The inverse association between resting heart rate (RHR) and longevity has been the subject of many studies, both in humans and across species [1]. The article by Zhao et al., titled, “Effect of resting heart rate on the risk of all-cause death in Chinese patients with hypertension: analysis of the Kailuan follow-up study” determines that resting heart rate > 76 beats-per-minute (bpm) is a predictor of mortality in Chinese hypertensive patients as well [2]. I applaud the authors for thoroughly adjusting for confounding factors and offering explanations for the association, but would like to bring to discussion key points that may help contextualize the findings.
Firstly, several studies have established that women have higher RHR than men and tend to have weaker associations between RHR and mortality [3]. Thus, it may be important to develop sex-specific quintiles when categorizing heart rate as women paradoxically also have higher life expectancy than men. Fortunately, this study has a large proportion of men which reduces misclassification bias but may also in turn reduce generalizability of the results to women.
There are peculiarities among the baseline characteristics by quintile of RHR that may warrant further attention. There seems to be markedly unequal sample sizes across the quintiles (e.g. Q2 = 7589 vs. Q1=10349), suggesting that there may be room to adjust the categories. Furthermore, there is a distinct...
The inverse association between resting heart rate (RHR) and longevity has been the subject of many studies, both in humans and across species [1]. The article by Zhao et al., titled, “Effect of resting heart rate on the risk of all-cause death in Chinese patients with hypertension: analysis of the Kailuan follow-up study” determines that resting heart rate > 76 beats-per-minute (bpm) is a predictor of mortality in Chinese hypertensive patients as well [2]. I applaud the authors for thoroughly adjusting for confounding factors and offering explanations for the association, but would like to bring to discussion key points that may help contextualize the findings.
Firstly, several studies have established that women have higher RHR than men and tend to have weaker associations between RHR and mortality [3]. Thus, it may be important to develop sex-specific quintiles when categorizing heart rate as women paradoxically also have higher life expectancy than men. Fortunately, this study has a large proportion of men which reduces misclassification bias but may also in turn reduce generalizability of the results to women.
There are peculiarities among the baseline characteristics by quintile of RHR that may warrant further attention. There seems to be markedly unequal sample sizes across the quintiles (e.g. Q2 = 7589 vs. Q1=10349), suggesting that there may be room to adjust the categories. Furthermore, there is a distinct pattern seen across several characteristics (i.e. physical exercise, smoking, drinking, antihypertensive medication use, history of myocardial infarction, and history of stroke) from Q1 to Q2 to Q3 [2; see Table 1]. There is a decrease from Q1 to Q2, followed by an increase from Q2 to Q3. Observing that Q1 has a higher average age than other quintiles, we speculate that Q1 is comprised of a mix of healthy, young individuals as well as older, unhealthy individuals who have lower RHR due to 1) use of rate control medication other than beta blockers, 2) undiagnosed heart failure (heart failure with preserved ejection fraction), or 3) other cardiac-related illness/therapies [4]. Furthermore, several comorbidities contribute to changes in heart rate, namely thyroid disorders, anemias, chronic inflammatory processes, and psychological illness. These are often associated with hypertension or diabetes diagnosis and thus should be accounted for in the analysis.
Both RHR and blood pressure fluctuate in the short- and long-term and have garnered attention in recent years due to potential prognostic value [5]. Furthermore, because RHR and blood pressure were measured in different positions, orthostatic variability may also become a confounding factor. Future studies should aim to measure RHR and blood pressure at each visit and treat variability as independent predictors of cardiovascular disease or all-cause mortality. It may be worthwhile to also stratify study populations by ejection fraction status or heart failure status. For those with left ventricular hypertrophy due to long-standing hypertension, increasing diastolic dysfunction may lead to compensatory increases in heart rate and contractility, possibly in part explaining the association between RHR and all-cause mortality in hypertensive patients. We also propose stratifying analysis in future studies by hypertension subtype (e.g. isolated systolic hypertension, isolated diastolic hypertension, systo-diastolic hypertension) to better classify individuals on the basis of physiological natural history of blood pressure.
Overall, I believe this article makes a strong case for the association between RHR and all-cause mortality. Further studies are necessary to better quantify the association and develop thresholds for pharmacologic interventions.
References:
1. Levine, H.J., 1997. Rest heart rate and life expectancy. Journal of the American College of Cardiology, 30(4), pp.1104-1106.
2. Zhao, M.X., Zhao, Q., Zheng, M., Liu, T., Li, Y., Wang, M., Yao, S., Wang, C., Chen, Y.M., Xue, H. and Wu, S., 2020. Effect of resting heart rate on the risk of all-cause death in Chinese patients with hypertension: analysis of the Kailuan follow-up study. BMJ open, 10(3), p.e032699.
3. Palatini, P., 2001. Heart rate as a cardiovascular risk factor: do women differ from men?. Annals of medicine, 33(4), pp.213-221.
4. Williams, B., Mancia, G., Spiering, W., Agabiti Rosei, E., Azizi, M., Burnier, M., Clement, D.L., Coca, A., De Simone, G., Dominiczak, A. and Kahan, T., 2018. 2018 ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH). European heart journal, 39(33), pp.3021-3104.
Sir
the difference between boys and girls 5 to 7 months post stress event is mentioned favoring the survival of girl fetuses. If true then historical data will show what were the happiest of the times when ( - minus 5 to 7 months) more boys were born. This can be a good anthropology historical tool to judge when people were happier.
Damacena et al. conducted a cross-sectional study to investigate the association of central obesity (CO) with sociodemographic, occupational, life habits, fitness and health status variables in 892 male firefighters (1). Adjusted odds ratios (95% confidence intervals) of the age range of 50 to 59 years old, low self-reported physical activity, low cardiorespiratory fitness, hyperglycaemia and hypertriglyceridaemia fasting status for CO were 2.93 (1.05 to 8.14), 1.95 (1.14 to 3.34), 5.15 (3.22 to 8.23), 1.70 (1.07 to 2.72) and 3.12 (1.75 to 5.55), respectively. I have two concerns about their study.
First, Yook investigated the association between occupational stress, cardiorespiratory fitness, arterial stiffness, heart rate variability and sleep quality in 705 male firefighters aged 40-50 years (2). Pearson’s moment correlation coefficients between occupational stress and cardiorespiratory fitness, arterial stiffness or sleep quality were -0.082, 0.085, 0.276, respectively. Although mental factors affected health status in male firefighters, risk assessment of occupational stress for cardiovascular diseases should be specified by a prospective study with a multivariate analysis.
Second, Kaipust et al. determined the association between sleep and on-duty injury among male career firefighters, stratified by body mass index (3). By multivariate analysis, more than half of on-duty injury reduction was observed by good sleep in obese firefighters. This significant...
Damacena et al. conducted a cross-sectional study to investigate the association of central obesity (CO) with sociodemographic, occupational, life habits, fitness and health status variables in 892 male firefighters (1). Adjusted odds ratios (95% confidence intervals) of the age range of 50 to 59 years old, low self-reported physical activity, low cardiorespiratory fitness, hyperglycaemia and hypertriglyceridaemia fasting status for CO were 2.93 (1.05 to 8.14), 1.95 (1.14 to 3.34), 5.15 (3.22 to 8.23), 1.70 (1.07 to 2.72) and 3.12 (1.75 to 5.55), respectively. I have two concerns about their study.
First, Yook investigated the association between occupational stress, cardiorespiratory fitness, arterial stiffness, heart rate variability and sleep quality in 705 male firefighters aged 40-50 years (2). Pearson’s moment correlation coefficients between occupational stress and cardiorespiratory fitness, arterial stiffness or sleep quality were -0.082, 0.085, 0.276, respectively. Although mental factors affected health status in male firefighters, risk assessment of occupational stress for cardiovascular diseases should be specified by a prospective study with a multivariate analysis.
Second, Kaipust et al. determined the association between sleep and on-duty injury among male career firefighters, stratified by body mass index (3). By multivariate analysis, more than half of on-duty injury reduction was observed by good sleep in obese firefighters. This significant association disappeared among normal or overweight firefighters, and the level of obesity might be a key factor for preventing on-duty injury. Anyway, controlling obesity is recommended to avoid accidents and to manage cardiovascular risks, and intervention trials are needed to verify the causal association (4).
References
1. Damacena FC, Batista TJ, Ayres LR, Zandonade E, Sampaio KN. Obesity prevalence in Brazilian firefighters and the association of central obesity with personal, occupational and cardiovascular risk factors: a cross-sectional study. BMJ Open 2020;10(3):e032933.
2. Yook YS. Firefighters' occupational stress and its correlations with cardiorespiratory fitness, arterial stiffness, heart rate variability, and sleep quality. PLoS One 2019;14(12):e0226739.
3. Kaipust CM, Jahnke SA, Poston WSC, et al. Sleep, obesity, and injury among US male career firefighters. J Occup Environ Med 2019;61(4):e150-e154.
4. Waldman HS, Renteria LI, McAllister MJ. Time-restricted feeding for the prevention of cardiometabolic diseases in high-stress occupations: a mechanistic review. Nutr Rev 2019 doi: 10.1093/nutrit/nuz090
Damacena et al. conducted a cross-sectional study to investigate the association of central obesity (CO) with sociodemographic, occupational, life habits, fitness and health status variables in 892 male firefighters (1). Adjusted odds ratios (95% confidence intervals) of the age range of 50 to 59 years old, low self-reported physical activity, low cardiorespiratory fitness, hyperglycaemia and hypertriglyceridaemia fasting status for CO were 2.93 (1.05 to 8.14), 1.95 (1.14 to 3.34), 5.15 (3.22 to 8.23), 1.70 (1.07 to 2.72) and 3.12 (1.75 to 5.55), respectively. I have two concerns about their study.
First, Yook investigated the association between occupational stress, cardiorespiratory fitness, arterial stiffness, heart rate variability and sleep quality in 705 male firefighters aged 40-50 years (2). Pearson’s moment correlation coefficients between occupational stress and cardiorespiratory fitness, arterial stiffness or sleep quality were -0.082, 0.085, 0.276, respectively. Although mental factors affected health status in male firefighters, risk assessment of occupational stress for cardiovascular diseases should be specified by a prospective study with a multivariate analysis.
Second, Kaipust et al. determined the association between sleep and on-duty injury among male career firefighters, stratified by body mass index (3). By multivariate analysis, more than half of on-duty injury reduction was observed by good sleep in obese firefighters. This significant association disappeared among normal or overweight firefighters, and the level of obesity might be a key factor for preventing on-duty injury. Anyway, controlling obesity is recommended to avoid accidents and to manage cardiovascular risks, and interventional trials are needed to verify the causal association (4).
References
1. Damacena FC, Batista TJ, Ayres LR, Zandonade E, Sampaio KN. Obesity prevalence in Brazilian firefighters and the association of central obesity with personal, occupational and cardiovascular risk factors: a cross-sectional study. BMJ Open 2020;10(3):e032933.
2. Yook YS. Firefighters' occupational stress and its correlations with cardiorespiratory fitness, arterial stiffness, heart rate variability, and sleep quality. PLoS One 2019;14(12):e0226739.
3. Kaipust CM, Jahnke SA, Poston WSC, et al. Sleep, obesity, and injury among US male career firefighters. J Occup Environ Med 2019;61(4):e150-e154.
4. Waldman HS, Renteria LI, McAllister MJ. Time-restricted feeding for the prevention of cardiometabolic diseases in high-stress occupations: a mechanistic review. Nutr Rev 2019 doi: 10.1093/nutrit/nuz090
I have read with interest Reece and colleagues (2016) paper, but some questions remain.
First, I think the authors have done a commendable job detailing most of their statistical methodology. However, some things are left to be desired, such as a description of the Statistical Power analysis. Using the Benjamini-Hochberg Procedure (a modified Bonferroni Procedure) on the data listed in their Supplementary materials, one can conclude that the authors' results were indeed statistically significant. What remains to be seen, however, is what the magnitude of these effects were, precisely, and what happened to the Power as these multiple comparisons were assessed, since Power decreases with increasing univariate statistical tests. One might assume Power to be sufficient given the N = 1,553, but these data have been parsed in many different ways, and it would be helpful to know the authors’ anticipated effect sizes and any Power analyses for these comparisons that were conducted prior to the start of the study.
Second, due to issues with boundary conditions and computational modeling, the method used in this paper for the mixed-effects linear model may not be quite right [1, 2]. There is often a misapplication of traditional AIC selection criteria in linear mixed effects (LME) modeling, owing to poor justification for use in longitudinal data analysis, due in part to error variance estimates [2], which is partially how this seemed to have been used here, in th...
I have read with interest Reece and colleagues (2016) paper, but some questions remain.
First, I think the authors have done a commendable job detailing most of their statistical methodology. However, some things are left to be desired, such as a description of the Statistical Power analysis. Using the Benjamini-Hochberg Procedure (a modified Bonferroni Procedure) on the data listed in their Supplementary materials, one can conclude that the authors' results were indeed statistically significant. What remains to be seen, however, is what the magnitude of these effects were, precisely, and what happened to the Power as these multiple comparisons were assessed, since Power decreases with increasing univariate statistical tests. One might assume Power to be sufficient given the N = 1,553, but these data have been parsed in many different ways, and it would be helpful to know the authors’ anticipated effect sizes and any Power analyses for these comparisons that were conducted prior to the start of the study.
Second, due to issues with boundary conditions and computational modeling, the method used in this paper for the mixed-effects linear model may not be quite right [1, 2]. There is often a misapplication of traditional AIC selection criteria in linear mixed effects (LME) modeling, owing to poor justification for use in longitudinal data analysis, due in part to error variance estimates [2], which is partially how this seemed to have been used here, in the Reece et al. paper.
Finally, and most importantly, the authors never detail the algorithm by which they have computed “vascular age” in this study. Cox proportional hazard estimates for vascular age have been proposed from Framingham Heart Study data, as well as the new “SCORE” method [3]. Should the authors have calculated their own VA score algorithm, this should have had some validity and reliability data published prior to the current article and should therefore be cited in the paper. Should they have used one of the other two methods, this should also be referenced, here, as their findings hinge entirely on ratio relations between VA and their other reference points, whether cannabis use or something else, such as BMI. If the VA calculations are inaccurate or the algorithm inappropriately selected for some reason, all the results drawn in this paper effectively become moot.
In sum, although the study was generally well conducted, I do think, taking into account some of the broader limitations (e.g., with respect to limited female participants in the Cannabis-only group, etc.), as well as the aforementioned methodological questions that remain, the authors’ conclusions are too widely generalized from a fairly unique and non-randomized population with no controls. I will look forward to more work from this group in the future.
1. Müller, S., Scealy, J. L., & Welsh, A. H. (2013). Model selection in linear mixed models. Statistical Science, 28(2), 135-167.
2. Liang, H., Wu, H., & Zou, G. (2008). A note on conditional AIC for linear mixed-effects models. Biometrika, 95(3), 773-778.
3. Cuende, J. I., Cuende, N., & Calaveras-Lagartos, J. (2010). How to calculate vascular age with the SCORE project scales: a new method of cardiovascular risk evaluation. European heart journal, 31(19), 2351-2358.
We carefully read the study protocol proposed by Heriot et al (1), regarding the development of a prospective registry of gynecological cancers in Australia. In fact, it is a heterogeneous group of pathologies, with different clinical presentations, diagnostic characteristics and therapeutic proposals (2,3). Together, this oncological complexity can restrict the daily practice of the professionals involved in this context and even impair the treatment of the women affected.
Oncological staging consists of a process to estimate the extent of the cancer present in the body of an affected person. Despite the particularities of each tumor site, it usually involves an evaluation obtained by physical examination associated with specific complementary examinations. However, in a real-world scenario, several factors can add limitations to this staging process (4).
Considering the staging of gynecological cancers, the interobserver variation in tumor measurement and clinical evaluation of patients stands out. In this context, if the tumor palpation varies by a few centimeters, the patient's clinical staging and prognostic classification are also altered. In addition, the disease itself can evolve throughout the diagnostic process, which can involve several months depending on the geographic region and specific socioeconomic conditions. Thus, professionals with less experience can make mistakes in defining the clinical stage and, consequently,...
We carefully read the study protocol proposed by Heriot et al (1), regarding the development of a prospective registry of gynecological cancers in Australia. In fact, it is a heterogeneous group of pathologies, with different clinical presentations, diagnostic characteristics and therapeutic proposals (2,3). Together, this oncological complexity can restrict the daily practice of the professionals involved in this context and even impair the treatment of the women affected.
Oncological staging consists of a process to estimate the extent of the cancer present in the body of an affected person. Despite the particularities of each tumor site, it usually involves an evaluation obtained by physical examination associated with specific complementary examinations. However, in a real-world scenario, several factors can add limitations to this staging process (4).
Considering the staging of gynecological cancers, the interobserver variation in tumor measurement and clinical evaluation of patients stands out. In this context, if the tumor palpation varies by a few centimeters, the patient's clinical staging and prognostic classification are also altered. In addition, the disease itself can evolve throughout the diagnostic process, which can involve several months depending on the geographic region and specific socioeconomic conditions. Thus, professionals with less experience can make mistakes in defining the clinical stage and, consequently, impair the interpretation of data from this variable.
In relation to ovarian and endometrial cancer, another issue must be highlighted: the definitive staging is only achieved after the surgical procedure, which may present differences in relation to the initial clinical diagnosis. In the assessment of lymph node status, divergence in relation to small pelvic lymph nodes is frequent, which may represent a reactive inflammatory state or metastatic involvement of the primary tumor (5). In addition, with the consolidation of neoadjuvant chemotherapy for locally advanced ovarian cancer (6), surgical staging must also be carefully collected.
Finally, it is worth noting that the staging of gynecological cancers is an important prognostic factor. The study of these factors is essential for the clinical follow-up and specific treatment of cancer patients (7,8). They are variables associated with overall survival and are indicators of several clinical outcomes involving the risk of recurrence or death. However, these prognostic factors should be interpreted with caution, especially when determined through small monocentric studies or restricted to a specific population. On the other hand, real-world studies allow an epidemiological analysis of different populations and can assist in the development of specific public policies (8). Thus, the proposal for a real-world registry, including several relevant variables on gynecological cancers, should be used as an example for other countries that do not yet have something similar. Nevertheless, we emphasize the relevance of staging these tumors and the rigor with which this variable must be treated.
References
Heriot N, Brand A, Cohen P, et al. Developing an Australian multi-module clinical quality registry for gynaecological cancers: a protocol paper. BMJ Open 2020;10:e034579. doi: 10.1136/bmjopen-2019-034579
Lheureux S, Braunstein M, Oza AM. Epithelial ovarian cancer: evolution of management in the era of precision medicine. CA Cancer J Clin 2019;69:280–304.doi:10.3322/caac.21559
Anuradha S, Webb PM, Blomfield P, et al. Survival of Australian women with invasive epithelial ovarian cancer: a population-based study. Med J Aust 2014;201:283–8.doi:10.5694/mja14.00132
Lawal IK, Ibrahim Abdullahi H, Obiokwonkwo AC. Revised (2018) FIGO stage IIB cervical cancer and prognostication in low-resource settings. Int J Gynaecol Obstet. 2020 Feb 13. doi: 10.1002/ijgo.13120. [Epub ahead of print]
Xu Y, Li H, Tong X, et al. How to evaluate the adequacy of staging for nodal-negative epithelial ovarian cancer? Use of nodal staging score. J Gynecol Oncol. 2019;30(2):e21. doi: 10.3802/jgo.2019.30.e21.
Coleridge SL, Bryant A, Lyons TJ, et al. Chemotherapy versus surgery for initial treatment in advanced ovarian epithelial cancer. Cochrane Database Syst Rev. 2019 Oct 31;2019(10). doi: 10.1002/14651858.CD005343.pub4.
Yamagami W1, Nagase S2, Takahashi F3, et al. A retrospective study for investigating the relationship between old and new staging systems with prognosis in ovarian cancer using gynecologic cancer registry of Japan Society of Obstetrics and Gynecology (JSOG): disparity between serous carcinoma and clear cell carcinoma. J Gynecol Oncol. 2020 Jan 13. doi: 10.3802/jgo.2020.31.e45. [Epub ahead of print]
Rosendahl M1, Høgdall CK, Mosgaard BJ. Restaging and Survival Analysis of 4036 Ovarian Cancer Patients According to the 2013 FIGO Classification for Ovarian, Fallopian Tube, and Primary Peritoneal Cancer. Int J Gynecol Cancer. 2016;26(4):680-7. doi: 10.1097/IGC.0000000000000675.
We read the article by Yuan et al. with great interest, which highlights different quality criteria in two breast cancer screening models in Canada (1).
Currently, mammographic screening for breast cancer is recommended by several medical institutions and government agencies (2,3), based on prospective studies that have shown reduced mortality and other favorable outcomes (4,5). However, in recent years, several authors have questioned the benefits of population screening due to the rates of overdiagnosis and overtreatment (6). Nevertheless, many of these questions are based in retrospective and population-based studies, whose methodological limitations restrict the extrapolation of data to the individualized clinical context.
The study conducted by Yuan et al. addresses an important issue of mammographic screening: the quality of the exams. Even in Canada, a high-income country with a consolidated health system, there are significant differences in the quality of screening between the centralized system (Screen Test, Alberta Cancer Agency) and community radiology clinics (1). Throughout the article, the authors also discuss several aspects related to technical criteria, such as cancer detection rate and false positive rate. However, as in most similar studies, nothing is discussed about the clinical quality control of the tests performed on both models.
Clinical quality control involves several criteria related to breast positioni...
We read the article by Yuan et al. with great interest, which highlights different quality criteria in two breast cancer screening models in Canada (1).
Currently, mammographic screening for breast cancer is recommended by several medical institutions and government agencies (2,3), based on prospective studies that have shown reduced mortality and other favorable outcomes (4,5). However, in recent years, several authors have questioned the benefits of population screening due to the rates of overdiagnosis and overtreatment (6). Nevertheless, many of these questions are based in retrospective and population-based studies, whose methodological limitations restrict the extrapolation of data to the individualized clinical context.
The study conducted by Yuan et al. addresses an important issue of mammographic screening: the quality of the exams. Even in Canada, a high-income country with a consolidated health system, there are significant differences in the quality of screening between the centralized system (Screen Test, Alberta Cancer Agency) and community radiology clinics (1). Throughout the article, the authors also discuss several aspects related to technical criteria, such as cancer detection rate and false positive rate. However, as in most similar studies, nothing is discussed about the clinical quality control of the tests performed on both models.
Clinical quality control involves several criteria related to breast positioning, image definition and contrast, presence of artifacts, adequate visualization of breast structures, among others (7,8). Taken together, these indicators are directly related to the accuracy of the method in the diagnosis of breast cancer and may influence the efficiency outcomes of population screening. However, despite some institutional initiatives (9), there is no effective international effort to control the quality of mammograms.
The impact of mammography quality on screening programs is particularly worrying in low- and middle-income countries. In Brazil, in a multicenter pilot study conducted by the National Cancer Institute (INCA), between 2007 and 2008, it was observed that about 30% of mammograms had quality below satisfactory standards (10). In the same period, a study conducted by the National Nuclear Energy Commission (CNEN) in the state of Goiás found that 40% of mammography services did not reach the acceptable level of 70% of compliance with quality standards, despite participating in a health program surveillance (11).
Within clinical quality control, non-conformities related to breast positioning correspond to the most common type of failure in mammography exams. In a study conducted with 5000 screening mammograms performed after the implementation of a clinical quality program, about 90% of the failures were related to breast positioning (8). When interpreting the data by Yuan et al., we consider that these failures in breast positioning may partially justify the results described. Nevertheless, continuing education and constant training of radiology technicians can reduce these failures and improve the final quality of mammograms.
References
1. Yuan Y, Vu K, Shen Y, et al. Importance of quality in breast cancer screening practice – a natural experiment in Alberta, Canada. BMJ Open 2020;10:e028766. doi: 10.1136/bmjopen-2018-028766
2. Urban LABD, Chala LF, Bauab SDP, Schaefer MB, Santos RPD, Maranhão NMA, et al. Breast Cancer Screening: Updated Recommendations of the Brazilian College of Radiology and Diagnostic Imaging, Brazilian Breast Disease Society, and Brazilian Federation of Gynecological and Obstetrical Associations. Rev Bras Ginecol Obstet. 2017;39(10):569-575.
3. Coldman A, Phillips N, Wilson C, Decker K, Chiarelli AM, Brisson J, et al. Pan-Canadian study of mammography screening and mortality from breast cancer. J Natl Cancer Inst. 2014;106(11).
4. Shapiro S. Evidence on screening for breast cancer from a randomized trial. Cancer. 1977;39(6 Suppl):2772-82.
5. Tabar L, Yen MF, Vitak B, Chen HH, Smith RA, Duffy SW. Mammography service screening and mortality in breast cancer patients: 20-year follow-up before and after introduction of screening. Lancet. 2003;361:1405–10.
6. Welch HG, Prorok PC, O'Malley AJ, Kramer BS. Breast-Cancer Tumor Size, Overdiagnosis, and Mammography Screening Effectiveness. N Engl J Med. 2016;375(15):1438-1447.
7. Sabino SMPS, Watanabe AHU, Vieira RAC. Qualidade do exame de mamografia em rastreamento mamográfico. Rev Bras Mastologia. 2013;23(2):31-35.
8. De Souza Sabino SM, Silva TB, Watanabe AH, Syrjänen K, Carvalho AL, Mauad EC. Implementation of a clinical quality control program in a mammography screening service of Brazil. Anticancer Res. 2014;34(9):5057-65.
9. Perry N, Broeders M, Wolf C, Tornberg S, Holland R, von Karsa L. European guidelines for quality assurance in breast cancer screening and diagnosis. Fourth edition-summary document. Ann Oncol. 2008;19(4):614-22.
10. Brasil. Ministério da Saúde. Instituto Nacional de Câncer (INCA). INCA propõem criação de Programa Nacional de Garantia de Qualidade em Mamografia. [Internet] Rio de Janeiro: Instituto Nacional do Câncer (INCA); 2008; Available from: http://www.inca.gov.br/releases/press_release_view.asp?ID=1970.
11. Corrêa RS, Freitas-Junior R, Peixoto JE, Rodrigues DC, Lemos ME, Dias CM, et al. Effectiveness of a quality control program in mammography for the Brazilian National Health System. Rev Saude Publica. 2012;46(5):769-76.
We read with interest, the study protocol by He. et al, comparing anticoagulation strategies in pregnant women with mechanical heart valves (MHVs)[1]. In their protocol, the authors propose the conduct of a network meta-analysis (NMA) to compare various strategies for anticoagulation in this population. The proposed protocol adds to a long list of recently-published systematic reviews on the topic, each of which adopted slightly different methodological approaches, resulting in the drawing of disparate clinical conclusions. The reason for this is the considerable clinical, methodological and statistical heterogeneity within published studies, most of which case series and small cohort studies[2]. Although this protocol has a number of strengths, which includes an exhaustive list of databases, clear definitions of outcomes and the use of GRADE methodology to assess the certainty in evidence and the strength of recommendations, there are a few concerns that must be addressed.
The choice of anticoagulant in pregnant women with MHVs is often based on resource availability and clinical factors. For example, the use of low molecular weight heparin is cost-prohibitive in low-resource settings and where serial anti-Xa levels cannot be monitored. In settings where a choice of all methods is available, those at highest risk, still receive a vitamin-K-antagonist-based regimen. Further, clinical outcomes are considerably different in lower resource setting...
We read with interest, the study protocol by He. et al, comparing anticoagulation strategies in pregnant women with mechanical heart valves (MHVs)[1]. In their protocol, the authors propose the conduct of a network meta-analysis (NMA) to compare various strategies for anticoagulation in this population. The proposed protocol adds to a long list of recently-published systematic reviews on the topic, each of which adopted slightly different methodological approaches, resulting in the drawing of disparate clinical conclusions. The reason for this is the considerable clinical, methodological and statistical heterogeneity within published studies, most of which case series and small cohort studies[2]. Although this protocol has a number of strengths, which includes an exhaustive list of databases, clear definitions of outcomes and the use of GRADE methodology to assess the certainty in evidence and the strength of recommendations, there are a few concerns that must be addressed.
The choice of anticoagulant in pregnant women with MHVs is often based on resource availability and clinical factors. For example, the use of low molecular weight heparin is cost-prohibitive in low-resource settings and where serial anti-Xa levels cannot be monitored. In settings where a choice of all methods is available, those at highest risk, still receive a vitamin-K-antagonist-based regimen. Further, clinical outcomes are considerably different in lower resource settings, where there is a predominance of rheumatic heart disease, affecting the mitral valve, and the use of more thrombogenic valves, vs. in higher-resource settings where less thrombogenic valves are used to correct congenital valvular disease that is more likely to affect the aortic valve, and access to multi-disciplinary care is less restricted.
There is therefore, a natural selection bias, which is evident in the published literature. This bias, and the heterogeneity between non-experimental studies means that the assumptions of non-parametric or student T-tests are violated, and this precludes any form of head-to-head comparison. It is for this reason we, and most systematic reviews have presented point estimates for anticoagulant strategy, and have refrained from performing pair-wise meta-analysis. The authors’ decision to perform NMA, by only including studies that have compared two regimens, only one of which is an experimental study, would not only eliminate most case series, which offer vital information, but would also result in erroneous conclusions, from not considering the confounding variables that contribute to the choice of anticoagulant in this population.
Common assumptions made in a NMA are homogeneity between studies, transitivity and consistency. The homogeneity assumption requires that studies included in the meta-analyses are similar. Transitivity is an assumption that two studies of which one has compared treatment A vs B and other has compared treatment A vs C do not differ with respect to effect modifiers and we can estimate what would be the treatment effect if treatment B and C are compared. This means that the population receiving treatment A is similar, and can therefore be compared with those receiving treatment B and treatment C. Consistency means that direct and indirect effect estimates between two treatments do not differ beyond the expectation by heterogeneity. This would be very crucial in this NMA where likelihood of obtaining direct estimates are very small as majority of studies are case series or small cohorts. In addition, there is no plan for evaluating quality of evidence using CINeMA or other framework which would be crucial in this exercise[3, 4]. Given the reasons outlined earlier, the assumptions of NMA, are difficult to defend for studies on anticoagulation in pregnant women with MHVs.
The management of anticoagulation in pregnant women with MHVs is a classic example of maternal-fetal conflict, wherein decision-making regarding the choice of anticoagulant depends on individual circumstances and the values and preferences of patients, which is better addressed through clinical decision-analysis[5]. Decision-analysis studies, as well as counselling this complex group of patients requires contemporary data that is best obtained through a prospective international database[6], which will allow for appropriate subgroup analysis, and tailoring the correct approach to each individual. Until a database of this kind is established to further inform clinical practice, systematic reviews should restrict their role to providing pooled estimates of maternal and fetal risks, and refrain from either providing head-to-head comparisons between anticoagulant strategies or attempt to derive indirect estimates.
1. He S, Zou Y, Li J, Liu J, Zhao L, Yang H, Su Z, Ye H: Anticoagulation regimens during pregnancy in patients with mechanical heart valves: a protocol for a systematic review and network meta-analysis. BMJ open 2020, 10(2):e033917.
2. D'Souza R, Ostro J, Shah PS, Silversides CK, Malinowski A, Murphy KE, Sermer M, Shehata N: Anticoagulation for pregnant women with mechanical heart valves: a systematic review and meta-analysis. Eur Heart J 2017, 38(19):1509-1516.
3. Salanti G, Del Giovane C, Chaimani A, Caldwell DM, Higgins JP: Evaluating the quality of evidence from a network meta-analysis. PloS one 2014, 9(7):e99682.
4. CINeMA: Confidence in Network Meta-Analysis [Software]. In. University of Bern: Institute of Social and Preventive Medicine; 2017.
5. D'Souza R, Shah PS, Sander B: Clinical decision analysis in perinatology. Acta Obstet Gynecol Scand 2018, 97(4):491-499.
6. D'Souza R, Silversides CK, McLintock C: Optimal Anticoagulation for Pregnant Women with Mechanical Heart Valves. Semin Thromb Hemost 2016, 42(7):798-804.
We read the original study by Wang et al1, published in the February 2020 issue of BMJ open, with much interest. In this study, the authors sought to evaluate the costs, quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER) of cetuximab plus FOLFOX-4 when compared to FOLFOX-4 alone among Chinese patients with RAS wild-type metastatic colorectal cancer.1 The authors used a Markov model that was structured around 3 health states [i.e., progression-free survival (PFS), progressive disease (PD) and death], with transition probabilities obtained from parametric fitting of PFS and OS curves from the published TAILOR clinical trial.2 Costs were measured in the societal perspective and the medication costs were calculated assuming with the specific height (161cm), weight (62kg) and a body surface area (1.66 m). Health utilities were obtained from existing literature. Based on the ICER of US$ 16,4044 per QALY and a willingness-to-pay threshold of US$ 28,106 per QALY, the authors concluded that cetuximab plus FOLFOX-4 is not a cost-effective treatment in the Chinese health care setting.
Although this paper contributes to a better understanding of the alignment between the price of cetuximab and its observed efficacy in the Chinese healthcare setting, we feel that further clarifications of the authors’ methodological choices are warranted for transparency and replication purposes. Below are 5 important points for the autho...
We read the original study by Wang et al1, published in the February 2020 issue of BMJ open, with much interest. In this study, the authors sought to evaluate the costs, quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER) of cetuximab plus FOLFOX-4 when compared to FOLFOX-4 alone among Chinese patients with RAS wild-type metastatic colorectal cancer.1 The authors used a Markov model that was structured around 3 health states [i.e., progression-free survival (PFS), progressive disease (PD) and death], with transition probabilities obtained from parametric fitting of PFS and OS curves from the published TAILOR clinical trial.2 Costs were measured in the societal perspective and the medication costs were calculated assuming with the specific height (161cm), weight (62kg) and a body surface area (1.66 m). Health utilities were obtained from existing literature. Based on the ICER of US$ 16,4044 per QALY and a willingness-to-pay threshold of US$ 28,106 per QALY, the authors concluded that cetuximab plus FOLFOX-4 is not a cost-effective treatment in the Chinese health care setting.
Although this paper contributes to a better understanding of the alignment between the price of cetuximab and its observed efficacy in the Chinese healthcare setting, we feel that further clarifications of the authors’ methodological choices are warranted for transparency and replication purposes. Below are 5 important points for the authors to consider.
1. Societal perspective: the authors took a societal perspective, which includes the social opportunity costs associated with receiving the treatment.3 According to this perspective, it is our understanding that all resources, including productivity losses due to the illness, should be identified and valued. The authors accounted for productivity losses (indirect costs) using a human capital approach, which consists of valuing people's contributions to society based on their salary or wages. For instance, the authors used the average salary of Chinese workers to account for social opportunity costs. We argue that this may be problematic because the human capital approach may bias against the patients who are not working (patients aged 65+), constituting 22.9% of the study population. This should have been acknowledged in the discussion section of the authors’ papers. One alternative to the human capital approach that the authors could have considered as a sensitivity analysis is the friction cost approach.4 This approach posits that the productivity loss accrued by society is a function of the time needed to replace the absentees (sick patients).
2. Double counting: A germane issue associated with the perspective is double counting indirect cost in the economic evaluation.5 6 Since the economic losses associated with the illness can theoretically be taken into account as part of QALYs estimation, including indirect cost will double count such costs, which might result in underestimating the cost-effectiveness of the intervention. The issue of double-counting costs and to what extent that might have affected the results of their study would be a great discussion point.
3. Transition probabilities: The authors claim that they applied the Weibull survival function to fit the Kaplan-Meier PFS and OS from the trial. It would be helpful for readers to know whether authors considered other parametric distributions such as exponential, gamma, log-normal besides Weibull.
4. Competing risk: The authors used a Markov model for their economic evaluation. As previously mentioned, they derived the transition probabilities from fitting parametric distributions to the Kaplan-Meier PFS and OS curves from the TAILOR trial.2 We argue that the method used by the authors did not explicitly account for competing risks. In estimating the transition probabilities from stable to progression, patients who died without progressing would act as competing events. In other words, the hazard of a progression cannot simply be derived from the probability of the PFS, because the ability to accurately capture survival is dependent upon the combination of the hazards of death and progression. We recommend using Dirichlet distributions, multi-state models or partitioned models that can handle these competing more explicitly than the authors presented.
5. A growing issue gaining significant attention in the literature is the impact of drug wastage on the estimation of incremental cost-effectiveness ratios. Economic evaluations are often conducted under the assumption that every milligram of a drug is effectively used. However, evidence has demonstrated that, in clinical practice, wastage of residual vial contents caused by the mismatch of vial size and individualized dosing based on the body surface area or weight has the potential to significantly affect overall drug expenditure.7 Since cetuximab is a parenteral drug and has the potential of drug wastage, it is necessary to explicitly take into account drug wastage in such economic evaluation. The authors claimed that the medication costs were calculated based on a case-patient. However, they did not provide detailed information on whether drug wastage was accounted for.
We would like to reiterate our appreciation of the paper by Wang et al.1 We hope our recommendations will help strengthen the value of their work.
Disclosures: No funding supported the writing of this letter. The authors report no conflicts of interest related to the subject of this letter.
References
1. Wang H, Huang L, Gao P, et al. Cost-effectiveness analysis of cetuximab combined with chemotherapy as a first-line treatment for patients with RAS wild-type metastatic colorectal cancer based on the TAILOR trial. BMJ Open 2020;10(2):e030738. doi: 10.1136/bmjopen-2019-030738 [published Online First: 2020/02/14]
2. Qin S, Li J, Wang L, et al. Efficacy and Tolerability of First-Line Cetuximab Plus Leucovorin, Fluorouracil, and Oxaliplatin (FOLFOX-4) Versus FOLFOX-4 in Patients With RAS Wild-Type Metastatic Colorectal Cancer: The Open-Label, Randomized, Phase III TAILOR Trial. J Clin Oncol 2018;36(30):3031-39. doi: 10.1200/jco.2018.78.3183 [published Online First: 2018/09/11]
3. Perspective [online].(2016). York; York Health Economics Consortium; 2016 2016 [Available from: https://yhec.co.uk/glossary/perspective/.
4. Brouwer WB, Koopmanschap MA. The friction-cost method : replacement for nothing and leisure for free? Pharmacoeconomics 2005;23(2):105-11. doi: 10.2165/00019053-200523020-00002 [published Online First: 2005/03/08]
5. Neumann PJ. Costing and perspective in published cost-effectiveness analysis. Med Care 2009;47(7 Suppl 1):S28-32. doi: 10.1097/MLR.0b013e31819bc09d [published Online First: 2009/06/19]
6. Jonsson B. Ten arguments for a societal perspective in the economic evaluation of medical innovations. Eur J Health Econ 2009;10(4):357-9. doi: 10.1007/s10198-009-0173-2 [published Online First: 2009/07/21]
7. Truong J, Cheung MC, Mai H, et al. The impact of cancer drug wastage on economic evaluations. Cancer 2017;123(18):3583-90. doi: 10.1002/cncr.30807 [published Online First: 2017/06/24]
CORRECTION/DISCLAIMER. As of the date of publication of the study protocol for a randomised, double-blind, placebo-controlled study evaluating the efficacy of cannabis-based Medicine Extract in slowing the disease progression of Amyotrophic Lateral sclerosis or motor neurone disease: the EMERALD trial (the “Study”), CannTrust Inc. (“CannTrust”) had received a Notice of Licence Suspension pursuant to the Cannabis Act (Canada). The Notice states that Health Canada has suspended CannTrust's authority to produce cannabis, other than cultivating and harvesting, and to sell cannabis. As such, the Notice constitutes a partial suspension of the Company's licence for standard cultivation and a full suspension of its licences for standard processing, medical sales, cannabis drugs and research issued under the Cannabis regulations. As a result, the EMERALD trial will proceed with another licensed provider of cannabis-based medicine extract.
A recent article in The Times asks: "How will this play out in the next decade, as the first cohort on puberty blockers come to terms with their probable infertility? Such experimental paediatric medicine has been politicised and shrouded in secrecy for too long. It is time to ask serious questions.”1
In the spirit of asking serious questions of the RCHGS Trans20 study, we stand by our previous claims and respond to the author’s comments, which clearly misrepresented our concerns. Based on our reading of the data, we are of the view that gender-affirming interventions, be they psychosocial or medical, do not have an adequate evidence base to warrant their widespread use as routine medical care in children and adolescents. In fact, the paper’s authors acknowledge this lack of evidence and highlight the “urgent need for more evidence to ensure optimal medical and psychosocial interventions”.
In their response to our comments, the authors justify their claim that the Trans20 study is an observational study by referring to the NIH definition that an observational study is one in which “participants may receive interventions that are part of their routine medical care”. We do not agree that gender affirmative treatments, particularly medical interventions, constitute “routine medical care”, especially when there are only two small follow-up studies that report short term outcomes of young people who have undergone puberty blockade.2,3 This view is supported...
A recent article in The Times asks: "How will this play out in the next decade, as the first cohort on puberty blockers come to terms with their probable infertility? Such experimental paediatric medicine has been politicised and shrouded in secrecy for too long. It is time to ask serious questions.”1
In the spirit of asking serious questions of the RCHGS Trans20 study, we stand by our previous claims and respond to the author’s comments, which clearly misrepresented our concerns. Based on our reading of the data, we are of the view that gender-affirming interventions, be they psychosocial or medical, do not have an adequate evidence base to warrant their widespread use as routine medical care in children and adolescents. In fact, the paper’s authors acknowledge this lack of evidence and highlight the “urgent need for more evidence to ensure optimal medical and psychosocial interventions”.
In their response to our comments, the authors justify their claim that the Trans20 study is an observational study by referring to the NIH definition that an observational study is one in which “participants may receive interventions that are part of their routine medical care”. We do not agree that gender affirmative treatments, particularly medical interventions, constitute “routine medical care”, especially when there are only two small follow-up studies that report short term outcomes of young people who have undergone puberty blockade.2,3 This view is supported by the Australia Council of Therapeutic Advisory Groups which recommends that off-label medication use in children and adolescents should only occur if there is high-quality evidence supporting its use in paediatric populations.4 In 2019, BMJ Evidence Based Medicine concluded that significant problems with the research into puberty blockade and cross-sex hormones prevent definitive conclusions being drawn and that these treatments should be regarded as experimental.5
The Trans20 study in fact meets the NIH definition of a clinical trial, namely “clinical research studies involving human participants assigned to an intervention in which the study is designed to evaluate the effect(s) of the intervention on the participant and the effect being evaluated is a health-related biomedical or behavioral outcome”6. We therefore stand by our position that this is an interventional study investigating what we and others consider to be an experimental treatment.
The “step-wise progression” we refer to is outlined in the paper itself. The RCH’s Multidisciplinary Assessment Clinic’s function is to provide: information, assessment, psychosocial support, puberty blockers and gender-affirming hormones. We did not assert that all patients being treated at the RCH Gender Clinic receive all of these interventions. We are also perplexed that we were understood to be stating that children as young as 3 could receive medical interventions, when it is clear that puberty blockade could only be administered just before or during puberty. When we argue that the Trans20 study will intervene in the developmental trajectories of trans-identifying youth, we see all steps in the RCH’s protocol, be they psychosocial or medical, as parts of a very particular intervention, namely gender-affirmation. We stand by our conclusion that this study will not be able to document the natural history of gender dysphoria in young people as this natural history is being altered by gender-affirming interventions.
We were very pleased to read the percentages of patients who receive puberty blockade and cross sex hormones. We have attempted to obtain this information from the RCH via Freedom Of Information and are still waiting for a response. Given that there are approximately 250 new referrals to the RCH gender clinic each year, the numbers of patients receiving puberty blockade (23%) and cross-sex hormones (20%) are substantial. It would be helpful to know how these percentages were derived. Do 23% of all patients referred to the clinic (including those who drop out) receive puberty blockers? Or is it 23% of patients who remain in contact with the clinic? Each of these present very different scenarios. Given that these figures represent averages over the last 10 years, it would be interesting to know whether the proportion of patients receiving medical treatment has increased in recent years.
Regarding the desistance data, we suspect the authors would be aware that there are several studies that document desistance rates, which largely replicate the findings of the Singh study.7 We also assume the authors are aware of the 2011 study by Dhejne et al,8 one of the most robust studies looking at outcomes of gender-affirming treatment in adults, which documents a very high suicide rate post-transition. The authors are correct in stating that robust suicide data for young people receiving gender-affirming treatments is lacking. Sadly, the paper by Turban which the authors refer to suffers from serious methodological limitations, including the use of a non-generalisable convenience sample and a failure to correlate psychiatric comorbidity with reports of suicidal ideation and attempts.
We continue ask: “what constitutes informed consent in the treatment of childhood gender dysphoria” and in the Trans20 study. The paper says very little about the informed consent procedure, other than that it is a “multistep process”. In our view, for any informed consent to be valid, it must include detailed information about the desistance rates (even if disputed by some), the unknown suicide risks, and the lack of long-term outcome data for gender-affirming interventions in young people. Further, Trans20 appears to be studying the outcome of what we and others believe are experimental treatments. Pang et al have made clear that these treatments are not intended or understood by the participants at the RCH Gender Clinic to be part of a clinical trial. This adds to our ethical concerns about the Trans20 study.
Dear Authors and Editorial Team,
The inverse association between resting heart rate (RHR) and longevity has been the subject of many studies, both in humans and across species [1]. The article by Zhao et al., titled, “Effect of resting heart rate on the risk of all-cause death in Chinese patients with hypertension: analysis of the Kailuan follow-up study” determines that resting heart rate > 76 beats-per-minute (bpm) is a predictor of mortality in Chinese hypertensive patients as well [2]. I applaud the authors for thoroughly adjusting for confounding factors and offering explanations for the association, but would like to bring to discussion key points that may help contextualize the findings.
Firstly, several studies have established that women have higher RHR than men and tend to have weaker associations between RHR and mortality [3]. Thus, it may be important to develop sex-specific quintiles when categorizing heart rate as women paradoxically also have higher life expectancy than men. Fortunately, this study has a large proportion of men which reduces misclassification bias but may also in turn reduce generalizability of the results to women.
There are peculiarities among the baseline characteristics by quintile of RHR that may warrant further attention. There seems to be markedly unequal sample sizes across the quintiles (e.g. Q2 = 7589 vs. Q1=10349), suggesting that there may be room to adjust the categories. Furthermore, there is a distinct...
Show MoreSir
the difference between boys and girls 5 to 7 months post stress event is mentioned favoring the survival of girl fetuses. If true then historical data will show what were the happiest of the times when ( - minus 5 to 7 months) more boys were born. This can be a good anthropology historical tool to judge when people were happier.
Damacena et al. conducted a cross-sectional study to investigate the association of central obesity (CO) with sociodemographic, occupational, life habits, fitness and health status variables in 892 male firefighters (1). Adjusted odds ratios (95% confidence intervals) of the age range of 50 to 59 years old, low self-reported physical activity, low cardiorespiratory fitness, hyperglycaemia and hypertriglyceridaemia fasting status for CO were 2.93 (1.05 to 8.14), 1.95 (1.14 to 3.34), 5.15 (3.22 to 8.23), 1.70 (1.07 to 2.72) and 3.12 (1.75 to 5.55), respectively. I have two concerns about their study.
First, Yook investigated the association between occupational stress, cardiorespiratory fitness, arterial stiffness, heart rate variability and sleep quality in 705 male firefighters aged 40-50 years (2). Pearson’s moment correlation coefficients between occupational stress and cardiorespiratory fitness, arterial stiffness or sleep quality were -0.082, 0.085, 0.276, respectively. Although mental factors affected health status in male firefighters, risk assessment of occupational stress for cardiovascular diseases should be specified by a prospective study with a multivariate analysis.
Second, Kaipust et al. determined the association between sleep and on-duty injury among male career firefighters, stratified by body mass index (3). By multivariate analysis, more than half of on-duty injury reduction was observed by good sleep in obese firefighters. This significant...
Show MoreI have read with interest Reece and colleagues (2016) paper, but some questions remain.
First, I think the authors have done a commendable job detailing most of their statistical methodology. However, some things are left to be desired, such as a description of the Statistical Power analysis. Using the Benjamini-Hochberg Procedure (a modified Bonferroni Procedure) on the data listed in their Supplementary materials, one can conclude that the authors' results were indeed statistically significant. What remains to be seen, however, is what the magnitude of these effects were, precisely, and what happened to the Power as these multiple comparisons were assessed, since Power decreases with increasing univariate statistical tests. One might assume Power to be sufficient given the N = 1,553, but these data have been parsed in many different ways, and it would be helpful to know the authors’ anticipated effect sizes and any Power analyses for these comparisons that were conducted prior to the start of the study.
Second, due to issues with boundary conditions and computational modeling, the method used in this paper for the mixed-effects linear model may not be quite right [1, 2]. There is often a misapplication of traditional AIC selection criteria in linear mixed effects (LME) modeling, owing to poor justification for use in longitudinal data analysis, due in part to error variance estimates [2], which is partially how this seemed to have been used here, in th...
Show MoreDear editor,
We carefully read the study protocol proposed by Heriot et al (1), regarding the development of a prospective registry of gynecological cancers in Australia. In fact, it is a heterogeneous group of pathologies, with different clinical presentations, diagnostic characteristics and therapeutic proposals (2,3). Together, this oncological complexity can restrict the daily practice of the professionals involved in this context and even impair the treatment of the women affected.
Oncological staging consists of a process to estimate the extent of the cancer present in the body of an affected person. Despite the particularities of each tumor site, it usually involves an evaluation obtained by physical examination associated with specific complementary examinations. However, in a real-world scenario, several factors can add limitations to this staging process (4).
Considering the staging of gynecological cancers, the interobserver variation in tumor measurement and clinical evaluation of patients stands out. In this context, if the tumor palpation varies by a few centimeters, the patient's clinical staging and prognostic classification are also altered. In addition, the disease itself can evolve throughout the diagnostic process, which can involve several months depending on the geographic region and specific socioeconomic conditions. Thus, professionals with less experience can make mistakes in defining the clinical stage and, consequently,...
Show MoreDear editor,
We read the article by Yuan et al. with great interest, which highlights different quality criteria in two breast cancer screening models in Canada (1).
Currently, mammographic screening for breast cancer is recommended by several medical institutions and government agencies (2,3), based on prospective studies that have shown reduced mortality and other favorable outcomes (4,5). However, in recent years, several authors have questioned the benefits of population screening due to the rates of overdiagnosis and overtreatment (6). Nevertheless, many of these questions are based in retrospective and population-based studies, whose methodological limitations restrict the extrapolation of data to the individualized clinical context.
The study conducted by Yuan et al. addresses an important issue of mammographic screening: the quality of the exams. Even in Canada, a high-income country with a consolidated health system, there are significant differences in the quality of screening between the centralized system (Screen Test, Alberta Cancer Agency) and community radiology clinics (1). Throughout the article, the authors also discuss several aspects related to technical criteria, such as cancer detection rate and false positive rate. However, as in most similar studies, nothing is discussed about the clinical quality control of the tests performed on both models.
Show MoreClinical quality control involves several criteria related to breast positioni...
Dear editor,
We read with interest, the study protocol by He. et al, comparing anticoagulation strategies in pregnant women with mechanical heart valves (MHVs)[1]. In their protocol, the authors propose the conduct of a network meta-analysis (NMA) to compare various strategies for anticoagulation in this population. The proposed protocol adds to a long list of recently-published systematic reviews on the topic, each of which adopted slightly different methodological approaches, resulting in the drawing of disparate clinical conclusions. The reason for this is the considerable clinical, methodological and statistical heterogeneity within published studies, most of which case series and small cohort studies[2]. Although this protocol has a number of strengths, which includes an exhaustive list of databases, clear definitions of outcomes and the use of GRADE methodology to assess the certainty in evidence and the strength of recommendations, there are a few concerns that must be addressed.
The choice of anticoagulant in pregnant women with MHVs is often based on resource availability and clinical factors. For example, the use of low molecular weight heparin is cost-prohibitive in low-resource settings and where serial anti-Xa levels cannot be monitored. In settings where a choice of all methods is available, those at highest risk, still receive a vitamin-K-antagonist-based regimen. Further, clinical outcomes are considerably different in lower resource setting...
Show MoreDear Editor,
We read the original study by Wang et al1, published in the February 2020 issue of BMJ open, with much interest. In this study, the authors sought to evaluate the costs, quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER) of cetuximab plus FOLFOX-4 when compared to FOLFOX-4 alone among Chinese patients with RAS wild-type metastatic colorectal cancer.1 The authors used a Markov model that was structured around 3 health states [i.e., progression-free survival (PFS), progressive disease (PD) and death], with transition probabilities obtained from parametric fitting of PFS and OS curves from the published TAILOR clinical trial.2 Costs were measured in the societal perspective and the medication costs were calculated assuming with the specific height (161cm), weight (62kg) and a body surface area (1.66 m). Health utilities were obtained from existing literature. Based on the ICER of US$ 16,4044 per QALY and a willingness-to-pay threshold of US$ 28,106 per QALY, the authors concluded that cetuximab plus FOLFOX-4 is not a cost-effective treatment in the Chinese health care setting.
Although this paper contributes to a better understanding of the alignment between the price of cetuximab and its observed efficacy in the Chinese healthcare setting, we feel that further clarifications of the authors’ methodological choices are warranted for transparency and replication purposes. Below are 5 important points for the autho...
Show MoreCORRECTION/DISCLAIMER. As of the date of publication of the study protocol for a randomised, double-blind, placebo-controlled study evaluating the efficacy of cannabis-based Medicine Extract in slowing the disease progression of Amyotrophic Lateral sclerosis or motor neurone disease: the EMERALD trial (the “Study”), CannTrust Inc. (“CannTrust”) had received a Notice of Licence Suspension pursuant to the Cannabis Act (Canada). The Notice states that Health Canada has suspended CannTrust's authority to produce cannabis, other than cultivating and harvesting, and to sell cannabis. As such, the Notice constitutes a partial suspension of the Company's licence for standard cultivation and a full suspension of its licences for standard processing, medical sales, cannabis drugs and research issued under the Cannabis regulations. As a result, the EMERALD trial will proceed with another licensed provider of cannabis-based medicine extract.
A recent article in The Times asks: "How will this play out in the next decade, as the first cohort on puberty blockers come to terms with their probable infertility? Such experimental paediatric medicine has been politicised and shrouded in secrecy for too long. It is time to ask serious questions.”1
In the spirit of asking serious questions of the RCHGS Trans20 study, we stand by our previous claims and respond to the author’s comments, which clearly misrepresented our concerns. Based on our reading of the data, we are of the view that gender-affirming interventions, be they psychosocial or medical, do not have an adequate evidence base to warrant their widespread use as routine medical care in children and adolescents. In fact, the paper’s authors acknowledge this lack of evidence and highlight the “urgent need for more evidence to ensure optimal medical and psychosocial interventions”.
In their response to our comments, the authors justify their claim that the Trans20 study is an observational study by referring to the NIH definition that an observational study is one in which “participants may receive interventions that are part of their routine medical care”. We do not agree that gender affirmative treatments, particularly medical interventions, constitute “routine medical care”, especially when there are only two small follow-up studies that report short term outcomes of young people who have undergone puberty blockade.2,3 This view is supported...
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