With great interest, I have read the review article entitled “Efficacy of mirror therapy and virtual reality therapy in alleviating phantom limb pain: a meta-analysis and systematic review” written by Rajendram et al (1). The authors conducted a meta-analysis to evaluate the effects of mirror therapy (MT) and virtual reality (VR) therapy on phantom limb pain (PLP). Both therapies led to a reduction of visual analogue scale (VAS) scores on PLP, and there was no statistically significant difference in pain alleviation between two therapies. The authors recommended that factors such as gender, cause of amputation, site of limb loss or length of time from amputation should be considered for the analysis. I present additional information regarding the effect of MT on PLP.
Wang et al. also conducted a meta-analysis, handling randomized controlled trials (RCTs) (2). The pooled standardized mean difference (SMD) (95% confidence interval [CI]) of MT group was -0.81 (-1.36 to -0.25), which was compared with other 6 methods (four covered mirror, one phantom exercise, three mental visualization, one sensorimotor exercise, one transcutaneous electrical nerve stimulation, and one tactile stimuli). They concluded that MT was beneficial for reducing phantom limb pain. There is a fact that the authors did not consider follow-up intervals, and a control group was consisted a complex of traditional treatments for patients with PLP. I suppose that heterogeneous treatments may have diff...
With great interest, I have read the review article entitled “Efficacy of mirror therapy and virtual reality therapy in alleviating phantom limb pain: a meta-analysis and systematic review” written by Rajendram et al (1). The authors conducted a meta-analysis to evaluate the effects of mirror therapy (MT) and virtual reality (VR) therapy on phantom limb pain (PLP). Both therapies led to a reduction of visual analogue scale (VAS) scores on PLP, and there was no statistically significant difference in pain alleviation between two therapies. The authors recommended that factors such as gender, cause of amputation, site of limb loss or length of time from amputation should be considered for the analysis. I present additional information regarding the effect of MT on PLP.
Wang et al. also conducted a meta-analysis, handling randomized controlled trials (RCTs) (2). The pooled standardized mean difference (SMD) (95% confidence interval [CI]) of MT group was -0.81 (-1.36 to -0.25), which was compared with other 6 methods (four covered mirror, one phantom exercise, three mental visualization, one sensorimotor exercise, one transcutaneous electrical nerve stimulation, and one tactile stimuli). They concluded that MT was beneficial for reducing phantom limb pain. There is a fact that the authors did not consider follow-up intervals, and a control group was consisted a complex of traditional treatments for patients with PLP. I suppose that heterogeneous treatments may have different effects on PLP improvement, and VR therapy should also be considered to compare with MT therapy.
Regarding follow-up intervals, Xie et al. conducted a meta-analysis to evaluate the effectiveness of MT for PLP, handling a total of 10 RCTs (3). Stratified analysis by follow-up intervals (1, 3, 6, and 12 months) was used for PLP evaluation. The SMD (95% CI) of MT group against control group for PLP score was -0.46 (-0.79 to -0.13) within 1 month. Although the SMD (95% C) of MT group for longer than 1 year was -0.46 (-0.85 to -0.07), there was no significant SMD between MT and control group within 1-year posttreatment. Although they concluded that MT for patients with long-term PLP might be an effective treatment, adequate explanation for the lack of significance in reducing PLP was not presented for patients with MT within 1-year posttreatment.
Severity of PLP may be related to subsequent prognosis by MT, and additional studies are needed for keeping stable estimates by a meta-analysis.
References
1. Rajendram C, Ken-Dror G, Han T, et al. Efficacy of mirror therapy and virtual reality therapy in alleviating phantom limb pain: a meta-analysis and systematic review. BMJ Mil Health 2022;168(2):173-177.
2. Wang F, Zhang R, Zhang J, et al. Effects of mirror therapy on phantom limb sensation and phantom limb pain in amputees: A systematic review and meta-analysis of randomized controlled trials. Clin Rehabil 2021;35(12):1710-1721.
3. Xie HM, Zhang KX, Wang S, et al. Effectiveness of mirror therapy for phantom limb pain: A systematic review and meta-analysis. Arch Phys Med Rehabil 2022;103(5):988-997.
Dear Editor
We read with interest the comments made by Cooper et al to our paper comparing experiences and mental health of personnel who joined service as junior entrants compared to adult entrants. Participants in the King's Centre for Military Health Research (KCMHR) cohort study were sampled from the trained and, consequently, deployable strength of the UK Armed Forces (UKAF) since the primary purpose of the cohort study was to measure the health consequences of deployment to Iraq and Afghanistan[1]. The participants were not sampled from personnel at recruitment but on the basis of their deployment to Iraq or Afghanistan. We had no data about individuals who joined service at the same time but who did not remain in service until the time of sampling and this is a fully acknowledged limitation in the paper. We have no evidence that there may have been differential attrition on the basis of mental health between the comparison groups. Those who joined before 2003 could represent a sub sample of particularly successful personnel (both those who joined as Junior Entrants and those who joined as adults). That is why we carried out a subgroup analysis of the smaller number of participants who had joined the trained strength after 2003 (the replenishment samples). In that analysis there were some significant associations that are of concern, but PTSD and common mental disorders were not, as suggested, among them as they were far from being statistically significan...
Dear Editor
We read with interest the comments made by Cooper et al to our paper comparing experiences and mental health of personnel who joined service as junior entrants compared to adult entrants. Participants in the King's Centre for Military Health Research (KCMHR) cohort study were sampled from the trained and, consequently, deployable strength of the UK Armed Forces (UKAF) since the primary purpose of the cohort study was to measure the health consequences of deployment to Iraq and Afghanistan[1]. The participants were not sampled from personnel at recruitment but on the basis of their deployment to Iraq or Afghanistan. We had no data about individuals who joined service at the same time but who did not remain in service until the time of sampling and this is a fully acknowledged limitation in the paper. We have no evidence that there may have been differential attrition on the basis of mental health between the comparison groups. Those who joined before 2003 could represent a sub sample of particularly successful personnel (both those who joined as Junior Entrants and those who joined as adults). That is why we carried out a subgroup analysis of the smaller number of participants who had joined the trained strength after 2003 (the replenishment samples). In that analysis there were some significant associations that are of concern, but PTSD and common mental disorders were not, as suggested, among them as they were far from being statistically significant. Your criticism that our paper does not have the same distribution for some military- demographic variables as the UKAF quarterly statistically is not relevant for our analysis because the individuals in the comparison groups were selected in the same way and we adjusted for potential confounders such as rank, service and age in the analysis. We hope that you will agree with us that our paper marks progress in the issue of junior recruitment because, at last, we have scientific data rather than anecdotes and impressions on this important topic.
Thank you for publishing the Rapid Response to our paper by Cooper et al. The authors agree with our findings that junior entrants to the Armed Forces have a lower risk of developing a severe mental health disorder compared with older entrants, but have noted that we found that all veterans were more likely to develop mental disorders (especially PTSD) then matched non-veterans.
The increased risk of mental health disorders in veterans overall compared with non-veterans is not a new observation. In our 2016 paper(1) we showed that overall, veterans were at 21% overall increased risk of having experienced mental ill-health compared with matched non-veterans, whilst Goodwin et al.(2) showed that serving personnel had more than double the odds of common mental disorders compared with a general population sample. In our 2016 paper we showed that the risk in veterans is highest in those with the shortest service; Early Service Leavers (ESL) were at 51% increased risk, whilst those with more than 9 years’ service were at no greater risk than the comparison population. ESL who did not complete training, and who could not have deployed operationally, had the highest risk; it is likely that their mental health outcomes (including PTSD) arose predominantly from pre-service vulnerabilities. In our new study, we showed that junior entrants were less likely to be ESL (a finding supported by a House of Commons Written Answer on length of service of junior...
Thank you for publishing the Rapid Response to our paper by Cooper et al. The authors agree with our findings that junior entrants to the Armed Forces have a lower risk of developing a severe mental health disorder compared with older entrants, but have noted that we found that all veterans were more likely to develop mental disorders (especially PTSD) then matched non-veterans.
The increased risk of mental health disorders in veterans overall compared with non-veterans is not a new observation. In our 2016 paper(1) we showed that overall, veterans were at 21% overall increased risk of having experienced mental ill-health compared with matched non-veterans, whilst Goodwin et al.(2) showed that serving personnel had more than double the odds of common mental disorders compared with a general population sample. In our 2016 paper we showed that the risk in veterans is highest in those with the shortest service; Early Service Leavers (ESL) were at 51% increased risk, whilst those with more than 9 years’ service were at no greater risk than the comparison population. ESL who did not complete training, and who could not have deployed operationally, had the highest risk; it is likely that their mental health outcomes (including PTSD) arose predominantly from pre-service vulnerabilities. In our new study, we showed that junior entrants were less likely to be ESL (a finding supported by a House of Commons Written Answer on length of service of junior entrants)(3), which is further consistent with our finding that they were at lower risk than older entrants.
We noted in our Discussion that we had found an increased risk of PTSD in the 1975-1985 birth cohort, irrespective of age at entry, and that it remains unexplained. In other work (unpublished) we have found that many of those affected had already left service prior to the start of operations in Afghanistan and Iraq. Bosnia and Kosovo remain possible factors, although there are also other factors which may have been operating at that time. We agree that it is of concern, and work on this remains in progress.
We fully accept that junior entrants may be susceptible to adverse mental health outcomes, as may any member of the Armed Forces or indeed the wider community, however the aim of our paper was to demonstrate that their risk was not disproportionately increased by having joined the Armed Forces as a junior entrant.
1. Bergman BP, Mackay DF, Smith DJ, Pell JP. Long-term mental health outcomes of military service: National linkage study of 57,000 veterans and 173,000 matched nonveterans. J Clin Psychiatry. 2016;77(6):793-8.
2. Goodwin L, Wessely S, Hotopf M, Jones M, Greenberg N, Rona R, et al. Are common mental disorders more prevalent in the UK serving military compared to the general working population? Psychol Med. 2015:1-11.
3. Soubry A. Army: Length of service. In: Commons Ho, editor.: Hansard; 2014. p. 809W.
Margaret Jones and colleagues’ study of armed forces personnel concluded that, for the study cohort as a whole, those who had joined up under the age of 17.5 years (‘junior entrants’) were no more likely than those who enlisted at older ages to report symptoms of mental health disorders. However, the study also found that junior entrants who had enlisted since 2003 showed significantly higher rates of alcohol misuse, somatic symptoms, and a lifetime history of self-harm, relative to older recruits. The study’s data further suggests that PTSD and common mental disorders may also be more prevalent among younger enlistees since 2003, although this is not statistically significant.
In recent decades, protections for armed forces recruits who are legally children have improved, including a legal prohibition on deployment to zones since 2002. Despite these developments, this study’s findings indicate continuing reason to be concerned about the impact of early enlistment on long-term mental health. It could be relevant that, as this study has shown, once junior entrants turn 18 and may be deployed, they are more likely to be in a combat role such as the frontline infantry.
Furthermore, the study sample may not reflect the relevant population accurately. Comparing Table 1 with UK armed forces quarterly personnel statistics,(1) higher-ranked personnel appear to be over-represented in the study sample, while those with the lowest ranks are under-repr...
Margaret Jones and colleagues’ study of armed forces personnel concluded that, for the study cohort as a whole, those who had joined up under the age of 17.5 years (‘junior entrants’) were no more likely than those who enlisted at older ages to report symptoms of mental health disorders. However, the study also found that junior entrants who had enlisted since 2003 showed significantly higher rates of alcohol misuse, somatic symptoms, and a lifetime history of self-harm, relative to older recruits. The study’s data further suggests that PTSD and common mental disorders may also be more prevalent among younger enlistees since 2003, although this is not statistically significant.
In recent decades, protections for armed forces recruits who are legally children have improved, including a legal prohibition on deployment to zones since 2002. Despite these developments, this study’s findings indicate continuing reason to be concerned about the impact of early enlistment on long-term mental health. It could be relevant that, as this study has shown, once junior entrants turn 18 and may be deployed, they are more likely to be in a combat role such as the frontline infantry.
Furthermore, the study sample may not reflect the relevant population accurately. Comparing Table 1 with UK armed forces quarterly personnel statistics,(1) higher-ranked personnel appear to be over-represented in the study sample, while those with the lowest ranks are under-represented. Also, the average career length in the sample is longer than a typical army career indicated by official data.(2) Hence the sample appears to be skewed towards long-career, well-promoted personnel. This could matter to the study’s conclusions, since junior entrants are more likely than older recruits to drop out of initial army training,(3) and early dropout is associated with mental health disorders.(4)
(3) For details, refer to House of Commons Defence Committee, ‘Written evidence submitted by Child Rights International Network to the Select Committee on the Armed Forces Bill’, 2021, https://committees.parliament.uk/writtenevidence/23832/pdf/, paragraphs 5.1 and 9.1.
(4) Buckman, J. E., Forbes, H. J., Clayton, T., et al., (2013, June). ‘Early Service leavers: a study of the factors associated with premature separation from the UK Armed Forces and the mental health of those that leave early’. European Journal of Public Health (Early EPub release 25 April 2012), 23(3), 410-415.
Dr. Bergman and colleagues’ retrospective cohort study of armed forces veterans in Scotland concluded that their study ‘provides no evidence to support the assertion that early entry to military service is associated with adverse long-term mental health outcomes’ and that concerns about early enlistment are ‘misplaced’ (p. 5).
This conclusion is justified on the grounds that junior entrants into the armed forces (below the age of 17.5) were found to have had a lower risk of developing a severe mental health disorder when compared to those recruited between the ages of 17.5 and 19; or between the ages of 20 and 24.
However, all veterans, including those who joined as junior entrants, were significantly more likely to develop mental disorders (especially PTSD) when compared to matched non-veterans. In addition, for the cohort of veterans born between 1975 and 1984, the data suggests that junior entrants have a higher risk of presenting with mental health disorders when compared to older recruits, although this is not statistically significant (Table 1). This cohort is important because it is associated with the multiple major combat deployments to Bosnia, Kosovo, Afghanistan and Iraq.
For these reasons, while modern day junior entrants to the armed forces in the UK are better protected when compared to ‘child soldiers’ in other countries, or to junior entrants from previous eras, concerns about their vulnerability to mental illness are...
Dr. Bergman and colleagues’ retrospective cohort study of armed forces veterans in Scotland concluded that their study ‘provides no evidence to support the assertion that early entry to military service is associated with adverse long-term mental health outcomes’ and that concerns about early enlistment are ‘misplaced’ (p. 5).
This conclusion is justified on the grounds that junior entrants into the armed forces (below the age of 17.5) were found to have had a lower risk of developing a severe mental health disorder when compared to those recruited between the ages of 17.5 and 19; or between the ages of 20 and 24.
However, all veterans, including those who joined as junior entrants, were significantly more likely to develop mental disorders (especially PTSD) when compared to matched non-veterans. In addition, for the cohort of veterans born between 1975 and 1984, the data suggests that junior entrants have a higher risk of presenting with mental health disorders when compared to older recruits, although this is not statistically significant (Table 1). This cohort is important because it is associated with the multiple major combat deployments to Bosnia, Kosovo, Afghanistan and Iraq.
For these reasons, while modern day junior entrants to the armed forces in the UK are better protected when compared to ‘child soldiers’ in other countries, or to junior entrants from previous eras, concerns about their vulnerability to mental illness are not entirely misplaced.
The paper by Dr Schmidt details the history of the first independent Research Ethics Committee (REC) at Porton Down in the 1960’s. This REC was created to address ethical and legal concerns about research on human subjects. Since the 1960’s the emphasis has rightly shifted from “the doctor/scientist is always right” to “the participants must be protected from any unnecessary harms”. This has led to an expansion of the ethics review process and level of scrutiny, which has left many junior researchers feeling frustrated when their plans are criticised or delayed.
This letter will list some advice for junior researchers in the Defence Medical Services on how to navigate the process and improve the quality of their research and the chance of a successful ethical approval for research involving human participants:
1. First, use the NHS Health Research Authority tool to confirm that your study design is research and that it requires ethical approval.
2. Read JSP 536 Pt 1 (48 pages) and 2 (64 pages).
3. Be familiar with the main tenets of medical ethics - respect for autonomy, beneficence, non-maleficence, justice and equipoise.
4. Involve patients and other stakeholders in the design of the study.
5. Do not underestimate the time required, it may take six to 12 months.
6. Be resilient and ensure you have support. It will be stressful.
7. The REC process is a combination of prestigious journal submission and viv...
The paper by Dr Schmidt details the history of the first independent Research Ethics Committee (REC) at Porton Down in the 1960’s. This REC was created to address ethical and legal concerns about research on human subjects. Since the 1960’s the emphasis has rightly shifted from “the doctor/scientist is always right” to “the participants must be protected from any unnecessary harms”. This has led to an expansion of the ethics review process and level of scrutiny, which has left many junior researchers feeling frustrated when their plans are criticised or delayed.
This letter will list some advice for junior researchers in the Defence Medical Services on how to navigate the process and improve the quality of their research and the chance of a successful ethical approval for research involving human participants:
1. First, use the NHS Health Research Authority tool to confirm that your study design is research and that it requires ethical approval.
2. Read JSP 536 Pt 1 (48 pages) and 2 (64 pages).
3. Be familiar with the main tenets of medical ethics - respect for autonomy, beneficence, non-maleficence, justice and equipoise.
4. Involve patients and other stakeholders in the design of the study.
5. Do not underestimate the time required, it may take six to 12 months.
6. Be resilient and ensure you have support. It will be stressful.
7. The REC process is a combination of prestigious journal submission and viva examination; preparation is the best anxiolytic.
8. Ensure you use the correct application form.
9. Always check for basic errors before asking your co-researchers and supervisor to double-check.
10. Most reviewers are empathetic and want to approve good studies but be prepared for concerns to be raised.
11. Accept that your draft can always be improved whether those are amendments from your colleagues or the REC. Acknowledge contradictory advice, be polite and justify your reasoning for any changes or omissions.
12. Ask your colleagues to prepare you for the hearing by challenging your study design, to destruction if necessary.
13. Research the REC members and know their ethical interests.
14. The panel may consist of as many as 20 members. You can ask your team to attend with you.
15. Treat the hearing as a job interview or court appearance. Arrive early, dress professionally and be polite for the full 30 minutes, no matter how adversarial the questions.
16. The REC outcome will be in writing and it will almost always require amendments before approval. It is good practice to use the REC response as a template in your formal reply. Respond to each issue with the detail of the amendment or a justification for ignoring it.
17. Receiving ethical approval is only the start. You now have an ethical duty to complete the research and report you results to the REC.
18. Good luck.
The report on vitamin C for preventing the common cold in the Republic of South Korea army recruits by Kim et al. [1] has several statistical problems.
First, Kim et al. did not follow the intention-to-treat [ITT] approach. Figure 1 shows that 49 participants were excluded because they “stopped intake of vitamin C”, and 84 participants were excluded because they “stopped intake of placebo” [1]. The CONSORT recommendation for ITT analysis states as follows [2, Box 6]: “participants who … did not take all the intended treatment ... exclusion of any participants for such reasons is incompatible with intention-to-treat analysis”.
Second, Altman et al. pointed out that “The odds ratio should not be interpreted as an approximate relative risk [RR] unless the events are rare in both groups (say, less than 20-30%)”[3]. The common cold is not rare. Over 50% of the participants in the Kim et al. trial had the common cold during the trial period which greatly exceeds the 20-30% limit. Furthermore, there is no need to use the OR as the approximation for RR, because the RR can be calculated from the trial data in Table 1, RR = 0.916 (= 0.538/0.587) [1].
Third, in their abstract, Kim et al. wrote “the vitamin C group had a 0.80-fold lower risk of getting a common cold” implying that vitamin C decreased the incidence of colds by 20%. However, the correct effect estimate is given by the RR above, which indicates only 8.4% lower risk of colds in the vitamin C group....
The report on vitamin C for preventing the common cold in the Republic of South Korea army recruits by Kim et al. [1] has several statistical problems.
First, Kim et al. did not follow the intention-to-treat [ITT] approach. Figure 1 shows that 49 participants were excluded because they “stopped intake of vitamin C”, and 84 participants were excluded because they “stopped intake of placebo” [1]. The CONSORT recommendation for ITT analysis states as follows [2, Box 6]: “participants who … did not take all the intended treatment ... exclusion of any participants for such reasons is incompatible with intention-to-treat analysis”.
Second, Altman et al. pointed out that “The odds ratio should not be interpreted as an approximate relative risk [RR] unless the events are rare in both groups (say, less than 20-30%)”[3]. The common cold is not rare. Over 50% of the participants in the Kim et al. trial had the common cold during the trial period which greatly exceeds the 20-30% limit. Furthermore, there is no need to use the OR as the approximation for RR, because the RR can be calculated from the trial data in Table 1, RR = 0.916 (= 0.538/0.587) [1].
Third, in their abstract, Kim et al. wrote “the vitamin C group had a 0.80-fold lower risk of getting a common cold” implying that vitamin C decreased the incidence of colds by 20%. However, the correct effect estimate is given by the RR above, which indicates only 8.4% lower risk of colds in the vitamin C group. Thus, using the OR as an inappropriate measure of effect gave a 2.4-fold multiplication of the actual percentage benefit from vitamin C administration. Furthermore, Table 1 shows that the 8.4% difference between the vitamin C and placebo groups was not statistically significant with P = 0.059 [1].
Fourth, standard textbooks on controlled trials are critical about adjustments of the effect estimate by numerous baseline variables, since “it is often possible to select specific covariates out of a large set in order to achieve a desired result” [4, p. 368]. Kim et al. used 15 variables to adjust the effect of vitamin C in their Table 2 [1]. Furthermore, 4 of those 15 variables were not baseline variables, as they were determined at the end of the trial: 1) “Do you think vitamin C intake helps prevent diseases such as a common cold? (End point)”, 2) “Do you prefer to take vitamin C? (End point)”, 3) “Did you experience physical vitality such as decreased fatigue after taking vitamin C? (End point)” and 4) “Intent to continue intake Vitamin C”. Therefore, they are unambiguously inappropriate to be used as baseline adjustment variables. Thus, the marginally significant P-value calculated for the over-adjusted statistical model in Table 2 (P = 0.0419) is statistically much less sound than the non-significant P-value calculated in Table 1 (P = 0.059) [1].
Fifth, at the start of the trial, Kim asked the participants the question: “Do you think vitamin C intake helps prevent diseases such as common cold?” and 1098 participants agreed or strongly agreed. At the end of the trial, only 320 participants agreed or strongly agreed in response to the same question. Thus, participation in the one-month trial led to a 71% decline in the opinion that vitamin C might prevent diseases such as the common cold. Half of the participants were given placebo and if all the placebo participants had lost their belief in vitamin C because of their personal experience of not getting any benefit, that would explain a decrease by only 50%. This implies that a great proportion of the vitamin C participants also changed their mind when they had actually taken 6 g/day of vitamin C for 30 days.
In parallel with the dramatic decline in the “agree” responses, there was an even more dramatic increase in the “disagree” responses to the same question. At the end of the trial, the “disagree” responses were 12 times higher than at the start (365 vs. 30) and the “strongly disagree” responses were 33 times higher than at the start (236 vs. 7) [1]. These dramatic changes towards negative opinions after having taken high doses of vitamin C for one month were not discussed by Kim et al.
Sixth, in the text section, the first paragraph of the Results, Kim et al. wrote “895 subjects were smokers …... 99 subjects were never smokers”. However, Table 1 states “never smoker: 895” and “former smoker: 99” and there is no category for current smokers in that table [1]. Evidently, one of those has been transposed but we do not know which one. The confusion in the smoking classification also makes the reader doubt the validity of the statement that the effect of vitamin C was stronger “among never smokers”. Does that refer to 99 or to 895 participants?
Finally, Kim et al. do not describe the background of the topic in sufficient detail to highlight the nuances of those findings. In 1996, a meta-analysis of 3 trials with 475 participants under short-term acute physical stress calculated that vitamin C decreased the risk of the common cold by RR = 0.50 (95% CI 0.35-0.69, P = 0.00003) [5]. Two later trials with similar participants found consistent results so that, after the inclusion of the two later trials, the estimate of effect was RR = 0.48 [6].
The 1996 paper stated [5] “One study was identified in which the experimental conditions are quite close to those in the [three] studies ... Pitt and Costrini carried out a randomized double-blind study with military recruits in a training camp in South Carolina [7]. They administered 2 g/day of vitamin C to the study group, but there was no difference (0%) in common cold incidence when compared to the placebo group. There were over 1200 common cold episodes in the study… and thus this study has great weight as regards the possible role of vitamin C in subjects under heavy stress. Nevertheless, there are several noteworthy differences between the Pitt and Costrini study and the three studies... Pitt and Costini's subjects were under a regular training program, the study lasted for 2 months and, furthermore, the tablet administration did not begin until their third week at the training camp. In contrast, the subjects of the [three] studies ... were under acute and unusual stress and the studies lasted for just few weeks”.
The Pitt and Costrini trial with US Marine recruits was large and recorded 1219 common cold episodes. The confidence interval around the null effect was very narrow with RR = 1.00 (95% CI: 0.90-1.12) [7,8]. This negative result with the narrow confidence interval is inconsistent with universal benefits of vitamin C supplementation for army recruits, but the US Marine recruit study was dismissed by Kim et al. Although there is strong evidence that vitamin C decreases common cold incidence in people under short-term physical stress [5,6], that benefit does not seem to extend substantially to conditions of long-term physical stress. Possibly the body may adapt more efficiently to regular stress than to acute stress [5].
We read with interest the article by Bayoumy et al. concerning the effects of hyperbaric oxygen therapy (HBOT) associated with corticosteroid therapy in military personnel with acute acoustic trauma1. This paper helps to discuss about the most appropriate treatment of sudden deafness (SD). As recently stated, a spontaneous recovery, in the general population, is less than 40%. The precise role of HBOT has not yet been clearly established2. Our clinical experience during the last 15 years in a second referral hyperbaric center indicates the need of clear guide-lines, for the treatment of this acute disease. Nowadays there are two main therapeutic approaches to SD of different origin, the corticosteroid medication and HBOT.
Clearly, at first, it has to be ascertained the nature of a deafness excluding, cerebral diseases, vascular, traumatic and neoplastic. A subsequent otolaryngology evaluation enables to ascertain possible associated vestibular diseases, and to measure Pure Tone Average. Medical contraindications to HBOT and corticosteroids medication have to be excluded. An early treatment, not beyond the first 48 hours after the acute event is recommended 1. Today the HBOT standardized protocol, consists in a daily oxygen 100% at 2.2-2.5 atmosphere for 90 minutes, for a minimum of 10 sessions in case of satisfying functional recovery. On the contrary, in case of absolutely negative results, the treatment should be interrupted. Otherwise, HBOT can be prolonged to a...
We read with interest the article by Bayoumy et al. concerning the effects of hyperbaric oxygen therapy (HBOT) associated with corticosteroid therapy in military personnel with acute acoustic trauma1. This paper helps to discuss about the most appropriate treatment of sudden deafness (SD). As recently stated, a spontaneous recovery, in the general population, is less than 40%. The precise role of HBOT has not yet been clearly established2. Our clinical experience during the last 15 years in a second referral hyperbaric center indicates the need of clear guide-lines, for the treatment of this acute disease. Nowadays there are two main therapeutic approaches to SD of different origin, the corticosteroid medication and HBOT.
Clearly, at first, it has to be ascertained the nature of a deafness excluding, cerebral diseases, vascular, traumatic and neoplastic. A subsequent otolaryngology evaluation enables to ascertain possible associated vestibular diseases, and to measure Pure Tone Average. Medical contraindications to HBOT and corticosteroids medication have to be excluded. An early treatment, not beyond the first 48 hours after the acute event is recommended 1. Today the HBOT standardized protocol, consists in a daily oxygen 100% at 2.2-2.5 atmosphere for 90 minutes, for a minimum of 10 sessions in case of satisfying functional recovery. On the contrary, in case of absolutely negative results, the treatment should be interrupted. Otherwise, HBOT can be prolonged to a maximum of 30 sessions, mainly in case of persisting vestibular signs or slow but progressive recovery. We underline the importance of an early corticosteroid treatment at the onset of clinical signs; it should be prolonged in the first ten HBOT sessions.
All this correlates to patho-physiological bases. The inner ear has limited possibility of collateral vascular network evident in case of acute ischemia/sub-ischemia, always considering that a constant 02 supply can prevent neuronal damage. HBOT increases the rate of diffused 02, opposes to the activation of inflammatory cascades, decreasing the release of pro-inflammatory cytokines, in particular alfa -TNF, IL 1, 1b and 6. At the same time, it improves the tissue concentration of anti-inflammatory IL-10 and heat shock protein 90, so reducing a precocious apoptosis3. Furthermore, the contemporary corticosteroid treatment helps to reduce the entire inflammatory process favoring a better functional recovery. Therefore HBOT cannot be considered a second line treatment, applied after failure of other therapeutic measures, but as first line even better associated with corticosteroids.
References
1) Bayoumy AB, van der Veen EL, van Ooij P-JAM, et al. J R Army Med Corps 2019; doi:10.1136/jramc-2018-001117
2) De Ru JA Bayoumy AB. Sudden deafness: hyperbaric oxygen therapy should be discussed. BMJ 2019;364;1758.
3)Muzzi, E., Zennaro, B., Visentin, et al. Hyperbaric oxygen therapy as salvage treatment for sudden sensorineural hearing loss: Review of rationale and preliminary report. J Laryngol Otol 2010;124(2) E2.
The article by Cohen and Wolstenholme provides a useful overview of Penthrox but is unfortunately incomplete.
Compared with modern anaesthetic agents, Penthrox is an unclean drug and would not get a product license if invented today. The high fat solubility means a tissue reservoir persists for ≈1 week. About 70% is biotransformed, and this continues after administration until the tissue reservoir is empty. Nephrotoxicity was not just “a concern” but actually happened; ≈20 people died [1].
It has only been possible to use Penthrox 5 million times safely because of essential pre-use checks to ensure no contraindications. It is worth remembering that methoxyflurane was used 10-12 million times before the nephrotoxic potential was established [1].
Penthrox produces nephrotoxic metabolites at all doses, but this only becomes clinically significant above a certain level. The claim that Penthrox use is not nephrotoxic is technically correct, however, the presence of other factors that can also induce renal injury will reduce the Penthrox safety net. Of relevance to military use, this includes crush injury, hypovolaemic shock and patients subsequently requiring nephrotoxic antibiotics. Other potential issues for military use: (1) Limit to ≈50min administration (two bottles); (2) Activated charcoal adsorber is only effective IF the patient exhales through it. The patient will continue to exhale small amounts of drug for hours after administration; (3) There i...
The article by Cohen and Wolstenholme provides a useful overview of Penthrox but is unfortunately incomplete.
Compared with modern anaesthetic agents, Penthrox is an unclean drug and would not get a product license if invented today. The high fat solubility means a tissue reservoir persists for ≈1 week. About 70% is biotransformed, and this continues after administration until the tissue reservoir is empty. Nephrotoxicity was not just “a concern” but actually happened; ≈20 people died [1].
It has only been possible to use Penthrox 5 million times safely because of essential pre-use checks to ensure no contraindications. It is worth remembering that methoxyflurane was used 10-12 million times before the nephrotoxic potential was established [1].
Penthrox produces nephrotoxic metabolites at all doses, but this only becomes clinically significant above a certain level. The claim that Penthrox use is not nephrotoxic is technically correct, however, the presence of other factors that can also induce renal injury will reduce the Penthrox safety net. Of relevance to military use, this includes crush injury, hypovolaemic shock and patients subsequently requiring nephrotoxic antibiotics. Other potential issues for military use: (1) Limit to ≈50min administration (two bottles); (2) Activated charcoal adsorber is only effective IF the patient exhales through it. The patient will continue to exhale small amounts of drug for hours after administration; (3) There is no evidence that it is superior to other analgesics in current use. Its time profile differs from e.g. fentanyl lozenges, but not necessarily the quality of analgesia; (4) Any hangover from opioid can be easily reversed with naloxone. This is not possible with Penthrox; (5) Cardiovascular stability is not guaranteed, as suggested in the review, so the manufacturers have specifically made cardiovascular instability a contraindication.
Penthrox is metabolised to fluoride (and dichloroacetic acid, which may have a role in nephrotoxicity). Sevoflurane is metabolised to subtoxic levels of fluoride ion [1]. This may be enhanced by concurrent administration of enzyme-inducing drugs, as it is for Penthrox [2], including smoking [3], and related to duration of administration [3]. Sub-toxic fluoride levels of the two drugs could be additive, and it is this concern that led authorities to state that sevoflurane is contraindicated after Penthrox. The research to confirm or refute this has not yet been done.
The manufacturer has identified nine items to be checked before administering Penthrox. Other analgesics must therefore still be available for people who should not receive it. Conclusion: Penthrox can be another analgesic in the armamentarium, but it is not the answer on its own.
References
1. Mazze RI. Methoxyflurane revisited. Tale of an anesthetic from cradle to grave. Anesthesiology 2006; 105: 843-6
2. European Medicines Consortium. Penthrox 3mL inhalation vapour, liquid. Summary of Product Characteristics (Updated 14-Jan-2019. Galen Limited)
3. Cabibel C, Gerard L, Maiter D, Collin V, Hantson P. Complete nephrogenic diabetes insipidus after prolonged sevoflurane sedation: a case report of 3 cases. Anesth Analg Case Rep 2019; 12: 155-9
Critical Care Air Transport Team and traumatic brain injury
Viroj Wiwanitkit1
1. Hainan Medical University, China
Correspondence
Professor Viroj Wiwanitkit
Email: wviroj@yahoo.com
I read this article on the "Critical Care Air Transport Team and traumatic brain injury" with a great interest [1]. Boyd et al. noted that "Air transport personnel must be prepared to provide standard critical care but also care specific to TBIs, including ICP control and management of diabetes insipidus. Although these patients and their potential complications are traditionally managed by neurosurgeons, those providers without neurosurgical backgrounds can be provided this training to help fill a wartime need." I agree that in the critical situation and resource limited (such as remote area or war zone), the use of available facilities and personnel is better than doing nothing or waiting for the specialty. For the military clinical practice, the question is on the skill of the medical military personnel. There should a specific training for any medical military personnel on this specific subject, which is different from non-military ones. Another interesting question that I and many readers might want to know is on the safety management of the medical personnel and military team in the war zone. The summary of experience on self-protection during caring the others will be a useful data. Referring...
Critical Care Air Transport Team and traumatic brain injury
Viroj Wiwanitkit1
1. Hainan Medical University, China
Correspondence
Professor Viroj Wiwanitkit
Email: wviroj@yahoo.com
I read this article on the "Critical Care Air Transport Team and traumatic brain injury" with a great interest [1]. Boyd et al. noted that "Air transport personnel must be prepared to provide standard critical care but also care specific to TBIs, including ICP control and management of diabetes insipidus. Although these patients and their potential complications are traditionally managed by neurosurgeons, those providers without neurosurgical backgrounds can be provided this training to help fill a wartime need." I agree that in the critical situation and resource limited (such as remote area or war zone), the use of available facilities and personnel is better than doing nothing or waiting for the specialty. For the military clinical practice, the question is on the skill of the medical military personnel. There should a specific training for any medical military personnel on this specific subject, which is different from non-military ones. Another interesting question that I and many readers might want to know is on the safety management of the medical personnel and military team in the war zone. The summary of experience on self-protection during caring the others will be a useful data. Referring to the terrorism in many areas around the world, the medical personnel are often focused as a target for attacking.
Conflict of interest
None
References
1. Boyd LR, Borawski J, Lairet J, Limkakeng AT Jr. Critical Care Air Transport Team severe traumatic brain injury short-term outcomes during flight for Operation Iraqi Freedom/Operation Enduring Freedom. J R Army Med Corps. 2017 Apr 6. pii: jramc-2016-000743. doi: 10.1136/jramc-2016-000743. [Epub ahead of print]
With great interest, I have read the review article entitled “Efficacy of mirror therapy and virtual reality therapy in alleviating phantom limb pain: a meta-analysis and systematic review” written by Rajendram et al (1). The authors conducted a meta-analysis to evaluate the effects of mirror therapy (MT) and virtual reality (VR) therapy on phantom limb pain (PLP). Both therapies led to a reduction of visual analogue scale (VAS) scores on PLP, and there was no statistically significant difference in pain alleviation between two therapies. The authors recommended that factors such as gender, cause of amputation, site of limb loss or length of time from amputation should be considered for the analysis. I present additional information regarding the effect of MT on PLP.
Show MoreWang et al. also conducted a meta-analysis, handling randomized controlled trials (RCTs) (2). The pooled standardized mean difference (SMD) (95% confidence interval [CI]) of MT group was -0.81 (-1.36 to -0.25), which was compared with other 6 methods (four covered mirror, one phantom exercise, three mental visualization, one sensorimotor exercise, one transcutaneous electrical nerve stimulation, and one tactile stimuli). They concluded that MT was beneficial for reducing phantom limb pain. There is a fact that the authors did not consider follow-up intervals, and a control group was consisted a complex of traditional treatments for patients with PLP. I suppose that heterogeneous treatments may have diff...
Dear Editor
Show MoreWe read with interest the comments made by Cooper et al to our paper comparing experiences and mental health of personnel who joined service as junior entrants compared to adult entrants. Participants in the King's Centre for Military Health Research (KCMHR) cohort study were sampled from the trained and, consequently, deployable strength of the UK Armed Forces (UKAF) since the primary purpose of the cohort study was to measure the health consequences of deployment to Iraq and Afghanistan[1]. The participants were not sampled from personnel at recruitment but on the basis of their deployment to Iraq or Afghanistan. We had no data about individuals who joined service at the same time but who did not remain in service until the time of sampling and this is a fully acknowledged limitation in the paper. We have no evidence that there may have been differential attrition on the basis of mental health between the comparison groups. Those who joined before 2003 could represent a sub sample of particularly successful personnel (both those who joined as Junior Entrants and those who joined as adults). That is why we carried out a subgroup analysis of the smaller number of participants who had joined the trained strength after 2003 (the replenishment samples). In that analysis there were some significant associations that are of concern, but PTSD and common mental disorders were not, as suggested, among them as they were far from being statistically significan...
Dear Editor,
Thank you for publishing the Rapid Response to our paper by Cooper et al. The authors agree with our findings that junior entrants to the Armed Forces have a lower risk of developing a severe mental health disorder compared with older entrants, but have noted that we found that all veterans were more likely to develop mental disorders (especially PTSD) then matched non-veterans.
Show MoreThe increased risk of mental health disorders in veterans overall compared with non-veterans is not a new observation. In our 2016 paper(1) we showed that overall, veterans were at 21% overall increased risk of having experienced mental ill-health compared with matched non-veterans, whilst Goodwin et al.(2) showed that serving personnel had more than double the odds of common mental disorders compared with a general population sample. In our 2016 paper we showed that the risk in veterans is highest in those with the shortest service; Early Service Leavers (ESL) were at 51% increased risk, whilst those with more than 9 years’ service were at no greater risk than the comparison population. ESL who did not complete training, and who could not have deployed operationally, had the highest risk; it is likely that their mental health outcomes (including PTSD) arose predominantly from pre-service vulnerabilities. In our new study, we showed that junior entrants were less likely to be ESL (a finding supported by a House of Commons Written Answer on length of service of junior...
Dear Editor
Margaret Jones and colleagues’ study of armed forces personnel concluded that, for the study cohort as a whole, those who had joined up under the age of 17.5 years (‘junior entrants’) were no more likely than those who enlisted at older ages to report symptoms of mental health disorders. However, the study also found that junior entrants who had enlisted since 2003 showed significantly higher rates of alcohol misuse, somatic symptoms, and a lifetime history of self-harm, relative to older recruits. The study’s data further suggests that PTSD and common mental disorders may also be more prevalent among younger enlistees since 2003, although this is not statistically significant.
In recent decades, protections for armed forces recruits who are legally children have improved, including a legal prohibition on deployment to zones since 2002. Despite these developments, this study’s findings indicate continuing reason to be concerned about the impact of early enlistment on long-term mental health. It could be relevant that, as this study has shown, once junior entrants turn 18 and may be deployed, they are more likely to be in a combat role such as the frontline infantry.
Furthermore, the study sample may not reflect the relevant population accurately. Comparing Table 1 with UK armed forces quarterly personnel statistics,(1) higher-ranked personnel appear to be over-represented in the study sample, while those with the lowest ranks are under-repr...
Show MoreDear Editor
Dr. Bergman and colleagues’ retrospective cohort study of armed forces veterans in Scotland concluded that their study ‘provides no evidence to support the assertion that early entry to military service is associated with adverse long-term mental health outcomes’ and that concerns about early enlistment are ‘misplaced’ (p. 5).
This conclusion is justified on the grounds that junior entrants into the armed forces (below the age of 17.5) were found to have had a lower risk of developing a severe mental health disorder when compared to those recruited between the ages of 17.5 and 19; or between the ages of 20 and 24.
However, all veterans, including those who joined as junior entrants, were significantly more likely to develop mental disorders (especially PTSD) when compared to matched non-veterans. In addition, for the cohort of veterans born between 1975 and 1984, the data suggests that junior entrants have a higher risk of presenting with mental health disorders when compared to older recruits, although this is not statistically significant (Table 1). This cohort is important because it is associated with the multiple major combat deployments to Bosnia, Kosovo, Afghanistan and Iraq.
For these reasons, while modern day junior entrants to the armed forces in the UK are better protected when compared to ‘child soldiers’ in other countries, or to junior entrants from previous eras, concerns about their vulnerability to mental illness are...
Show MoreDear Sir,
The paper by Dr Schmidt details the history of the first independent Research Ethics Committee (REC) at Porton Down in the 1960’s. This REC was created to address ethical and legal concerns about research on human subjects. Since the 1960’s the emphasis has rightly shifted from “the doctor/scientist is always right” to “the participants must be protected from any unnecessary harms”. This has led to an expansion of the ethics review process and level of scrutiny, which has left many junior researchers feeling frustrated when their plans are criticised or delayed.
This letter will list some advice for junior researchers in the Defence Medical Services on how to navigate the process and improve the quality of their research and the chance of a successful ethical approval for research involving human participants:
Show More1. First, use the NHS Health Research Authority tool to confirm that your study design is research and that it requires ethical approval.
2. Read JSP 536 Pt 1 (48 pages) and 2 (64 pages).
3. Be familiar with the main tenets of medical ethics - respect for autonomy, beneficence, non-maleficence, justice and equipoise.
4. Involve patients and other stakeholders in the design of the study.
5. Do not underestimate the time required, it may take six to 12 months.
6. Be resilient and ensure you have support. It will be stressful.
7. The REC process is a combination of prestigious journal submission and viv...
The report on vitamin C for preventing the common cold in the Republic of South Korea army recruits by Kim et al. [1] has several statistical problems.
First, Kim et al. did not follow the intention-to-treat [ITT] approach. Figure 1 shows that 49 participants were excluded because they “stopped intake of vitamin C”, and 84 participants were excluded because they “stopped intake of placebo” [1]. The CONSORT recommendation for ITT analysis states as follows [2, Box 6]: “participants who … did not take all the intended treatment ... exclusion of any participants for such reasons is incompatible with intention-to-treat analysis”.
Second, Altman et al. pointed out that “The odds ratio should not be interpreted as an approximate relative risk [RR] unless the events are rare in both groups (say, less than 20-30%)”[3]. The common cold is not rare. Over 50% of the participants in the Kim et al. trial had the common cold during the trial period which greatly exceeds the 20-30% limit. Furthermore, there is no need to use the OR as the approximation for RR, because the RR can be calculated from the trial data in Table 1, RR = 0.916 (= 0.538/0.587) [1].
Third, in their abstract, Kim et al. wrote “the vitamin C group had a 0.80-fold lower risk of getting a common cold” implying that vitamin C decreased the incidence of colds by 20%. However, the correct effect estimate is given by the RR above, which indicates only 8.4% lower risk of colds in the vitamin C group....
Show MoreWe read with interest the article by Bayoumy et al. concerning the effects of hyperbaric oxygen therapy (HBOT) associated with corticosteroid therapy in military personnel with acute acoustic trauma1. This paper helps to discuss about the most appropriate treatment of sudden deafness (SD). As recently stated, a spontaneous recovery, in the general population, is less than 40%. The precise role of HBOT has not yet been clearly established2. Our clinical experience during the last 15 years in a second referral hyperbaric center indicates the need of clear guide-lines, for the treatment of this acute disease. Nowadays there are two main therapeutic approaches to SD of different origin, the corticosteroid medication and HBOT.
Show MoreClearly, at first, it has to be ascertained the nature of a deafness excluding, cerebral diseases, vascular, traumatic and neoplastic. A subsequent otolaryngology evaluation enables to ascertain possible associated vestibular diseases, and to measure Pure Tone Average. Medical contraindications to HBOT and corticosteroids medication have to be excluded. An early treatment, not beyond the first 48 hours after the acute event is recommended 1. Today the HBOT standardized protocol, consists in a daily oxygen 100% at 2.2-2.5 atmosphere for 90 minutes, for a minimum of 10 sessions in case of satisfying functional recovery. On the contrary, in case of absolutely negative results, the treatment should be interrupted. Otherwise, HBOT can be prolonged to a...
The article by Cohen and Wolstenholme provides a useful overview of Penthrox but is unfortunately incomplete.
Compared with modern anaesthetic agents, Penthrox is an unclean drug and would not get a product license if invented today. The high fat solubility means a tissue reservoir persists for ≈1 week. About 70% is biotransformed, and this continues after administration until the tissue reservoir is empty. Nephrotoxicity was not just “a concern” but actually happened; ≈20 people died [1].
It has only been possible to use Penthrox 5 million times safely because of essential pre-use checks to ensure no contraindications. It is worth remembering that methoxyflurane was used 10-12 million times before the nephrotoxic potential was established [1].
Penthrox produces nephrotoxic metabolites at all doses, but this only becomes clinically significant above a certain level. The claim that Penthrox use is not nephrotoxic is technically correct, however, the presence of other factors that can also induce renal injury will reduce the Penthrox safety net. Of relevance to military use, this includes crush injury, hypovolaemic shock and patients subsequently requiring nephrotoxic antibiotics. Other potential issues for military use: (1) Limit to ≈50min administration (two bottles); (2) Activated charcoal adsorber is only effective IF the patient exhales through it. The patient will continue to exhale small amounts of drug for hours after administration; (3) There i...
Show MoreCritical Care Air Transport Team and traumatic brain injury
Viroj Wiwanitkit1
1. Hainan Medical University, China
Correspondence
Professor Viroj Wiwanitkit
Email: wviroj@yahoo.com
I read this article on the "Critical Care Air Transport Team and traumatic brain injury" with a great interest [1]. Boyd et al. noted that "Air transport personnel must be prepared to provide standard critical care but also care specific to TBIs, including ICP control and management of diabetes insipidus. Although these patients and their potential complications are traditionally managed by neurosurgeons, those providers without neurosurgical backgrounds can be provided this training to help fill a wartime need." I agree that in the critical situation and resource limited (such as remote area or war zone), the use of available facilities and personnel is better than doing nothing or waiting for the specialty. For the military clinical practice, the question is on the skill of the medical military personnel. There should a specific training for any medical military personnel on this specific subject, which is different from non-military ones. Another interesting question that I and many readers might want to know is on the safety management of the medical personnel and military team in the war zone. The summary of experience on self-protection during caring the others will be a useful data. Referring...
Show More