) were categorised as having low health self-efficacy. Multivariate logistic regression was applied to investigate the independent effect of health-related self-efficacy on lifetime suicidal thought and attempt after separate and successive inclusion of other independent variables in the model. The independent effects of health- related self-efficacy on associations with future suicide intent were performed. The subgroup here was those with life-time suicidal ideation. The model was adjusted for age, gender, marital status, history of psychiatric disorders, substance abuse and self-rated physical & mental health. We modelled whether self-efficacy would be independently associated with different assessments of suicidality . All statistical analyses were performed using the SPSS v21, and statistical significance was defined as a value of t = 55.8, p < 0.001. Participants with psychological distress and substance abuse of drug or alcohol represented in 15 and 2.9% of the sample, respectively. One-fourth (25.4%) reported poor self-rated physical health and 14.4% had poor self-rated mental health. Suicidality measured as lifetime suicidal ideation and prior attempted suicide were reported to be 12.6 and 2.7%, respectively. Among those with suicide ideation, 9.8% had thoughts of future intention of suicide.We obtained available information on suicide behaviours for the analysis of 2110 participants. Among the cohort, 53.2% were women. People who aged 15–19 years represented 20.1% of the sample; nearly half were those aged between 30 and 60 years (52.2%), and 27.7% was aged 60 years and above. About two-third (65.6%) of the participants was married and 28.2% was single. Sample characteristics were reported in Table Age and gender were not associated with suicidal behaviours in our sample Table . HoweverPoor self-rated mental health and physical health also showed associations with suicidality. The risk for suicidal ideation among those with poor self-rated mental health was . The risk increases for attempted suicide  and future suicide intent . For those with poor self-rated physical health the risk for suicidal ideation was , suicidal attempt  and future intent of suicide .Low health self-efficacy was associated with suicidal behaviours. The risks for suicidal ideation, attempted suicide and future suicide intent were ;  and  respectively. Tables Among those with lifetime suicidal ideation, stepwise logistic regression demonstrated an association between low health self-efficacy and future suicide intent Table . Low heaIn a large community-based telephone interview in Taiwan, we demonstrated that lower levels of health-related self-efficacy were associated with suicidality . The study findings were generally typical of the literature globally and for the region. In our sample, 12.6% had suicidal ideation and 2.7% attempted suicide. Globally, the estimated lifetime prevalence (SE) of suicidal ideation, plan, and attempt in cross-national sample is 9.2% (0.1), 3.1% (0.1), and 2.7% (0.1) . In the Our study and others have shown that female gender, low education, people living alone or separated, history of psychiatric disorders and substance abuse were associated with suicidality –24. In pWe demonstrated an increased risk of lifetime suicidal thought or suicidal attempt with low self-efficacy was independent of perceived mental and physical health. Importantly, among those with lifetime suicidal thought, health-related self-efficacy was an independent predictor of having thoughts for suicide actions in the future. A growing body of evidence supports the relationship between self-efficacy and sense of personal control over behaviour change. Indeed self-efficacy has an important role in patient health outcomes , 30. SelThe sensitivity of the association between health self-efficacy and suicidality was confirmed in our subgroup analyses. For example, among those with lifetime suicidal ideation, low health self-efficacy was associated with future suicide intent. Hence, health self-efficacy assessment may be a sensitive cognitive substrate to screen people with predisposed risk factors for suicide. Moreover, health self-efficacy assessment is simple and can be used by health professionals without much stigmatisation associated with binary mental health assessment scales. Increasing self-regulation, planning behaviour, positive feedback and empowerment can increase self-efficacy in carrying out lifestyle changes. There is evidence that mental health self-efficacy influences symptom outcomes when clients use a self-guided mobile phone and web-based psychotherapeutic intervention . HoweverOur study has salient strengths. The CATI survey has been conducted by the TSPC over a decade. The findings were derived from a large sample size randomly selected, thus ensuring representativeness. In this study, we simultaneously measured suicidality outcomes  in a random sample. Given that the topic is sensitive and complex, the responders could reply to these questions more comfortably via telephone interview due to anonymity. We controlled from major confounding factors known to be associated with suicidality, including self-perception of mental health and physical health. This emphasizes that health self-efficacy is an independent construct that is not superimposed or biased by self-perception of health. The main limitation of the study was that the findings were based on cross-sectional analyses, hence the causal inference could not be achieved. It is possible that participants with lower health-related self-efficacy may have difficulties managing their health and indulge in risky behaviours such as substance abuse. Indeed substance abuse is associated with suicidal behaviours. We had not measured factors such as whether lower health literacy was associated with reduced health-related self-efficacy and suicidal behaviours. On the other hand as we report in our study lower self-efficacy may serve as a marker for suicidal behaviours. Further, telephone interviews have innate limitations. For example, we drew landline numbers based on the registration list in computer directories and did not include mobile phone users, thus the results could only generalize to people who have landlines. However, CATI is a professional technique in collecting research data. Although such interviews may be influenced by participant environmental factors, which the researcher has limited control, structured questions and standard operating procedures developed by the researchers at the TSPC were followed by experienced personnel with specific training, thus ensuring that reliable data were acquired. Moreover, the research team has careful inspection of the yearly results drew from CATI for more than 12 years and published articles elsewhere , which pRegardless of these limitations, the study has implications for identifying and intervening individuals with suicidal risk. We have shown for the first time an association between health-related self-efficacy and lifetime suicidal thought and behaviour in Taiwan; and that the association was robust and was independent of factors known to be associated with suicidality. The authors concluded that health-related self-efficacy was associated with suicide risks in different time points. Perceived efficacy in health was significantly affected current or prior suicide ideation and future suicide intent. Our study adds to the literature on potentially modifiable factors and that evaluation of the progress of self-efficacy in health may be long-term targets of intervention in suicide prevention strategies.


WHO proposed the WHO Maternal Near Miss (MNM) tool, classifying women according to several  life-threatening conditions, to monitor and improve quality of obstetric care. The objective of this study is to analyse merged data of one high- and two low-resource settings where this tool was applied and test whether the tool may be suitable for comparing severe maternal outcome (SMO) between these settings.Using three cohort studies that included SMO cases, during two-year time frames in the Netherlands, Tanzania and Malawi we reassessed all SMO cases  with the WHO MNM tool . Main outcome measures were prevalence of MNM criteria and case fatality rates (CFR).A total of 3172 women were studied; 2538 (80.0%) from the Netherlands, 248 (7.8%) from Tanzania and 386 (12.2%) from Malawi. Total SMO detection was 2767 (87.2%) for disease-based criteria, 2504 (78.9%) for intervention-based criteria and 1211 (38.2%) for organ dysfunction-based criteria. Including every woman who received ≥1 unit of blood in low-resource settings as life-threatening, as defined by organ dysfunction criteria, led to more equally distributed populations. In one third of all Dutch and Malawian maternal death cases, organ dysfunction criteria could not be identified from medical records.Applying solely organ dysfunction-based criteria may lead to underreporting of SMO. Therefore, a tool based on defining MNM only upon establishing organ failure is of limited use for comparing settings with varying resources. In low-resource settings, lowering the threshold of transfused units of blood leads to a higher detection rate of MNM. We recommend refined disease-based criteria, accompanied by a limited set of intervention- and organ dysfunction-based criteria to set a measure of severity.The online version of this article (doi:10.1186/s12884-017-1370-0) contains supplementary material, which is available to authorized users. One of the Millennium Development Goals was to reduce global maternal mortality in 2015 by three quarters as compared to the level of 1990 .The World Health Organisation (WHO) has defined a MNM as a ‘woman who nearly died but survived a complication that occurred during pregnancy, childbirth or within 42 days of termination of pregnancy’ , 4. WHO According to WHO, uniformity of this MNM classification should make it possible to compare the quality of obstetric care between different settings in different countries, which would be useful in improving health care delivery. However, in some low-resource settings application of the WHO MNM tool showed underreporting of life-threatening maternal morbidity. This may be due to lack of blood for transfusion, absence of laboratory diagnostics and poor clinical monitoring, which are all needed to identify MNM –8.In a nationwide cohort, we previously found that also in the Netherlands, a high-resource setting, organ dysfunction-based criteria failed to identify almost 60% of women with severe acute maternal morbidities as MNM . If thesOur previous studies have highlighted difficulties in finding universal criteria to identify MNM and raise questions about the applicability of the MNM tool in general, and its focus on organ dysfunction-based criteria in particular –9. The oIn this current study, we used merged data available from SMO databases collected in the Netherlands, Tanzania and Malawi. Data for the Netherlands were extracted from a two-year nationwide cohort study (the LEMMoN-study), for Tanzania from a two-year cross-sectional study at Haydom Lutheran Hospital and for Malawi from a two-year study of maternal morbidity and mortality at Thyolo District Hospital (the ‘4 M-study’). A general description of the three study populations can be found in Table Women with SMO were included according to definitions established by the original studies Table . We reasData from the three studies were collected into a single database containing the following variables: age , parity , units of blood given , duration of hospital stay, maternal mortality, and classification according to the three WHO MNM tool criteria groups . If women had multiple conditions or interventions they were included into more than one criteria group, with each included criterion titled a separate ‘event’. Case fatality rates (CFR) were calculated for the corresponding populations.All parameters were compared between each country’s population and those women who sustained life-threatening conditions as per WHO definition. Outcomes for the three countries were analysed individually and compared for differences. Finally, the life-threatening group was corrected by including every Tanzanian and Malawian woman (where giving five or more units is an exception even in life-threatening haemorrhage ) who recData were analysed using chi-square tests for categorical data and independent sample t-tests for numerical data. Statistical analysis was performed using SPSS statistics, version 20.0 . All three initial studies had ethical approval and for present study anonymous data were used.A total of 3172 women were analysed: 2538 (80.0%) from the Netherlands, 248 (7.8%) from Tanzania, and 386 (12.2%) from Malawi. General characteristics of all three populations are shown in Table After assessment with the WHO MNM tool, out of the 2538 Dutch women, 2308 (90.9%) fulfilled one or more disease-based criteria, 2116 (83.4%) any intervention-based criterion and 1024 (40.3%) any organ dysfunction-based criterion. In Tanzania there were 123 (49.6%) women fulfilling disease-based, 231 (85.9%) intervention-based, and 103 (41.5%) organ dysfunction-based criteria. For Malawi these numbers were 336 (87.0%), 175 (45.3%), and 84 (21.8%), respectively. The detection in the combined study population of 3172 women was 2767 (87.2%) women for disease-based, 2504 (78.9%) for intervention-based, and 1211 (38.2%) for organ dysfunction-based criteria. Only this final group sustained ‘life-threatening conditions’ according to WHO methodology. The CFRs were 48/2538 (1.9%) for the Netherlands, 32/248 (12.9%) for Tanzania and 46/386 (11.9%) for Malawi. Of these maternal deaths, 17 (35%) women in the Netherlands and 15 (33%) women in Malawi could not be identified as having had a ‘life-threatening’ condition. In Tanzania, all maternal deaths could be defined.For the total population, analysis of the events detected by the WHO MNM tool subcategories is shown in Table Among women with life-threatening conditions  can be seen in Tables Our results indicate that the WHO MNM tool, in its current form, is not useful for comparison between different resource settings. Detection differs between high- and low-income countries and organ dysfunction-based criteria detect only 38.2% of all women with SMO as defined by the three cohort studies.mortality and based on the specified criteria, organ dysfunction could not be identified from the medical records in 17 out of 48 cases (35%) in the Netherlands and 15 out of 46 cases (33%) in Malawi. We believe that a revision of the WHO MNM tool and specifically the organ dysfunction-based criteria is needed to enable meaningful comparison between different resource settings.Moreover, in cases of maternal A recent study by Menezes et al. states that the WHO criteria perform well . In thisThe underestimation of severe maternal outcome when applying the WHO MNM tool in its current form remains an important issue. Overall, disease-based criteria show the highest detection of SMO (87.2%) in each type of setting. An explanation for the low detection rate (49.6%) in the Tanzanian population could be the local SMO criteria used in that study. For example, this led to fewer women with PPH (according to the WHO MNM definition of blood loss above one liter) in this cohort, as PPH as such was no separate inclusion criterion in the Tanzanian cohort  and women were only included if they had received blood transfusion. The intervention-based criteria detected 78.9% of all SMO cases. An explanation for the low detection (45.3%) in the Malawian population is the absence of interventional radiology and an ICU. Both disease-based and intervention-based criteria show higher SMO detection in each setting compared to organ dysfunction-based criteria. The CFRs of the potentially life-threatening populations (fulfilling only disease-based criteria) in low-resource settings remain high . This implies that there is hardly any ‘over-inclusion’ in such settings and that these women should be picked up as SMO in the ‘potentially life-threatening phase’ of their conditions.The lack of laboratory and clinical diagnostics for detecting organ dysfunction explains underreporting in low-resource settings –9. SimilDifferent criteria for SMO used in the three cohorts are the most important limitation of this study. SMO cases, as identified differently by local criteria, are being compared according to a single WHO MNM tool. The consequence may be an underestimation of SMO in low-resource settings as Tanzania and Malawi due to limited available diagnostics. However, this limitation also stresses the fact that application of the WHO MNM tool may differ in different contexts.Another major issue is that, although WHO uses a threshold of five units, there is no consensus about the number of units of blood transfused, which identifies organ dysfunction –9. AfterAlthough it is clear that there is an urgent need for monitoring health care delivery in both high- and low-resource settings, it remains difficult to determine which set of criteria should be used. In our opinion, disease-based criteria remain important in all settings, since detection rate is high and does not depend on local protocols. In contrast, for the same reason, intervention-based criteria (such as ICU admission) are of limited use. To prevent ‘over-inclusion’ for disease-based criteria, especially in high-income countries, more strict operational definitions (such as the blood loss threshold defining ‘severe postpartum haemorrhage’) are needed. For low-resource settings, supplemented clinical markers such as gasping, oliguria or jaundice could be included. Also, the threshold of received units of blood should be lowered for organ dysfunction-based criteria .In conclusion, we have shown that applying solely organ dysfunction-based criteria may lead to underreporting of SMO. Therefore, a tool based on defining MNM only upon establishing organ failure is of limited use for comparing settings with varying resources. It is important to enact the discussion and eventually reach consensus for a tool that is usable in all resource settings and detects the highest percentage of the actual rate of SMO. We recommend refined disease-based criteria, accompanied by a limited set of (intervention- and organ dysfunction-based) criteria to set a measure of severity. We believe that with these adjustments, the MNM tool may be more valuable and could ultimately lead to more comparable assessments of the quality of obstetric health care across different settings.


Since 2004, artemisinin-based combination therapy (ACT) has been the first-line treatment for uncomplicated malaria in Benin. In 2016, a medicine outlet survey was implemented to investigate the availability, price, and market share of anti-malarial treatment and malaria diagnostics. Results provide a timely and important benchmark to measure future interventions aimed at increasing access to quality malaria case management services.Between July 5th to August 6th 2016, a cross sectional, nationally-representative malaria outlet survey was conducted in Benin. A census of all public and private outlets with potential to distribute malaria testing and/or treatment was implemented among 30 clusters (arrondissements). Outlets were eligible for inclusion in the study if they met at least one of three study criteria: (1) one or more anti-malarials reportedly in stock on the day of the survey; (2) one or more anti-malarials reportedly in stock within the 3 months preceding the survey; and/or (3) provided malaria blood testing. An audit was completed for all anti-malarials, malaria rapid diagnostic tests (RDT) and microscopy.7260 outlets with the potential to sell or distribute anti-malarials were included in the census and 2966 were eligible and interviewed. A total of 17,669 anti-malarial and 494 RDT products were audited. Quality-assured ACT was available in 95.0% of all screened public health facilities and 59.4% of community health workers (CHW), and availability of malaria blood testing was 94.7 and 68.4% respectively. Sulfadoxine–pyrimethamine (SP) was available in 73.9% of public health facilities and not found among CHWs. Among private-sector outlets stocking at least one anti-malarial, non-artemisinin therapies were most commonly available (94.0% of outlets) as compared to quality-assured ACT (36.1%). 31.3% of the ACTs were marked with a “green leaf” logo, suggesting leakage of a co-paid ACT into Benin’s unsubsidized ACT market from another country. 78.5% of the anti-malarials distributed were through the private sector, typically through general retailers . ACT comprised 44% of the private anti-malarial market share. Private-sector price of quality-assured ACT ($1.35) was three times more expensive than SP ($0.42) or chloroquine ($0.41). Non-artemisinin therapies were cited as the most effective treatment for uncomplicated malaria among general retailers and itinerant drug vendors.The ACTwatch data has shown the importance of the private sector in terms of access to malaria treatment for the majority of the population in Benin. These findings highlight the need for increased engagement with the private sector to improve malaria case management and an immediate need for a national ACT subsidy.The online version of this article (doi:10.1186/s12936-017-1808-x) contains supplementary material, which is available to authorized users. In Benin, important gains in malaria control have been achieved in recent years, however, malaria remains a leading cause of morbidity and mortality. In 2015, the World Health Organization (WHO) reported over two million confirmed malaria cases and 1416 deaths in the country  and amonIn 2004, the policy for malaria management in Benin changed when the National Malaria Control Programme (NMCP) introduced artemisinin-based combination therapy (ACT), artemether–lumefantrine (AL), for treatment of uncomplicated malaria . Up to tAs a means to promote universal coverage of first-line treatment and increase rates of confirmatory testing, the NMCP took significant steps to improve malaria case management services across the country. In 2011, public-sector initiatives included free malaria case management to children under 5 years of age and pregnant women. Prior to this, public health facilities had charged fees for consultation, medications, and procedures . The 201There has been a substantial increase in the procurement of ACT and malaria rapid diagnostic tests (RDT) as a means to increase universal access to malaria commodities. In 2014, over 1.3 million RDT were procured and in 2015, this increased to almost 1.5 million  was calculated to demonstrate price dispersion. Anti-malarial price was collected in West African Communauté Financière Africaine (CFA) and converted to United States (US) dollars based on official exchange rates for the six-week data collection period.Provider perceptions regarding the most effective first-line treatment was assessed by administering questions to the senior most provider at all anti-malarial-stocking outlets. Providers were asked to describe what medicine they believed was the most effective treatment for treating uncomplicated malaria in a child and in an adult.A total of 7260 outlets were screened for availability of anti-malarials and/or malaria blood testing services. Of screened outlets 2966 met one of the three screening criteria, including 2959 who were stocking anti-malarials on the day of the survey or within the past three months or provided malaria testing. A total of 17,669 anti-malarial and 494 RDT products were audited  compared to private for-profit facilities, general retailers, and itinerant drug vendors . 31.3% of ACTs in the private sector were marked with the ‘green leaf’ logo. Adult quality-assured ACT was available in 24.6% of private-sector outlets. The three child formulations were available in less than 15% of the private sector  and SP (36.4%), though there were several differences across outlet types. For example, chloroquine was most commonly stocked by general retailers (71.3%) while SP was most commonly available among itinerant drug vendors (68.1%) and oral quinine was available in 70.5% private for-profit facilities.Figure 21.5% of the anti-malarial market share was distributed by the public sector, which was comprised mostly of quality-assured ACT without the ‘green leaf’ logo  and of SP .Almost 80% of the anti-malarials distributed were through the private sector (78.5%). Quality-assured ACT with the ‘green leaf’ logo comprised 15.6% of the total anti-malarial market share, followed by non-quality assured ACT (without the logo), which comprised 14.3%. SP made up the largest market share of non-artemisinin therapies (24.7%), followed by chloroquine (13.3%) and oral quinine (6.5%).Overall, general retailers dominated the anti-malarial market, accounting for 47.6% of the total market share in Benin, and these providers distributed most of the quality-assured ACT with the ‘green leaf’ logo , SP (14.7%), and chloroquine (12.0%).Figure Most of the malaria testing was performed through the public sector, which accounted for 82.2% of the total diagnostic testing market share. Microscopy testing was rare across both the public and the , 14.8 and 6.8% respectively.Within tprivate sectorhe private sector, malaria blood testing market share was dominated entirely by private for-profit health facilities since none of the other private sector outlets reportedly distributed or sold malaria testing in the seven days before the survey.Private sector price of AETD quality-assured ACT  was three times more expensive than SP  or chloroquine . The price of AETD quinine was $3.54 (IQR $2.83–$4.25)—2.6 times much more expensive than one quality-assured ACT.When providers were asked what they perceived to be the most effective anti-malarial for the treatment of uncomplicated malaria in children or adults, results from the public sector illustrate that most providers cited an ACT. Among public health facility providers, 94.6 and 96.4% perceived ACTs was the most effective treatment in adults and in children respectively Figs. , 4. SpecIn the private sector, most 62.7% of private for-profit and 93% of pharmacy providers cited an ACT as the most effective treatment for adults, and 73.4 and 94.9% respectively cited this as most effective for children. Non-artemisinin therapies, typically chloroquine and quinine, were cited as most effective treatment among general retailers  and itinerant drug vendors . SP was commonly cited as the most effective treatment for adults by itinerant drug vendors (29.8%).The 2016 outlet survey provided a complete picture of the malaria testing and treatment landscape across the public and private sectors, providing information on availability, market share, price, and provider perceptions. The findings point to recommendations for improving private-sector malaria case management in Benin.Public health facilities showed high readiness for appropriate case management in Benin. There was nearly universal coverage of quality-assured ACT treatment and malaria blood testing in these facilities. These findings reflect national strategies that have been in place since 2011, which stipulate confirmatory testing prior to treatment for all ages and at all levels of care . The curThree-quarters of public health facilities had SP available for IPTp treatment, reflecting an increase over time, from 17.2% in 2011 and 44.7% in 2014. This suggests substantial progress has been made with regards to the scale-up of SP for IPTp . This isAccording to the 2015 national guidelines, injectable quinine followed by oral quinine are still the recommended treatment for severe malaria, which could explain the high levels of quinine availability in public health facilities. However, it is possible that quinine is being used for uncomplicated malaria given it is widely available throughout all types of public health facilities. Quinine should only be administered at hospitals, which would be equipped to manage patients with severe malaria. Furthermore, while a full course of quinine tablets are indicated for treatment of severe malaria, this should only be administered after a primary treatment with injectable quinine. However, market share data illustrate that oral quinine comprises one in every fifth anti-malarial distributed in the public sector, while quinine injection is negligible, suggesting that oral quinine may be routinely administered for uncomplicated malaria. Indeed, a recent household study in southern Benin found quinine was the second most used anti-malarial for self-medication (after ACT) suggesting that efforts are needed to ensure the appropriate administration of this anti-malarial . DespiteSince 2014, the reach of the public sector has been extended to the community-level through the training and equipping of CHWs with malaria case management skills and supplies (AL and RDT). Since then, several investments have been made to increase the capacity and coordination of these providers . The resResults from the study confirmed the dominant role of the private sector across Benin, where almost 80% of all anti-malarials passed through this sector, mainly through general retailers—which accounted for almost half of the anti-malarial market share in 2016 (47.6%). Of the 5600 general retail outlets that were screened for anti-malarials, over one in four had anti-malarials in stock, reflecting a three-fold increase from previous surveys , 18. GenGiven a large portion of the private-sector case management is being channeled through these informal outlets, there may be several opportunities to strengthen the malaria case management services provided by these vendors. There are examples in the literature of innovative strategies that have focused on general retailers and itinerant drug vendors to improve access to quality-assured ACT . There iThe private sector was generally less well-equipped to test and appropriately treat malaria infections as compared with the public sector. Only one-third of private-sector outlets were stocking quality-assured ACT. Non-artemisinin therapies were more commonly available and distributed. Availability of malaria testing was also negligible and consistent with these findings, most malaria tests were administered by the public sector, which comprised over 80% of the diagnostic market share. Given most private-sector outlets were not stocking malaria tests suggests that presumptive treatment is widespread.While the AMFm or subsequent CPM programme was not implemented in Benin, most of the quality-assured ACT reportedly distributed in the private sector had the AMFm ‘green leaf’ logo. This indicates leakage of anti-malarials’ from other countries and suggests that anti-malarials are being illegally traded into non-subsidized private markets.The widespread availability and distribution of quality-assured ACT with the logo is perhaps not surprising considering Benin’s supply chain . The domAvailability and distribution of other non-quality assured ACT was also high, comprising 14.3% of the anti-malarial market and reflecting a slight increase from earlier survey rounds. This is of concern given that non-quality assured ACT medicines have not received pre-qualification, meaning that these medicines have not necessarily been manufactured according to quality standards yielding safe and efficacious medicines. Moreover, non quality-assured ACT have an increased likelihood of being poor quality as evidenced by studies that have tested the pharmacological properties of the medicines . The widWhile the strength of all first-line AL tablets for treatment of uncomplicated malaria is indeed the same, the implementation of the AL policy includes delivery of four different AL pack sizes  suitable for management of four different weight categories of patients . In the private sector, as well as the public sector, availability of the different weight categories was relatively poor. For example, in the private sector, only 11.4% of the private for-profit facilities and 58.6% of pharmacies had AL treatments for children under 5.Maintaining a consistent supply of age/weight appropriate commodities will be key to ensure that ACT commodities are administered according to the recommended age and weight band of each patient and to prevent medicine packages from being cut or tampered with. This is particularly important given evidence that AL treatment is up to six times more likely to be prescribed if the weight specific pack is in stock . While sOver a decade after the change in first-line treatment for uncomplicated malaria, non-artemisinin therapies, including SP, oral quinine, and chloroquine, accounted for the majority (57.7%) of the market share in the private sector. SP made up over half of the non-artemisinin therapies reportedly distributed. While most of the SP distribution was through itinerant drug vendors and general retailers, SP was also commonly distributed by pharmacies. The widespread distribution of this medicine implies that it is being used for malaria case management rather than exclusively for IPTp as recommended. Widespread availability and distribution of oral quinine, particularly among general retailers and itinerant drug vendors, also indicates this is being used for the treatment of uncomplicated malaria.Widespread distribution of non-artemisinin therapies in Benin might be explained by a number of factors. This may in part be attributed to price, given that SP and chloroquine were three times less expensive than quality-assured ACT. Alternatively, access may also be an important factor. Non artemisinin therapies were more widely available than quality-assured ACT—particularly among general retailers where most anti-malarials were distributed. Another reason may be around provider perceptions of the most effective treatment for uncomplicated malaria. In 2016, most of the itinerant drug vendors and general retailers perceived non-artemisinin therapies  as the most effective treatment for uncomplicated malaria.To improve private-sector case management, removal of non-artemisinin therapies from the market is paramount and new strategies are necessary to curtail their consumption and promote the use of quality-assured ACT and RDT in the private sector. Several programmes have been implemented across sub-Saharan Africa to improve private sector readiness for appropriate malaria case management that could be relevant in the Benin context. A similar nation-wide subsidy to that of the AMFm may be an immediate means to overcome ACT access and affordability issues for this treatment, as evidence by the pilot initiative , 35. OncOral artemisinin monotherapy poses a serious threat to the continued efficacy of artemisinins, and as such this anti-malarial was banned in Benin in 2008. In 2016, no oral artemisinin monotherapy was detected in the market. This is of promise given ACTwatch outlet survey findings from neighboring Nigeria which show that availability of oral artemisinin monotherapy in the private sector has increased from 24.6% in 2013 to 37.3% in 2015 . FurtherThe ACTwatch outlet survey design has limitations that have been documented and reported , 15, 19.Other specific limitations to Benin’s outlet survey include the use of two different forms of data collection (electronic and paper questionnaires). While electronic data collection has the advantage of recording the data instantly with all the relevant checks and skip patterns built into the programme, it may have had an impact on respondents’ fear that they were being recorded or investigated. In addition, some itinerant vendors could have been missed during the survey given these vendors may work late at night and, for security reasons, interviewers only worked during the day and early evening.The public sector in Benin is typically well equipped to test and appropriately treat malaria according to national treatment guidelines. However, the private sector is responsible for most of the anti-malarial distribution, typically through general retailers, and this channel most commonly distributes non-artemisinin therapies. There is also evidence of leakage of subsidized ACT from neighbouring countries. A national strategy to scale up access to first-line, quality-assured, subsidized treatment as a means to improve coverage and quality of malaria case management services is needed. Strategies to increase coverage of malaria commodities should be supported by interventions to address provider perceptions, as well as consumer behaviours, and innovative approaches to either engage or regulate Benin’s informal private sector are needed.Additional file 1. Sampling weights.Additional file 2. Detailed sample description.Additional file 3. Availability of quality-assured AL among all screened public sector outlets.Additional file 4. Availability of quality-assured AL among anti-malarial stocking private outlets.


Carbapenem-resistant Enterobacteriaceae (CRE) is a concern in South Africa and worldwide. It is therefore important that these organisms be accurately identified for infection prevention control purposes.blaNDM,blaKPC,blaOXA-48&variants,blaGES,blaIMP and blaVIM) was screened for using a multiplex real-time PCR.In this study 1193 suspected CREs from 46 laboratories from seven provinces in South Africa were assessed to confirm the prevalence of carbapenemase genes from our referral diagnostic isolates for the period 2012 to 2015. We compared the antimicrobial susceptibility testing method used in the reference laboratory to the polymerase chain reaction (PCR) which is used as the gold standard. Organism identification and antimicrobial susceptibility testing were performed using automated systems and DNA was extracted using a crude boiling method. The presence of carbapenemase-producing genes (n = 812) of the isolates harboured a carbapenemase-producing gene; the three most common genes included: blaNDM,blaOXA-48&variants and blaVIM. Majority of the carbapenemase producing Enterobacteriaceae (CPE) isolates were Klebsiella species (71 %). The Microscan® Walkaway system used for the screening of carbapenemase production was 98 % sensitive with a minimal inhibitory concentration (MIC) breakpoint of less than 0.5 as susceptible for ertapenem and a low specificity (13 %).Sixty-eight percent (From this study we can conclude that carbapenemase-producing Enterobacteriaceae is increasing in South Africa and the use of phenotypic methods for detection of CPEs showed good sensitivity but lacked specificity. Klebsiella pneumoniae carbapenemases (KPC) [Enterobacter cloacae was reported in the Gauteng province in 2011 and then almost a year later in KwaZulu-Natal. Klebsiella pneumoniae isolates harbouring KPC, OXA-48 and OXA-181were reported in Gauteng 2011. An outbreak of OXA-181 in Klebsiella pneumoniae was documented in the Western Cape in 2012 and the presence of OXA-48, VIM and IMP in Enterobacter cloacae isolates isolated from patients in the Eastern Cape has also been reported [via combinations of ampicillin class C (AmpC) enzymes, extended-spectrum beta-lactamases (ESBL) and membrane impermeability), and CPEs (which are as a result of carbapenemase production exclusively) [Multidrug resistant organisms are a major public health concern , 2. Theres (KPC) . The emees (KPC) –6. Carbaes (KPC) . Carbapees (KPC)  that hydes (KPC) , 9. Carbes (KPC) , 11 resues (KPC) . The prees (KPC) –32. In Sreported –32. The usively) . Furtherusively) .In this study, we evaluated1193 suspected CREs to estimate the prevalence of CPEs in our sample population in South Africa. This was not a surveillance study but nonetheless provided us with baseline information regarding the extent of CPEs in the country and the organisms producing them. We also evaluated one of the phenotypic methods routinely used for antimicrobial susceptibility testing (AST) to determine its efficacy and accuracy and report on its ability to screen for CREs based on confirmed CPE genes received at the reference laboratory.® II  and/or the Microflex MALDI-ToF  and antimicrobial susceptibility testing (AST) was carried out on the automated MicroScan® Walkaway system  using the Gram-negative MIC Panel Type 44 . The Sensititre instrument  was used to clarify and confirm questionable Microscan results . For this procedure, microtitre trays with two-fold dilutions of antibiotics were inoculated with a standardised inoculum of the bacteria and incubated under standardised conditions. The minimal inhibitory concentration (MIC) was recorded the next day as the lowest concentration of antimicrobial agent with no visible growth. The interpretation of susceptibility was done according to the Clinical and Laboratory Standards Institute (CLSI) guidelines [blaNDM, blaKPC, blaOXA-48 and its variants , blaGES ,blaIMP  and blaVIM (VIM-1-36) using a multiplex real-time polymerase chain reaction (PCR) .The national Antimicrobial Resistance Laboratory (AMRL) for the public healthcare sector, which majority of the South African population have access to, have been testing referred suspected CPE isolates for the presence of selected carbapenemases. Clinically significant phenotypically identified carbapenem non-susceptible Enterobacteriaceae isolates were voluntarily submitted from 46 laboratories to the AMRL at the Centre for Opportunistic, Tropical and Hospital Infections (COTHI), National Institute for Communicable Diseases (NICD) for confirmation of carbapenemase-producing genes as part of a routine diagnostic programme. Isolates received for the period 2012–2015 were analysed; it is important to note that each isolate was analysed individually . When the isolate was received at the AMRL, organism identification was performed using automated systems  harboured at least one or a combination of CPE genes. Of these, 469 (57 %) were blaNDM-positive, 219 (26 %) were blaOXA-48-positive (including variants), 89 (10 %) were blaVIM-positive, 35 (4 %) were blaIMP-positive, 18 (2 %) were blaGES-positive and 11 (1 %) were blaKPC-positive. Combinations consisted of blaNDM- and blaOXA-48-positive (n = 8), blaNDM- and blaIMP-positive (n = 4), blaNDM- and blaVIM-positive (n = 3), blaNDM- and blaKPC-positive, blaKPC- and blaVIM-positive, blaIMP- and blaOXA-48-positive, blaVIM- and blaOXA-48-positive (n = 2 each) and blaNDM- and blaGES-positive and blaGES- and blaOXA-48-positive (n = 1 each).From a total of 1193 isolates, 68 %  followed by Enterobacter spp. , Serratia marcescens , Escherichia coli , Citrobacter spp. , Providencia spp.  and Morganella morganii and Raoultella spp. . The predominating genotype in most organism species was blaNDM with the exception of Enterobacter spp. which also included blaIMP. In E. coli the predominating genotype was blaOXA-48 and its variants which were also commonly found in all other organisms except in Providencia spp., Morganella morganii and Raoultella spp. , urine , swabs , body fluids , catheter tip , sputum  and smaller percentages ranging from 0.1 % (n = 1) to 1.9 % (n = 16) for bone marrow, cerebrospinal fluid, stool, upper respiratory tract, lower respiratory tract and tissue specimens. Up to 26 % (n = 212) of the isolates specimen types were unknown or the data were not available  followed by blaOXA-48 and its variants . In 2013, 16 % (n = 32) were blaIMP-positive whereas in 2014 and 2015 there were higher numbers of blaVIM-positive isolates   i.e. there was a significant increase in the number of genotypes detected from 2012 compared to 2015.n = 794) of the carbapenemase producing isolates indicating that the phenotypic method used was fairly sensitive. Eighteen (2 %) isolates produced an ertapenem-susceptible result although a CPE gene was present . Three of these isolates were fully susceptible to the third and fourth generation cephalosporins  as well as to the remaining carbapenems . These isolates contained the following genes: blaNDM (n = 2) and blaOXA-48 and variants (n = 1). Interestingly, 12 of these ertapenem-susceptible isolates showed non-susceptibility to imipenem; two of these were also non-susceptible to meropenem. Majority  of these were blaVIM-positive with one isolate also positive for blaOXA-48 and its variants. The remaining two isolates contained blaNDM  in 2013, 1.6 % (n = 5) in 2014 and 3.72 % (n = 10) in 2015), however overall the percentage susceptibility was low.Antimicrobial susceptibility testing profiles of these carbapenemase producing isolates were analysed. Ertapenem proved to be a reliable indicator of carbapenemase production. Ertapenem non-susceptibility was observed in 98 % (Eighteen  % isolatn = 643) and 79 % (n = 661) of the carbapenemase producing isolates, respectively. A decrease in the percentage susceptibility was also seen for imipenem, meropenem and doripenem over time. It should be noted that the instrument panel did not initially consist of doripenem and it was therefore not tested for, accounting for the low percentage obtained in 2013.Imipenem and meropenem were fairly good indicators of carbapenemase production with non-susceptibility observed in 77 %  followed by Enterobacter spp. , Escherichia coli , Morganella morganii , Serratia marcescens , Proteus mirabilis.  and Citrobacter freundii. . Specimen types varied: urine , blood , swabs , body fluids , catheter tip , sputum  and smaller percentages ranging from 0.3 % (n = 1) to 1.6 % (n = 6) for cerebrospinal fluid, upper respiratory tract, lower respiratory tract and tissue specimens. Up to 18 % (n = 70) of the isolates specimen types were unknown or the data were not available.Of the 381 non-CPE isolates 333 (87 %) were phenotypically non-susceptible to ertapenem; 88 (23 %) were non-susceptible to imipenem and 155 (41 %) were non-susceptible to meropenem indicating that the phenotypic method used lacks specificity particularly in the case of ertapenem. Majority of the non-CPE isolates were ® Walkaway system). The sensitivities, specificities, positive and negative predicted values for ertapenem, imipenem and meropenem can be seen in Table The overall antimicrobial susceptibility and PCR (gold standard) results were compared to determine the sensitivity, specificity, positive predictive value and negative predictive value of the phenotypic method routinely used  of the isolates harboured at least one or a combination of carbapenemase-producing genes. It should be noted that although genotypic methods are remarkably reliable, there are some potential limitations. False-negative results may be obtained as genes may not be detected due to the presence of genetic variants and/or rare carbapenemase types that were not included in the screening e.g. SPM, SIM, IMI etc. This could suggest that variants and other carbapenemases may potentially have been missed suggesting that the actual prevalence of CPEs in our study population could be higher. This is worrisome as the rate of CPEs in South Africa is increasing as indicated by the number of studies reporting occurrences and outbreaks –32.Klebsiella spp.  followed by Enterobacter spp. , Escherichia coli  and Citrobacter spp.  were also present to a smaller extent. Interestingly, we observed that 10.7 % (n = 90) of the carbapenemase producing isolates belonged to one of the following organisms: Serratia marcescens , Providencia spp.  and Morganella morganii . Carbapenem resistance is particularly worrying in organisms such as these as well as Proteus spp. as these organisms are intrinsically resistant to colistin and if carbapenem cannot be used for treatment, the management of patients infected with these organisms is all the more challenging. Overall, in addition to the carbapenems other antibiotics were analysed for all carbapenemase producing isolates; with the exception of a few  which showed high susceptibility, majority of the isolates showed varying degrees of resistance to the other antibiotics . Resistance to these antibiotics may also be due to the presence of AmpCs and/or ESBLs. Screening for these would provide useful information for management purposes, however this was not done.Majority of the CPE isolates (those harbouring carbapenemases) were blaNDM  followed by blaOXA-48 and its variants . BlaVIM,blaIMP,blaGES and blaKPC were also present but on a smaller scale . This is consistent with previous findings in South Africa where these genotypes have been confirmed in both the public and private sector hospitals in various provinces [blaNDM and blaOXA-48 and its variants from 2012 to 2015. This is a matter of concern as it may indicate a possible emergence of these genotypes which have the potential to become endemic. The significant increase in the number of genotypes detected from 2012 compared to 2015 further highlights this.The most predominant genotype in the carbapenemase producing Enterobacteriaceae group was rovinces –32, 35. n = 24) were non-susceptible to ertapenem but susceptible to the cephalosporins. According to the Clinical and Laboratory Standards Institute, isolates displaying non-susceptibility to ertapenem usually also test resistant to one or more cephalosporin subclass III agents , however some isolates producing carbapenemases still continue to test susceptible to these cephalosporins [blaNDM was not performed which would further provide subtype information. Non-traditional AST profiles were also seen in other carbapenemase producing isolates which were carbapenem non-susceptible but susceptible to cefotaxime, ceftazidime or cefepime (Table n = 12) of ertapenem-susceptible isolates showed non-susceptibility to imipenem with a further subset  being non-susceptible to meropenem as well. Majority of these were VIM-producers suggesting that low MICs to ertapenem can be typical of certain VIM types, as VIM-producers have variable kinetics for the different carbapenems. Hence there is heterogeneity in expression within the same clone and amongst different species [Phenotypically, ertapenem non-susceptibility is the most sensitive indicator of carbapenemase production . This waosporins , a possiosporins . One of  species , 37 and  species , 32.While ertapenem has shown to be a reliable indicator of resistance in the carbapenemase producing Enterobacteriaceae group, phenotypic methods may not be ideal as observed in the non-CPE group as indicated by the high percentage (87 %) of non-CPE ertapenem-non-susceptible isolates indicating that this method lacks specificity. Imipenem and meropenem showed better specificity  suggesting that all three antibiotics results should be used to enhance specificity for CRE detection. It should be noted however, that in instances where the phenotypic method indicates resistance and the PCR result is negative for all genes tested, resistance may be due to other carbapenemases, AmpC and or ESBL gene/s not screened for by the PCR. Alternatively, other mechanisms of resistance may be present e.g. efflux pumps and porin mutations. The former statement may be supported for example by the low cefoxitin susceptibility rate (10.8 %) suggesting that plasmid-mediated AmpC enzymes are very prevalent in our sample population. Similarly, the low susceptibility rates for the penicillins and cephalosprins (0.6–13 %) are indicative of ESBLs. We have not screened for these. However, the possibility remains that these isolates could in fact be non-CPE. This is worrying as phenotypic methods are routinely utilised and if ertapenem non-susceptibility is strictly used as an indication to treat patients with carbapenems even though a carbapenemase is not present, this would result in further implications towards potential antimicrobial resistance. This stresses the need for specific tests that can routinely be used.Overall the phenotypic method used for the detection of carbapenemase production was highly sensitive for ertapenem (98 %) but the specificity was low (13 %), an indication that the method may possibly be over-reporting results potentially influencing clinicians to prescribe unnecessary antibiotics. For imipenem and meropenem, the specificities were satisfactory but the sensitivities were not. These antibiotics would therefore not be the ideal antibiotic of choice for this purpose.blaNDM-positive. Controlling the spread and limiting the impact of CPEs in South Africa will require intensive efforts in both the public and private healthcare sectors. The use of phenotypic methods for detection of CPEs using ertapenem is sensitive but lacks specificity and can be used if there is no access to molecular methods. However, conventional AST methods coupled with molecular genotypic testing for the detection of carbapenemase-producing Enterobacteriaceae is more definitive and therefore advantageous.We have shown an increase in carbapenemase-producing Enterobacteriaceae over a three year period with close to 40 % of all isolates received being


Obesity and depression are of two of the largest contributors to the global burden of disease in men. Although lifestyle behavior change programs can improve participants’ weight and depressive symptoms, the evidence is limited by a lack of male participants and a reliance on face-to-face treatment approaches, which are not accessible or appealing for many men.This study examined the effect of a gender-tailored electronic health  program on the depressive symptoms of a community sample of overweight and obese men with or without depression. A secondary aim was to determine whether the eHealth, self-directed format of the program was a feasible and acceptable treatment approach for the subgroup of men with depression at baseline.In total, 209 overweight/obese men from the Hunter Region of Australia were assessed before and after completing a self-administered eHealth weight loss program over 3 months. To increase engagement, most program elements were socio-culturally targeted to appeal specifically to men and included printed materials, a DVD, motivational text messages, online- or app-based self-monitoring, and other weight loss tools . Depressive symptoms were measured with the validated 8-item Patient Health Questionnaire (PHQ-8). Program feasibility and acceptability were assessed with a process questionnaire plus recruitment and retention rates. Changes in depressive symptoms and weight were examined using intention-to-treat linear mixed models, adjusted for the centered baseline score and other covariates. Effect sizes were estimated with Cohen’s d.P=.44). At posttest, depressive symptoms had reduced by 1.8 units  for the whole sample. These improvements were particularly notable in the subgroup of men with depression  and 72.2% (26/36) of this subgroup no longer met the criterion for depression at posttest. A corresponding, albeit smaller, intervention effect on depressive symptoms was also observed in men without depression . The overall intervention effect on weight was -4.7 kg (d=1.3), which did not vary significantly by depression status. Program acceptability, feasibility, and online engagement metrics were also comparable between men with and without depression.At baseline, the mean weight and age of the sample was 105.7 kg (standard deviation [SD] 14.0) and 46.6 years (SD 11.3), respectively. Overall, 36 men  were experiencing depression (PHQ-8 score ≥10). Retention rates were comparable between men with and without depression  Obesity and major depressive disorder, henceforth referred to as depression, are two of the largest global health concerns in men ,2. In adEncouragingly, behavior change programs have shown initial efficacy to generate clinically meaningful improvements in participants’ body weight  and deprSelf-Help, Exercise and Diet using Information Technology (SHED-IT) program is an electronic health  weight loss intervention that is socio-culturally tailored to appeal specifically to men  of change). Differences between men with and without depression for categorical outcomes were assessed with Chi-square tests.2=0.6; degrees of freedom=1; P=.44).As reported elsewhere , 209 of As seen in No significant differences were detected between men with and without baseline depression for the program acceptability questions included in the posttest process evaluation . OverallUsage rates for the online program components were comparable between men with and without depression . Of the This study revealed that an eHealth weight loss program designed specifically for men concurrently and significantly reduced men’s weight and depressive symptoms. Although a recent review determined that lifestyle modification could effectively reduce depressive symptoms , 80% of Despite the self-administered nature of SHED-IT, the intervention effect on men’s depressive symptoms was comparable to those observed in more intensive interventions . FurtherThis study has some limitations to acknowledge. Although previous studies have established the effectiveness of the SHED-IT program over a control group , this pr