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Poor sleep has been considered as a risk of Alzheimer's disease incidence. Thomas et al. reported a protocol paper regarding the effect of long-term work-related poor sleep on cognition and amyloid accumulation in healthy middle-aged maritime pilots (1). The same authors reported some results in another journal (2). They investigated the effects of work-related sleep loss on subsequent cognitive impairment and early dementia symptoms in 50 male maritime pilots with a history of >25 years of work with irregular job schedules, which resulted in sleep loss. They concluded that long-term exposure to work-related sleep loss had no relation to subsequent cognitive decline or early dementia symptoms in retired maritime pilot. I have two concerns about their study.
First, Diem et al. examined the association between objective sleep-wake measures and risk of incident cognitive impairment (3). Longer average sleep efficiency and latency, but not total sleep time, were significantly associated with higher odds of developing cognitive impairment. They conducted a prospective study with average follow-up of 4.9 years, and risk assessment by longer follow-up is needed by considering sex, age and other factors.
Second, the authors cited a reference by kang et al. concerning the mechanism of the association between sleep and Alzheimer's disease in "Sleep Medicine Research", but this paper was retracted. I recommend a review of the same authors, which d...
Poor sleep has been considered as a risk of Alzheimer's disease incidence. Thomas et al. reported a protocol paper regarding the effect of long-term work-related poor sleep on cognition and amyloid accumulation in healthy middle-aged maritime pilots (1). The same authors reported some results in another journal (2). They investigated the effects of work-related sleep loss on subsequent cognitive impairment and early dementia symptoms in 50 male maritime pilots with a history of >25 years of work with irregular job schedules, which resulted in sleep loss. They concluded that long-term exposure to work-related sleep loss had no relation to subsequent cognitive decline or early dementia symptoms in retired maritime pilot. I have two concerns about their study.
First, Diem et al. examined the association between objective sleep-wake measures and risk of incident cognitive impairment (3). Longer average sleep efficiency and latency, but not total sleep time, were significantly associated with higher odds of developing cognitive impairment. They conducted a prospective study with average follow-up of 4.9 years, and risk assessment by longer follow-up is needed by considering sex, age and other factors.
Second, the authors cited a reference by kang et al. concerning the mechanism of the association between sleep and Alzheimer's disease in "Sleep Medicine Research", but this paper was retracted. I recommend a review of the same authors, which describes precise information with bidirectional association (4). In addition, Peter-Derex et al. summarized the relationship in combination with perspective and future direction of the research (5), especially long-term longitudinal studies on the relationship between chronic sleep deprivation and cognitive decline. Anyway, the effect of long-term poor sleep on cognitive decline should be specified by further studies.
References
1. Thomas J, Ooms S, Verbeek M, et al. Sleep-Cognition Hypothesis In maritime Pilots, what is the effect of long-term work-related poor sleep on cognition and amyloid accumulation in healthy middle-aged maritime pilots: methodology of a case-control study. BMJ Open 2019;9(6):e026992.
2. Thomas J, Overeem S, Claassen JAHR. Long-Term Occupational Sleep Loss and Post-Retirement Cognitive Decline or Dementia. Dement Geriatr Cogn Disord 2019;48(1-2):105-112.
3. Diem SJ, Blackwell TL, Stone KL, et al. Measures of sleep-wake patterns and risk of mild cognitive impairment or dementia in older women. Am J Geriatr Psychiatry 2016;24(3):248-258.
4. Kang DW, Lee CU, Lim HK. Role of sleep disturbance in the trajectory of Alzheimer's disease. Clin Psychopharmacol Neurosci 2017;15(2):89-99.
5. Peter-Derex L, Yammine P, Bastuji H, Croisile B. Sleep and Alzheimer's disease. Sleep Med Rev 2015;19:29-38.
Alexis Guillaume1, MD, Marc de Kock2, MD, PhD, Marco Ghignone3, MD, FRCPC, FCCP, Luc Quin-tin4, MD, PhD.
Anesthesia/Critical Care, Polyclinique de Franche Comté1, Besançon, France, Centre Hospitalier de Wallonie Picarde2, Tournai, Belgique, JF Kennedy North Hospital3, West Palm Beach, Florida, USA, Hôpital d’Instruction des Armées Desgenettes4, Lyon, France.
Correspondence: L Quintin, 120 Rue de la Pagère, 69500 Lyon-Bron, France, luc-quintinx@gmail.com
Beloeil et al [1] should be commended for addressing the postoperative side-effects of anesthesia without opioids («opioid free anesthesia»: OFA). Nevertheless,
1) The protocol is unclear to us: « Propofol 1.5-2 mg.kg-1, lidocaine 1.5 mg/kg…, ketamine 0.5 mg/kg…., cisatracurium 0.15 mg/kg…., dexamethasone 8 mg… and target-controlled infusion (TCI) of remifentanil (3–5 ng/mL) (control) or [our emphasis] intravenous dexmedetomidine 0.4–1.4 μg.kg-1» [1]. Does the control group receive lidocaine, ketamine and dexamethasone in addition to remifen-tanil? Would our understanding be correct, standard OFA [2] (alpha-2 agonist supplemented with multimodal non-opioid analgesics), is compared with opioid+multimodal anti-nociception. In this respect, enkephalins are one out of many transmitters involved in nociception [3]. Therefore, standard balanced anesthesia (hypnotic+myorelaxant+opioid) is to be compared to OFA (hypnot-ic+myorelaxant+multimodal nonopioid analgesi...
Alexis Guillaume1, MD, Marc de Kock2, MD, PhD, Marco Ghignone3, MD, FRCPC, FCCP, Luc Quin-tin4, MD, PhD.
Anesthesia/Critical Care, Polyclinique de Franche Comté1, Besançon, France, Centre Hospitalier de Wallonie Picarde2, Tournai, Belgique, JF Kennedy North Hospital3, West Palm Beach, Florida, USA, Hôpital d’Instruction des Armées Desgenettes4, Lyon, France.
Correspondence: L Quintin, 120 Rue de la Pagère, 69500 Lyon-Bron, France, luc-quintinx@gmail.com
Beloeil et al [1] should be commended for addressing the postoperative side-effects of anesthesia without opioids («opioid free anesthesia»: OFA). Nevertheless,
1) The protocol is unclear to us: « Propofol 1.5-2 mg.kg-1, lidocaine 1.5 mg/kg…, ketamine 0.5 mg/kg…., cisatracurium 0.15 mg/kg…., dexamethasone 8 mg… and target-controlled infusion (TCI) of remifentanil (3–5 ng/mL) (control) or [our emphasis] intravenous dexmedetomidine 0.4–1.4 μg.kg-1» [1]. Does the control group receive lidocaine, ketamine and dexamethasone in addition to remifen-tanil? Would our understanding be correct, standard OFA [2] (alpha-2 agonist supplemented with multimodal non-opioid analgesics), is compared with opioid+multimodal anti-nociception. In this respect, enkephalins are one out of many transmitters involved in nociception [3]. Therefore, standard balanced anesthesia (hypnotic+myorelaxant+opioid) is to be compared to OFA (hypnot-ic+myorelaxant+multimodal nonopioid analgesics: alpha-2 agonist, non-steroidal anti-inflammatory agents, ketamine, lidocaine, magnesium, etc.).
Alpha-2 agonists evoke reduced hypnotic requirement, anti-nociception, absence of respiratory de-pression. As anti-nociception is postulated from absence of tachycardia or hypertension (reflex de-pression [4], “protection neurovégétative” [5], suppression of the “somato-sympathetic reflex” [3]), comparing dexmedetomidine vs. remifentanil is “methodologically-correct” but clinically counterpro-ductive. Early trials were high dose opioid vs high dose opioid half-dose+clonidine [6], then balanced anesthesia+clonidine vs balanced anesthesia half-dose+clonidine [7]. This was simplified to clonidine vs clonidine+sufentanil «as needed» [8]. Additive properties between opioids and alpha-2 agonists lead to low heart rate and cardiac output [9], thus to unequal design.
As the absence of respiratory depression is one hallmark of OFA and as the postoperative period was studied, patients with sleep apnea syndrome were excluded, with no rationale.
2) No circulatory parameter is within the primary outcome. However, alpha-2 agonists are parasym-pathomimetics and sympathetic inhibitor in the healthy supine conscious volunteer and sympathetic deactivator in the setting of critical care and anesthesia, where sympathetic hyperactivity occurs.
3) Despite attempts to get the official reason for stopping the study from the promotor (Rennes Teaching Hospital, France) and the primary investigator, this rationale is unknown to us. Did severe bradycardia occur?
a) Bolus: Is high dose dex (0.4-1.4 µg.kg-1) i.v. bolus in addition to propofol high-dose (1.5-2 mg.kg-1) bolus relevant on induction? Both suppress pre-sympathetic motoneurons activity [10, 11], low-ering venous return with added positive pressure ventilation. In elderly, frail patients (Edmonton Frail scale), the dose of dex (here: 0.4-1.4 µg.kg-1) [1] has to be much lowered.
Clonidine was tested as a nasal decongestant to stimulate alpha-1 receptors [12]. In fact, it evoked prolonged sedation and hypotension/bradycardia [12], via alpha-2 receptors. When administered as a bolus, the alpha-2 agonist stimulates alpha-1 receptors leading to transient hypertension and as-sociated cardiac parasympathetic bradycardia (baroreflex-linked). Following dilution, alpha-2 recep-tors lead to cardiac and vasomotor sympathetic deactivation. Therefore, alpha-2 agonists were introduced in the ‘60s as centrally acting anti-hypertensives. In the operating room, bradycardia and hypotension (more accurately: normalized tachycardia and hypertension) are required to blunt the cardiac and vasomotor sympathetic hyperactivity evoked by surgery. Also, alpha-2 agonists sensitize the Bezold-Jarrisch reflex [13] with bradycardia/sinus pause, of relevance during coeli-oscopy or carotid surgery. An earlier trial in the setting of cardiac anesthesia, two decades ago, was stopped following sino-atrial block. Inadequate management [14, 15] leads to arrest.
Rather than using bolus injection, dex is most often used as an i.v. infusion over 20 min before in-duction. If bolus injection is selected, repeated small bolus of dex (10 µg i.v.), titrated-to-effect, lead to no side-effects (Guillaume, de Kock and Ghignone, unpublished data). Simpler, upfront oral [6, 7] and/or transdermal [16] alpha-2 agonists achieve a stable intraoperative course.
b) Volume: Filling pressure, diastolic or systolic performance are not addressed [1]. Volume load before induction in the presence of alpha-2 agonists [6] or intraoperative optimization based on pulse variation [17] are to be considered.
4) The surgery is not delineated («major or intermediate non-cardiac surgery» [1]), with issues: a) systemic lidocaine performs better in the setting of visceral rather than orthopedic surgery, with OFA to perform better in the visceral setting. Equal inclusion of patients with chronic pain is needed. b) should minor vs major [18] surgery be differentiated, to delineate clear-cut benefit/risk?
5) Preliminary « physiological » [19] or « pharmacological » trials should identify the salient criteria and refine the protocol, before engaging within multicentric randomized trials.
1. Beloeil H, Laviolle B, Menard C, Paugam-Burtz C, Garot M, Asehnoune K, et al. POFA trial study protocol: a multicentre, double-blind, randomised, controlled clinical trial comparing opioid-free versus opioid anaesthesia on postoperative opioid-related adverse events after major or intermediate non-cardiac surgery. BMJ Open 2018;8:e020873. DOI: 10.1136/bmjopen-2017-020873.
2. Mauermann E, Ruppen W, Bandschapp O. Different protocols used today to achieve total opioid-free general anesthesia without locoregional blocks. Best Pract Res Clin Anaesthesiol 2017;31:533-45. DOI: 10.1016/j.bpa.2017.11.003.
3. Cividjian A, Petitjeans F, Liu N, Ghignone M, de Kock M, Quintin L. Do we feel pain during anesthesia? A critical review on surgery-evoked circulatory changes and pain perception. Best Pract Res Clin Anaesthesiol 2017;31:445-67. DOI: 10.1016/j.bpa.2017.05.001.
4. Gray C. A reassessment of the signs and levels of anaesthesia. British Journal of Anaesthesia 1959;419:499-507. DOI: 10.1007/bf02951436.
5. Laborit H. La notion de "reaction oscillante post agressive". Therapie 1951;6:207-10.
6. Ghignone M, Quintin L, Duke PC, Kehler CH, Calvillo O. Effects of clonidine on narcotic requirements and hemodynamic response during induction of fentanyl anesthesia and endotracheal intubation. Anesthesiology 1986;64:36-42.
7. Ghignone M, Calvillo O, Quintin L. Anesthesia and Hypertension : the effect of clonidine on perioperative hemodynamics and isoflurane requirements. Anesthesiology 1987;67:3-10.
8. De Kock M, Wiederkehr P, Laghmiche A, Scholtes JL. Epidural clonidine used as the sole analgesic agent during and after abdominal surgery. Anesthesiology 1997;86:285-92.
9. Bourelli B, Bernard JM, Pinaud M, Lechevalier T, Bainvel JV. Additive effects of oral clonidine and fentanyl on isoflurane-induced hypotension : a double-blind randomized study. Anesthesiology 1988;69:A68.
10. Sun MK, Guyenet P. Effect of clonidine and gamma-aminobutyric acid on the discharges of medullo-spinal sympathoexcitatory neurons in the rat. Brain Research 1986;368:1-17.
11. Krassioukov AV, Gelb AW, Weaver LC. Action of propofol on central sympathetic mechanisms controlling blood pressure. Can J Anaesth 1993;40:761-9. DOI: 10.1007/BF03009773.
12. Stahle H. A historical perspective: development of clonidine. Bailliere's Clinical Anaesthesiology 2000;14:236-46. DOI: 10.1053/bean.2000.0079.
13. Harron DWG, Kobinger W. Facilitation of the Bezold-Jarisch reflex by central stimulation of alpha-2 adrenoceptors in dogs. Naunyn-Schmiedeberg's Archives of Pharmacology 1984;325:193-7.
14. Ingersoll-Weng E, Manecke GRTPA. Dexmedetomidine and cardiac arrest. Anesthesiology 2004;100:738-9.
15. Talke PO, Maze M. Expecting the unexpected. Anesth Analg 2008;106:1605-6. DOI: 10.1213/ane.0b013e31816c3f69.
16. Segal IS, Jarvis DJ, Duncan SR, White PF, Maze M. Clinical efficacy of oral-transdermal clonidine combination during the perioperative period. Anesthesiology 1991;74:220-5.
17. Forget P, Lois F, de Kock M. Goal-directed fluid management based on the pulse oximeter-derived pleth variability index reduces lactate levels and improves fluid management. Anesth Analg 2010;111:910-4. DOI: 10.1213/ANE.0b013e3181eb624f.
18. Oliver MF, Goldman L, Julian DG, Holme I. Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary disease. Anesthesiology 1999;91:951-61.
19. Dreyfuss D. Should we continue to make randomised studies? Rev Mal Respir 2005;22:381-5. Faut-il continuer a faire des etudes randomisees?
1. We were rather concerned to learn of your confusion regarding our reasons for stopping the COMPACT-2 trial. We will try to better clarify what happened. In our report communicating our intention to interrupt the trial, we openly reported the results of our interim analysis, which were also summarized in our comment to your paper. We reiterate that we observed a close to significant difference in the trial’s primary endpoint (last hospital mortality), suggesting higher mortality in patients randomized to CPFA (59.6% vs. 41.3%; p=0.076). We observed significantly higher 3-day mortality in patients randomized to CPFA (32.8% vs. 12.5%; p=0.02). We observed higher mortality in the CPFA group at the survival analysis performed in the first 90 days after randomization (Log Rank test, p=0.03; Pet test, p=0.01). On the basis of these results, we concluded that: “The interim analysis requested by the EDSMC shows higher mortality for the CPFA group compared to the controls, particularly in the first days of treatment. Although the absolute number of treated patients is relatively small, the results raise concern that the use of CPFA may cause harm or worsen the clinical condition of septic shock patients”. In our understanding, the aim of this conclusion was to report exactly what we observed (significantly higher mortality in the CPFA group, particularly in the first days of treatment), while underlining th...
1. We were rather concerned to learn of your confusion regarding our reasons for stopping the COMPACT-2 trial. We will try to better clarify what happened. In our report communicating our intention to interrupt the trial, we openly reported the results of our interim analysis, which were also summarized in our comment to your paper. We reiterate that we observed a close to significant difference in the trial’s primary endpoint (last hospital mortality), suggesting higher mortality in patients randomized to CPFA (59.6% vs. 41.3%; p=0.076). We observed significantly higher 3-day mortality in patients randomized to CPFA (32.8% vs. 12.5%; p=0.02). We observed higher mortality in the CPFA group at the survival analysis performed in the first 90 days after randomization (Log Rank test, p=0.03; Pet test, p=0.01). On the basis of these results, we concluded that: “The interim analysis requested by the EDSMC shows higher mortality for the CPFA group compared to the controls, particularly in the first days of treatment. Although the absolute number of treated patients is relatively small, the results raise concern that the use of CPFA may cause harm or worsen the clinical condition of septic shock patients”. In our understanding, the aim of this conclusion was to report exactly what we observed (significantly higher mortality in the CPFA group, particularly in the first days of treatment), while underlining that that this could not be taken as definitive evidence of the harmful effect of CPFA. Indeed, the second sentence of our conclusion (not reported in your citation) clearly acknowledges that we did not consider these results to be conclusive. In summary, we collected evidence of potential harm associated with the use of CPFA in patients with septic shock. For this reason, we prematurely stopped the trial for futility, acknowledging, by openly presenting the results, the possibility that the treatment might have harmful effects. We did not use the term “futility” in our communication but, when you stop a trial due to suspicion of a harmful effect, futility is out of the question.
4. We are happy you agree that excluding from the analysis the patients assigned to the experimental arm who died before receiving the treatment, would have introduced an important bias. Indeed, our comment referred to a couple of sentences in your paper, specifically: “Since a significant number of patients died in the first 3 days and were unable to receive the technique (n=3, 15.8%) we decided to perform the analysis by actual intervention received (AIR). Although this analysis was not initially planned (clinicaltrials.gov), the fact that one out of six patients did not receive the intervention necessitated it”; and “if what we are considering is the potential harmfulness of the technique in a non-prespecified subgroup of an underpowered sample size, we cannot ignore the fact that the technique was not applied”. These sentences probably misled us. We firmly support the “intention-to-treat” approach in trial analysis and, along with many statisticians and methodologists, assign the “treatment received” or “protocol adherence” approaches to limited, specific situations, or to the assessment of the effects of protocol violations.
5. We are pleased to hear that you do not feel our communication forced you to stop your trial. By letting you know about our results and decisions even before any official communication, it was our intention to act in the framework of the data sharing principle.
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.
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.
Poor sleep has been considered as a risk of Alzheimer's disease incidence. Thomas et al. reported a protocol paper regarding the effect of long-term work-related poor sleep on cognition and amyloid accumulation in healthy middle-aged maritime pilots (1). The same authors reported some results in another journal (2). They investigated the effects of work-related sleep loss on subsequent cognitive impairment and early dementia symptoms in 50 male maritime pilots with a history of >25 years of work with irregular job schedules, which resulted in sleep loss. They concluded that long-term exposure to work-related sleep loss had no relation to subsequent cognitive decline or early dementia symptoms in retired maritime pilot. I have two concerns about their study.
First, Diem et al. examined the association between objective sleep-wake measures and risk of incident cognitive impairment (3). Longer average sleep efficiency and latency, but not total sleep time, were significantly associated with higher odds of developing cognitive impairment. They conducted a prospective study with average follow-up of 4.9 years, and risk assessment by longer follow-up is needed by considering sex, age and other factors.
Second, the authors cited a reference by kang et al. concerning the mechanism of the association between sleep and Alzheimer's disease in "Sleep Medicine Research", but this paper was retracted. I recommend a review of the same authors, which d...
Show MoreAlexis Guillaume1, MD, Marc de Kock2, MD, PhD, Marco Ghignone3, MD, FRCPC, FCCP, Luc Quin-tin4, MD, PhD.
Anesthesia/Critical Care, Polyclinique de Franche Comté1, Besançon, France, Centre Hospitalier de Wallonie Picarde2, Tournai, Belgique, JF Kennedy North Hospital3, West Palm Beach, Florida, USA, Hôpital d’Instruction des Armées Desgenettes4, Lyon, France.
Correspondence: L Quintin, 120 Rue de la Pagère, 69500 Lyon-Bron, France, luc-quintinx@gmail.com
Beloeil et al [1] should be commended for addressing the postoperative side-effects of anesthesia without opioids («opioid free anesthesia»: OFA). Nevertheless,
1) The protocol is unclear to us: « Propofol 1.5-2 mg.kg-1, lidocaine 1.5 mg/kg…, ketamine 0.5 mg/kg…., cisatracurium 0.15 mg/kg…., dexamethasone 8 mg… and target-controlled infusion (TCI) of remifentanil (3–5 ng/mL) (control) or [our emphasis] intravenous dexmedetomidine 0.4–1.4 μg.kg-1» [1]. Does the control group receive lidocaine, ketamine and dexamethasone in addition to remifen-tanil? Would our understanding be correct, standard OFA [2] (alpha-2 agonist supplemented with multimodal non-opioid analgesics), is compared with opioid+multimodal anti-nociception. In this respect, enkephalins are one out of many transmitters involved in nociception [3]. Therefore, standard balanced anesthesia (hypnotic+myorelaxant+opioid) is to be compared to OFA (hypnot-ic+myorelaxant+multimodal nonopioid analgesi...
Show MoreDear colleagues,
We would like to respond to your comments.
1. We were rather concerned to learn of your confusion regarding our reasons for stopping the COMPACT-2 trial. We will try to better clarify what happened. In our report communicating our intention to interrupt the trial, we openly reported the results of our interim analysis, which were also summarized in our comment to your paper. We reiterate that we observed a close to significant difference in the trial’s primary endpoint (last hospital mortality), suggesting higher mortality in patients randomized to CPFA (59.6% vs. 41.3%; p=0.076). We observed significantly higher 3-day mortality in patients randomized to CPFA (32.8% vs. 12.5%; p=0.02). We observed higher mortality in the CPFA group at the survival analysis performed in the first 90 days after randomization (Log Rank test, p=0.03; Pet test, p=0.01). On the basis of these results, we concluded that: “The interim analysis requested by the EDSMC shows higher mortality for the CPFA group compared to the controls, particularly in the first days of treatment. Although the absolute number of treated patients is relatively small, the results raise concern that the use of CPFA may cause harm or worsen the clinical condition of septic shock patients”. In our understanding, the aim of this conclusion was to report exactly what we observed (significantly higher mortality in the CPFA group, particularly in the first days of treatment), while underlining th...
Show MoreWe 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...
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