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Medicine Correspondence Blog

The Medicine Correspondence Blog allows authors to post Letters to the Editors, Reviews, and other editorial writings that are not considered original research.

Friday, April 17, 2020

Post-stroke status is commonly associated to muscular weakness, not only on limbs, but also on respiratory system. As so, respiratory muscle training (RMT) emerged as an option to increase respiratory strength and function(1).

We compliment Liaw et al. for highlighting the importance of RMT in patients with post-stroke respiratory muscle weakness and dysphagia(2). Nevertheless, there are some methodological considerations that need further clarification to assure validity of their findings and conclusions.

Information regarding measurement of Maximal Static Inspiratory (PImax) and Expiratory Pressure (PEmax) is scarce, namely regarding which measurement protocol was used and whether there was only a single measurement or an average or maximum value of multiple measurements.

The authors state this was a single-blinded study, whereby only the technician doing assessments was unaware of patient group allocation. Lack of blinding in randomized clinical trials has been shown to result in overestimation of intervention effects by 9%(3). Information regarding the intervention in the control group is scant with no clear description on whether sham inspiratory muscle training (IMT) was used in the control group and, if so, with which parameters.  Not using a sham-IMT would be a major methodological pitfall since both patients and health personnel would know which allocation group the patient was assigned to, introducing significant bias from both patient (change compliance with study protocol, seek additional treatments, recall bias) and health personnel (systematic differences in care and prompting during treatment - performance bias) perspectives (4). This can be especially problematic when using, as primary endpoint, volitional measurements of respiratory muscle strength such as maximum inspiratory and expiratory pressure relying on patient cooperation(5). Furthermore, no information was given whether randomization was done using a computer-generated allocation sequence and which steps, if any, were made to assure allocation concealment.

Regarding the intervention, on the experimental group, it is stated that two breathing trainers were used (DT11 ad DT14), having different pressure limits (with DT11 included in DT14 pressure ranges), but no explanation was provided on the rational of using different devices, how patients transitioned between them and how this could have influenced treatment response. Furthermore, there is no information on how progression of training pressures was implemented and whether the respiratory training was exclusively performed at patient's home or at  the center. Respiratory muscle training effect is highly dependent on patient compliance with treatment protocol, but the authors do not give a clear definition of compliance with treatment nor any information regarding session number and their duration

In conclusion, despite being an innovative the aforementioned methodological concerns warrant further clarification to assure study's validity and reproducibility. Several aspects need further evidence from larger high-quality trials: What is the clinical and functional impact of respiratory muscle weakness in stroke patients? Which respiratory muscle training protocol is more effective? What is the impact of improvement of respiratory strength and endurance on functional outcomes and stroke patients' morbidity and mortality?


Author Correspondence

Ana Vaz, Physical and Rehabilitation Medicine Department, Centro Hospitalar e Universitário de São João, Portugal

Tiago Moreira, Physical and Rehabilitation Medicine Department, Centro Hospitalar e Universitário de São João, Portugal

Fernando Parada, Physical and Rehabilitation Medicine Department, Centro Hospitalar e Universitário de São João, Portugal

Afonso Rocha, Cardiovascular Rehabilitation Unit, Physical and Rehabilitation Medicine Department, Centro Hospitalar e Universitário de São João, Portugal


References

[1] Menezes KK, Nascimento LR, Ada L, Polese JC, Avelino PR, Teixeira-Salmela LF. Respiratory muscle training increases respiratory muscle strength and reduces respiratory complications after stroke: a systematic review. J Physiother. 2016;62(3):138-44.

[2] Liaw MY, Hsu CH, Leong CP, Liao CY, Wang LY, Lu CH, et al. Respiratory muscle training in stroke patients with respiratory muscle weakness, dysphagia, and dysarthria - a prospective randomized trial. Medicine (Baltimore). 2020;99(10):e19337.

[3] Forbes D. Blinding: an essential component in decreasing risk of bias in experimental designs. Evid Based Nurs. 2013;16(3):70-1.

[4] Moustgaard H, Clayton GL, Jones HE, Boutron I, Jorgensen L, Laursen DRT, et al. Impact of blinding on estimated treatment effects in randomised clinical trials: meta-epidemiological study. BMJ. 2020;368:l6802.

[5] American Thoracic Society/European Respiratory S. ATS/ERS Statement on respiratory muscle testing. Am J Respir Crit Care Med. 2002;166(4):518-624.

Tuesday, April 7, 2020

At present, the use of drainage and the drainage type in spinal surgery remain controversial. We have read with great interest the article entitled " Drainage after posterior single-level instrumented lumbar fusion natural pressure vs negative pressure " by Chen et al(1) in a recent issue of the journal. The authors conduct a retrospective review of different methods of drainage after single-level posterior lumbar interbody fusion (PLIF). We are appreciated that the authors provide us the worthy clinical results, especially the safety and efficacy of the natural pressure drainage. In this communication, we would like to propose some opinions to the authors.

First, the authors compared the difference in age, height, weight, operation time and intraoperative blood loss between both groups. Other than these factors, the history of hypertension and taking medication such as anticoagulant drugs or blood thinners are other crucial factors affecting drainage and hematoma(2, 3). Furthermore, research shows that compared to blood loss and body mass index, medication is far more important to influence the decision to place a drain(4). Although patients with abnormal coagulation function were excluded, to make the study more complete and convincing, it's necessary to complement measurements of preoperative coagulation and blood routine, history of hypertension and medication taking in the two groups.

In addition, we notice that the authors evaluate the inflammatory absorption by means of measurement of postoperative body temperature within two days. However, some studies have found that the duration of postoperative fever is 3-4 days(5), and some even found significant temperature changes do not occur until 6 days after surgery(6). We wondered whether the results would be different if we took temperature longer. Moreover, the temperature measuring time is shorter than the drainage time and the fluctuation trend of body temperature in the two groups was inconsistent which there was an slight increase in the natural pressure group (day1 vs day2, 37.18±0.54 vs 37.22±0.55 ) while an decrease in the negative pressure group (day1 vs day2, 37.21±0.60 vs 37.15±0.53 ). Hence, it may be somewhat limited to monitor the temperature for only 2 days to explore the difference of postoperative fever in two groups and the time of temperature measurement should be extended at least to the removal of the drain.

What's more, the drainage constitution was equivalent for both groups, except for whether absorbing ball squeezed. To our knowledge, the disposable drainage device with a negative pressure absorbing ball is more expensive than that without. We have no idea whether it's authors' routine practice to use the device with an absorbing ball regardless of the type of drainage after PLIF. In our view, the utilization of ordinary drainage device without the absorbing ball can not only keep natural pressure but also reduce cost. It may be more reasonable to take the cost into consideration as well as effective clinical outcomes.

In conclusion, it is meaningful that the authors have provided us with such a novel idea focus on a better choice of drainage method. Although leaving us some questions to explore, they provided us with valuable guidance for carrying out clinical work. We look forward to more supplementary data for more information in the future.


Author Correspondence

Hong Du, 16th Department, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China

Dong Zhang, 16th Department, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China

Ningdan Ma, 8th Department, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China

Xiaolei Jin,16th Department, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China, E-mail professor.jin@yahoo.com


References

[1] Chen T, Chang H, Liu K, Shi M, Song C, Meng X. Drainage after posterior single-level instrumented lumbar fusion: Natural pressure vs negative pressure. Medicine (Baltimore) 2020;99(7):e19154.

[2] Liao Y, Tian Y, Ye R, Tang C, Tang Q, Ma F, et al. Risk and treatment of symptomatic epidural hematoma after anterior cervical spine surgery: A retrospective clinical study. Medicine (Baltimore) 2020;99(2):e18711.

[3] Kim JE, Choi DJ, Kim MC, Park EJ. Risk Factors of Postoperative Spinal Epidural Hematoma After Biportal Endoscopic  Spinal Surgery. World Neurosurg 2019;129:e324-e329.

[4] von Eckardstein KL, Dohmes JE, Rohde V. Use of closed suction devices and other drains in spinal surgery: results of an online, Germany-wide questionnaire. Eur Spine J 2016;25(3):708-15.

[5] Liang J, Qiu G, Chua S, Shen J. Comparison between subcutaneous closed-suction drainage and conventional closed-suction drainage in adolescent idiopathic scoliosis patients undergoing posterior instrumented spinal fusion: a randomized control trial. J Spinal Disord Tech 2013;26(5):256-9.

[6] Ovadia D, Drexler M, Kramer M, Herman A, Lebel DE. Closed Wound Subfascial Suction Drainage in Posterior Fusion Surgery for Adolescent Idiopathic Scoliosis: A Prospective Randomized Control Study. Spine (Phila Pa 1976) 2019;44(6):377-383.

Tuesday, April 7, 2020

We read with great interest the meta-annalysis by Yang et al[1] entitled "Effects of Teriparatide Compared with Risedronatein the Treatment of Osteoporosis: A Meta-Analysis of Randomized Controlled Trials" We congratulate the authors for publishing their study in this journal. Yet upon review of this article, there are serious  issues that nullify the conclusions.We seek certain clarifications from the author.

First, the authors extensively searched the published literature through electronic databases (PubMed, Web of Science, Embase and Cochrane library) and manually retrieved the references of the included studies., but these databases seemed to be not enough to retrieve all the eligible studies. Alternatively, other databases do exist, such as NLM Gateway, and BIOSIS previews as well as unpublished data like grey literature, which may contribute to get a more comprehensive collection of eligible studies.

Secondly, about adaptation of systematic review guidelines and registrations, there have been systematic review and meta-analysis protocol registration established that help to maintain a level of homogeneity and quality across all meta-analyses and systematic reviews being conducted. PRISMA, Cochrane, JBI, and MOOSE are a few examples of such guidelines[2,3]. This raises the question whether any such guideline was not used or just not mentioned. Given these limitations, registering a systematic review or meta-analysis is recommended when aiming to conduct one.Not only do the registration provides transparency in the review, but also improves the quality of conduct of the review and its subsequent reporting.

Thirdly, generally, the weighted mean differences (WMD) are only used for continuous data with identical scales.However, the standardized mean difference (SMD) should be adapted in the following conditions: different measurement tools, inconsistent measurement time point, and the mean or standard deviation with a difference of more than ten times between the studies[4]. From the forest plot showed by the author, we found that there were differences in the follow-up of the included studies and the measurement time of partial outcome indicator. Therefore, it is inappropriate to calculate WMD in their study.

Fourthly, 7 randomized controlled trials included in this meta-analysis were ensured the relatively high quality of the included studies. The literature 24 was done on the cohort of Postmenopausal females with osteoporotic vertebral fractures, while males with glucocorticoid-induced osteoporosis was used as the research object in literature 27 .So given the number of cases, the mean and standard deviation of two papers of subjects were exactly the same, we doubt this is the case. The same is true for the literature 28 and 30. Scrutinizing the literature 24, a main difference we found was in the Risedronate  group with a mean of 71.6 ± 8.1 in 350 cases and 70.5 ± 8.8 in 360 cases in Teriparatide group. If extracting duplicate or erroneous data for the sample, it would be likely to lead to an incorrect conclusion, misleading clinical practice. Therefore, in case that several articles from the same trial were published, the study that had the most relevant information or the longest follow-up period might be most appropriate. Finally, we hope that the authors address the points presented and that the overall discussion of the presented points will only serve to benefit the research community at large.


Author Correspondence

Qiujiang Li, MS, Graduate School of Ningxia Medical University, Yinchuan, Ningxia province, China and Department of spine surgery, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia province, China

Xingxia Long, MS, Graduate School of Huzhou Normal University, Huzhou, Zhejiang province, China 

Lijun Cai, Department of spine surgery, People's Hospital of Ningxia Hui Autonomous Region, No. 56, Zhengyuan Street, Yinchuan, 750000, Ningxia Province, China 

Email: cqsgklqj@163.com


References

[1] Yang C, Le G, Lu C, et al., Effects of teriparatide compared with risedronate in the treatment of osteoporosis: A meta-analysis of randomized controlled trials. Medicine (Baltimore) 2020. 99: p. e19042.

[2] David M, Alessandro L, Jennifer T, et al., Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009. 151: p. 264-9, W64.

[3] Stroup Donna F, Berlin Jesse A, Morto Sally C, et al., Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000.283: p. 2008-12.

[4] Tian L., Inferences on standardized mean difference: the generalized variable approach. Stat Med, 2007. 26(5): p. 945-53.

Wednesday, March 25, 2020

We thank SV Jargin for his second Letter to the Editor1 addressing our response2 to his first letter3 concerning our original article4. We are especially grateful for supplementation and clarification of several citations in our response2. However, those added and corrected details by SV Jargin do not change the overall picture and do not alter our results and the interpretations of our findings. One main motivation of SV Jargin seems to be the believe in a (practical) threshold for effects of external or internal radiation exposure by artificial radionuclides. Often, if not exclusively, such believe is founded in the scientifically invalid conclusion: 'No observed effect is evidence of no-effect'. With such a mindset, all negative, poorly designed, or statistically underpowered studies provide evidence of 'no-effect' ending in the fundamentally flawed concepts of 'low dose and low dose-rate': < 100 mSv and < 6 mSv/h5-7.

SV Jargin's statement 'This argumentation is based on the linear no-threshold theory (LNT) that has never been satisfactorily proven' is in contrast to the established scientific view: The random nature of radioactive decay and the interaction of radioactive materials and ionizing radiation with biologic matter and bio-/epi-genetic processes may trigger detrimental genetic effects even at minute doses by, e.g., incorporated xenobiotics like Cs-137/134, I-129/131, H-3, C-14. Moreover, natural repair-mechanisms may be compromised or may fail, subjected to artificial radiation. Consequently, ICRP 99 (2005) summarized: 'Current understanding of mechanisms and quantitative data on dose and time–dose relationships support the LNT hypothesis. Emerging results with regard to radiation-related adaptive responses, genomic instability, and bystander effects suggest that the risk of low-level exposure to ionizing radiation is uncertain, and a simple extrapolation from high-dose effects may not be wholly justified in all instances. However, although there are intrinsic uncertainties at low doses and low dose rates, direct epidemiological measures of radiation cancer risk necessarily reflect all mechanistic contributions including those from induced genomic instability, bystander effects, and, in some cases, adaptive responses, and therefore may provide insights about these contributions.', see http://www.icrp.org/publication.asp?id=ICRP%20Publication%­2099.

Health related demographic and epidemiologic data before and after the Chernobyl and Fukushima nuclear power plant accidents support LNT by disclosing monotonically or linearly increasing dose-response relations between ionizing radiation and radiation induced genetic effects from zero additional dose8-14. Note, zero additional dose is present before the accidents and may be assumed in negligibly contaminated regions after the accidents. Such situations motivate and enable powerful spatiotemporal ecological dose-response analyses11,15,16.

Employing the data of the Fukushima Health Management Survey (FHMS), we found strong associations between thyroid cancer and the external dose-rate below 2 µSv/h4. Therefore, it may be of general interest concerning the robustness of our findings to analogously consider the association between thyroid cancer and the thyroid average absorbed doses in the Fukushima municipalities as estimated by UNSCEAR in its Report 2013, Attachments C-16 and C-18. We, therefore, considered the counts of all municipality-specific thyroid cancers and the overall person-years as published in our article4. Table 1 below supplements this information with the total thyroid absorbed dose to 10-year old children as determined using UNSCEAR Report 2013 Attachments C-16 and C-1817. These internal thyroid doses are compiled in the last column of Table 1.

Figure 1 demonstrates associations of the thyroid cancer detection rate (DR) with the total thyroid absorbed dose. Below the dose of 25 mGy, the dose response association is strong and highly significant (p-value 0.0004), see red data points and red regression line in Figure 1. Based on all data, indicated by the combined red and blue data-points and the blue dashed line in Figure 1, the association gets weaker but remains significant p=0.0241. The dashed black curve in Figure 1 is a Poisson regression function of a rational (linear in numerator and denominator) transform of the dose. This dashed black cure in Figure 1 reflects an optimum compromise between the steep association for low doses and the flat association for higher doses. The disproportionate relation between radiation exposure and thyroid cancer can be expected given the known nonlinearity of the association between thyroid cancer occurrence and internal or external exposure 4,18-20. Again, these results, based on the officially announced absorbed dose to the thyroid, support LNT by a dose-dependent risk of thyroid cancer at doses as low as between 15 to 25 mGy, albeit dose-levels might be systematically underestimated by UNSCEAR due to the difficulties of determining valid internal thyroid doses. Moreover, it is unrealistic that the significant dose-response association (p-value 0.0004) in the narrow dose range 15 to 25 mGy can be explained by soft psychological or behavioral factors precisely differentiating the moderately impacted municipalities, not least because such factors can hardly be and have not yet been defined and measured with sufficient precision.

SV Jargin states: 'If even there are correlations between deposition values and individual doses, they do not prove causality and hence do not justify extrapolations, the more so as thyroid doses are caused predominantly by I-131'. We agree that to current paradigm relevant thyroid doses are caused by I-131. However, there is no need to extrapolate statistical dose-response associations. On the contrary, as mentioned above, the restriction of dose-rates to below 2 µSv/h yielded a strong and significant dose-response relation4, which is getting even stronger restricting to thyroid doses below 25 mGy: detection rate ratio (DRR) per µSv/h 2.248, 95%-CI (1.324, 3.819), p-value 0.0027. Employing the relations in the UNSCEAR data between Cs-137 and µSv/h on the one hand, and between Cs-137 and thyroid absorbed dose for 10-year old children on the other hand, it shows that an increase of 1 µSv/h dose-rate corresponds to an increase of 5.61 mGy thyroid absorbed dose; data see Table 1. This relation between µSv/h and mGy yields a DRR per 5.61 mGy (equivalent to DRR per 1.00 µSv/h) of 2.088, 95%-CI (1.392, 3.133), p-value 0.0004. This demonstrates an excellent agreement between the external and internal dose concepts. These statistical dose-response associations independent of the dose concept in moderately contaminated regions with little or no evacuations and little differential stress clearly provide evidence of causality.

In conclusion, we emphasize that it is essential and informative to impartially scrutinize and evaluate pertinent radiological exposure and health related data. The established dose concept in radiology (energy/mass) is too crude to precisely characterize the biologic effects of ionizing radiation6,7. It is important to properly quantify how vulnerable the organism's genes are to the slightest radiation. Insisting on reportedly low doses in anthropogenic exposure scenarios while ignoring real data reflects pro-nuclear ideology impeding scientific progress. 

Author Correspondence

Hidehiko Yamamoto, Medical Doctor (MD), Osaka Red Cross Hospital attached facility of physically handicapped children, 5-30 Fudegasaki-cho, Tennouji-ku Osaka-Shi 543-8555 Osaka, Japan 

Keiji Hayashi, Medical Doctor (MD), Hayashi Children’s Clinic, 4-6-11-1F Nagata, Joto-ku Osaka-Shi 536-0022 Osaka, Japan 

Hagen Scherb, Dr. rer. nat. Dipl.-Math., https://orcid.org/0000-0002-2730-5619; Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Computational Biology; D-82223 Eichenau, Germany, E-Mail hagen.scherb@gmail.com.


Municipalityperson-years thyroid cancers detection rate (DR) per 100,000 UNSCEAR (2013)
total thyroid dose for
10-year-old children (mGy)
Kawamata Machi5,790234.5429.04
Namie Machi8,304448.1783.75
Iitate Mura2,50200.0055.92
Minamisoma Shi29,333620.4535.32
Date Shi30,411929.5922.61
Tamura Shi17,133529.1819.42
Hirono Machi2,35900.0041.19
Naraha Machi3,40100.0085.26
Tomioka Machi6,812114.68121.31
Kawauchi Mura7551132.4541.32
Okuma Machi5,933350.56112.68
Futaba Machi2,47500.0028.72
Katsurao Mura52100.0067.17
Fukushima Shi146,2132215.0528.73
Nihonmatsu Shi29,623620.2527.41
Motomiya Shi17,788633.7321.00
Otama Mura4,777241.8723.96
Koriyama Shi192,0184322.3922.82
Koori Machi6,298115.8824.72
Kunimi Machi4,80800.0019.61
Ten-ei Mura3,00900.0020.47
Shirakawa Shi36,846719.0018.81
Nishigo Mura12,499216.0019.69
Izumizaki Mura3,954125.2918.08
Miharu Machi9,695110.3119.87
Iwaki Shi195,3533115.8731.16
Sukagawa Shi48,513510.3118.82
Soma Shi20,54614.8717.47
Kagamiishi Machi8,262112.1017.85
Shinchi Machi4,51500.0017.26
Nakajima Mura3,524128.3816.39
Yabuki Machi11,35418.8116.86
Ishikawa Machi9,559110.4615.80
Yamatsuri Machi3,50000.0015.59
Asakawa Machi4,84000.0016.36
Hirata Mura3,929125.4516.30
Tanagura Machi10,042219.9217.30
Hanawa Machi5,526118.1016.23
Samegawa Mura2,31700.0016.39
Ono Machi6,23700.0016.54
Tamakawa Mura4,51300.0015.99
Furudono Machi3,67700.0016.37
Hinoemata Mura30000.0015.32
Minamiaizu Machi8,28800.0015.45
Kaneyama Machi61200.0015.41
Showa Mura44700.0015.80
Mishima Machi57400.0015.97
Shimogo Machi3,047132.8215.40
Kitakata Shi26,455311.3418.44
Nishiaizu Machi2,96800.0015.58
Tadami Machi2,220145.0516.03
Inawashiro Machi8,435111.8616.53
Bandai Machi1,89300.0016.61
Kitashiobara Mura1,75200.0019.46
Aizumisato Machi11,71318.5416.10
Aizubange Machi9,570110.4519.90
Yanaizu Machi1,75500.0015.91
Aizuwakamatsu Shi67,951811.7716.64
Yugawa Mura2,342142.7018.46
 Total or Mean1,079,78618417.0426.96

Table 1. Data of the combined PBLS and FFSS FHMS programs4: municipality, person-years, thyroid cancers, detection rate, and UNSCEAR (2013) total thyroid absorbed dose of 10-year-old children [mGy] in the first year after Fukushima derived from Attachments C-16 and C-1817.


Fig1.PNG

Figure 1. Association between thyroid cancer and thyroid absorbed dose in 59 municipalities of Fukushima after the nuclear accidents (Table 1); solid red line: Poisson regression of the detection rate on the log10 of the absorbed dose restricted to doses below 25 mGy, p-value for trend 0.0004; dashed blue line: Poisson regression of the detection rate on the log10 of the absorbed dose for all data, p-value for trend 0.0242; black dashed line: Poisson regression of the detection rate on a rational function of the absorbed dose for all data, p-value for trend 0.0101; one outlying data point at absorbed dose 41.3 mGy not shown: Kawauchi Mura, 1 TC case in 755 person-years, DR 132.45.


References

[1] Jargin SV. Second Letter to Editor: Association between the detection rate of thyroid cancer and radiation dose-rate after the Fukushima nuclear power plant accident. Medicine (Baltimore) Correpondence Blog. https://journals.lww.com/md-journal/Blog/MedicineCorrespondenceBlog/pages/post.aspx?PostID=120. Accessed March 16, 2020.

[2] Yamamoto H, Hayashi K, Scherb H. Letter to Editor: Authors’ reply: Letter to Editor: Association between the detection rate of thyroid cancer and the external radiation dose-rate after the Fukushima nuclear power plant accident. https://journals.lww.com/md-journal/Blog/MedicineCorrespondenceBlog/pages/post.aspx?PostID=113. Accessed March 16, 2020.

[3] Jargin SV. Letter to Editor: Association between the detection rate of thyroid cancer and the external radiation dose-rate after the Fukushima nuclear power plant accident. Medicine (Baltimore) Correpondence Blog. https://journals.lww.com/md-journal/Blog/MedicineCorrespondenceBlog/pages/post.aspx?PostID=111. Accessed January 20, 2020.

[4] Yamamoto H, Hayashi K, Scherb H. Association between the detection rate of thyroid cancer and the external radiation dose-rate after the nuclear power plant accidents in Fukushima, Japan. Medicine (Baltimore). 2019;98(37):e17165.

[5] Tang FR, Loke WK, Khoo BC. Low-dose or low-dose-rate ionizing radiation-induced bioeffects in animal models. Journal of radiation research. 2017;58(2):165-182.

[6] Scherb H, Mori K, Hayashi K. Letter to Editor: Authors’ reply: Letter to the Editor by Sergei V. Jargin: Increases in perinatal mortality in prefectures contaminated by the Fukushima nuclear power plant accident. https://journals.lww.com/md-journal/Blog/MedicineCorrespondenceBlog/pages/post.aspx?PostID=42. Accessed March 16, 2020.

[7] Palmans H, Rabus H, Belchior AL, et al. Future development of biologically relevant dosimetry. The British journal of radiology. 2015;88(1045):20140392.

[8] Scherb H, Weigelt E, Brüske-Hohlfeld I. Regression analysis of time trends in perinatal mortality in Germany, 1980-1993. Environmental Health Perspectives. 2000;108(2):159-165.

[9] Scherb H, Weigelt E. Congenital Malformation and Stillbirth in Germany and Europe Before and After the Chernobyl Nuclear Power Plant Accident. Environmental Science and Pollution Research, Special Issue. 2003;1:117-125.

[10] Scherb H, Voigt K. The human sex odds at birth after the atmospheric atomic bomb tests, after Chernobyl, and in the vicinity of nuclear facilities. Environ Sci Pollut Res Int. 2011;18(5):697-707.

[11] Scherb H, Mori K, Hayashi K. Increases in perinatal mortality in prefectures contaminated by the Fukushima nuclear power plant accident in Japan: A spatially stratified longitudinal study. Medicine (Baltimore). 2016;95(38):e4958.

[12] Korblein A, Kuchenhoff H. Perinatal mortality after the Fukushima accident: a spatiotemporal analysis. J Radiol Prot. 2019;39(4):1021-1030.

[13] Scherb H, Mori K, Hayashi K. Comment on 'Perinatal mortality after the Fukushima accident'. J Radiol Prot. 2019;39(2):647-649.

[14] Scherb H, Masao F. Perinatalsterblichkeit in Japan – Fortschreibung der Trendanalysen: 2001 bis 2018. Strahlentelex für FUKUSHIMA - Unabhängiger Informationsdienst zu FUKUSHIMA. http://strahlentelex-fukushima.de/blog/fukushima-02-2020/. Accessed March 16, 2020.

[15] Scherb H, Weigelt E, Brüske-Hohlfeld I. European stillbirth proportions before and after the Chernobyl accident. International Journal of Epidemiology. 1999;28(5):932-940.

[16] Scherb H, Voigt K. Analytical ecological epidemiology: exposure-response relations in spatially stratified time series. Environmetrics. 2009;20(6):596-606.

[17] UNSCEAR. Report 2013, Volume I, United Nations Scientific Committee on the Effects of Atomic Radiation, REPORT TO THE GENERAL ASSEMBLY, SCIENTIFIC ANNEX A: Attachments for UNSCEAR 2013 REPORT Vol. I, https://www.unscear.org/unscear/en/publications/2013_1_Attachments.html. Accessed February 11, 2020.

[18] Cardis E, Kesminiene A, Ivanov V, et al. Risk of thyroid cancer after exposure to 131I in childhood. J Natl Cancer Inst. 2005;97(10):724-732.

[19] Zablotska LB, Ron E, Rozhko AV, et al. Thyroid cancer risk in Belarus among children and adolescents exposed to radioiodine after the Chornobyl accident. Br J Cancer. 2011;104(1):181-187.

[20] Zupunski L, Ostroumova E, Drozdovitch V, et al. Thyroid Cancer after Exposure to Radioiodine in Childhood and Adolescence: (131)I-Related Risk and the Role of Selected Host and Environmental Factors. Cancers (Basel). 2019;11(10):1481.

Thursday, March 12, 2020

The author is sincerely grateful to Dr. Hidehiko Yamamoto et al. (hereafter H.Y.) for their reply1 to the letter2. The following citations from the reply should be further commented because they are essential for the argument.

H.Y.: Increased thyroid cancer (TC) risks were found after exposure to doses above 50 mGy3.

Author: In the cited review3 it is written: "The risk is significantly increased for radiation doses to the thyroid of 50-100 mGy"3 with reference to4, where it is stated: "For persons exposed to radiation before age 15 years, linearity best described the dose response, even down to 0.10 Gy."4 The low figures had primarily come from a study of Israeli children who received radiotherapy for scalp ringworm, whereas an estimated thyroid dose 90 mGy was linked to a fourfold increase of TC and a twofold increase of benign thyroid tumors5. Considering the low doses and pathogenetic differences between TC and benign tumors, the causality was questioned, the data being regarded as outstanding and needing experimental verification6,7. Apparently, these latter results could have been caused by an observation bias or screening effect with detection of thyroid nodules.

H.Y.: According to the UNSCEAR 2013 report8 (Appendix C-16), the thyroid dose to a 10-year old child increases linearly with the Cs-137 deposition by 49.2 mGy per every MBq/m2 Cs-137. The same report8 in its Appendix C-9 documents an estimated total Cs deposition in 1 km2 grid cells from 12 March-1 April 2011 of up to 9.8 MBq/m2… the realistic maximum thyroid doses certainly exceeded 500 mGy.

Author: If even there are correlations between deposition values and individual doses, they do not prove causality and hence do not justify extrapolations, the more so as thyroid doses are caused predominantly by I-131.

H.Y.: Cardis et al. demonstrate a relative risk for thyroid cancer of 5.0 per Gy or equivalently of 1.0016 per mGy9

Author: This argumentation is based on the linear no-threshold theory (LNT) that has never been satisfactorily proven. In brief, the LNT postulates that linear dose-effect correlations, proven to some extent for higher doses, can be extrapolated down to minimal doses. However, the DNA damage and repair are permanent processes in a dynamic balance. Living organisms have probably been adapted to the natural radiation background (NRB) in a similar way as to other environmental factors. Natural selection is slow; adaptation to a changing factor would probably correspond to some average from the past. The NRB has been decreasing during the time of life existence. The conservative nature of mutation repair mechanisms in living organisms suggests that these mechanisms evolved in the past and that organisms may have retained some capability of efficient reparation of damage from a higher NRB than that existing today. Considering the above, with the dose rates tending to the wide range NRB level, radiation-related risks would tend to zero, and can even fall below zero in accordance with the concept of hormesis; details and references are in6,7.

H.Y.: Mathews et al. report significant relative risks for thyroid cancer in the range of 1.5 for CT-scans exposing children's thyroid glands to about 20 mGy external radiation per scan10,11.

Author: The causality is not proven, which can be seen from the following citations from the same sources10,11: "We cannot, however, necessarily assume that all the excess cancers seen during the current period of follow-up were caused by CT scans, because scanning decisions are based on medical indications and are not allocated at random… whereby symptoms of precancerous conditions (including genetic conditions) or early symptoms of the cancer itself might themselves prompt a CT scan."10 "Paralleling the increasing use of medical radiation is an increase in the incidence of papillary thyroid cancer. At present, it is unclear how much of this increase is related to increased detection of subclinical disease from the increased utilization of ultrasonography and fine-needle aspiration, how much is due to a true increase in thyroid cancer, and how much, if any, can be ascribed to medical radiation exposure."11

H.Y.: One strength of the Fukushima Health Management Survey is a uniform screening procedure covering all eligible residents. If this screening detected only insignificant cases, it would have detected them in all municipalities uniformly at random and irrespective of their geographic location, radiological contamination, or the timing of the examinations.

Author: Dose-effect correlations can be caused or overestimated due the screening-effect, dose-dependent quality of diagnostics, selection and self-selection2. There have been methodological differences of the screening in different areas after the Fukushima accident12. Both the screened people and medical personnel were informed about the contamination level in a given area, so that their action might have been consciously or subconsciously influenced by doses.

H.Y.: …the association between the TC increase and radiation has been clearly demonstrated13.

Author: the correlations by themselves do not prove causality being at least in part caused by factors and bias not related to radiation; commented in6,7,14 with references also to9,13 Please see also the preceding comment.

H.Y.: SV Jargin questioned the increase in TC after the Chernobyl accident….

Author: The TC incidence increase after the Chernobyl accident has never been questioned. Neither was it denied that TC could have resulted from radiation exposures. However, according to the author's hypothesis, the quantity of radiogenic cases after Chernobyl has been overestimated6,7,14.

H.Y.: However, the frequent occurrence of TC in contaminated regions after Chernobyl was evident and subsequent screenings of children born in the same regions after the decay of I-131 demonstrated the absence of frequent TC15.

It is written in the cited article: "Nowadays, 20 years after the Chernobyl tragedy, incidence of thyroid cancer in children in the affected countries decreased to the levels just somewhat elevated compared to the pre-accident rate"15, which is not exactly the same as the above citation from1; but this latter statement also needs a comment. Prior to the Chernobyl accident, the registered incidence of pediatric TC had been considerably lower in the former SU than in other developed countries15,16 probably due to an insufficient coverage of the population by medical checkups. Accordingly, there must have been neglected TC in the population 6,7,14. For the period 1981-1985, the TC incidence among children ≤15 years old in the northern regions of Ukraine (overlapping with the areas contaminated after the Chernobyl accident) was 0.1, and in Belarus – 0.3 per million per year16. After the accident, the TC incidence in Belarusians ≤18 years old has remained on an enhanced level - 15.7 per million per year (reported in 2012) or at least thrice the level of other countries17,18, although the radiation factor has no longer been present. This indicates that other mechanisms such as enhanced attention and improved diagnostics have contributed to the higher detection rate.

H.Y.: SV Jargin states 'The screening detected not only small nodules, but also late-stage TC interpreted as rapidly growing radiogenic cancers. Unlike Chernobyl, most cases after the Fukushima accident were of the classical papillary TC (PTC) type'. This perception is incorrect… In Fukushima, the percentage of PTC was 100/101 (99.0%) in the first screening and 49/50 (98%) in the second round, totaling 149/151 (98.7%), which is not much different from PTC after Chernobyl.

Author: If not the whole sentence is cited, dots of the ellipsis … are required. The complete sentence in2 was follows: "Unlike Chernobyl, most cases after the Fukushima accident were of the classical PTC type (not the less differentiated solid variant)19 which indicates that there were virtually no neglected advanced TC in the Japanese population"2. From the incomplete citation resulted a misunderstanding. The "less differentiated solid variant" of PTC and its high prevalence among first wave post-Chernobyl (diagnosed during ~10 years after the accident) TC is well known. The first wave TC following the Chernobyl accident were averagely larger and higher grade than those detected later20 presumably due to old neglected cases gradually sorted out by the screening 6,7,14.

H.Y.: Screening effects or overdiagnosis have yet to be proven unequivocally in sufficiently representative epidemiological studies in unexposed populations.

Author: For example, in the United States the incidence rate of thyroid tumors detected between 1974 and 1979 during a screening program was 21 times higher than that before the screening21. Obviously, an ultrasonic screening would find thyroid nodules. Among others, overdiagnosis means detection of thyroid tumors histologically diagnosed as cancers that would not, if left untreated, result in symptoms or death22.

H.Y.: In one of SV Jargin's references reportedly showing a "screening effect"23, 36 occult thyroid cancers were found in 101 (selected) autopsies, 34 of which in the age group 40-100.

Author:  the autopsies were not selected but consecutive23. "The rate … did not correlate to the age of the patients."23 "According to the study, occult papillary carcinoma can be regarded as a normal finding which should not be treated when incidentally found."23

The inexact citations specified in this letter potentially interfere with objective debates. More argumentation is in6,7,14. In conclusion, a monitoring of populations exposed to low-dose radiation is important but will hardly add reliable information about health risks. It can be reasonably assumed that the screening effect and increased attention of exposed people to their own health will result in new reports on the elevated cancer and other health risks, which would prove no cause-effect relationships. Dose-response correlations at low doses can be further studied in large-scale animal experiments. The life duration is known to be a sensitive endpoint attributable to radiation exposures24. To enable extrapolations to humans, the doses and dose rates in experiments must be comparable to those in corresponding human populations, taking into account the radiosensitivity and life duration of animal species.


Author Correspondence

Sergei Jargin, MD, Peoples' Friendship University of Russia, Clementovski per 6–82, 115184 Moscow, Russia

Email: sjargin@mail.ru


References

[1] Yamamoto H, Hayashi K, Scherb H. Authors' reply: Letter to the Editor by SV Jargin: Association between the detection rate of thyroid cancer and the external radiation dose-rate after the Fukushima nuclear power plant accident. Medicine (Baltimore) Correspondence Blog, January 21, 2020 https://journals.lww.com/md-journal/Blog/MedicineCorrespondenceBlog/pages/post.aspx?PostID=113

[2] Jargin SV. Letter to Editor: Association between the detection rate of thyroid cancer and the external radiation dose-rate after the Fukushima nuclear power plant accident. Medicine (Baltimore) Correspondence Blog, January 15, 2020 https://journals.lww.com/md-journal/Blog/MedicineCorrespondenceBlog/pages/post.aspx?PostID=111

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