We appreciate the opportunity to address the concerns raised by D’Angelo and colleagues in relation to our recently published protocol for the Trans20 study [1]. While we certainly welcome feedback on our study, D’Angelo and colleagues focus much of their commentary on the clinical care of young people with gender dysphoria rather than on the Trans20 study protocol itself. In addition, the letter contains a number of inaccuracies and misconceptions that we feel must be clarified.
Firstly, the authors claim not only that the study “intervenes in the developmental trajectories of all 600 expected participants” and that the model involves “a uniformly stepwise progression through the social and biological stages of transition”, but also that The Royal Children’s Hospital (RCH) Gender Service offers biological interventions to children as young as three. These assertions are incorrect. While patients and families attending the RCH Gender Service routinely receive mental health input to assess, explore and support their gender identity, the use of medical interventions occurs in only a minority of patients, reflecting the highly individualised approach to care. More specifically, a recent 10-year audit of the service from 2007-16 (up until the inception of Trans20) revealed that only 23% of patients received puberty blockers, while an even lower figure of 20% received gender-affirming hormones, and no patient under 10 years of age received either of these medical interven...
We appreciate the opportunity to address the concerns raised by D’Angelo and colleagues in relation to our recently published protocol for the Trans20 study [1]. While we certainly welcome feedback on our study, D’Angelo and colleagues focus much of their commentary on the clinical care of young people with gender dysphoria rather than on the Trans20 study protocol itself. In addition, the letter contains a number of inaccuracies and misconceptions that we feel must be clarified.
Firstly, the authors claim not only that the study “intervenes in the developmental trajectories of all 600 expected participants” and that the model involves “a uniformly stepwise progression through the social and biological stages of transition”, but also that The Royal Children’s Hospital (RCH) Gender Service offers biological interventions to children as young as three. These assertions are incorrect. While patients and families attending the RCH Gender Service routinely receive mental health input to assess, explore and support their gender identity, the use of medical interventions occurs in only a minority of patients, reflecting the highly individualised approach to care. More specifically, a recent 10-year audit of the service from 2007-16 (up until the inception of Trans20) revealed that only 23% of patients received puberty blockers, while an even lower figure of 20% received gender-affirming hormones, and no patient under 10 years of age received either of these medical interventions (Tollit et al, unpublished data).
Secondly, the authors assert that “good data” already exists “on the natural history of gender confusion which shows that a majority of children desist at puberty”. To support this claim, the authors reference a doctoral dissertation [2] based on data originating from a controversial gender clinic in Toronto that was shut down by Canadian health authorities in 2015. A key aim of that clinic was to “help children feel more comfortable with their biological sex” [2], which led to suggestions that it was practising “conversion therapy” and questions over the validity of natural history data from this clinic [3]. Moreover, Kenneth Zucker himself, who led the Toronto clinic and oversaw these studies, has subsequently stated that their results are unlikely to generalise to contemporary cohorts of transgender children, and he instead predicts that persistence rates will become “extremely high” [4]. Consistent with this, Professor Zucker has also written that “we require more comparative data to draw conclusions about the natural history of GID [gender identity disorder] in children and its relation to contextual factors” [5]. This is precisely one of the aims of Trans20.
Thirdly, D’Angelo and colleagues appear to conflate observational studies with clinical trials. As defined by the US National Institutes of Health, an observational study is one in which participants may receive interventions that are part of their routine medical care; these interventions are not assigned to them by the research team as occurs in a clinical trial [6]. At the RCH Gender Service, hormonal interventions are initiated on a case-by-case basis by a patient’s clinicians, and the Trans20 study simply observes the resultant outcomes. In this way, the authors’ assertion that Trans20 “more closely resembles an ‘interventional’ clinical trial” is inaccurate and misleading.
Fourthly, the authors refer to high suicide rates and psychiatric morbidity post-transition. This is disingenuous, since meaningful interpretation of such rates requires either longitudinal analysis and/or comparison to a suitable control group given the high rates of suicidality and psychiatric morbidity in young transgender individuals pre-transition [7]. Unfortunately, such data are lacking, although a recent study by Turban et al from Harvard Medical School’s Department of Psychiatry indicates that puberty suppression in transgender adolescents is associated with a significantly lower odds ratio (0.3) in lifetime suicidal ideation compared to transgender individuals who were unable to access this intervention [8].
Lastly, the authors raise concerns and questions regarding the process of informed consent. It is clear that their comments pertain to the consent process that occurs as part of clinical care at the RCH Gender Service and is distinct from consent to participate in the Trans20 research study, the process for which is clearly detailed in our protocol [1].
References
1 Tollit MA, Pace CC, Telfer M, et al. What are the health outcomes of trans and gender diverse young people in Australia? Study protocol for the Trans20 longitudinal cohort study. BMJ Open 2019;9.
2 Singh D. A follow-up study of boys with Gender Identity Disorder. Doctoral dissertation, University of Toronto.
3 Temple Newhook J, Pyne J, Winters K, et al. A critical commentary on follow-up studies and “desistance” theories about transgender and gender-nonconforming children. Int J Transgenderism 2018;19:212–24.
4 Zucker KJ. The myth of persistence: Response to “A critical commentary on follow-up studies and ‘desistance’ theories about transgender and gender non-conforming children” by Temple Newhook et al. (2018). Int J Transgenderism 2018;19:231–45.
5 Zucker KJ, Wood H, Singh D, et al. A developmental, biopsychosocial model for the treatment of children with Gender Identity Disorder. J Homosexuality 2012;59:369–97. doi:10.1080/00918369.2012.653309
6 Learn About Clinical Studies - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/about-studies/learn#ObservationalStudies (accessed 14 Jan 2020).
7 Olson J, Schrager SM, Belzer M, et al. Baseline physiologic and psychosocial characteristics of transgender youth seeking care for gender dysphoria. J Adolesc Health 2015;57:374–80.
8 Turban JL, King D, Carswell JM, et al. Pubertal suppression for transgender youth and risk of suicidal ideation. Pediatrics 2020;145:e20191725.
Petrie et al. asks the interesting question of where optimal weekly work hours lie for junior doctors, which is ultimately the question policy makers and advocates want to answer, with the aim of safeguarding the wellbeing and promoting satisfaction of junior medical doctors. Having recently (Dec 2019) published a large study (n=4012) in Medical Education examining factors related to Australian specialist trainee doctors we thought that there were several points of discussion made that may be distilled by our findings.
There are a number of salient points to discuss:
1. Satisfaction and Mental Illness - Our study examined specialist trainee’s satisfaction rather than mental illness or suicidal ideation with the idea being that a shift in the drive for policy from illness avoidance to promotion of satisfaction may be considered. In our Australia wide study, we found that one in five respondents worked more than 56 hours per week and, corroborating Petrie et al., that they were 24% less likely to be satisfied than those working 45 - 50 hours (median working hours).
2. Optimal work hours - In contrast to the findings of Petrie et al. we found that those working 51 - 56 hours were the most satisfied group, 21% more satisfied than those working 45 - 50 hours (p=0.006). The demands and priorities of a trainee undertaking a specialist pathway, which include: taking time with patients to build a sufficient case load to become proficient, taking time to study,...
Petrie et al. asks the interesting question of where optimal weekly work hours lie for junior doctors, which is ultimately the question policy makers and advocates want to answer, with the aim of safeguarding the wellbeing and promoting satisfaction of junior medical doctors. Having recently (Dec 2019) published a large study (n=4012) in Medical Education examining factors related to Australian specialist trainee doctors we thought that there were several points of discussion made that may be distilled by our findings.
There are a number of salient points to discuss:
1. Satisfaction and Mental Illness - Our study examined specialist trainee’s satisfaction rather than mental illness or suicidal ideation with the idea being that a shift in the drive for policy from illness avoidance to promotion of satisfaction may be considered. In our Australia wide study, we found that one in five respondents worked more than 56 hours per week and, corroborating Petrie et al., that they were 24% less likely to be satisfied than those working 45 - 50 hours (median working hours).
2. Optimal work hours - In contrast to the findings of Petrie et al. we found that those working 51 - 56 hours were the most satisfied group, 21% more satisfied than those working 45 - 50 hours (p=0.006). The demands and priorities of a trainee undertaking a specialist pathway, which include: taking time with patients to build a sufficient case load to become proficient, taking time to study, attending and contributing to department meetings. These responsibilities contribute to their training and may mean that they are not satisfied being restricted to a 40 hour working week. Further, as Petrie et al points out, simply putting on these restrictions may have other corollary negative effects.
3. Classification of Junior Doctors - Discrepancies between the findings of our study and Petrie et al. may exist because we captured different groups. Namely, Petrie et al. has studied a cohort that is all junior doctors vs our study which looks at specialist trainees. We would argue that within Australian junior doctors there are multiple sufficiently distinct groups and that they should be studied separately. First, interns and residents who do not have the stressors of examinations or specific learning courses and tend to be younger. Second, unaccredited trainees that are similar to junior doctors, but have added pressures of getting onto training programs and responsibilities of registrars without protections from colleges. Finally, specialist trainees who have the stressors of looming exams, lectures, study courses, applying for impending consultant employment, tend to be older and have a greater burden of family responsibility. The optimal working hours, ceiling threshold for working hours and its impact on satisfaction, wellbeing, and mental health may differ between these groups.
4. Effects of pay on the relationship between hours worked and satisfaction - while Petrie et al. controlled for a number of factors there were several confounders that were not included, particularly pay. We found that those working longer hours were generally paid more and those in the highest quintile of pay (>125k/yr) were the most satisfied group, although there was a ceiling effect (i.e. those earning >150k/yr were significantly less satisfied than those earning a median income). It may be that there is a particular effect on satisfaction or mental illness when there is significant amounts of unpaid overtime or if remuneration is inconsistent with the workload and difficulty of tasks performed.
5. Interpretation of causality - although the authors avoided making statements of causality in their study the second line of the media release from their study states “More than a quarter of junior doctors (JDs) are working unsafe hours that double their risk of developing mental health problems and suicidal ideation” (2). That the working hours “double” the risk of mental health problems is not demonstrated. There are many confounders that need to be considered. For example, it is just as plausible that those who score more highly on the GHQ-28 tend to be more anxious, conscientious and try to do a more comprehensive job at work which is why they work longer hours.
Sincerely
Dr Matthew Lennon, MD
Dr Claire Mok, MD
The authors had no declarations to make.
(1) Lennon, MJ, McGrail, MR, O'Sullivan, B, et al. Understanding the professional satisfaction of hospital trainees in Australia. Med Educ. 2020; 00: 1– 8. https://doi.org/10.1111/medu.14041
We appreciate the authors’ interest for our paper, and we would like to thank them for the opportunity to discuss the problems raised in their letter (1).
First of all, we would like to emphasize that in our study we didn’t try to investigate the pathophysiology of atherosclerosis, but tried to see how the generally accepted risk factors of atherosclerosis correlate with significant coronary heart disease evaluated by CAD-RADS score in the Romanian population (2). The design of our research was cross-sectional, retrospective, therefore our purpose was not to establish the causality between dyslipidemia and cardiovascular disease. We agree with the authors that there is a difference between causality and association and our current study was based on evaluating the association between the presence of risk factors and the burden of atherosclerotic coronary disease evaluated using CCTA method. We chose dyslipidemia among the atherosclerosis risk factors studied based on the most current guidelines on cardiovascular disease prevention at the time (3).
Regarding the pathophysiology of atherosclerosis, the role of lipids and lipoproteins in the development of atheromatous plaque is proven by many studies (4-7). This complex process, based on an inflammatory response, is initiated by the infiltration of apoB containing lipoproteins into the arterial wall, which cause wall injuries and promote infiltration of monocytes into the subendothelial space. Secondly, the ma...
We appreciate the authors’ interest for our paper, and we would like to thank them for the opportunity to discuss the problems raised in their letter (1).
First of all, we would like to emphasize that in our study we didn’t try to investigate the pathophysiology of atherosclerosis, but tried to see how the generally accepted risk factors of atherosclerosis correlate with significant coronary heart disease evaluated by CAD-RADS score in the Romanian population (2). The design of our research was cross-sectional, retrospective, therefore our purpose was not to establish the causality between dyslipidemia and cardiovascular disease. We agree with the authors that there is a difference between causality and association and our current study was based on evaluating the association between the presence of risk factors and the burden of atherosclerotic coronary disease evaluated using CCTA method. We chose dyslipidemia among the atherosclerosis risk factors studied based on the most current guidelines on cardiovascular disease prevention at the time (3).
Regarding the pathophysiology of atherosclerosis, the role of lipids and lipoproteins in the development of atheromatous plaque is proven by many studies (4-7). This complex process, based on an inflammatory response, is initiated by the infiltration of apoB containing lipoproteins into the arterial wall, which cause wall injuries and promote infiltration of monocytes into the subendothelial space. Secondly, the macrophages internalize the apoB, resulting in foam cell formation, which is the hallmark of the fatty streak phase of atherosclerosis. In the process of atherosclerosis, LDL is not involved in its native form, but it has to suffer oxidative modifications in order to facilitate its uptake by the macrophages. The inflammatory cascade lead to proliferation of smooth muscle cells, which produce extracellular matrix, contributing to the formation of a stable fibrous plaque. However, if the inflammation is unresolved, this will result in the formation of a vulnerable plaque.
Pertaining to the role of hypercholesterolemia in the atherosclerotic cardiovascular diseases, the recently published guidelines of the European Society of Cardiology on dyslipidemias and the consensus statement from the European Atherosclerosis Society Consensus Panel confirm that the retention of LDL cholesterol (LDL-C) is the key initiating event of atherosclerosis based on preclinical studies (4-6, 8-10). LDL-C doesn’t only contribute to initiation of atherosclerosis, but also to its progression; the level of LDL-C corelates to the burden of atherosclerotic plaques and progression of atherosclerotic cardiovascular disease in a dose-dependent manner as demonstrated by multiple meta-analysis and Mendelian randomization studies (7,9,12-15). Another proof of the causal link between LDL-C and atherosclerosis are the meta-analysis showing that the LDL-C lowering therapies reduce the risk of cardiovascular events (9,16,17).
The European Atherosclerosis Society based its conclusion that the causal relation between LDL-C and atherosclerosis is certain on a great body of evidence including > 200 studies, with > 2 million participants and > 20 million person-years of follow-up and >150 000 cardiovascular events (9). Our study also showed a positive relation between dyslipidemia and obstructive coronary disease defined as CAD-RADS score ≥ 3 that is in concordance with published literature (2).
Nevertheless, we are aware of the studies which do not support the causality between LDL-cholesterol and cardiovascular disease (18,19). We appreciate the work of the researchers; however we consider that these studies are too few in comparison with the meta-analyses to completely reject this relation.
All in all, we consider that the “universal truth” lies maybe somewhere in between and there is a need for more prospective, long-term studies to research other causes of atherosclerosis besides the presence of dyslipidemia, its dynamics over time with or without lipid-lowering treatment and the progress of coronary artery atherosclerosis assessed using CCTA classification systems.
References
1. Ravnskov U, Diamond DM, Sherif Sultan. Dyslipidemia is an unlikely cause of atherosclerosis. BMJ 22 January 2020
2. Popa LE, Petresc B, Cătană C et al. Association between cardiovascular risk factors and coronary artery disease assessed using CAD-RADS classification: a cross-sectional study in Romanian population. BMJ Open 2020;10:e031799. doi:10.1136/ bmjopen-2019-031799
3. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315–81.
4. Camejo G, Lopez A, Vegas H et al. The participation of aortic proteins in the formation of complexes between low density lipoproteins and intima-media extracts. Atherosclerosis 1975;21:77–91.
5. Skalen K, Gustafsson M, Rydberg EK et al. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis.Nature 2002;417:750–754
6. Tabas I, Williams KJ, Bore´n J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 2007;116:1832–1844.
7. Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 2015;161:161–172.
8. Mach F, Baigent C, Catapano AL et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS), European Heart Journal 2020;41:111–188, https://doi.org/10.1093/eurheartj/ehz455
9. Ference BA, Ginsberg HN, Graham I et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-2472.
10. Schwenke DC, Carew TE. Initiation of atherosclerotic lesions in cholesterol-fed rabbits. II. Selective retention of LDL vs. selective increases in LDL permeability in susceptible sites of arteries. Arteriosclerosis 1989;9:908–918.
11. Frank JS, Fogelman AM. Ultrastructure of the intima in WHHL and cholesterolfed rabbit aortas prepared by ultra-rapid freezing and freeze-etching. J Lipid Res 1989;30:967–978.
12.Di Angelantonio E, Gao P, Pennells L, Kaptoge S et al. Lipid-related markers and cardiovascular disease prediction. JAMA 2012;307:2499–2506.
13. Lewington S, Whitlock G, Clarke R et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 2007;370:1829–1839.
14. Ference BA, Yoo W, Alesh I et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol 2012;60:2631–2639.
15. Holmes MV, Asselbergs FW, Palmer TM et al.Mendelian randomization of blood lipids for coronary heart disease. Eur Heart J 2015;36:539–550.
16. Baigent C, Blackwell L, Emberson J et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet 2010;376:1670–1681.
17. Collins R, Reith C, Emberson J et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388:2532–2561.
18. Ravnskov U, de Lorgeril M, Diamond DM et al LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature. Expert Rev Clin Pharmacol. 2018;11(10):959-970.
19. Ravnskov U, Diamond DM, Hama R et al Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open. 2016;6(6):e010401
Thank you for your comments on our manuscript.
Firstly, we applied meta-analysis to pool diagnostic accuracy for NBI, HAL and 5-ALA techniques for patients with NMIBC in comparison with WLC as the reference standard, which demonstrated the superior diagnostic performance of new imaging techniques in bladder detection compared with conventional WLC. These new imaging techniques are promising diagnostic interventions to improve clinical procedures in bladder cancer detection.
We described The SROC curves for NBI, HAL and 5-ALA in Figure 3A and the pooled DOR for NBI, HAL and 5-ALA were 40.09 (95% CI, 20.08-80.01, Figure 2A), 78.14 (95% CI, 31.42-194.28, Figure 2B) and 18.14 (95% CI, 4.28-76.87, Figure 2C), showing significant diagnostic superiority compared with white light cystoscopy (WLC) at the lesion level. While SROC curves for NBI, HAL and 5-ALA were showed in Figure 3B, DOR for NBI and HAL were 358.71 (95% CI, 44.50-2891.71, Figure 2D) and 59.95 (95% CI, 24.30-147.92, Figure 2E), presenting better performance compared with WLC. Figure 3 showed HAL and NBI exhibits similar SROC curves in lesion level, NBI performed significant excellent SROC curve in patient level. For patient-level analysis, NBI showed highest median sensitivity (SSY) 100%, median positive predictive value (PPV) 90.75%, median negative predictive value (NPV) 100% and median false positive rate (FPR) 31.55% in supplementary Table 1. And supplementary Table 2 showed similar narrative outcome...
Thank you for your comments on our manuscript.
Firstly, we applied meta-analysis to pool diagnostic accuracy for NBI, HAL and 5-ALA techniques for patients with NMIBC in comparison with WLC as the reference standard, which demonstrated the superior diagnostic performance of new imaging techniques in bladder detection compared with conventional WLC. These new imaging techniques are promising diagnostic interventions to improve clinical procedures in bladder cancer detection.
We described The SROC curves for NBI, HAL and 5-ALA in Figure 3A and the pooled DOR for NBI, HAL and 5-ALA were 40.09 (95% CI, 20.08-80.01, Figure 2A), 78.14 (95% CI, 31.42-194.28, Figure 2B) and 18.14 (95% CI, 4.28-76.87, Figure 2C), showing significant diagnostic superiority compared with white light cystoscopy (WLC) at the lesion level. While SROC curves for NBI, HAL and 5-ALA were showed in Figure 3B, DOR for NBI and HAL were 358.71 (95% CI, 44.50-2891.71, Figure 2D) and 59.95 (95% CI, 24.30-147.92, Figure 2E), presenting better performance compared with WLC. Figure 3 showed HAL and NBI exhibits similar SROC curves in lesion level, NBI performed significant excellent SROC curve in patient level. For patient-level analysis, NBI showed highest median sensitivity (SSY) 100%, median positive predictive value (PPV) 90.75%, median negative predictive value (NPV) 100% and median false positive rate (FPR) 31.55% in supplementary Table 1. And supplementary Table 2 showed similar narrative outcomes in subgroup analysis. These results indicated NBI may be potentially the most promising diagnostic intervention.
Secondly, our study has applied stringent methodology and inclusion criteria to synthesize obtained evidence. The PRISMA flow chart in Figure 1 demonstrated 103 full-text articles were processed in eligibility process. In order to perform diagnostic meta-analysis, diagnostic outcomes of SSY, SPY, NPV, PPV, FPR and FNR for individual studies should be obtained in studies with intra-patient comparison. Therefore, while 77 studies were excluded in final inclusion process with 41 studies providing non intra-patient comparison outcome. Furthermore, diagnostic performance of new imaging techniques should be calculated with the reference standard of WLC following standardized definitions: SSY was defined as the proportion of positive patients or lesions with index test in all cases of WLC-positive findings. SPY was defined as the proportion of negative patients or lesions with index test in all cases of WLC-negative findings. NPV was defined as the proportion of true negatives findings (both negative in index test and WLC) in all index test-negative cases or lesions; PPV was defined as the proportion of true positives findings (both positive in index test and WLC) in all index test-positive cases or lesions. FNR was defined as the proportion of index test-negative findings in all cases of WLC-positive cases or lesions; FPR was defined as the proportion of index test-positive findings in all cases of WLC-negative cases or lesions.
Thirdly, our systematic review indicated that the pooled diagnostic performance of NBI, HAL or 5-ALA showed excellent efficacy compared with WLC. While the description “NBI could potentially be the most promising diagnostic intervention for patients with NMIBC, with advantages in terms of simplicity, cost, and reliability” in Discussion Session was inferred by results and references.
Our results suggested HAL and NBI exhibits similar SROC curves in lesion level, NBI performed significant excellent SROC curve in patient level. For patient-level analysis, NBI showed highest median sensitivity (SSY) 100%, median positive predictive value (PPV) 90.75%, median negative predictive value (NPV) 100% and median false positive rate (FPR) 31.55% in supplementary Table 1. And supplementary Table 2 showed similar narrative outcomes in subgroup analysis. Based on the review describing consensus in clinical practice of PDD, HAL is provided in a kit as 100mg of powder needed to be diluted within 2h before instillation. Then bladder should be emptied via a catheter and HAL solution is instilled. Patient must retain HAL solution in the bladder of 1-3h to ensure optimum fluorescence and receive cystoscopy[1]. While NBI avoid the need for pre-operative preparation, intravesical contrast administration and may be widely applied to detect bladder cancer as clinical routine.
Pharmacoeconomic analysis indicated that the use of HAL leads to overall cost savings with longer recurrence-free intervals than WLC. Kutwin et al [2] performed a review demonstrating new imaging techniques in the management of bladder cancer. It suggested PDD and NBI improve the detection of bladder cancer and decrease recurrence rates of bladder tumors, which are cost-effective method for bladder cancer. It was also inferred that PDD has a stronger evidence base, NBI is still perceived as a reasonable alternative to PDD because of its simplicity. Studies suggested NBI could reduce recurrence rate of bladder cancer significantly[3,4]. While Lee et al[5] performed a network meta-analysis of comparing therapeutic outcomes among NBI, PDD and WLC, which suggested PDD- and NBI-assisted TUR decreased recurrence rate compared with WLC and did not significantly differ in recurrence rate. Also, we are going to further explore comparative efficacy outcomes among NBI, PDD and WLC with updated Bayesian network meta-analysis, which are in the process of submission. We found NBI (OR: 0.56, 95% CrI: 0.31-0.91), HAL (OR: 0.60, 95% CrI: 0.41-0.87) and 5-ALA (OR: 0.64, 95% CrI: 0.38-0.99) demonstrated benefits in reducing recurrence rate compared with WLC, and the cumulative probabilities of rank best were 49%, 27% and 24% in 1-year recurrence rate; NBI (OR: 0.37, 95% CrI: 0.13-0.99), HAL (OR: 0.49, 95% CrI: 0.25-0.91), and 5-ALA (OR: 0.51, 95% CrI: 0.26-0.88) showed lower recurrence rate than WLC, and the cumulative probabilities of rank best were 60%, 22% and 18% in 2-year recurrence rate; moreover, NBI (OR: 0.40, 95% CrI: 0.17-0.99), 5-ALA (OR: 0.54, 95% CrI: 0.28-0.95) and HAL (OR: 0.64, 95% CrI: 0.44-0.91) also presented significant lower recurrence rate compared with WLC in 5-year recurrence rate, the cumulative probabilities of rank best were 70%, 24% and 6%, respectively. Though NBI has not been evaluated in cost effective analysis, the above results inferred NBI may be the most promising intervention for bladder cancer. Despite of the inference, further cost effective analysis among NBI, PDD and WLC should be explored in addition to these diagnostic and therapeutic pooled analysis.
Our study has applied stringent methodology, rigorous screening and data extraction process, standardized definition and analysis to guarantee reliable results and conclusion. New imaging techniques showed superior diagnostic performance in bladder detection compared with conventional WLC. These new imaging techniques are promising diagnostic interventions to improve clinical procedures in bladder cancer detection. NBI may be NBI is potentially the most promising diagnostic intervention.
We hope the comments could resolve your questions.
Reference
[1] Daneshmand S, Schuckman AK, Bochner BH, et al. Hexaminolevulinate blue-light cystoscopy in non-muscle-invasive bladder cancer: review of the clinical evidence and consensus statement on appropriate use in the USA. Nat Rev Urol 2014;11(10):589-96. doi: 10.1038/nrurol.2014.245 [published Online First: 2014/09/24]
[2] Kutwin P, Konecki T, Cichocki M, et al. Photodynamic Diagnosis and Narrow-Band Imaging in the Management of Bladder Cancer: A Review. Photomed Laser Surg 2017;35(9):459-64. doi: 10.1089/pho.2016.4217 [published Online First: 2017/05/26]
[3] Naselli A, Introini C, Timossi L, et al. A randomized prospective trial to assess the impact of transurethral resection in narrow band imaging modality on non-muscle-invasive bladder cancer recurrence. Eur Urol 2012;61(5):908-13. doi: 10.1016/j.eururo.2012.01.018 [published Online First: 2012/01/28]
[4] Naito S, Algaba F, Babjuk M, et al. The Clinical Research Office of the Endourological Society (CROES) Multicentre Randomised Trial of Narrow Band Imaging-Assisted Transurethral Resection of Bladder Tumour (TURBT) Versus Conventional White Light Imaging-Assisted TURBT in Primary Non-Muscle-invasive Bladder Cancer Patients: Trial Protocol and 1-year Results. Eur Urol 2016;70(3):506-15. doi: 10.1016/j.eururo.2016.03.053 [published Online First: 2016/04/28]
[5] Lee JY, Cho KS, Kang DH, et al. A network meta-analysis of therapeutic outcomes after new image technology-assisted transurethral resection for non-muscle invasive bladder cancer: 5-aminolaevulinic acid fluorescence vs hexylaminolevulinate fluorescence vs narrow band imaging. BMC Cancer 2015;15:566. doi: 10.1186/s12885-015-1571-8 [published Online First: 2015/08/02]
Dear Editor,
Socioeconomic status (SES) has long been found to be significantly associated with increased risk of morbidity and mortality. It is related to health at all levels (1). A weak association between SES and maternal health care is found in countries where females are more educated (2). In developing countries like Pakistan where maternal mortality is still high despite efforts been made (3). This poor maternal health care use leads to maternal depression leading to CMH (Child Mental Health) issues (4). Therefore, efforts should be targeted to improve maternal health care use in order to ensure physical and mental health of the future generation irrespective of their SES.
1. Adler NE, Boyce WT, Chesney MA, Folkman S, Syme SL. Socioeconomic inequalities in health. No easy solution. Jama. 1993;269(24):3140-5.
2. McTavish S, Moore S, Harper S, Lynch J. National female literacy, individual socio-economic status, and maternal health care use in sub-Saharan Africa. Social science & medicine. 2010;71(11):1958-63.
3. Mumtaz Z, Salway S, Shanner L, Zaman S, Laing L. Addressing disparities in maternal health care in Pakistan: gender, class and exclusion. BMC pregnancy and childbirth. 2012;12(1):80.
4. Maselko J, Sikander S, Bangash O, Bhalotra S, Franz L, Ganga N, et al. Child mental health and maternal depression history in Pakistan. Social psychiatry and psychiatric epidemiology. 2016;51(1):49-62.
In their recent paper Chen et al. presented a meta-analysis on the diagnostic performance of image technique based transurethral resection for non-muscle invasive bladder cancer: They claim in their conclusion that narrow band imaging (NBI) showed the best diagnostic performance outcomes in a comparison to blue light cystoscopy with hexaminolevulinate (HAL) and 5-aminolevulinic acid (5-ALA). We cannot find the evidence for this in the result they present which deserves commenting.
In the abstract it is written that NBI showed significant diagnostic superiority compared with white light cystoscopy (WLC) at the lesion level (Pooled sensitivity 0.94, 95% CI 0.82 to 0.98; Pooled specificity 0.79, 95% CI 0.73 to 0.85; Diagnostic odds ratio (DOR) 40.09, 95% CI 20.08 to 80.01; Area under the receiver operating characteristic curve 0.88, 95% CI 0.85 to 0.91). That HAL showed superior lesion level detection results in all measured parameters is not mentioned. It is further stated that NBI presented the highest DOR (358.71, 95% CI 44.50 to 2891.71) in the patient level. The subgroup analysis, evaluating diagnostic performance in studies with low to moderate risk of bias and in studies with more than 100 patients, is only presented in supplementary material and similarly show how HAL and 5-ALA achieve comparable or improved diagnostic performance compared to NBI. Despite these results, the authors emphasize and conclude on behalf of NBI throughout the paper.
While the con...
In their recent paper Chen et al. presented a meta-analysis on the diagnostic performance of image technique based transurethral resection for non-muscle invasive bladder cancer: They claim in their conclusion that narrow band imaging (NBI) showed the best diagnostic performance outcomes in a comparison to blue light cystoscopy with hexaminolevulinate (HAL) and 5-aminolevulinic acid (5-ALA). We cannot find the evidence for this in the result they present which deserves commenting.
In the abstract it is written that NBI showed significant diagnostic superiority compared with white light cystoscopy (WLC) at the lesion level (Pooled sensitivity 0.94, 95% CI 0.82 to 0.98; Pooled specificity 0.79, 95% CI 0.73 to 0.85; Diagnostic odds ratio (DOR) 40.09, 95% CI 20.08 to 80.01; Area under the receiver operating characteristic curve 0.88, 95% CI 0.85 to 0.91). That HAL showed superior lesion level detection results in all measured parameters is not mentioned. It is further stated that NBI presented the highest DOR (358.71, 95% CI 44.50 to 2891.71) in the patient level. The subgroup analysis, evaluating diagnostic performance in studies with low to moderate risk of bias and in studies with more than 100 patients, is only presented in supplementary material and similarly show how HAL and 5-ALA achieve comparable or improved diagnostic performance compared to NBI. Despite these results, the authors emphasize and conclude on behalf of NBI throughout the paper.
While the conclusion is not supported by the results presented in the analysis, the major objection to the presented study is the limited number of studies that have been included in the analysis. Although recognized by the authors as being a limitation of the study, especially the patient-level analysis appears anecdotal and highlights how the selection of underlying studies is crucial for a reliable meta-analysis. Twenty-six studies were included in this diagnostic meta-analysis, some with less than 20 patients. Without detailing, we found 39 other studies that seemed to fulfil the search criteria stipulated. Among them, several large multicentre studies [1–7] that probably would have made it possible to calculate the patient level results that the authors now state “could not be calculated because few studies included these data”.
Further strengthening of the results could also have been possible if independent patient data had been used by the authors as in the meta-analysis by Burger et al. [8]. In that report, there were 25% patients with at least one additional Ta/T1 tumour seen with HAL, and 27% of patients with CIS was detected only by HAL. The improved detection lead to a reduction of recurrence and the report showed how the benefit was independent of the level of risk and evident in patients with Ta, T1, CIS, primary, and recurrent cancer. A similar analysis including both NBI and 5-ALA could have made an important contribution to the field of diagnosis and management of non-muscle-invasive bladder cancer.
Finally, the authors state that one of the advantages of NBI is that it is cheaper. Such a conclusion should preferably be based on a cost effective analysis, where the effect of the improved diagnosis on the rate of recurrence and progression has to be included. Several studies have consistently shown the reduced recurrence rate with HAL while the data of NBI in this regard are limited. That HAL-guided surgery is a cost-effective tool through an effect on both diagnosis and recurrence, thereby reducing the burden of disease for patients and the health care system have been shown in several reports [9,10]. Similar results for NBI has not been published.
In summary several flaws in the analysis is evident.
References
1 Stenzl A, Burger M, Fradet Y, et al. Hexaminolevulinate Guided Fluorescence Cystoscopy Reduces Recurrence in Patients With Nonmuscle Invasive Bladder Cancer. J Urol 2010;184:1907–14. doi:10.1016/j.juro.2010.06.148
2 Bach T, Bastian PJ, Blana A, et al. Optimised photodynamic diagnosis for transurethral resection of the bladder (TURB) in German clinical practice: results of the noninterventional study OPTIC III. World J Urol 2017;35:737–44. doi:10.1007/s00345-016-1925-0
3 Grossman HB, Gomella L, Fradet Y, et al. A phase III, multicenter comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of superficial papillary lesions in patients with bladder cancer. J Urol 2007;178:62–7. doi:10.1016/j.juro.2007.03.034
4 Stenzl A, Penkoff H, Dajc-Sommerer E, et al. Detection and clinical outcome of urinary bladder cancer with 5-aminolevulinic acid-induced fluorescence cystoscopy. Cancer 2011;117:938–47. doi:10.1002/cncr.25523
5 Schumacher MC, Holmäng S, Davidsson T, et al. Transurethral resection of non-muscle-invasive bladder transitional cell cancers with or without 5-aminolevulinic acid under visible and fluorescent light: Results of a prospective, randomized, multicentre study. Eur Urol 2010;57:293–9.
6 Drejer D, Béji S, Oezeke R, et al. Comparison of White Light, Photodynamic Diagnosis, and Narrow-band Imaging in Detection of Carcinoma In Situ or Flat Dysplasia at Transurethral Resection of the Bladder: the DaBlaCa-8 Study. Urology 2017;102:138–42. doi:10.1016/j.urology.2016.11.032
7 Drejer D, Béji S, Munk Nielsen A, et al. Clinical relevance of narrow-band imaging in flexible cystoscopy: the DaBlaCa-7 study. Scand J Urol 2017;:1–4. doi:10.1080/21681805.2017.1295101
8 Burger M, Grossman HB, Droller M, et al. Photodynamic diagnosis of non-muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data. Eur Urol 2013;64:846–54. doi:10.1016/j.eururo.2013.03.059
9 Rose JB, Armstrong S, Hermann GG, et al. Budget impact of incorporating one instillation of hexaminolevulinate hydrochloride blue-light cytoscopy in transurethral bladder tumour resection for patients with non-muscle-invasive bladder cancer in Sweden. BJU Int 2016;117:E102-113. doi:10.1111/bju.13261
10 Garfield SS, Gavaghan MB, Armstrong SO, et al. The cost-effectiveness of blue light cystoscopy in bladder cancer detection: United States projections based on clinical data showing 4.5 years of follow up after a single hexaminolevulinate hydrochloride instillation. Can J Urol 2013;20:6682–9.
I would like to thank Ng, Lynch, Kelly and Mba for their article analyzing the views of medical students who had participated in a mentoring programme whilst on their Obstetrics & Gynaecology attachment in the UK.
Devising methods of improving the learning experiences for medical students whilst on placement is vital to ensuring their professional readiness1 in facing their upcoming roles as junior doctors, practically and emotionally.
In the introduction, the authors provide a beautiful definition of a mentor from SCOPME2. I’d like to highlight that this definition includes the mentor being a ‘guide’ and being ‘empathic’. A guide is traditionally someone who shows another the way in a new environment to prevent them from getting lost; in many settings a guide is imperative. One could argue that students are given a Personal Tutor at the beginning of university who is a mentor in a way. This could be a good starting point, especially for more pastoral care – yet a clinical guide who is working closely with the student may be imperative as well, for the reasons emphasized by the student quotes in this article. The authors, therefore, concluded that clinical placement mentors for medical students should be more of a widespread practice.
Another key feature of these mentors is that they ‘volunteered’ to sign up, which identifies a key element of willingness to participate in the programme. If this programme became more widespread or...
I would like to thank Ng, Lynch, Kelly and Mba for their article analyzing the views of medical students who had participated in a mentoring programme whilst on their Obstetrics & Gynaecology attachment in the UK.
Devising methods of improving the learning experiences for medical students whilst on placement is vital to ensuring their professional readiness1 in facing their upcoming roles as junior doctors, practically and emotionally.
In the introduction, the authors provide a beautiful definition of a mentor from SCOPME2. I’d like to highlight that this definition includes the mentor being a ‘guide’ and being ‘empathic’. A guide is traditionally someone who shows another the way in a new environment to prevent them from getting lost; in many settings a guide is imperative. One could argue that students are given a Personal Tutor at the beginning of university who is a mentor in a way. This could be a good starting point, especially for more pastoral care – yet a clinical guide who is working closely with the student may be imperative as well, for the reasons emphasized by the student quotes in this article. The authors, therefore, concluded that clinical placement mentors for medical students should be more of a widespread practice.
Another key feature of these mentors is that they ‘volunteered’ to sign up, which identifies a key element of willingness to participate in the programme. If this programme became more widespread or mandatory, it may take away from the willingness of the volunteers stepping forward; and hence the general enthusiasm and empathy necessary to be a mentor.
One student stated that the mentorship programme helped him feel more welcomed to the team. For medical students, this is vital in improving confidence3, which in turn, increases subsequent exposure to learning opportunities as students are more likely to step forward after recognizing opportunities. For example, one student mentioned that she had the opportunity to take a collateral stroke history in an acute and emotive setting.
Overall, there seems to be many benefits to medical students of receiving mentorship whilst on placement, which are detailed in the article. Not mentioned, are the many benefits to the mentor as well. Mentorship helps develop skills of teaching, empathy and teamwork. Ongoing development of these skills as a doctor is crucial.
In order to implement this study more nationally, it needs to be reproducible in different Trusts- a limitation identified by the authors. Even so, a more informal programme would still benefit the students in a Trust that is less equipped.
Personally, I had a mentor who was a junior doctor as I was applying for medical school. Being totally new to the field, she gave me insider, experiential knowledge of medicine and guided me as I reflected on why I would like to be a doctor. Now, as a 4th year medical student, I feel I and my peers would exceedingly benefit from this mentorship programme at our Trusts. It would significantly abate our nervousness as soon to be doctors and improve our clinical competence.
Thank you and best wishes,
Sophia
References
1. Hägg-Martinell A, Hult H, Henriksson P, et al
Medical students' opportunities to participate and learn from activities at an internal medicine ward: an ethnographic study
BMJ Open 2017;7:e013046. doi: 10.1136/bmjopen-2016-013046
2. Standing Committee on Postgraduate Medical and Dental Education. Supporting doctors and dentists at work: an enquiry in to mentoring. London: SCOPME, 1998.
3. Hameed Y, et al. Improving Medical Student Placements in Psychiatry: Review of Literature And A Practical Example. BJMP 2017;10(1):a1008.
4. Junior doctors need Continuous Professional Development (CPD) in soft skills [Internet]. The CPD Standards Office. 2016 [cited 27 January 2020]. Available from: https://www.cpdstandards.com/news/junior-doctors-need-continuous-profess...
This article mainly focuses on knowledge about health related states and events for women in South Asian region i.e in Pakistan and India . Mostly women presenting in public hospitals for their antenatal checkup belongs to poor socioeconomic status and cannot afford a good living to maintain a healthy lifestyle . So, despite of having adequate knowledge about good health they can not afford one . So, i think hospitals should compile data of such women and share with concerned authorities who can provide them in this regard.
Psychological support should be freely available for pregnant women during their antenatal visit by experts .
Farren et al (1) state that they, ”were surprised by the prevalence of PTSD symptoms in our study”, and that, ”Future research should be aimed at assessing the risk factors for PTSD”.
My research of 1993, into Post Traumatic Stress Disorder in women who have undergone Obstetric and/or Gynaecological Procedures (2), which was widely reported in the press, obstetric and midwifery literature, including the N.I.C.E Guidelines, identified several risk factors for the development of PTSD in the women affected.
The key areas in the procedures seem to be those concerning the level of control which the woman has, the attitude of the doctor, the degree to which the patient’s views are heeded, and whether or not consent was perceived to have been given for the procedure. The gender of the examiner did not seem to be relevant.
The women were asked in the questionnaire to describe their experiences, some of which were quite explicit and reminiscent of assault: “dehumanising and painful”; “degrading and distressing….no account was taken of my feelings”; “my opinions were dismissed as irrelevant although it was my body which was being invaded”; “I came away hurting and feeling violated”; “very brutal internal was excruciating”; “you begin to feel like a thing”; “I cried and shouted but was held down and told to stop making a noise”; “humiliation…as if it happened yesterday”; “I felt assaulted and then abandoned”; “I felt abused…like a piece of meat on a slab”; “the mo...
Farren et al (1) state that they, ”were surprised by the prevalence of PTSD symptoms in our study”, and that, ”Future research should be aimed at assessing the risk factors for PTSD”.
My research of 1993, into Post Traumatic Stress Disorder in women who have undergone Obstetric and/or Gynaecological Procedures (2), which was widely reported in the press, obstetric and midwifery literature, including the N.I.C.E Guidelines, identified several risk factors for the development of PTSD in the women affected.
The key areas in the procedures seem to be those concerning the level of control which the woman has, the attitude of the doctor, the degree to which the patient’s views are heeded, and whether or not consent was perceived to have been given for the procedure. The gender of the examiner did not seem to be relevant.
The women were asked in the questionnaire to describe their experiences, some of which were quite explicit and reminiscent of assault: “dehumanising and painful”; “degrading and distressing….no account was taken of my feelings”; “my opinions were dismissed as irrelevant although it was my body which was being invaded”; “I came away hurting and feeling violated”; “very brutal internal was excruciating”; “you begin to feel like a thing”; “I cried and shouted but was held down and told to stop making a noise”; “humiliation…as if it happened yesterday”; “I felt assaulted and then abandoned”; “I felt abused…like a piece of meat on a slab”; “the most terrifying I have ever experienced….I was a carcass to be dealt “; “I felt mutilated by the procedure”; “traumatic and brutal”; “I was offered no information whatever, hence my extreme fear”; “it felt undeniably like rape”.
There appear to be similarities between a traumatic obstetric/gynaecological experience and the experience of sexual assault, particularly where the woman perceived herself to be powerless. PTSD is a recognised sequela of sexual assault and factors influencing its onset seem to be related to experiences which are perceived as painful, humiliating, mutilating and occurring in an unsympathetic environment in which the woman feels powerless to resist.
Perhaps the authors could return to the patients in the study and ask them to identify the features of their experiences which may have triggered their PTSD?
Dr Janet Menage M.A. M.B. Ch.B., GP (retired); qualified psychological counsellor.
Competing interests: None
(1) Farren J, Jalmbrant M, Ameye L, et al. Post-traumatic stress, anxiety and depression following miscarriage or ectopic pregnancy: a prospective cohort study. BMJ Open 2016;6:e011864. doi:10.1136/bmjopen-2016011864
(2) Menage, J (1993) Post-traumatic stress disorder in women who have undergone obstetric and/or gynaecological procedures: A consecutive series of 30 cases of PTSD. Journal of Reproductive and Infant Psychology, Vol 11, pp221-228
The study by Popa et al. (1) is potentially of value in identifying adverse influences on cardiovascular health. Their study, however, suggests that dyslipidemia causes cardiovascular disease (CVD). We feel compelled to show that the broader literature is not consistent with this perspective and that their finding of an association between dyslipidemia and CVD is influenced by a methodological flaw in their design.
First, there is no evidence that dyslipidemia causes atherosclerosis. Already in 1936 Lande ́ and Sperry found that when corrected for age, healthy people with low total cholesterol (TC) were just as atherosclerotic as healthy people with high TC (2) and their finding has been verified and replicated later by many research groups (2). A strong contradiction has also been documented by sixteen angiographic trials where the authors had calculated exposure-response, which was present in only two of them (2). Furthermore, a study of the coronary arteries of 304 asymptomatic women by Hecht and Superco showed that the role of high LDL-cholesterol (LDL-C) is questionable as well. By using electron beam tomography, they found that neither the calcium percentile or the calcium score were associated with LDL-C (3). Also contradictory is, that In five studies of people with familial hypercholesterolemia there were no association between degree of atherosclerosis and LDL-C (4).
Second, numerous observations and experiments have shown that dyslipidemia does no...
The study by Popa et al. (1) is potentially of value in identifying adverse influences on cardiovascular health. Their study, however, suggests that dyslipidemia causes cardiovascular disease (CVD). We feel compelled to show that the broader literature is not consistent with this perspective and that their finding of an association between dyslipidemia and CVD is influenced by a methodological flaw in their design.
First, there is no evidence that dyslipidemia causes atherosclerosis. Already in 1936 Lande ́ and Sperry found that when corrected for age, healthy people with low total cholesterol (TC) were just as atherosclerotic as healthy people with high TC (2) and their finding has been verified and replicated later by many research groups (2). A strong contradiction has also been documented by sixteen angiographic trials where the authors had calculated exposure-response, which was present in only two of them (2). Furthermore, a study of the coronary arteries of 304 asymptomatic women by Hecht and Superco showed that the role of high LDL-cholesterol (LDL-C) is questionable as well. By using electron beam tomography, they found that neither the calcium percentile or the calcium score were associated with LDL-C (3). Also contradictory is, that In five studies of people with familial hypercholesterolemia there were no association between degree of atherosclerosis and LDL-C (4).
Second, numerous observations and experiments have shown that dyslipidemia does not cause CVD (5). The strongest contradiction is that several follow-up studies including more than 600 000 individuals of all ages have shown that people with high TC or high LDL-C live just as long or longer than people with normal or low values, whether they are on statin treatment or not (6-9). These findings are most likely due to the anti-infectious role played by LDL (10).
It is correct, as mentioned by Popa et al. (1). that many studies have shown an association between dyslipidemia and CVD. However, most of them have only included young and middle-aged people, and association is not the same as causation. Many studies have shown that mental stress may cause atherosclerosis and CVD and mental stress is most likely more common among young and middle-aged people than among retired citizens. Mental stress may raise cholesterol (11,12) but it may cause CVD by other ways, for instance by hypercoagulation (13).
An explanation of the findings by Popa et al. may be that they have defined the presence of dyslipidemia as high TC or the presence of cholesterol-lowering treatment. It is a fact that long-time statin-treatment increases the degree of arterial calcification (14,15). Such treatment may therefore have contributed to the degree of atherosclerosis.
Considering the many contradictions mentioned above, we hypothesize that one of the main causes of atherosclerosis and CVD is hypercoagulation, either inborn as in familial hypercholesterolemia (4) or induced by stress. There is also much evidence that infections, which may increase LDL-C as a component of an immune response, may contribute to atherosclerosis and CVD (10).
References
1. Popa LE, Petresc B, Cătană C et al. Association between cardiovascular risk factors and coronary artery disease assessed using CAD-RADS classification: a cross-sectional study in Romanian population. BMJ Open 2020;10:e031799. doi:10.1136/ bmjopen-2019-031799
2. Ravnskov U. Is atherosclerosis caused by high cholesterol? QJM 2002;95:397–403. doi.org/10.1093/qjmed/95.6.397
3. Hecht HS, Superko HR. Electron beam tomography and National Cholesterol Education Program guidelines in asymptomatic women. J Am Coll Cardiol 2001;37:1506-11. doi.org/10.1016/s0735-1097(01)01211-6
4. Ravnskov U, de Lorgeril M, Kendrick M, Diamond DM. Inborn coagulation factors are more important cardiovascular risk factors than high LDL- cholesterol in familial hypercholesterolemia. Med Hypotheses 2018;121:60-3. doi: 10.1016/j.mehy.2018.09.019.
5. Ravnskov U, de Lorgeril M, Diamond DM et al. LDL-C does not cause cardiovascular disease: a comprehensive review of current literature. Expert Rev Clin Pharmacol 2018;11:959-70. doi.org/10.1080/17512433.2018.1519391
6. Ravnskov U, Diamond DM, Hama R, et al. Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open 2016;6: e010401. doi:10.1136/ bmjopen-2015-010401
7. Charlton J, Ravindrarajah R, Hamada S et al. Trajectory of total cholesterol in the last years of life over age >80 years: cohort study of 99,758 participants. J Gerontol A Biol Sci Med Sci 2018;73:1083-9. doi: 10.1093/gerona/glx184.
8. Sung KC, Huh JH, Ryu S et al. Low levels of low-density lipoprotein cholesterol and mortality outcomes in non-statin users. J Clin Med 2019;8. pii: E1571. doi: 10.3390/jcm8101571.
9. Gnanenthiran SR, Ng ACC, Cumming R et al. Low total cholesterol is associated with increased major adverse cardiovascular events in men aged >70 years not taking statins. Heart 2019 pii: heartjnl-2019-315449. doi: 10.1136/heartjnl-2019-315449.
10. Ravnskov U, McCully KS. Infections may be causal in the pathogenesis of atherosclerosis. Am J Med Sci 2012;344:391-94. doi.org/10.1097/MAJ.0b013e31824ba6e0
11. Rosenman RH. Relationships of neurogenic and psychological factors to the regulation and variability of serum lipids. Stress Med 1993;9:133-40.
12. Dimsdale JE, Herd A. Variability of plasma lipids in response to emotional arousal. Psychosom Med 1982;44:413-30. doi.org/10.1097/00006842-198211000-00004
13. Thrall G, Lane D, Carroll D, Lip GY. A systematic review of the effects of acute psychological stress and physical activity on haemorheology, coagulation, fibrinolysis and platelet reactivity: Implications for the pathogenesis of acute coronary syndromes. Thromb Res 2007;120:819-47. doi.org/10.1016/j.thromres.2007.01.004
14. Saremi A, Bahn G, Reaven PD, et al. Progression of vascular calcification is increased with statin use in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care 2012;35:2390-2. doi: 10.2337/dc12-0464.
15. Nakazato R, Gransar H, Berman DS, et al. Statins use and coronary artery plaque composition: results from the International Multicenter CONFIRM Registry. Atherosclerosis 2012;225:148-53. doi.org/10.1016/j.atherosclerosis.2012.08.002
We appreciate the opportunity to address the concerns raised by D’Angelo and colleagues in relation to our recently published protocol for the Trans20 study [1]. While we certainly welcome feedback on our study, D’Angelo and colleagues focus much of their commentary on the clinical care of young people with gender dysphoria rather than on the Trans20 study protocol itself. In addition, the letter contains a number of inaccuracies and misconceptions that we feel must be clarified.
Show MoreFirstly, the authors claim not only that the study “intervenes in the developmental trajectories of all 600 expected participants” and that the model involves “a uniformly stepwise progression through the social and biological stages of transition”, but also that The Royal Children’s Hospital (RCH) Gender Service offers biological interventions to children as young as three. These assertions are incorrect. While patients and families attending the RCH Gender Service routinely receive mental health input to assess, explore and support their gender identity, the use of medical interventions occurs in only a minority of patients, reflecting the highly individualised approach to care. More specifically, a recent 10-year audit of the service from 2007-16 (up until the inception of Trans20) revealed that only 23% of patients received puberty blockers, while an even lower figure of 20% received gender-affirming hormones, and no patient under 10 years of age received either of these medical interven...
Petrie et al. asks the interesting question of where optimal weekly work hours lie for junior doctors, which is ultimately the question policy makers and advocates want to answer, with the aim of safeguarding the wellbeing and promoting satisfaction of junior medical doctors. Having recently (Dec 2019) published a large study (n=4012) in Medical Education examining factors related to Australian specialist trainee doctors we thought that there were several points of discussion made that may be distilled by our findings.
There are a number of salient points to discuss:
1. Satisfaction and Mental Illness - Our study examined specialist trainee’s satisfaction rather than mental illness or suicidal ideation with the idea being that a shift in the drive for policy from illness avoidance to promotion of satisfaction may be considered. In our Australia wide study, we found that one in five respondents worked more than 56 hours per week and, corroborating Petrie et al., that they were 24% less likely to be satisfied than those working 45 - 50 hours (median working hours).
2. Optimal work hours - In contrast to the findings of Petrie et al. we found that those working 51 - 56 hours were the most satisfied group, 21% more satisfied than those working 45 - 50 hours (p=0.006). The demands and priorities of a trainee undertaking a specialist pathway, which include: taking time with patients to build a sufficient case load to become proficient, taking time to study,...
Show MoreWe appreciate the authors’ interest for our paper, and we would like to thank them for the opportunity to discuss the problems raised in their letter (1).
First of all, we would like to emphasize that in our study we didn’t try to investigate the pathophysiology of atherosclerosis, but tried to see how the generally accepted risk factors of atherosclerosis correlate with significant coronary heart disease evaluated by CAD-RADS score in the Romanian population (2). The design of our research was cross-sectional, retrospective, therefore our purpose was not to establish the causality between dyslipidemia and cardiovascular disease. We agree with the authors that there is a difference between causality and association and our current study was based on evaluating the association between the presence of risk factors and the burden of atherosclerotic coronary disease evaluated using CCTA method. We chose dyslipidemia among the atherosclerosis risk factors studied based on the most current guidelines on cardiovascular disease prevention at the time (3).
Regarding the pathophysiology of atherosclerosis, the role of lipids and lipoproteins in the development of atheromatous plaque is proven by many studies (4-7). This complex process, based on an inflammatory response, is initiated by the infiltration of apoB containing lipoproteins into the arterial wall, which cause wall injuries and promote infiltration of monocytes into the subendothelial space. Secondly, the ma...
Show MoreThank you for your comments on our manuscript.
Show MoreFirstly, we applied meta-analysis to pool diagnostic accuracy for NBI, HAL and 5-ALA techniques for patients with NMIBC in comparison with WLC as the reference standard, which demonstrated the superior diagnostic performance of new imaging techniques in bladder detection compared with conventional WLC. These new imaging techniques are promising diagnostic interventions to improve clinical procedures in bladder cancer detection.
We described The SROC curves for NBI, HAL and 5-ALA in Figure 3A and the pooled DOR for NBI, HAL and 5-ALA were 40.09 (95% CI, 20.08-80.01, Figure 2A), 78.14 (95% CI, 31.42-194.28, Figure 2B) and 18.14 (95% CI, 4.28-76.87, Figure 2C), showing significant diagnostic superiority compared with white light cystoscopy (WLC) at the lesion level. While SROC curves for NBI, HAL and 5-ALA were showed in Figure 3B, DOR for NBI and HAL were 358.71 (95% CI, 44.50-2891.71, Figure 2D) and 59.95 (95% CI, 24.30-147.92, Figure 2E), presenting better performance compared with WLC. Figure 3 showed HAL and NBI exhibits similar SROC curves in lesion level, NBI performed significant excellent SROC curve in patient level. For patient-level analysis, NBI showed highest median sensitivity (SSY) 100%, median positive predictive value (PPV) 90.75%, median negative predictive value (NPV) 100% and median false positive rate (FPR) 31.55% in supplementary Table 1. And supplementary Table 2 showed similar narrative outcome...
Dear Editor,
Socioeconomic status (SES) has long been found to be significantly associated with increased risk of morbidity and mortality. It is related to health at all levels (1). A weak association between SES and maternal health care is found in countries where females are more educated (2). In developing countries like Pakistan where maternal mortality is still high despite efforts been made (3). This poor maternal health care use leads to maternal depression leading to CMH (Child Mental Health) issues (4). Therefore, efforts should be targeted to improve maternal health care use in order to ensure physical and mental health of the future generation irrespective of their SES.
1. Adler NE, Boyce WT, Chesney MA, Folkman S, Syme SL. Socioeconomic inequalities in health. No easy solution. Jama. 1993;269(24):3140-5.
2. McTavish S, Moore S, Harper S, Lynch J. National female literacy, individual socio-economic status, and maternal health care use in sub-Saharan Africa. Social science & medicine. 2010;71(11):1958-63.
3. Mumtaz Z, Salway S, Shanner L, Zaman S, Laing L. Addressing disparities in maternal health care in Pakistan: gender, class and exclusion. BMC pregnancy and childbirth. 2012;12(1):80.
4. Maselko J, Sikander S, Bangash O, Bhalotra S, Franz L, Ganga N, et al. Child mental health and maternal depression history in Pakistan. Social psychiatry and psychiatric epidemiology. 2016;51(1):49-62.
In their recent paper Chen et al. presented a meta-analysis on the diagnostic performance of image technique based transurethral resection for non-muscle invasive bladder cancer: They claim in their conclusion that narrow band imaging (NBI) showed the best diagnostic performance outcomes in a comparison to blue light cystoscopy with hexaminolevulinate (HAL) and 5-aminolevulinic acid (5-ALA). We cannot find the evidence for this in the result they present which deserves commenting.
Show MoreIn the abstract it is written that NBI showed significant diagnostic superiority compared with white light cystoscopy (WLC) at the lesion level (Pooled sensitivity 0.94, 95% CI 0.82 to 0.98; Pooled specificity 0.79, 95% CI 0.73 to 0.85; Diagnostic odds ratio (DOR) 40.09, 95% CI 20.08 to 80.01; Area under the receiver operating characteristic curve 0.88, 95% CI 0.85 to 0.91). That HAL showed superior lesion level detection results in all measured parameters is not mentioned. It is further stated that NBI presented the highest DOR (358.71, 95% CI 44.50 to 2891.71) in the patient level. The subgroup analysis, evaluating diagnostic performance in studies with low to moderate risk of bias and in studies with more than 100 patients, is only presented in supplementary material and similarly show how HAL and 5-ALA achieve comparable or improved diagnostic performance compared to NBI. Despite these results, the authors emphasize and conclude on behalf of NBI throughout the paper.
While the con...
Dear Editor,
I would like to thank Ng, Lynch, Kelly and Mba for their article analyzing the views of medical students who had participated in a mentoring programme whilst on their Obstetrics & Gynaecology attachment in the UK.
Devising methods of improving the learning experiences for medical students whilst on placement is vital to ensuring their professional readiness1 in facing their upcoming roles as junior doctors, practically and emotionally.
In the introduction, the authors provide a beautiful definition of a mentor from SCOPME2. I’d like to highlight that this definition includes the mentor being a ‘guide’ and being ‘empathic’. A guide is traditionally someone who shows another the way in a new environment to prevent them from getting lost; in many settings a guide is imperative. One could argue that students are given a Personal Tutor at the beginning of university who is a mentor in a way. This could be a good starting point, especially for more pastoral care – yet a clinical guide who is working closely with the student may be imperative as well, for the reasons emphasized by the student quotes in this article. The authors, therefore, concluded that clinical placement mentors for medical students should be more of a widespread practice.
Another key feature of these mentors is that they ‘volunteered’ to sign up, which identifies a key element of willingness to participate in the programme. If this programme became more widespread or...
Show MoreDear Editor ,
This article mainly focuses on knowledge about health related states and events for women in South Asian region i.e in Pakistan and India . Mostly women presenting in public hospitals for their antenatal checkup belongs to poor socioeconomic status and cannot afford a good living to maintain a healthy lifestyle . So, despite of having adequate knowledge about good health they can not afford one . So, i think hospitals should compile data of such women and share with concerned authorities who can provide them in this regard.
Psychological support should be freely available for pregnant women during their antenatal visit by experts .
Farren et al (1) state that they, ”were surprised by the prevalence of PTSD symptoms in our study”, and that, ”Future research should be aimed at assessing the risk factors for PTSD”.
Show MoreMy research of 1993, into Post Traumatic Stress Disorder in women who have undergone Obstetric and/or Gynaecological Procedures (2), which was widely reported in the press, obstetric and midwifery literature, including the N.I.C.E Guidelines, identified several risk factors for the development of PTSD in the women affected.
The key areas in the procedures seem to be those concerning the level of control which the woman has, the attitude of the doctor, the degree to which the patient’s views are heeded, and whether or not consent was perceived to have been given for the procedure. The gender of the examiner did not seem to be relevant.
The women were asked in the questionnaire to describe their experiences, some of which were quite explicit and reminiscent of assault: “dehumanising and painful”; “degrading and distressing….no account was taken of my feelings”; “my opinions were dismissed as irrelevant although it was my body which was being invaded”; “I came away hurting and feeling violated”; “very brutal internal was excruciating”; “you begin to feel like a thing”; “I cried and shouted but was held down and told to stop making a noise”; “humiliation…as if it happened yesterday”; “I felt assaulted and then abandoned”; “I felt abused…like a piece of meat on a slab”; “the mo...
The study by Popa et al. (1) is potentially of value in identifying adverse influences on cardiovascular health. Their study, however, suggests that dyslipidemia causes cardiovascular disease (CVD). We feel compelled to show that the broader literature is not consistent with this perspective and that their finding of an association between dyslipidemia and CVD is influenced by a methodological flaw in their design.
First, there is no evidence that dyslipidemia causes atherosclerosis. Already in 1936 Lande ́ and Sperry found that when corrected for age, healthy people with low total cholesterol (TC) were just as atherosclerotic as healthy people with high TC (2) and their finding has been verified and replicated later by many research groups (2). A strong contradiction has also been documented by sixteen angiographic trials where the authors had calculated exposure-response, which was present in only two of them (2). Furthermore, a study of the coronary arteries of 304 asymptomatic women by Hecht and Superco showed that the role of high LDL-cholesterol (LDL-C) is questionable as well. By using electron beam tomography, they found that neither the calcium percentile or the calcium score were associated with LDL-C (3). Also contradictory is, that In five studies of people with familial hypercholesterolemia there were no association between degree of atherosclerosis and LDL-C (4).
Second, numerous observations and experiments have shown that dyslipidemia does no...
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