The objective of this research was to investigate the effect of pulsed electric field (PEF) processing on the volatile compounds produced in onion cultivars. The changes in the volatile compounds of onions were assessed comparing results observed while measured immediately and 24 h after PEF treatment using headspace solid-phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS). Significant increases in the concentrations of propanethial S-oxide, propenyl propyl thiosulfinate, 2-methyl-2-pentenal, dipropyl disulfide, propenyl propyl disulfide, methyl propyl disulfide, and methyl propenyl disulfide were observed immediately after PEF treatment. The concentrations of propenyl propyl thiosulfinate, dipropyl disulfide, methyl propyl disulfide, dipropyl trisulfide, methyl propyl trisulfide, and propenyl propyl trisulfide increased after 24 h compared to initial concentrations. It is postulated that these changes are due to PEF-induced cell permeabilisation that facilitates enzyme-substrate reactions after the PEF treatment. Pulsed electric field (PEF) technology has stimulated intense research as an alternative processing technique to achieve cellular disruption since the 1960s . This prAllium cepa and Allium fistulosum) are commonly used for culinary purposes .,27.26,27The alkyl thiosulfinates are rapidly formed via self- or cross-condensation of sulfenic acids upon enzymatic initiation of the reaction cascade . The conAfter 24 h incubation following PEF treatment, the concentration of thiosulfinates significantly increased in all the onion varieties. The highest relative concentration of thiosulfinates upon PEF treatment was obtained at different treatment intensities in the onion varieties. The highest concentration of thiosulfinate in the spring onions was obtained after 24 h incubation with a high-PEF treatment. However, the highest concentration of thiosulfinate in the Yellow Sweet Spanish bulbs was obtained upon 24 h incubation with a medium-PEF treatment. Application of high-PEF treatment intensity resulted in a relatively low concentration of thiosulfinate after 24 h of the PEF treatment in the bulbs. The relative drop in the concentration of thiosulfinate in the Yellow Sweet Spanish bulbs could be due to the extensive disintegration of the plasma and vacuole membrane resulting in the leaching of the alkenyl cysteine sulfoxides from the cell cytoplasm, thus reducing the available precursor substrate for the reaction ,30.2-Methyl-2-pentenal (2M2P) was the only aldehyde detected in the onion samples in this study. 2M2P is a self-condensation product formed from propanal  and is rp ≤ 0.05) increased the concentration of disulfide compounds, categorised in Group 2  detected in the onion headspace . It is sIn this study, the PEF treatment of intact onions were studied at electric field strengths lower than 2 kV/cm. Future research could investigate the impact of other PEF parameters such as specific energy, frequency, and number of pulses. The changes in volatile compositions in onion cultivars may affect the perception of onion flavour in culinary applications. Further work would be required to understand the relationship between volatile concentrations and flavour perception.The study demonstrated that the application of PEF treatment influenced the volatile profile of onions based on the applied electric field strengths. The intensity of PEF treatment was correlated to the differences in the extent of cellular disruption, which resulted in the mixing of enzyme and substrates, thus facilitating reactions to generate the volatile compounds of interest. The impact of PEF treatment on the volatile compounds were found to be consistent between the three onion cultivars tested. However, quantitative differences in the volatile concentrations were observed between the cultivars, correlating to tissue type and maturity. The highest concentrations of volatile sulfur compounds were observed after 24 h incubation following a high-PEF treatment, compared to the untreated samples. Across all three cultivars, the volatile sulfur-containing compounds such as DPDS, PPrDS, DPTS, MPDS, PPrTS, and MPTS, were found to be significantly affected by PEF treatment intensities and could act as markers of cell membrane damage. This study also suggests that PEF treatment could be tailored for different applications based on the specific fruit and vegetable tissue. Moreover, these volatile compounds could also be used as markers to detect damage or deterioration in fruit and vegetables tissues.


The health consequences of the 9/11 World Trade Center (WTC) terrorist attacks are well documented, but few studies have assessed the disaster’s impact on employment among individuals exposed to the disaster. We examined the association between 9/11-related health conditions and early retirement among residents and workers who resided and/or worked near the WTC site on 9/11, and the association between such conditions and post-retirement income loss. The study included 6377 residents and/or area workers who completed the WTC Health Registry longitudinal health surveys in 2003–2004 and 2006–2007, and the 2017–2018 Health and Employment Survey. Logistic regression models were used to examine the associations. We found that 9/11-related health conditions were significantly associated with the likelihood of early retirement. Residents and/or area workers with more physical health conditions, especially when comorbid with posttraumatic stress disorder (PTSD), were more likely to retire before age 60 than those with no conditions. For retirees, having PTSD or PTSD comorbid with any number of physical conditions increased the odds of reporting substantial post-retirement income loss. Disaster-related outcomes can negatively impact aging individuals in the form of early retirement and income loss. Long-term effects of major disasters must continue to be studied. Many studies have documented the short-term health impacts of the World Trade Center (WTC) 11 September 2001 attacks, while longer-term observations of various chronic physical and mental health conditions continue to be reported among individuals exposed to the disaster . HoweverUnlike our first published work that focused on the 9/11 economic impact for non-uniformed rescue and recovery workers , this anRetirement trends were shifting during the mid-1990s into the 2000s irrespective of the effects of the 9/11 disaster, as fewer people were retiring at younger ages compared to the 1970s and 1980s . Trends Poor health has been linked to early retirement in numerous studies for different population groups or countries. Self-perceived poor health was a risk factor for early exit from the labor force through early retirement, unemployment, or both ,18,19,20Previous studies of 9/11 health impact showed elevated prevalence of many chronic physical conditions, posttraumatic stress disorder (PTSD), and physical-mental comorbidity among disaster survivors ,30,31,32In 2017–2018, the WTC Health Registry conducted an in-depth study on health and employment for a sub-sample of its enrollees. Detailed information on employment, retirement, health insurance, and other economic indicators collected from this survey, coupled with detailed health data collected from the Registry’s longitudinal surveys administered in waves since 2003, provided an opportunity to further investigate the impact of 9/11-related health on retirement and post-retirement well-being. As in our previous study [The WTC Health Registry maintains a longitudinal cohort that was established in 2002 following the 11 September 2001 terrorist attacks with the aim of monitoring the long-term health outcomes in individuals exposed to the events of 9/11 in NYC. In 2003–2004, the Registry enrolled 71,426 rescue or recovery workers, Lower Manhattan residents, area workers, passersby, and students or school staff by conducting its first health survey (Wave 1). Eligible enrollees have since been invited to participate in three additional health surveys in 2006–2007 (Wave 2), 2011–2012 (Wave 3), and 2015–2016 (Wave 4) as well as a number of in-depth studies. Previous Registry publications provide a more detailed description of this cohort . From September 2017 to March 2018, the Registry conducted the Health and Employment Survey (HES) with a sample pool of English-speaking enrollees under 75 years of age (as of 2017) who completed at least Waves 1 and 2. Enrollees who reported retirement or unemployment due to disability/health at any of the three follow-up surveys (Waves 2–4) were invited to participate in the HES study along with a roughly equivalent number of not-yet retired age-matched enrollees. In total, 23,036 enrollees were invited to complete the HES, and the response rate reached 65%. The US Centers for Disease Control and Prevention (3793) and the NYC Department of Health and Mental Hygiene (02058) institutional review boards approved the Registry protocol and the HES protocol (17047), including the use of the data. This study used data collected from the HES and was limited to those who lived or worked near the WTC site on 11 September 2001. During analyses, the HES data were merged with the Registry’s four waves of health survey data to obtain 9/11-related health information for the study sample. We excluded 341 enrollees who had retired before the 9/11 disaster, as our focus was on the link between 9/11-related health and retirement. The final study sample was 6377 enrollees, which included 3486 retired and 2891 not-yet-retired enrollees. Of the 3486 retirees, 1234 retired before age 60, 2143 retired at or after age 60, and 109 did not report time of retirement. Additionally, 2395 enrollees reported post-retirement income loss.In the HES, enrollees were asked if they were currently retired and, if retired, for the month and year of retirement. This information was used to calculate retirement age. In the analytical model, a dichotomous outcome variable was created for early retirement which was defined as having retired before reaching the age of 60. Those self-reporting retirement in the HES were also asked if their total post-retirement personal income after taxes changed as compared to pre-retirement and in which direction; if they responded that their income had decreased, a follow-up question asked for the percentage of decrease . A dichotomous outcome variable for post-retirement income loss was created for those who reported substantial income loss which was defined as having over 50% of income decrease. Starting in Wave 1, Registry enrollees were asked in each of the follow-up wave surveys whether they had ever been told by a doctor or other health professional that they had any of more than a dozen listed health conditions and the year of first diagnosis if diagnosed. For this study, asthma, heart disease , stroke, lung disease , diabetes, gastroesophageal reflux disease, and autoimmune disease  were selected, as all have been reported to be elevated among 9/11 exposed individuals ,37,38,39The total number of chronic physical conditions, comorbid with PTSD or not, was used as the health indicator in the analytical models.Sociodemographic characteristics of the study sample were measured by sex, age at 11 September 2001, race/ethnicity, household income, education, and marital status. A quantitative 9/11 exposure measure was also included in the analysis as it is closely associated with PTSD [p is the probability of our outcome occurring, Two logistic regression models were used to calculate the adjusted odds ratio (AOR) and 95% confidence intervals (95% CI) to measure the association between 9/11-related health conditions and our study outcomes. The equation for these models isThe first model included 4125 non-retired enrollees and early retirees, and aimed to demonstrate the relationship between poor health  and the likelihood of retiring before age 60, while adjusting for sociodemographic factors and disaster exposure.The second model included 2395 enrollees who reported income loss after retirement and investigated the association between 9/11-related health conditions and substantial post-retirement income loss while adjusting for disaster exposure and all sociodemographic characteristics included in the first model except for age at 11 September 2001. Even though post-retirement income decreases are common and subject to lower tax rates and less work-related expenses , this anThe analyses for this study were conducted in SAS version 9.4 .Among 4125 residents and area workers who lived or worked near the WTC site on 9/11, 1234 (29.9%) reported having retired before age 60 . Sociodep < 0.0001) were all significant with the retirement age decreasing by an average of two to three years compared to those who did not have any 9/11-related chronic conditions (results not shown).Having chronic 9/11-related physical health conditions without PTSD was found to be significantly associated with early retirement in a dose-response manner with the odds of reporting early retirement increasing as the number of conditions increased  . When chp < 0.0001). Because of the significant association of 9/11-related poor health and early retirement demonstrated in Approximately 73% of retirees in the study sample reported that their post-retirement income had decreased as compared to their pre-retirement income, while 19% reported no significant income changes, and 8% reported increased post-retirement income. Although post-retirement income loss seemed to be a norm for retirees regardless of their retirement age, among those who reported decreased income, a significantly higher proportion . PTSD comorbid with one or more physical health conditions had a similar effect on enrollees’ odds of experiencing substantial income loss as PTSD alone.The impact of the 9/11 disaster on early retirement and post-retirement well-being among survivors has rarely been studied until now. This study examined the association of 9/11-related health and early retirement for residents and area workers who resided and/or worked near the WTC site on 9/11. Furthermore, we assessed the longer-term impact of 9/11-related health on post-retirement income loss among survivors.Sixteen years after the 9/11 disaster, among the 3486 retired residents and area workers in our study sample, about 35% had retired before reaching 60 years of age. Early retirement was found to be significantly associated with chronic 9/11-related physical health conditions in a dose-response manner, and a sensitivity analysis estimating the magnitudes of the effects in terms of years of work lost found consistent results. More specifically, the likelihood of reporting early retirement versus not-yet retired grew as the number of physical health conditions increased. The odds of reporting early retirement increased further when these conditions were comorbid with PTSD but not when PTSD was reported in the absence of any 9/11-related physical conditions. These findings suggest that residents or area workers who suffered from 9/11-related PTSD but not other chronic physical conditions were not more likely to retire early due to this mental health condition alone; several explanations may clarify this. One reason is that PTSD may not severely impact daily working life, especially if the PTSD is mild. Only 6% of the early retirees in this study sample reported having Accidental Disability Retirement (ADR), a benefit available to members of certain plans if they become permanently physically or mentally incapacitated and are unable to perform the duties of their job due to an accident that took place on the job . The perDespite the fact that PTSD alone did not show a significant association with reporting early retirement, this study found that residents and area workers with PTSD alone or PTSD comorbid with any number of physical conditions were significantly more likely to experience substantial income loss post-retirement. PTSD comorbid with one or more physical health conditions had a similar effect, in terms of significance and magnitude, on the odds of experiencing substantial income loss as PTSD alone. Having any number of physical conditions (including three or more conditions) in the absence of PTSD was not significantly associated with substantial post-retirement income loss, which suggests PTSD is the key and driving factor in this association. The economic impact of 9/11-related PTSD, although not directly reflected in the form of early retirement, tended to be stronger in the long-term as individuals suffering PTSD were less likely to assume income-generating activities that could ultimately lead to significant income loss. Like having PTSD alone, disaster exposure did not show a significant association with early retirement but was highly related to post-retirement income loss. The absence of exposure’s effect in the model for early retirement is likely a result of having the 9/11-related health measure in the same model absorbing its effect. We re-ran our model for Similar to the findings in our earlier study , those wThis study provided evidence of a strong association between 9/11-related poor health and early retirement among survivors who lived and worked near the WTC site. Furthermore, with additional information collected from the HES, we demonstrated, for the first time, the significant impact of 9/11-related PTSD and 9/11-related physical–mental comorbidity on substantial post-retirement income loss. Our findings suggest that after labor force exit, poor health, especially PTSD, continued to adversely affect survivors’ overall well-being in the form of considerable income reduction. The compromised post-retirement well-being as a result of poor health did not come as a surprise because many of the affected people could have involuntarily experienced early retirement before securing their full retirement benefits; or, they might be less likely to participate in any income-generating activities, particularly if they experienced mental health or physical–mental comorbidity issues after retirement. This lasting effect of poor health, along with the fact that certain race/ethnicity (Hispanic and non-Hispanic black) and low education groups are more likely to retire early, should direct future 9/11-related resources by placing a greater focus on limiting sharp income loss and providing adequate and affordable health care services to retirees from various vulnerable groups to maintain a certain level of quality of life. One notable advantage of this study is that we directly assessed the relationship between 9/11-related health and post-retirement income loss using statistical modeling. This investigation provides the first look at one aspect of survivors’ well-being beyond retirement and will lead to additional exploration of the economic impact of 9/11, such as the relationship between substantial income loss and worsening health and its associated high medical cost, poor health reducing survivors’ ability to re-enter the workforce to compensate for post-retirement income loss, and how survivors’ retirement plans directly affect their post-retirement well-being. In addition, future research should also assess other aspects of post-retirement well-being such as retirees’ current health status or health-related quality of life (as in an ongoing study by our group) and insurance coverage. These results will not only give us a broader picture of retirees’ overall well-being but also help estimate the realistic gap on health care access in terms of making policy recommendations.This study found that 9/11-related health conditions were significantly associated with the likelihood of early retirement among residents and area workers who survived the 9/11 attacks. The likelihood of reporting early retirement increased as the number of health conditions increased. Having PTSD alone was not associated with early retirement; however, PTSD was the driving factor out of all 9/11-related health conditions studied that was linked to substantial income loss post-retirement. For future studies of 9/11 economic impact, our findings emphasize the key role that PTSD may play in the longer-term.


Incidence and mortality rates of cervical cancer in Bolivia are the highest in Latin America. Vaginal cell self-sampling can improve screening coverage. Information on common reasons for low screening coverage and preferences for future screening are essential to reduce cervical cancer incidence. We aimed to evaluate the knowledge about human papillomavirus (HPV) and cervical cancer of Bolivian women from urban, peri-urban and rural areas of Cochabamba and to determine their degree of acceptability and confidence towards vaginal HPV self-sampling. In addition, we assessed the impact of self-sampling on cervical cancer screening coverage in a selected peri-urban area.We gathered information from women living in urban, peri-urban and rural areas of Cochabamba province in Bolivia using two different structured questionnaires. In Survey1, we collected information from 222 women about their knowledge on HPV and cervical cancer. In Survey 2, the acceptance and confidence towards vaginal HPV self-sampling compared to the physician-sampling was assessed in 221 women. A non-probabilistic stratified sampling by areas was carried out for the two questionnaires. In the third phase of the study, we determined the impact of HPV self-sampling collection on screening coverage in a peri-urban area of Cochabamba.Bolivian women knew little or nothing about cervical cancer and HPV infection in all areas. They all found self-sampling collection easier to perform (86.9 to 93.2%) and more comfortable (79.4 to 83.3%) compared to physician sampling. Sampling accuracy to detect cervical cancer was probably higher in their point of view when it was taken by physician (35.1 to 63.5%). However in rural areas women preferred self-sampling. Accordingly, the campaign of vaginal HPV self-sampling in this peri-urban area increased screening coverage, reaching in three months the annual rate average.The knowledge about cervical cancer and HPV infection is poor in Bolivia. Despite greater acceptance of the vaginal HPV self-sampling in all areas, women kept greater confidence in the screening performed by the gynecologist although HPV self-sampling improved coverage rate.The online version of this article (10.1186/s12889-019-6401-5) contains supplementary material, which is available to authorized users. The development of cervical cancer depends on high-risk human papillomavirus (HR-HPV) persistent infection in the uterine cervix . The 2–1Cervical cancer-related deaths have nevertheless declined significantly in developed countries because of extensive cytology screening. However, similar initiatives in developing countries have not been equally successful because of the complexity of the required elements, such as laboratory expertise, depending on high operating costs , 4. It iPrevention of cervical cancer in Bolivia is primarily based on Papanicolaou smear cytology test (Pap) and more recently on visual inspection under acetic acid (VIA) , 8. ScreThe health personnel estimated that 50 to 80% of Pap screened women were lost to follow-up, mainly because of delays in result delivery .Bolivia’s Ministry of health has introduced the HPV vaccine in 2016 as an alternative to reduce the incidence of cervical cancer. In 2017, 80% of the target population (girls between 10 and 12 year old) were vaccinated with the first dose .Bolivia is characterized by significant disparities between rural and urban areas, including education and access to basic health services as some of the variables contributing to this difference , 11. AltThe screening coverage rate is a key component in cervical cancer prevention programs. Vaginal self-testing of HR-HPV could reduce screening barriers for those women and therefore increase their screening coverage –18. IndeThe objectives of this study were to obtain information among the Bolivian women about their level of knowledge on HPV and cervical cancer and to evaluate the degree of the vaginal self-sampling test acceptability and confidence in comparison to gynecologist sampling at urban, peri-urban and rural areas, in order to evaluate the need for an adapted strategy within each three geographical areas, potentially corresponding to a characteristic population. Furthermore, this study assessed the impact of the HR-HPV self-sampling test on screening coverage in a restricted Bolivian peri-urban area.This cross sectional study is based on the analysis of two surveys with a non-probabilistic stratified sampling by geographical areas . The evaluation of coverage impact through self-sampling was performed in a peri-urban area, with a mixed population . The Bio-ethical committee of “Universidad Mayor de San Simon” approved the study protocol . The signed informed consent was an indispensable requirement for the inclusion of patients. Pregnant women over 20 weeks, calculated on the basis of last menstrual period, and women with hysterectomy were excluded from this study. This study was divided in three phases. For surveys, a person speaking Quechua and Spanish was available to read and help to fill the survey files in case of analphabetism.n = 96), the peri-urban (surrounding area n = 66) and the rural  areas with a range of age between 20 and 64 years. One structured questionnaire was conducted with four multiple selection questions in the three geographic areas mentioned above to determine the degree of knowledge about cervical cancer and HPV, , we obtained information from 222 women about their knowledge on HPV and cervical cancer and their prevention. The target population was women from the urban , the peri-urban (surrounding area n = 63) and the rural  areas, with a range of age between 25 to 64 years.The second phase of the study (survey 2) assessed 221 women through eight closed-ended questions after self-sampling and physician-sampling to determine their acceptance and confidence towards vaginal HPV self-sampling. The target population was women from the urban . This was carried out through campaigns with the participation of volunteers . All of them were trained for three days to give correct information on cervical cancer, HPV and on the self-sampling technique and procedure. Two strategies to promote and collect self-samplings were performed: 1) direct contact with the population through visits at home, informing and offering the self-sampling device, 2) installation of tents with isolated cubicles in populated areas, generating a favorable environment for self-sampling. This was carried out during 9 one-day campaigns over a three month period. Cervical cancer screening was also promoted for 8 months in the primary Health Centers of District 9 Cochabamba, starting four months before the beginning of the self-sampling campaigns. The device for the vaginal and cervical cell self-collection was the same as in phase 2. The results in the coverage achieved through this intervention were estimated for twelve months and compared to the cytology coverage obtained in the previous year.All cervico-vaginal samples in this study were analyzed for HR-HPV DNA within two weeks after they were collected. The procedure for DNA extraction from samples transported and conserved on glass slides has been described previously . Only DNP value greater than 0.05), assuming that differences in education between the geographic residences of women are not influencing the survey responses. This null hypothesis is justified to detect any difference between areas on the survey responses.Statistical analyses were performed using hypothesis test for proportion (Chi-square). The null hypothesis was that there are no differences between the responses of the urban, peri-urban and rural areas, .In the first and second phase of the study, most of the population (83% for the survey 1 and 95% for the survey 2) was in the range of 20 to 49 years (data not shown). As expected, the level of education of the survey 1 population decreased in relationship with the distance to the urban region .As summarized in Table P value> 0.05). Compared to self-sampling, samples taken by physicians with vaginal speculum seemed less comfortable (from 40.5 to 71.6%), and more painful, especially in rural areas , in peripheral areas of Cochabamba city and in the central area of Cochabamba city survey 2). Three questions were asked to evaluate the easiness, the comfort and the experienced sensation of pain using the cotton swab for the self-sampling . However, in regards to the question: what test would you recommend? women from the rural areas tended to recommend the self-sampling with a significant statistical difference in the three areas .In Survey 2, women were also asked for their long term screening strategy preference: physician-sampling versus self-sampling procedure Table . There was Table . SimilarIn 2015, starting in January, we promoted cervical cancer screening in District 9 health centers. Health personnel from 8 public health primary care centers in the intervention area were informed and trained about the relationship between HR-HPV and cervical cancer, prevention and molecular detection of HPV. Women attending those primary health care centers were encouraged to visit gynecologists to request the physician-collected HPV and Pap smear test. The purpose of this activity was to be able to respond to the demand for information and / or follow-up of any woman in the area requesting it.Four months later, we started campaigns (9 days distributed in a three month period), to collect self-sampling from the same population. Campaigns were performed informing and offering the self-sampling device either by visiting women from house to house or by meeting them in populated areas under a tent with isolated cubicles, providing favorable environment for self-sampling. This 9 days campaign allowed collecting 902 HPV self-sampling tests from the same population. From 902 100%) women who underwent self-sampling, 792 (87%) samples were analyzed, 95 (12%) were HR-HPV positive, and only 13 (13.7% of women with HR-HPV) came back for follow-up Three women had a low-grade intraepithelial lesion and two had a high-grade intraepithelial lesion. The coverage calculation in District 9 was performed taking into account the population assigned to the eight health centers . The Pap smear test coverage achieved in the year 2014 was 3.9%, and coverage obtained in 2015 in three months by the HPV self-sampling test was 4.6%, making an estimated annual coverage that could achieve 18.6%, namely 4.7 fold higher with respect to the Pap coverage of the previous year  were always provided 2–3 weeks after collection (by physician or self-sampling), while cytology results, when available, were mostly provided after 3 months.In order to reduce the cervical cancer incidence and mortality in the department of Cochabamba in Bolivia, we aimed to develop and assess a low cost HPV self-sampling screening. We believe that this strategy could improve the poor screening programs developed in our country. Not only the HPV DNA detection rate in self-sampling has been reported to be in good agreement with physician-sampling, but also the self-sampling method seems better accepted among women , 25. It In our study, in the Survey 1, we confirmed that the level of knowledge about cervical cancer and HPV, in the three geographical areas, was low, diminishing in function of the distance between the area of residence and the capital city (urban area), and of the education level (the null hypothesis is rejected). A study in Cameroon mentioned that education about HPV and cervical cancer is associated to a greater acceptability towards the HPV self-sampling test. The provided information had a positive impact on the patient’s concerns, about her ability to perform the test . TherefoAccording to the results obtained in the survey 2, most of the women found, in the three geographic areas, self-sampling easy, comfortable and without pain. The level of the self-sampling acceptance was thus good, allowing to consider it as a promising screening tool to break sociocultural barriers. A similar result was observed in a study performed on three different populations  as 75% women found that self-sampling was easy and 90% found it very comfortable . HoweverA meta-analysis in which six studies were reviewed about self-sampling acceptability revealed that the majority of women interviewed preferred the self-sampling test which did not require a gynecological examination . The vagIn our third study, assessing self-sampling on cervical cancer screening coverage in a peri-urban area (9th District), we observed up to a 4.7 fold higher screening coverage compared to the previous year Pap coverage. Similarly, another study in South America mentioned a 4 fold increase in screening coverage using self-sampling  and simiIf self-sampling would be routinely used in Bolivia, additional infrastructures and guidelines will be needed, especially to provide clear information, among others to prevent insecurity feelings during samplings, to increase appropriated patient engagement, to improve the follow-up rate, but also to reduce the risk of patient anxiety after a positive result diagnosis transfer .In conclusion, the self-sampling is well accepted by the Bolivian surveyed women, regardless of demographic differences. This suggested that in Bolivia also, cervical cancer detection coverage can be expanded using this form of cervical sampling (self-sampling). Knowledge about cervical cancer and HPV should be optimized to improve cervical cancer prevention programs. This aspect is fundamental to improve confidence and motivation of women performing self-sampling Studies to assess follow-up efficacy in regards to screening strategy should be further performed.Additional file 1:Survey 1: Level of knowledge about HPV and cervical cancer. Multiple choice questionnaire in the three geographical areas of study to determine the degree of knowledge about cervical cancer and HPV. (PDF 414 kb)Additional file 2:HPV self-sampling kit. Self-sampling kit consisting of a cotton swab and a glass slide for cervical / vaginal sampling (TIF 222 kb)


Use of everolimus-eluting stents (EES) has proven to be clinically effective and safe in patients with ST-segment elevation myocardial infarction but it remains unclear whether it is cost-effective compared to bare-metal stents (BMS) in the long-term. We sought to assess the cost-effectiveness of EES versus BMS based on the 5-year results of the EXAMINATION trial, from a Spanish health service perspective.Decision analysis of the use of EES versus BMS was based on the patient-level clinical outcome data of the EXAMINATION trial. The analysis adopted a lifelong time horizon, assuming that long-term survival was independent of the initial treatment strategy after the end of follow-up. Life-expectancy, health-state utility scores and unit costs were extracted from published literature and publicly available sources. Non-parametric bootstrapping was combined with probabilistic sensitivity analysis to co-assess the impact of patient-level variation and parameter uncertainty. The main outcomes were total costs and quality-adjusted life-years. The incremental cost-effectiveness ratio was expressed as cost per quality-adjusted life-years gained. Costs and effects were discounted at 3%.The model predicted an average survival time in patients receiving EES and BMS of 10.52 and 10.38 undiscounted years, respectively. Over the life-long time horizon, the EES strategy was €430 more costly than BMS , but went along with incremental gains of 0.10 quality-adjusted life-years. This resulted in an average incremental cost-effectiveness ratio over all simulations of €3,948 per quality-adjusted life-years gained and was below a willingness-to-pay threshold of €25,000 per quality-adjusted life-years gained in 86.9% of simulation runs.Despite higher total costs relative to BMS, EES appeared to be a cost-effective therapy for ST-segment elevation myocardial infarction patients due to their incremental effectiveness. Predicted incremental cost-effectiveness ratios were below generally acceptable threshold values. Percency PCI  and demoency PCI .Given strained healthcare budgets and the higher acquisition costs of EES over BMS, economic considerations need to complement the assessment of clinical effectiveness. It is still unclear whether in a STEMI clinical scenario, EES are also preferable over BMS in terms of long-term, incremental cost-effectiveness. Such information is essential for decision makers at the clinical and health policy levels.The purpose of the present study was to evaluate the long-term cost-effectiveness of EES versus BMS from a Spanish health service perspective. The analysis was designed to assess incremental costs and quality-adjusted life years (QALYs) during a life-long time horizon, based on the 5-year results of the EXAMINATION trial.We used the 5-year, patient-level clinical outcome data of the EXAMINATION trial. Within-trial analysis was combined with modelling elements to incorporate quality of life and costs, and to extend the analysis beyond the 5-year trial observation period. Required life-expectancy estimates, health-state utility scores and unit costs representing 2016 prices were extracted from published literature. Clinical effectiveness was assessed by translating the reduction in clinical event occurrence into estimates of clinical effectiveness expressed as QALYs gained. It was assumed that long-term survival is independent of the initial treatment strategy after the end of follow-up. The model evaluated and compared total costs and QALYs between the EES and BMS strategies. On this basis, the cost-effectiveness of EES versus BMS was expressed as the incremental cost-effectiveness ratio (ICER), which is the difference in total costs between the two treatments divided by the difference in QALYs gained. Costs and effects were discounted at 3%. Non-parametric bootstrapping was combined with probabilistic sensitivity analysis to co-assess the impact of patient-level variation and parameter uncertainty. Details are provided in the following sections.Details of the EXAMINATION trial have been reported elsewhere . In shorEligible patients were randomly assigned to receive either EES or BMS in a 1:1 ratio. In total, 1498 patients, 751 in the EES and 747 in the BMS group, were followed over a 5-year period or until death. Primary endpoint of the study was the patient-oriented, combined endpoint of all-cause death, any myocardial infarction, or any revascularization at 1 year as suggested by the Academic Research Consortium (ARC) . SecondaThe trial showed a reduction in the rate of the combined patient-oriented endpoint of EES over BMS. The benefit was mainly attributable to reduced all-cause death (9% vs. 12%), non-cardiac death (2% vs. 4%) and target-lesion revascularization rates (4% vs. 7%). It occurred immediately after implantation and also at long-term follow-up for up to five years. Very late hazards in the extended clinical follow-up, such as stent thrombosis or target vessel myocardial infarction, were been reported.Long-term survival beyond five years of follow-up was based on the average life expectancy by age group using World Life Expectancy estimates  for SpaiHealth-state utility scores based on European Quality of Life-5 Dimensions (EQ-5D) population norms for Spain, using country-specific time trade-off values , were inClinical events and procedures which happened up to one day apart were considered as a single event, with an impact on utility equivalent to that of the more serious of the events involved. Other events were treated separately.The final utilities were applied to the relevant time periods, and summed to compute QALYs over a life-long time horizon.We examined the difference in direct medical costs between the EES and BMS treatment group from a Spanish health service perspective. Drivers of resource use and resource items taken into account during the initial hospitalization period and until the end of follow-up included the number of stents, PCI and CABG procedures, as well as clinical events such as repeat MI, STT, revascularization and death. Corresponding unit costs representing 2016 prices were derived from the Spanish diagnosis-related group-based system of hospital reimbursement  see Tab. InitialLong-term annual cardiovascular treatment costs were estimated from a published UK model of thrombolysis versus primary PCI in MI patients . It was Actual patient-level data from the EXAMINATION trial  were empThe main outcomes were total costs and QALYs for the two treatment strategies, as well as the ICER (expressed as cost per QALY gained). The ICER was compared to a willingness-to-pay threshold of €25,000 per QALY gained, which roughly corresponds to three times the gross domestic product per capita for Spain in 2016 .The analysis was subject to two main types of uncertainty: uncertainty over assumptions and the choice of values for parameters not covered by the trial data, as well as stochastic uncertainty due to variation in the sampled data. Parameter uncertainty results from imperfect information on analysis parameters, while stochastic uncertainty arises from the random variability in outcomes between identical patients. In order to address both types of uncertainty simultaneously and to estimate a total uncertainty range for incremental costs, we combined non-parametric bootstrapping with probabilistic sensitivity analysis . The booThe main model run on all individual observations for 10,000 replications using bootstrapping implemented in Stata/MP 13.1 for Windows . Analysis parameters subject to uncertainty were varied with each iteration. Ranges of variation and distribution types that reflect parameter uncertainty are provided in The robustness of model results was assessed via a deterministic sensitivity analysis and scenario analyses run in Stata/MP 13.1. For the sensitivity analysis, all observations from the patient-level data were included but the model additional analysis parameters subject to uncertainty were varied on a one-by-one basis, while all other parameters were fixed at their base case values. The sensitivity models were run without bootstrapping in order to describe the impact of each parameter on outcomes without the additional impact of stochastic uncertainty. In order to establish a reference point under similar conditions, all parameters were treated as fixed at their expected values, which resulted in deterministic estimates of the outcomes. The sensitivity results were then compared with those of this reference analysis to identify the most influential parameters. The models were run for 1,000 replications each.An additional sensitivity analysis was implemented to assess the impact of stent costs on estimated patient lifetime costs and ICER. Different prices per EES were explored, ranging from €440 and €840 in steps of €50, to allow for price differences between EES and BMS of €0 up to €400. Each model was run for 1,000 replications accounting for parameter uncertainty in all parameters but without bootstrapping. The combined results of each model were averaged and 95% uncertainty intervals were generated using the percentile method.Three different scenario analyses based on the main model were performed to assess the impact of (i) a discount rate of 0%, (ii) a discount rate of 6%, and (iii) exclusion of the patient-level data from Italy and the Netherlands. Assumptions on long-term life expectancy, health-state utility values and unit costs were drawn from published literature on Spain only, but the full EXAMINATION dataset included data from Italy and the Netherlands as well. Hence, the patient-level data from Spain only were used in scenario (iii) in order to assess the possible influence of between-country variability. All three scenario models were run for 10,000 iterations.The results of the main analysis  indicatePatient lifetime costs were €430 higher in the EES than in the BMS strategy, with a 95% uncertainty range between €58 and €797 indicating statistical significance. This was mainly driven by higher stent costs. Only in 1.4% of model runs, the total discounted costs of the BMS strategy exceeded the costs of the EES strategy. Significant cost savings in the EES strategy were observed for revascularizations , which was related to lower revascularization event rates.The model appeared to be stable after the first 400–500 replications when comparing the results of the first 10 to 1,000 replications (results not presented). Costs and QALYs at 1,000 replications , 5.22 (5.11–5.33); BMS: €7,876 , 5.12 (4.99–5.24)) were almost identical with the full set of 10,000 replications for both treatment strategies indicating high accuracy of the estimates at 10,000 replications.The joint distribution of incremental costs and effectiveness is shown in The average ICER over all simulations was €3,948  per QALY gained and was below a willingness-to-pay threshold of €25,000 per QALY gained in 86.9% of the simulations, indicating cost-effectiveness of EES over BMS. The probability of cost-effectiveness based on different levels of willingness-to-pay is presented in The main analysis addressed the uncertainty due to random variability in the trial data and the uncertainty over the choice of analysis parameter values from sources external to the trial, simultaneously. The uncertainty introduced by each of the external parameters , applying a model without non-parametric bootstrapping, is presented in The impact of varying costs per EES on the ICER is shown in The first scenario analysis with a discount rate of 0% (i) generated incremental costs of €420, similar as in the main analysis, which indicated that a large proportion of the cost difference was attributable to the first few years after the original STEMI event. The incremental effectiveness of 0.12 QALYs was increased as compared to the main analysis. The ICER was €2,142 per QALY gained . In 79% of the replications, the willingness-to-pay threshold of €25,000 per QALY gained was met.With a discount rate of 6% (ii), the incremental costs (€422) remained again similar but the incremental effectiveness was reduced to 0.08 QALYs. The estimated ICER was €5,986 per QALY gained . The willingness-to-pay threshold of €25,000 per QALY gained was met in 88% of the replications.The scenario analysis based on the Spanish EXAMINATION patients only (iii) contained about 76%  of the patient-level observations. The predicted incremental costs increased by 24% compared to the main analysis (€533 vs. €430), while the incremental effectiveness remained the same (0.10 QALYs). The increased costs were mainly due to larger differences between the simulated repeat MI, revascularization and cardiovascular treatment costs. The average ICER was estimated to be €4,728  per QALY gained. About 83% of the results were below a willingness-to-pay threshold of €25,000 per QALY gained.Our analysis based on the 5-year follow-up of the EXAMINATION trial indicated that the use of EES in STEMI patients is clinically effective as well as cost-effective compared to the use of BMS, despite higher total costs. It is likely to be preferable from a Spanish health service perspective, with an ICER estimate of €3,948 per QALY gained. Cost-effectiveness estimates remained stable in sensitivity analyses and were highly consistent in scenario analyses.versus BMS in PCI based on a Markov state transition model including patient-level data from meta-analysis of randomized controlled trials [We performed the first incremental cost-effectiveness analysis of the EXAMINATION trial, and, as far as we are aware, the first cost-effectiveness analysis of EES versus BMS with a lifelong time horizon and with a focus on STEMI patients. Another recent economic evaluation, by Ferko et al., addressed the cost-effectiveness of cobalt chromium EES d trials . The autd trials  also repVery recently, Poder et al.  presenteThe EXAMINATION trial was a large multicenter, multinational, prospective, randomized, two-arm, single-blind, controlled trial allowing for a high level of internal validity and predominantly conducted in Spain. The use of local data on life-expectancy, utility scores representing health-related quality of life, and unit costs allowed us to reflect the Spanish health service environment. As about one quarter of the EXAMINATION data were from patients enrolled in Italy and the Netherlands, we performed an additional scenario analysis based on data from Spain only. This resulted in consistent incremental effectiveness and somewhat higher incremental costs. Nevertheless, the results still indicated the use of EES to be cost-effective.versus BMS. On top of this, BMS were also less expensive than DES so that STEMI was a niche for BMS use. The EXAMINATION trial demonstrated that DES were superior to BMS in terms of major adverse clinical events, showing also a lower rate of thrombosis. Nevertheless, in some non-European Union countries, use of BMS in STEMI is still defended due to its lower cost compared to DES. For this reason, our first aim was to explore whether the higher efficacy of DES counterbalances their higher cost compared to BMS. We believe that our findings are still of interest even though DES became widely used in many settings as such large studies with long-term patient-level clinical data are rare and given the continued use of BMS at least in resource-restricted settings. The presented results might also be used in network meta-analyses which draw inference from different studies that share certain treatments in order to compare treatments of interest for which there is no head-to-head comparison available.When the EXAMINATION trial was designed the anticipated start of the study was in late 2008. By that time, it was unclear whether drug-eluting stents (DES) would be superior to BMS in a pro-thrombotic scenario like STEMI, given the evidence at that time of a higher thrombosis rate of DES The EXAMINATION trial had broad inclusion and few exclusion criteria to ensure an all-comers population of adult STEMI patients which is representative of routine clinical practice . SpecifiGiven the patient-level clinical data of the EXAMINATION trial, we were able to account for uncertainty in input parameters external to the trial data, and patient-level variation reflected in the trial data, simultaneously using non-parametric bootstrapping coupled with a probabilistic sensitivity analysis. Bootstrapping methods are still commonly used in cost-effectiveness analyses in health technology assessment , 23. An All input parameters external to the trial data (e.g. unit costs) were varied widely in sensitivity analysis. The effect on the main outcomes was low. The upper bounds of the ICER confidence intervals remained below €8,000 per QALY gained. Even for parameters for which we needed to rely on relatively uncertain assumptions, such as those representing cardiovascular treatment costs or utility scores for clinical events after the initial STEMI event, the amount of uncertainty introduced into the analysis was small and the EES strategy remained cost-effective over BMS.We made an assumption that clinical events and procedures happening up to one day apart were to be considered as a single event in terms of their impact on utility. We applied, in such cases, the effect of the more serious event or procedure. This may have introduced an element of error in the estimation of utility decrements, and hence, QALYs gained.For the analysis, we focused on the first occurrence of each type of clinical event that was recorded for each patient. Several revascularization, repeat MI or STT events may have occurred in some patients, implying an underestimation of event rates. This may have introduced an error to our cost and effectiveness estimates, such that effectiveness may have been overestimated and costs underestimated. However, the occurrence of repeat events is rather low and was lower in the EES group . Hence, The model assumed that long-term survival after the 5-year follow-up period was the same between the two treatment groups. However, differential survival rates might occur even after such an extended follow-up period. If the survival advantage was sustained in the EES group, which might be a plausible assumption, incremental effectiveness would increase, as well as incremental costs due to larger long-term cardiovascular treatment costs. However, the survival advantage could also be used up over time, resulting in a lower incremental effectiveness of EES and hence the advantage of EES over BMS could become less clear-cut.Main drivers of the €430 higher lifetime cost in the EES strategy were stent, cardiovascular treatment and repeat MI costs. During the five years of follow-up, the difference in the outpatient cardiovascular treatment and drug costs, including antiplatelet therapy costs, was only €17. Hence, most of the difference in treatment costs was accumulated after the follow-up period and was substantially driven by higher survival of EES patients and the resulting prolonged period on cardiovascular treatment. In contrast, the costs for STT and revascularization events were lower in the EES than in the BMS group due to higher clinical event rates of patients receiving BMS.We consider the analysis to remain reasonably accurate considering current clinical practice, which can be different from guidelines. In any case, as cost estimation was performed in the same way in the two groups compared, we would not expect any related differences to strongly influence our results.Our model currently assumes that clopidogrel is used as part of the lifetime outpatient cardiovascular treatment. If we assume that ticagrelor, which is a more expensive alternative drug, would be used instead, the incremental costs would increase due to enlarged treatment cost. Hence, cost-effectiveness of the EES strategy would decrease. However, even at three times higher costs of ticagrelor in comparison with clopidogrel and assuming that there is no effect on survival as well as utilities, the resulting ICER would remain below a willingness-to-pay threshold of €25,000 per QALY gained and the EES strategy would remain preferable over BMS.While the World Health Organisation's (WHO's) Choosing Interventions that are Cost–Effective project is recommending a cost-effectiveness threshold of three times the national gross domestic product per capita , there iWhile clinical outcomes may be comparable across different healthcare systems, other elements such as unit costs, utilities, long-term survival, healthcare costs, policies governing stent use and geographic context are often not. Given the focus on Spain, our results may not allow to draw direct inferences for other countries. However, since the average ICER was well below typically used cost-effectiveness thresholds, it may be reasonable to expect that the EES strategy is also cost-effective in comparison with the BMS strategy in other European countries with a similar socio-economic structure. Specific assessments for additional jurisdictions would imply to re-run the analyses with local estimates for the above-listed non-trial based elements, assuming that the clinical outcomes would be similar to those obtained from the EXAMINATION trial.We focused on comparing EES against BMS from a Spanish health service perspective. Drawing firm conclusions for different settings would require to obtain patient-level clinical data from a variety of countries. Furthermore, it would be important to obtain even longer-term data to assess whether the survival advantage of EES patients and reduction in clinical event rates can be sustained.In STEMI patients requiring emergency PCI, the use of EES instead of BMS appeared to be a cost-effective therapy from a Spanish health service perspective due to its clinical benefits and incremental effectiveness despite of higher total costs. Predicted ICERs were below generally accepted threshold values which was confirmed by sensitivity analyses.S1 Dataset(XLSX)Click here for additional data file.


Thestudy sought to evaluate near-peer tutors’ teaching of critical appraisalskills to medical students as an aspect of Evidence-based Medicine.In arandomized crossover trial, 241 students completing a Clinical Epidemiology andEvidence-based Medicine (CE-EBM) module in the Faculty of Medicine UniversitasIndonesia (FMUI) were randomly assigned to intervention or control groups.During tutorial sessions, intervention group participants were assigned tonear-peer tutors, who were newly graduated doctors, and those in the controlgroups were assigned to staff tutors. After two tutorial sessions, interventionand control groups exchanged tutors for the next two sessions. Outcomes weremeasured using written knowledge and skills multiple choice questions (MCQ)test, the Evidence-based Practice Confidence Scale (EPIC) and a studentattitude questionnaire, along with student evaluation of tutors to evaluate theprocess.(239) = 1.553,p=0.122), as well as overall Evidence-based Practice Confidence Scale scores (F(2/170)= 0.179, p = 0.673) and attitude scores (t(219) =-0.676, p = 0.085).In the tutor evaluations, the students rated their near-peer tutored sessionsas better than those tutored by staff in most respects.Oncompletion of the module, the written test scores of intervention groupstudents were similar to those of the control group (tNear-peertutors were as effective as and more readily accepted than staff tutors inteaching critical appraisal skills. These findings support the broaderimplementation of peer-teaching in other areas of medical education. Medical students must, therefore, be prepared to learn and master these skills, and various approaches have been implemented to that end.Among the limited number of studies comparing student-led tutorials (SLT) and faculty-led tutorials (FLT), Kassab and colleaguesAlthough the literature notes many benefits of peer-assisted learning, these are largely confined to the acquisition of psychomotor skills. In light of the growing need for innovative ways of incorporating EBM into medical school curricula, especially where human resources are limited, the present study aimed to evaluate the effectiveness of recently graduated medical doctors as near-peer tutors as compared to experienced medical staff. Specifically, we hypothesized that near-peer tutors would be as effective as medical staff in teaching critical appraisal skills to medical students as part of a Clinical Epidemiology and Evidence-based Medicine (CE-EBM) program.The study was designed as a randomized crossover trial. The participants were fourth-year medical students completing the CE-EBM module in the Faculty of Medicine Universitas Indonesia (FMUI) in the academic year 2014–2015. As the CE-EBM module is compulsory for fourth-year students, the entire cohort of 241 students participated. The module was conducted in two rotations: 116 students in rotation 1 (May–June 2015) and 125 students in rotation 2 (June–July 2015).  The crossover design meant that every student had an equal opportunity of being tutored by staff members or recently graduated medical doctors. The Research Ethics Committee of FMUI granted ethical clearance.,The content and structure of the CE-EBM module at FMUI has been described elsewhere.Skills for critical appraisal of scientific papers were practiced during four 2-hour tutored group discussions. Journal articles on diagnosis, therapy, prognosis, or etiologic studies were provided by the module coordinators to ensure that the studies in question were well designed and could be appraised by students at this level. Led by a tutor, the participating students undertook a critical appraisal of the studies in their respective groups, using the worksheets provided by the Oxford Centre for EBM.The voluntary near-peer tutors were recruited from FMUI’s newly graduated medical doctors, who had passed the CE-EBM module in their fourth year and had been practising EBM during their clerkship. The selected candidates were trained in a three-day training of teachers (TOT) that focused on tutoring skills and group dynamics. These new graduates were selected as near-peer tutors on the basis of their level and proximity in age to the fourth-year medical students. Five recently graduated medical doctors who were awaiting internship placement ultimately participated as near-peer tutors (of whom four participated in both rotations while one participated only in the first rotation).The control groups were taught by experienced medical staff who had already participated in a two-day EBM course conducted by FMUI or in a three-day EBM course by Oxford CEBM and were practicing EBM in their clinical work. In total, 15 medical staff from various departments participated as tutors (seven in rotation 1 and eight in rotation 2), having attended a similar three-day TOT on EBM.The students were randomly assigned to groups of 10 or 11. For the first two group discussion sessions, each group was randomly scheduled to be tutored either by medical staff or junior doctors. During the last two group discussion sessions, the groups were crossed over see . RandomiEvaluation of the teaching strategies was conducted in accordance with the Classification Rubric for Evidence-based Practice Assessment Tools in Education (CREATE) frameworkStudent knowledge and skills were evaluated using a written test comprising 30 multiple choice questions (MCQ) with five options  scale;Attitudes were measured using part of the Knowledge Attitudes and Behaviors questionnaire developed by Johnston and colleagues,Finally, student educational experience was also evaluated, although EBP steps were not explicitly measured. This final questionnaire assessed more general aspects of the tutorial process as evaluated by students; it was previously utilized by Knobe and colleaguesThe primary outcome measure was the difference in mean score between intervention and control groups; independent t-testing was used to assess the significance of any discrepancies. For outcomes that differed significantly from baseline scores, analysis of covariance (ANCOVA) was utilized, using the baseline score as a covariate. The analysis was based on the intention-to-treat principle. All analyses were performed using SPSS version 22.0.The mean + SD age of participating students was 22.1+1.1 years (range 18.9–26.7 years), of whom 89 (36.9%) were male. The median age of near-peer tutors was 24 years (range 23–26 years). The median age of staff tutors was 41.5 years (range 37–55 years).(241) = -1.520, p = 0.130) between mean + SD of written test scores for the near-peer tutored group (65.89 + 12.86) and the staff-tutored group (63.18 + 13.69). The groups then exchanged tutors for the next two discussion sessions. At the end of the module, the difference in mean + SD of written test scores for the near-peer tutored group (68.20 + 12.50) and the staff-tutored group (70.61+10.99) was again statistically non-significant (t(241) = 1.553, p = 0.122).A mid-evaluation following the first two discussion sessions found no statistically significant difference  at the beginning of the module was also comparable for both groups . HoweverIn the present study, near-peer tutored students and staff-tutored students achieved comparable scores on knowledge, skills, attitudes, and confidence in relation to critical appraisal skills. Although confirming what has been reported in earlier studies, these findings must nevertheless be interpreted with a degree of caution. For example, the similarity of these results, especially on the written test, may reflect the fact that all students attended lectures delivered by experts in clinical epidemiology. Another possible explanation (as suggested by ten Cate and colleagues)Additionally, students scored better on the tutorials led by near-peer tutors than on those led by medical staff tutors. Tolsgaard and colleagues reported a similar result in a study employing second-year medical students as tutors to teach IV access and bladder catheterization to first-year medical students at the University of Copenhagen.A systematic review by Burgess and colleaguesAs well as the benefits for the medical students, the peer tutors also gained, as the teaching experience motivated them to learn more and to deepen their understanding of the subject. This is an expected aspect of EBM skills, which are currently seen as one of the core competencies of medical doctors. Experience in teaching and preparation of teaching materials is also known to build leadership capability and confidence.Although peer teaching has been widely implemented in medical education, we are not aware of any previous studies of this kind from Indonesia, although in our experience the practice is undoubtedly performed informally. We recognize that as educational interventions are generally complex, it is often difficult to distinguish which element accounts for which effect or to what extent it might be adapted to local circumstances while remaining effective.The present findings confirm that near-peer tutors can be as effective as and more readily accepted than staff tutors. This is based on the performance of students in critical appraisal skills in EBM, extending the evidence of the benefits of peer-assisted learning beyond the area of psychomotor skills. This study also provides preliminary evidence that medical school educational policy will be accommodated to the assignment of trained near-peer tutors to teach critical appraisal skills to medical students.We would like to express our gratitude to the Dean, the Vice Dean for Education, Research, and Student Affairs and the Manager of Education and Student Affairs at FMUI for lending their full support to this study. The study received full financial support from the Medical Education Unit of FMUI.The authors declare that they have no conflict of interest.


We have previously developed and validated the Arthritis Research UK Musculoskeletal Health Questionnaire (MSK-HQ) for use across musculoskeletal care pathways, showing encouraging psychometric test results. The objective of this study was to determine the responsiveness of MSK-HQ following MSK treatments and to determine the minimally important change (MIC).We collected data in four cohorts from community physiotherapy and secondary-care orthopaedic hip, knee and shoulder clinics.592 individuals were recruited; 210 patients treated with physiotherapy for a range of MSK conditions in primary care; 150 patients undergoing hip replacement, 150 patients undergoing knee replacement and 82 undergoing shoulder surgery in secondary care.Preoperative data were collected including the MSK-HQ, European Quality of Life-5D (EQ-5D) and the OHS, OKS or OSS in each joint-specific group. The same scores, together with anchor questions, were collected postintervention at 3 months for the physiotherapy group and 6 months for all others. Following COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) guidelines, responsiveness was assessed using correlation between scores and the MIC was calculated for the entire cohort using receiver operating characteristic curve analysis.The MSK-HQ demonstrated strong correlation (R=0.73) with EQ-5D across the entire cohort and with each of the joint-specific Oxford scores . Moderate correlation was seen between MSK-HQ and EQ-5D across each individual group , apart from the hip group where correlation was strong (R=0.77). The effect size with MSK-HQ was 0.93, in the entire cohort, double that measured with EQ-5D (0.43). In all subgroups, MSK-HQ measured a greater treatment effect compared with EQ-5D. The MIC is 5.5 (95% CI 2.7 to 8.3).Our study demonstrates that the MSK-HQ questionnaire is responsive to change across a range of musculoskeletal conditions, supporting its use as a generic MSK measurement instrument. The Musculoskeletal Health Questionnaire (MSK-HQ) has been shown to be responsive across a range of musculoskeletal (MSK) conditions.The MSK-HQ performed well in comparison with other quality-of-life-based questionnaires, including the European Quality of Life-5D score.The minimally important change value for the MSK-HQ in the general MSK population has been calculated.A limitation of the study is that the MSK-HQ has not been tested across all MSK conditions.Musculoskeletal (MSK) health problems affect one in four of the adult population and managing this diverse spectrum of conditions is expensive, for instance in the National Health Service (NHS) accounting for approximately £5 billion of spending annually.To address this need, the Arthritis Research UK Musculoskeletal Health Questionnaire (MSK-HQ) was developed.The specific aim of this study was to determine the responsiveness of the MSK-HQ in measuring clinical change as a single generic MSK measure following treatment across different MSK pathways. In addition, the study aimed to determine the minimally important change (MIC) for MSK-HQ.We have developed a series of cohorts of patients to validate the MSK-HQ as previously described.Patients were recruited from community MSK physiotherapy clinics in five UK West Midlands towns , where NHS treatment is offered after referral by the General Practitioner (GP). Patients were invited to take part and recruited directly in the clinic having received a study information pack. The inclusion criteria were age >18 years and referral from a GP for physiotherapy treatment. No further inclusion/exclusion criteria were used, creating a study group with a heterogeneous range of unspecified MSK problems. Patients consented to fill out questionnaires pretreatment and at 3 months after first consultation.From the Nuffield Orthopaedic Centre in Oxford, we recruited separate knee, hip and shoulder cohorts from patients who had been listed for surgery. Patients were approached in their preassessment clinic appointment prior to surgery having received a study information pack. Inclusion criteria were age >18 years and patient listed for (1) knee replacement surgery, (2) hip replacement surgery and (3) shoulder surgery including open and arthroscopic procedures (excluding instability surgery). Patients consented to fill out a preoperative questionnaire and again at 6-month postsurgery. The shoulder cohort had been expanded to 82 compared with the 60 previously reported.All participants were asked to complete the MSK-HQ and EQ-5D-5L (the primary reference measure) as baseline and final follow-up as the second time point. The MSK-HQ is a 14-item questionnaire assessing pain severity, physical function, work interference, social interference, sleep, fatigue, emotional health, physical activity, independence, understanding, confidence to self-manage and overall impact. When reporting the MSK-HQ, all 14 items are summed together  providing a range from 0 to 56, with higher scores indicating better MSK health status.This was a longitudinal study and in each group the same scores were recorded at final follow-up (3 months for physiotherapy and 6 months for orthopaedic cohorts) corresponding to the normal clinic practice in each clinical setting. The questionnaires are all patient reported and were filled out by the patients with no assistance from the research or clinical teams.For each of the prospectively collected cohorts, we compared the baseline and follow-up scores (3 months for the physiotherapy cohort and 6 months for orthopaedic cohorts). There is no gold standard measurement tool in this context and so we could not apply area under the curve methodology. Following COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) guidelines, we therefore used the construct approach and we set a priori hypotheses of expected positive associations at the moderate or above level between MSK-HQ and the reference measurement tools  . To testWe then performed subgroup analysis calculating and comparing the standardised effect size (SES—the mean change score divided by the SD of the measure at baseline) and the standardised response mean (SRM—the mean change score divided by the SD of the change scores) for the outcome measure used within each cohorts collected.For the entire cohort, the clinically relevant change (improvement or deterioration) was determined by calculating the MIC using receiver operating characteristic (ROC) curve analysis. For the external anchor, we used the following transition item from the Outcome and Experience Questionnaire to identify change in clinical state compared with baseline .We followed COSMIN guidelines for evaluation of responsiveness and calculation of MIC.All analyses were conducted in STATA/IC V.14 , SPSS V.22  and Statistical software-R V.3.2.2 .The MSK-HQ questionnaire in a PROM and its development has involved patients in each of the following stages: development of the research question, development of the outcome measures itself and participating in the research.There were 592 patients in total who consented to participate in the four cohort studies . Baseline population characteristics for the overall sample and by each cohort are summarised in There was a strong correlation between change scores for MSK-HQ and non-disease-specific EQ-5D across the entire cohort with an R value of 0.73 . There wAcross all cohorts, the MSK-HQ measured a relatively large mean effect size for treatment ranging between 2.14 in the hip cohort and 0.93 in the physiotherapy cohort. Within the physiotherapy cohort, greater responsiveness was shown with MSK-HQ compared with EQ-5D, with over twice the effect size measured at 3 months. In the knee cohort, MSK-HQ measured a similar effect size to the OKS  at 6 months, both of which were greater than that calculated using EQ-5D (0.94). A similar pattern was seen within the hip cohort. Within the shoulder cohort, the pattern was different with MSK-HQ measuring a greater effect size than OSS and EQ-5D, which delivered similar results across the cohort (both 0.73). The findings were supported by the calculated standardised response mean values .The MIC for MSK-HQ was 5.5 (95% CI 2.7 to 8.3) based on the optimal cut-off value with specificity 0.66 and sensitivity 0.65, with area under the ROC curve 0.66 see .The results of this study demonstrate that the MSK-HQ PROM is responsive to change across patients with a range of MSK conditions. When considering change scores across the entire cohort, the MSK-HQ performed well compared with EQ-5D with a strong correlation between the scores. Within the subgroups, the MSK-HQ correlated very well with change measured using the OHS, OKS and OSS. This was supported by measured effect sizes, particularly for OKS and OHS. For the community physiotherapy group, the correlation with EQ-5D was moderate but there was a much larger measured effect size using the MSH-HQ. The trend for the new score to measure a larger effect size when compared with EQ-5D was seen across all the cohorts.The requirement to integrate PROMs into clinical management and outcome-based commissioning in primary and intermediate care has expanded.Despite the MSH-HQ not being joint or condition specific, the new score performed well in responsiveness when compared with the OHS, OKS and OSS. In particular, the score appears to measure change in response to hip and knee arthroplasty in a similar manner to the OKS and OHS with very high measured correlation coefficients and similar effect sizes. The follow-up sample size for the shoulder cohort was inadequate, and further work is required to determine responsiveness in this group of patients.Our study does have a number of limitations that must be addressed. We have not collected any information regarding detailed nature of pathology or treatment within each cohort, such as stage of disease, time to treatment or detail of reconstructive surgery. Our aim was not to explore these issues but only to measure change in the MSK-HQ before and after treatment to calculate responsiveness across the whole MSK cohort. Our study does have missing data from the follow-up cohort. However, overall the effective response rate for the entire cohort was 70%, which is considered acceptable.In the our previous publication regarding the production of MSK-HQ, we laid out a set of prerequisites that should be met for its creation.The expansion of MSK intermediate care within the NHS has highlighted the need for a generic PROM to assist in developing outcome-based commissioning of care. The measurement property profile of the MSK-HQ PROM appears to support its use in this area, although its role is still evolving. Increasingly, there is a common clinical pathway for most MSK patients within the NHS. Patients initially seek advice and treatment from their GP and if their condition does not settle are referred to an MSK intermediate care referral hub, which acts as a gateway to secondary care. The pathway is not joint or condition specific, so a generic MSK PROM to measure clinical change and response to treatment is required for the process. The MSK-HQ appears to demonstrate the appropriate measurement properties and responsiveness to fulfil this role.In summary, the findings from this study show that the MSK-HQ appears to be responsive to change across a range of MSK conditions, performing favourably when compared with EQ-5D.


There has been increasing interest in pyroptosis as a novel form of pro-inflammatory programmed cell death. The mechanism of pyroptosis is significantly different from other forms of cell death in its morphological and biochemical features. Pyroptosis is characterized by the activation of two different types of caspase enzymes—caspase-1 and caspase-4/5/11, and by the occurrence of a proinflammatory cytokine cascade and an immune response. Pyroptosis participates in the immune defense mechanisms against intracellular bacterial infections. On the other hand, excessive inflammasome activation can induce sterile inflammation and eventually cause some diseases, such as acute or chronic hepatitis and liver fibrosis. The mechanism and biological significance of this novel form of cell death in different liver diseases will be evaluated in this review. Specifically, we will focus on the role of pyroptosis in alcoholic and non-alcoholic fatty liver disease, as well as in liver failure. Finally, the therapeutic implications of pyroptosis in liver diseases will be discussed. Programmed cell death (PCD) contributes to the development of liver disease , 2. RecePyroptosis is an innate immune defense against intracellular bacteria. HoweverApoptosis and necrosis are common types of PCD found in the liver. MorpholApoptosis is mechanically similar to pyroptosis as they are both triggered by caspases. The caspases in apoptosis can be stratified into initiator caspases (caspase-2/8/9/10) and effector caspases (caspase-3/6/7), 10, 11.The differences in the morphological and molecular pathways between the different forms of cell death are listed in Table 1Pyroptosis is an effective immune defense against intracellular bacterial infection -19. PyroIn general, the balance between chronic inflammatory injury and the healthy immune response of pyroptosis is precisely regulated. When the balance is disrupted, excessive host immune response and massive cell death during pyroptosis can lead to serious disease. Inflammasome activation, which occurs at the onset of pyroptosis, is mechanically believed to be involved in the development and progression of the following diseases: Alzheimer's disease , systemiThere are two different pyroptosis pathways : canonicStimulatory signals are received by inflammasomes in canonical pyroptosis. Inflammasomes are intracellular, multiprotein complexes that usually consist of three parts: a cytosolic sensor, a bridging adaptor and an effector. The role of inflammasome activation in liver diseases has been extensively reviewed by Szabo and Petrasek .The sensor component of the inflammasome system is formed by nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). According to different cytosolic pattern recognition receptor (PRR) proteins, NLRs can be categorized as NLRP1, NLRP3, NAIPs (NLR family apoptosis inhibitory proteins), NLRC4, or AIM2 (absent in melanoma-2)-36.Apoptosis-associated speck-like protein containing caspase recruitment domains (ASCs) are the bridge adaptor of the inflammatory complexes. It contains two domains: one is the pyrin domain (PYD) which interacts with the PRR of the sensor, and the other is the caspase-recruitment domain (CARD) which interacts with pro-caspase-1 effector. Through these two domains (pyrin and CARD), ASC can interact with the cell death executioner and act as an essential adapter for inflammasome integrity , 38.The effector in canonical pyroptosis is pro-caspase-1. AlthougIn noncanonical pyroptosis, pro-caspase-4/5 caspase-11 in mice) is the sensor and can be directly activated by LPS independent of TLR4 in mice . The lipThe initiation of pyroptosis begins with the aforementioned recognition of PAMPs and DAMPs. The receptors help to translate extracellular signals into cells. The subsequent activation of caspases is the key step in pyroptosis signaling pathways.Caspase-1 is the only reported caspase involved in canonical pyroptosis. The activation of caspase-1 by the NLRP3 inflammasome leads to cleavage of pro-IL-1β and pro-IL-18 and the production of mature, biologically active cytokines , 35. Add+ efflux and ultimately leads to IL-1β production and release [In noncanonical pyroptosis, caspase-4/5/11 cleaves and activates GSDMD. This process is similar to canonical pyroptosis. In addition, caspase-1 is activated by cleaved GSDMD through the combination of NLRP3 and ASC. Caspase release . Through. Unlike GSDMD, the N-terminus of GSDMB does not directly induce cell death. It binds to the CARD domain of caspase-4, which is required for the cleavage of GSDMD in noncanonical pyroptosis, and activates it [In addition to GSDMD, other members of the gasdermin family also participate in pyroptosis. A recent study showed that gasdermin B (GSDMB) promotes pyroptosisvates it . Genome-vates it  and asthvates it . Anothervates it , 54. Intvates it  found thGSDMD pores in the cell membrane are detrimental to the cell. If the number of pores in the plasma membrane is small, a normal cellular emergency response can patch up the porous membrane . HoweverOn the other hand, the IL-1 family cytokines (IL-1β/IL-18) that are released through the GSDMD pore during pyroptosis will recruit immune cells to the site of inflammation, stimulate secondary cytokine production and trigger acute-phase signaling responses . Beside Inflammasomes can be stimulated by different kinds of substances, from PAMPs released by pathogens  to DAMPs released by dying cells. InteresThe liver is the first line of defense against diverse microbial particles from circulating blood. Inflammasomes, as the receptor of pyroptosis, are highly expressed in macrophages, stellatThere are two phenotypes of macrophages in the liver: infiltrating macrophages and resident macrophages (KCs). Both types are the first cells to detect the presence of danger signals in the liver. Pyroptosis in macrophages is responsible for the development of liver diseases. For instance, rare-earth oxide can initiate NLRP3 inflammasome and caspase-1 activation and eventually lead to pyroptosis in KCs, bone marrow-derived macrophages, and other macrophage cell lines such as J774A.1 and RAW 264.7 cells . HoweverThe activation of inflammasomes in HSCs plays vital roles in the development of fibrosis. Liver fInfiltration of eosinophilic leucocytes has been found in many liver diseases, including hepatic allograft rejection, drug-inInflammasomes are detectable in hepatocytes. Many recent studies have uncovered the direct role of inflammasome activation in hepatocyte injury, 77. In A recent study even suggested that activation of the hepatocyte-specific NLRP3 inflammasome and subsequent pyroptosis might be a more important contributor to liver injury and fibrosis than previously thought. This indirect evidence comes from Wree et al., who devNAFLD is characterized by lipid accumulation in the liver in the absence of significant alcohol intake, medication use or other medical conditions that cause hepatic steatosis. It can be pathologically classified into different degrees of severity, from simple steatosis to steatohepatitis (NASH) and fibrosis, 80. LowInflammasome activation in both bone marrow-derived cells and liver parenchymal cells activates caspases and promotes inflammation and fibrosis in MCD diet-induced NAFLD in mice. TypicalGrowing evidence shows that pyroptosis is an inflammatory link between simple steatosis and NASH, as NLRP3 activation is seldom observed in an animal model of simple steatosis without inflammation-99. NLRP. Those DAMPs and cytokines bind to receptors located on HSCs and induce upregulation of fibrotic markers, thus leading to liver fibrosis[Pyroptosis in hepatocytes and macrophages is also involved in the development of liver fibrosis in NAFLD. After injury, these cells release DAMPs and danger signals such as IL-1β/IL-18 and inflammasome particles fibrosis.Interestingly, another cytokine cleaved by caspases during pyroptosis—mature IL-18—seems to be play a different role in NAFLD/NASH progression. In the IL-18 knock-out mouse model, the expression of gluconeogenesis genes in the liver is substantially higher. Those mice are prone to develop obesity, hyperphagia and insulin resistance. It seemAlthough there have been many studies on pyroptosis in NAFLD, many questions remain unanswered. For example, as steatohepatitis and fibrosis only account for a small proportion of the NAFLD population, 111, whALD is a general term used to refer to alcohol-related liver injuries. The clinical spectrum includes steatosis, fibrosis, alcoholic hepatitis (AH), cirrhosis, and hepatocellular carcinoma (HCC). ActivatEthanol can induce pyroptosis through different ways. One effect of ethanol on pyroptosis is via the microRNA-148a pathway. Alcohol can decrease microRNA -148a expression in hepatocytes through FoxO1 and induce the overexpression of TXNIP, a member of the α-arrestin family. TXNIP tAnother impact of alcohol on pyroptosis is triggered by PAMPs (derived from the gut) and DAMPs . The DAMAcute liver failure (ALF) is characterized by an abrupt onset of severe liver injury with gross hepatocyte dysfunction. Acetami. TNF receptor superfamily member 4(OX40), which is expressed in liver invariant natural killer T (iNKT) cells, is also involved in the development of liver failure.OX40 activates caspase-1 via TNF receptor-associated factor 6-mediated recruitment of the paracaspase MALT1, which consequently leads to massive pyroptotic death of iNKT cells and liver injury[Most studies of pyroptosis in liver failure are conducted in animal models. Significantly elevated levels of NLRP3, cleaved caspase-1 and IL-1β and predominant pyroptotic cell death have been observed in the livers of concanavalin (ConA) and D-gaer injury. IL-1 reer injury. Pretreaer injury.Although massive cell death and inflammation are important in the development of liver failure, the correlation between pyroptosis and liver failure has only been investigated in animal models but rarely been investigated in patients. Moreover, the role of pyroptosis has never been studied in another fatal subtype of liver failure, acute chronic liver failure (ACLF) in which systemic inflammation is believed to be a major pathogenic mechanism, 133. ACNLRP3 expression is upregulated in hepatocytes and macrophages with HCV, 135. PrHepatitis B virus (HBV) is a global health problem and more than 350 million people are chronically infected. Chronic HBV infection leads to liver fibrosis, cirrhosis, liver failure and hepatocellular carcinoma; however, no cure for chronic HBV has been found to date. HepatitPyroptosis has been shown to play a vital role in immune cell activation and amplification of liver inflammation in sepsis-related liver injury. Sepsis Given the growing evidence for the role of pyroptosis in liver injury and fibrosis, targeting liver pyroptosis represents a promising therapeutic option for the treatment of liver disease.There are currently two major strategies for pharmacological inhibition of pyroptosis. One is to inhibit NLRP3 through regulatory pathways; for example, the NLRP3 inhibitor MCC950 effectively reduces liver injury and inflammation, type 1 GSDMD is the executive molecule in pyroptosis, but molecule targeting of GSDMD is rarely studied. There is only one study suggesting that necrosulfonamide, a known anti-necroptosis molecule, attenuates pyroptosis by directly binding gasdermin D and preventing pore formation in the membrane of septic mice. The theSome herbal extracts and dietary components that have protective effects on the liver also inhibit pyroptosis. Silybin has long been known to inhibit NLRP3 inflammasome assembly through the nicotinamide adenine dinucleotide+/sirtuin 2(NAD+/SIRT2) pathway in mice with NAFLD. ScutellThe details of current research regarding anti-pyroptosis in liver disease are listed in In summary, pyroptosis is essential for the liver defense against pathogens and danger signals, but excessive pyroptosis promotes pathogenesis of various liver diseases. The pyroptotic process is complex, and its detailed molecular mechanism in liver disease requires further studies. For example, the role of pyroptosis has not been extensively studied in HBV- related diseases and in ACLF. A single study reveals the impact of renal DAMPs on the liver, yet the effects of liver DAMPs on the kidney remain unknown. The role of pyroptosis in the crosstalk between liver and the other organs requires further investigation.There is no doubt that pyroptosis is a promising therapeutic target for inflammatory diseases. Inhibition of pyroptosis by blocking related molecules  influences the progression of liver disease and provides a potential treatment approach for liver disease. However, as pyroptosis is an essential defensive line against pathogens, inhibition of pyroptosis may have a potential downside; for example, it may increase the risk of opportunistic infection. Therefore, safety is always an unavoidable concern. Much research is still required before the translation to clinical treatments. Further study of pyroptosis will contribute to the understanding of the mechanisms of hepatocellular injury and to the development of pharmaceutical inhibitors of pyroptosis.