Displaying 1-10 letters out of 172 published
Determining the direction of effect
I was interested to read Callander et al's recent article entitled 'Chronic health conditions and poverty: a cross-sectional study using a multidimensional poverty measure'. While the study is of high quality, I would argue that the authors have been remiss to exclude the possibility that it is just as likely that poverty is impacting on health, and not just poorer health leading to increased poverty. Given that the Survey of Disability, Ageing and Carers is cross-sectional in nature, it is not possible to distinguish the temporal nature of the relationship between economic circumstances and health. Different disciplines may approach the questions of the association between health and (socio)economic circumstances from different perspectives. For example, as a health inequalities researcher I would typically focus on health as the outcome, but when using cross-sectional data it would be important to acknowledge that 'health selection' is a valid and alternative, or more likely complimentary, explanation of the poverty-health association. It is important to acknowledge this limitation, especially when recommending policy measures.
Conflict of Interest:
Comment on the article: Acute exacerbation (AE) in rheumatoid arthritis associated interstitial lung disease: a retrospective case control study.
Regarding the article of Hozumi H et. al. (1) I am concerned about the conclusions obtained with an invalid analysis of the data. Hazard ratios (HR) are not the appropriate measure of strength of association in the information presented by Hozumi et. al. First, it seems that patients received different treatments during follow up, in order to correctly use Cox regression analysis to obtain HR, patients must have being receiving methotrexate during all follow up, not only at final visit or at AE onset. Indeed, it seems that at least some control patients have also received methotrexate at some time of their follow up. In this case, a better measure of strength of association is the odds ratio (OR). In the case of using OR in a small sample size, a stratified analysis is possible using the Mantel Haenzal test to asses for confounders and interactions. In this particular case, an OR of the association between AE and methotrexate adjusted for the UIP pattern is mandatory. Methotrexate is not only widely used to treat RA. Methotrexate is indeed the cornerstone of RA treatment nowadays. Methotrexate has improved the wellbeing and the survival of RA patients.(2;3) Wolfe et al. (4) have assessed the hypothesis that methotrexate or other drugs used in the treatment of RA may be associated with severe interstitial lung disease, finding no association. Hozumi et. al. must have included this data in the discussion section of their manuscript.
Jorge Rojas Serrano, MD, PhD Attending physician and professor of statistics Interstitial lung disease unit Instituto Nacional de Enfermedades Respiratorias, Ismael Cosio Villegas Facultad de Medicina, Universidad Nacional Autonoma de Mexico.
(1) Hozumi H, Nakamura Y, Johkoh T, Sumikawa H, Colby TV, Kono M et al. Acute exacerbation in rheumatoid arthritis-associated interstitial lung disease: a retrospective case control study. BMJ Open 2013; 3(9):e003132.
(2) Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 2002; 359(9313):1173-1177.
(3) Wasko MC, Dasgupta A, Hubert H, Fries JF, Ward MM. Propensity- adjusted association of methotrexate with overall survival in rheumatoid arthritis. Arthritis Rheum 2013; 65(2):334-342.
(4) Wolfe F, Caplan L, Michaud K. Rheumatoid arthritis treatment and the risk of severe interstitial lung disease. Scand J Rheumatol 2007; 36(3):172-178.
Conflict of Interest:
Adherence to antiretroviral drug therapy in adult patients who are HIV-positive in Northwest Ethiopia: a study protocol
In their proposed study protocol of Adherence to ART among HIV positive patients in North West Ethiopia, Bezabhe et al properly noted the scarcity of information on determinants of long-term adherence to ART medications in Ethiopian context. Given the importance of adherence to long term treatment outcomes, understanding its determinants can be beneficial to improve the quality of healthcare provision to patients and minimising cost of treatment. We examined this behaviour sometime ago among HIV/AIDS patients in south and central Ethiopia.1
Similar to what proposed by the authors of this protocol we employed multiple methods for investigating determinants and prevalence rate of adherence to ART. However, we found that using some of the methods was challenging. It would be interesting if the investigators present their detail plan on how to handle the shortcomings of each technique for measuring adherence. For instance, the protocol lacks clarity about the proposed pill count technique. There are two different techniques for counting pills, namely announced and unannounced pill count. However, the authors did not specify which pill count technique to use for the study. From our experience, using announced pill count (i.e., where patients informed to bring their medicine container on their date of appointment) might be challenging in resource limited settings. One of such a challenge is the technique cannot identify medicines that were shared among patients. Studies in developed countries where there is better health care access reported higher prevalence rates of prescription medicine sharing among family members, friends, or acquaintances2-4; particularly this might be a concern for HIV positive partners who are on the same type of medication. I could imagine that sharing medicine may be a common practice in Ethiopia where most of HIV patients are from lower socioeconomic background and might have difficulty to pay for transportation to collect their medicines from health care facilities.
The other challenge with pill count technique is pill dumping, this is particularly important for the proposed study, it seems from the explanation given the authors will use pharmacists as data collectors; this is a bit worrisome for me. The study participants might feel being spied by their health care providers about their medication use behaviours, and they might dump some of their unused pills before their medical appointment date. Thus, I suggest to the authors to use neutral data collectors (preferably those that don't have involvement in healthcare provision for the study cohort). In our past study we tried to handle the situation by using unannounced pill count technique; however, it was costly as it required us to go to patients' home and getting their consent to count their unused pills.
1. Beyene KA, Gedif T, Gebre-Mariam T, et al. Highly active antiretroviral therapy adherence and its determinants in selected hospitals from south and central Ethiopia. Pharmacoepidemiol Drug Saf 2009;18:1007-15.
2. Petersen EE, Rasmussen SA, Daniel KL, et al. Prescription medication borrowing and sharing among women of reproductive age. J Womens Health 2008;17(7):1073-80.
3. Goldsworthy R, Schwartz N, Mayhorn C. Beyond Abuse and Exposure: Framing the Impact of Prescription-Medication Sharing. Am J Public Health 2008;98(6):1115-21
4. Goulding E, Murphy M, Di Blasi Z. Sharing and borrowing prescription medication: a survey of Irish college students. Ir J Med Sci 2011;180(3):687-90.
Conflict of Interest:
Re:Reply to Rapuch et al.
We thank Sarah Rapuch and colleagues for their interest in our article.
We agree that the expressed units for estimated creatinine clearance (eCrCl based on the Cockcroft-Gault equation) and estimated glomerular filtration rate (eGFR based on the 4-variable MDRD equation) are different but disagree with the conclusions they draw from this. With regard to points 1,2 and 4, whatever the advantages or disadvantages of the two methods in the true estimation of renal function, the eCrCl was the method used in the clinical trials but the eGFR is what many clinicians will use for treatment and dosing decisions. Since efficacy and safety have been based on the eCrCl and not the eGFR or any other method of estimation of renal function, we think it is important that the former is the method used in clinical practice where the potential for overdosing exists with serious adverse consequences. On the ethnicity issue, approximately 75% of the patients with atrial fibrillation were of White ethnic group and only 10% were of Black ethnicity and this is unlikely to have affected the findings.
Conflict of Interest:
Reply to MacCallum et al.
To the editor, We read with interest the article entitled "Patient safety and estimation of renal function in patients prescribed new oral anticoagulants for stroke prevention in atrial fibrillation: a cross-sectional study" by MacCallum et al. (1). Although this article shows well the difficulties encountered by physicians in prescribing the new oral anticoagulants dabigatran and rivaroxaban in the elderly and/or in patients having a decline in their renal function, we would like to discuss the questionable methods and the interpretation of the results. First of all, the authors compared an estimation of patients' Creatinine Clearance (CrCl) calculated with the Cockcroft and Gault (CG) (2) formula with an estimation of the Glomerular Filtration Rate (eGFR) calculated with the abbreviated or 4-variable MDRD equation (Modification of Diet in Renal Disease study equation). However, the estimated CrCl with the CG formula gives results expressed in mL/min while the aMDRD equation calculates the eGFR in mL/min/1.73 m2 (3). Raw results of the calculations can thus not be compared directly. Such comparisons require conversion into the same units. If the body surface area (BSA) of the patients did not differ significantly from 1.73 m2, this has limited consequences. However, there are no data that may answer this key issue. Secondly, the authors used the correction for ethnicity in the aMDRD formula, as required. However, the correction factor in the aMDRD equation has been validated for afro-americans. Other studies showed that Afro- europeans do not require the same correction factor and possibly no correction factor at all (4). The study being conducted in the London area, patients were most probably Afro-Europeans rather than Afro- Americans. This point is of importance since it results in an overestimation of the eGFR of around 20% for Afro-Europeans. Thirdly, it is recommended that drug dosage adjustment must be performed according to the actual renal function of the patients, according to their actual BSA, thus in mL/min and not in mL/min/1.73 m2 (5). Indeed, in the study of MacCallum et al., the results obtained by the MDRD formula expressed in mL/min/1.73 m2 should thus not be used to determine the appropriate dosage adjustment of dabigatran and rivaroxaban. Finally, in the present study, 0.9% of the patients receiving dabigatran are considered misclassified by the aMDRD formula. Besides, the proportions of patients receiving rivaroxaban and considered misclassified or requiring a reduced dose according to the use of the MDRD formula were 0.1% and 4.5% respectively. How can the authors claim that the use of the MDRD formula gives a wrong classification? The authors outlined the fact that all biochemistry laboratories in UK provide an MDRD-derived eGFR (mL/min/1.73 m2) in keeping with national guidance. Indeed, the United- States National Kidney Foundation's Kidney Disease Outcomes Quality Initiative and the international group Kidney Disease: Improving Global Outcomes (KDOQI-KDIGO) emphasized that the CG formula was developed before the standardization of creatinine assays and cannot be re-expressed for use with standardized creatinine assays. Besides, they also reminded that the MDRD Study equation was developed in 1999 and is currently recommended for eGFR reporting in adults by the National Kidney Disease Education Program (NKDEP) and by the Department of Health in the United Kingdom (6). Therefore, considering the CG formula as a reference is not acceptable in 2013. Besides, it has been shown that, especially in the elderly (age over 65), the MDRD formula had a better accuracy and a better performance than the CG formula (7-9). In fact, 74% of the patients included in this study were older than 65, and thus the results of CG calculations are simply false. We agree however on the fact that dosing guidelines for these drugs are expressed according to the CG formula, as specified in the drugs' Summary of Product Characteristics (SmPC). It is of a major importance to keep in mind that drug dosage adjustment must be performed according to the patients' renal function, and that this latter must be estimated, if not measured, using the most appropriate method depending on the patient. In this study, given the age of the patients, the aMDRD equation is the method of choice to calculate the eGFR of the patients. Dosage adjustment must be determined according to the result of this calculation, once the result has been converted into ml/min, using the actual BSA of the patient. This is the official international recommendation from the KDIGO, publicly released 2 years ago (10). This study thus presents with several serious limitations and bias. We strongly disagree with its methodology and conclusions. It is of an utmost importance that the readers be aware of these limitations and do not take into account the conclusions of the authors, which lack robustness.
References: (1) MacCallum PK, Mathur R, Hull SA, Saja K, Green L, Morris JK, Ashman N. Patient safety and estimation of renal function in patients prescribed new oral anticoagulants for stroke prevention in atrial fibrillation: a cross- sectional study. BMJ Open 2013; 3(9): e003343. (2) Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41. (3) Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999; 130(6): 461-470. (4) Flamant M, Boulanger H, Azar H, Vrtovsnik F. [Plasma creatinine, Cockcroft and MDRD: validity and limitations for evaluation of renal function in chronic kidney disease]. Presse Med 2010; 39(3): 303-11. (5) Stevens LA, Levey AS. Use of the MDRD study equation to estimate kidney function for drug dosing. Clin Pharmacol Ther 2009; 86(5): 465-7. (6) Stevens PE, Levin A; Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med 2013; 158(11): 825-30. (7) Cirillo M, Anastasio P, De Santo NG. Relationship of gender, age, and body mass index to errors in predicted kidney function. Nephrol Dial Transplant 2005; 20(9): 1791-8. (8) Michels WM, Grootendorst DC, Verduijn M, Elliott EG, Dekker FW, Krediet RT. Performance of the Cockcroft-Gault, MDRD, and new CKD-EPI formulas in relation to GFR, age, and body size. Clin J Am Soc Nephrol. 2010; 5(6): 1003-9. (9) Froissart M, Rossert J, Jacquot C, Paillard M, Houillier P. Predictive performance of the modification of diet in renal disease and Cockcroft- Gault equations for estimating renal function. J Am Soc Nephrol 2005; 16(3): 763-73. (10) Matzke GR, Aronoff GR, Atkinson AJ Jr, Bennett WM, Decker BS, Eckardt KU, Golper T, Grabe DW, Kasiske B, Keller F, Kielstein JT, Mehta R, Mueller BA, Pasko DA, Schaefer F, Sica DA, Inker LA, Umans JG, Murray P. Drug dosing consideration in patients with acute and chronic kidney disease-a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2011; 80(11): 1122-37.
Conflict of Interest:
Re:Response to "Specificity and sensitivity of transcranial sonography of the substantia nigra in the diagnosis of Parkinson's disease: prospective cohort study in 196 patients"
We would like to thank drs Mahlknecht, Seppi, and Berg for compliments on a study well designed and executed.
They do, however, raise two major and one minor criticism to our study.
Firstly, the DAT-SPECT data in our study were not in accordance with the clinical data, suggesting 'that clinical classification of the patients was suboptimal'. Secondly, the TCS data were disappointing, because, among other considerations, 'the authors had more problems in scanning with this machine than other groups'. Thirdly, our study results do not accord with current guidelines.
1. We disagree with their statement that DAT-SPECT should have a specificity close to 100% in differentiating neurodegenerative parkinsonian syndromes such as Parkinson's disease (PD) and atypical parkinsonian disorders (APD) . They cite 2 studies [1,2] to support this, but this is not a representative sample of the complete literature. A meta -analysis of all published studies showed that our DAT-SPECT data generally do not differ from other studies: there are substantial numbers of early stage PD patients with a normal SPECT scan . We thus do not think that our clinical diagnosis was compromised.
Mahlknecht et al feel that 'such diagnostic accuracy data suggest not to use DAT-SPECT in the diagnostic work-up of patients presenting with a parkinsonian syndrome of recent onset which is against current recommendations'. We think that recommendations in themselves are not a valid argument in this discussion (See below), and, as we explicitly stated in our paper, our gold standard diagnosis of PD was a clinical one. For this clinical diagnosis we used the UK Brain Bank criteria, as also proposed by the EFNS guideline, of which both Daniela Berg and Klaus Seppi are co-authors .
Additionally, as Mahlknecht et al suggested, we have recalculated the diagnostic accuracy of TCS in the subjects, whose final clinical diagnosis was also 'supported' by their DAT-scan. TCS was positive in 35% and negative in 65%. Diagnostic accuracy did thus not improve.
2. We do not think that our sonographers would be less competent than others. One of us (WM) is an internationally recognised sonography expert, who had done additional training with Daniela Berg in T?bingen, especially for this project. We also did an interobserver study to assure reliability of our sonographies . Up till this study our TCS results accorded with those reported in the literature . We thus think that our TCS competency is in line with others.
TCS diagnostic accuracy in early stage parkinsonian syndromes is simply absent in a carefully executed prospective study.
In response to Mahlknecht et al that there are more prospective studies: we would like to point out that ours was the only one with this specific research question that was prospectively registered.
As we reported in the earlier paper, newer ultrasound systems will reveal hyperechointensity of the SN in more patients , but it remains to be seen whether that will increase diagnostic accuracy, since this enhanced sensitivity migh decrease specificity.
3. Mahlknecht et al are concerned that our data do not accord with guidelines for the use of DAT-SPECT and TCS [6-7]. We are sorry that our results do not support these guidelines, but fail to see how that would invalidate our data. Guideline development is not a scientifically impartial process and frequently biased by conflicts of interest .
We do agree with Mahlknecht's final conclusion that, when studying TCS, careful consideration should be given to the way methods are applied and data are analysed.
The conclusion of our earlier meta-analysis is still true: the clinical significance of substantia nigra hyperecho-intensity remains unclear .
References 1. Marshall VL, Reininger CB, Marquardt M. Parkinson's disease is overdiagnosed clinically at baseline in diagnostically uncertain cases: a 3-year European multicenter study with repeat [123I]FP-CIT SPECT. Mov Disord 2009;24:500-8. 2. Jennings DL, Seibyl JP, Oakes D, Eberly S, Murphy J, Marek K. (123I) beta-CIT and single-photon emission computed tomographic imaging vs clinical evaluation in Parkinsonian syndrome: unmasking an early diagnosis. Arch Neurol 2004;61:1224-9. 3. Vlaar AM, van Kroonenburgh MJ, Kessels AG, et al. Meta-analysis of the literature on diagnostic accuracy of SPECT in parkinsonian syndromes. BMC Neurol 2007;7:27 4. Vlaar A, Tromp SC, Weber WE, Hustinx RM, Mess WH. The reliability of transcranial duplex scanning in parkinsonian patients: comparison of different observers and ultrasound systems. Ultraschall Med. 2011 Jan;32 Suppl 1:S83-8. 5. Vlaar AM, de Nijs T, van Kroonenburgh MJ et al. The predictive value of transcranial duplex sonography for the clinical diagnosis in undiagnosed parkinsonian syndromes: comparison with SPECT scans. BMC Neurol 2008;8:42. 6. Berardelli A, Wenning GK, Antonini A, et al. EFNS/MDS-ES/ENS [corrected] recommendations for the diagnosis of Parkinson's disease. Eur J Neurol 2013;20:16-34. 7. Suchowersky O, Reich S, Perlmutter J, Zesiewicz T, Gronseth G, Weiner WJ. Practice parameter: diagnosis and prognosis of new onset Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66:968- 75. 8. Holloway RG, Mooney CJ, Getchius TS, Edlund WS, Miyasaki JO. Invited Article: Conflicts of interest for authors of American Academy of Neurology clinical practice guidelines. Neurology. 2008 Jul 1;71(1):57-63. 9. Vlaar AM, Bouwmans A, Mess WH, Tromp SC, Weber WE. Transcranial duplex in the differential diagnosis of parkinsonian syndromes: a systematic review. J Neurol. 2009 Apr;256(4):530-8.
Conflict of Interest:
The surgical safety checklist-mainly a challenge for anaesthesia mortality in low-income countries?
Working on a daily basis in the theatres of the largest hospital in a low-income country (Malawi) we were pleased to read the study of Aveling and colleagues . They demonstrated in a clear, quite comprehensive and critical manner challenges involved with the surgical safety checklist in resource poor situations.
Continuously experiencing the real life situation in Africa we do think that there is an important consideration still lacking when we discuss challenges for the implementation of the surgical safety checklist, challenges which are not the same in low-income and high-income countries.
Many of the surgical safety checklists items  are not really part of the surgical, but much more of the anaesthesiological field. This is true for the check of the anaesthesia machine, the pulse oximeter, the difficult airway, the aspiration risk, the i.v. access, the application of the antibiotic prophylaxis, the treatment in the (usually anaesthetic) recovery room etc. Excluding the not immediately life threatening problems we count 11 of 18 (61%) questions to be answered by the anaesthesiologist .
When anaesthesia plays such a crucial part than it is evident that we have to consider anaesthesia mortality in Africa as an integral part of the surgical safety checklist. In many sub-Saharan countries pure anaesthesia mortality is incredibly high. It was shown to be for Togo 1 death per 133 anaesthesias given , for Malawi 1 avoidable death per 504  and for Nigeria 1 avoidable death per 387 obstetric interventions ). Added surgical mortality than accounts for an overall mortality for caesarean section e.g. in Malawi of 1 death in 95 operations .
These results have to be compared with the pure anaesthetic mortality of 2.5 per 100,000 found by Bainbridge et al.  for countries with a high "Human development Index", the findings of Lienhart et al. for France with 0.68 deaths per 100,000  and Vila et al. for Florida with 0.78 deaths per 100,000 .
Even when all these numbers have to be evaluated cautiously - exactly here we find the reasoning for the different impact the surgical safety checklist will have in low and high-income countries. To improve the low mortality in high-income countries is difficult and we need to ask e.g. whether a pneumonectomy is done on the correct side. In the poor countries these questions might reduce to a minimal degree mortality too, but they do not really address the reason why our patients die hundreds of times more often than in the high-income countries (and that is still not the whole truth, because for the fit and young patients anaesthesia mortality decreases drastically in the high-income countries and some high risk procedures are almost never done in most low-income countries ).
Besides the many challenges mentioned by the authors as specific to low-income countries we experience further problems which interfere with the surgical safety checklist but are not represented there. Often no pre- anaesthetic visitations are possible, we often are unable to diagnose the cardiovascular or respiratory condition of the patient, antibiotics are not only not available but actively embezzeled in the procurement process, patients travel for hours or even days to the hospitals, almost no postoperative ICU care is available and we might have an anaesthesia machine to check but no oxygen to use etc.
But even with these problems we can deal and they are not the frontline were we have to fight for the life of our patients - when one other condition is fulfilled:
In order to prevent patients from harm through their disease or the medical intervention we need first and foremost - anaesthetic and surgical staff. We need much higher numbers of well trained, dedicated non-physician anaesthetists and surgeons as the backbone of service provision, university trained Bachelors committed to the management of all the above daily life problems in our theatres and intensive care units in the large district hospitals (maybe including an adapted version of the surgical safety checklist) and finally specialists, trained in our own African Master of Medicine (MMed) programmes, for the central hospitals supervision, the implementation of new ideas and the sustainable countrywide development of the specialties.
The limited usefulness of the surgical safety checklist in its current form - as useful it might be in the high-income countries - will distract our attention and our extremely limited personal resources from the really important tasks for anaesthesia and surgery in the low-income countries of the world.
References: 1. Aveling E-L, McCulloch P, Dixon-Woods M: A qualitative study comparing experiences of the surgical safety checklist in hospitals in high-income and low-income countries, BMJ Open 2013 3: doi: 10.1136/bmjopen-2013- 003039
2. Hynes AB, Weise GT, Berry WR Surgical checklist to reduce morbidity and mortality in a global population. N Engl J med 2009; 360:491 -499
3. Ouro-Bang?na Maman AF, Tomta K, Ahouangb?vi S, Chobli M: Deaths associated with anaesthesia in Togo, West Africa. Trop Doct 2005; 35:220- 25
4. Hansen D, Gausi SC, Merikebu M. Anaesthesia in Malawi: complications and deaths, Trop Doct 2000; 30: 146
5. Enohumah KO, Imarangiayo CO : Factors associated with anaesthesia relatedmaternal mortality in a tertiar hospital in Nigeria ; Acta Anaesthesiol Scand 2006; 50: 206-210
6. Fenton PM, Whitty CJM, Reynolds F: Caesarean section in Malawi: prospective study of early maternal and perinatal mortality, BMJ, Volume 327, 13. September 2003
7. Bainbridge D et al.: Perioperative and anaesthetic-related mortality in developed and developing countries: a systematic review and meta-analysis The Lancet, 380, 9847, pp 1075 - 1081, 2012
8. Lienhart A, Auroy Y, Pequignot F et al (2006): survey of Anaesthesia-related Mortality in France. Anesthesiology 105: 1087-1097
9. Vila H Jr, Soto R, Cantor AB, Mackey D (2003) Comparative outcomes analysis of procedures performed in physician offices and ambulatory surgery centers. Arch surg 138:991-995
10. Cohen MM, Duncan PG, Tate RB (1988) Does anaesthesia contribute to operative mortality? JAMA 260: 2859-2863
Conflict of Interest:
An old story: the GPRD does not provide credible autism data
CORRECTED - PLEASE DELETE EARLIER SUBMISSION
There have now been many studies using the General Practitioners' Research Database relating to autism and vaccination including by the present authors, which invariably have resulted in some reassuring conclusion. Several - like this one - have received wide media coverage, and it is therefore salutary to read the pre-publication peer reviews by Alan Emond and Katherine M Keyes  of this paper by Brent Taylor, Hershel Jick and Dean MacLaughlin  and ask why it was ever published.
"4 in a 1000 boys" in 2008 is not only a lot less than "11 in a thousand boys" in the USA it is a lot a less than the 1 in 100 figure for all children in the UK suggested by National Statistics c. 2004 in a document I can no longer find on line. It is also a rise on the 2.5 boys (25 per 10,000) showing on the graph (Fig 1) for 1998-2001, apparently a rise of 60% (after it was supposed to have plateaued?).
And I also note it is a lot more than the figures derived from the same database in an earlier paper by Jick which recorded "The incidence of diagnosed autism rose approximately 25%/year, from 1.6/10,000 boys born in 1993 to a peak of 9.5/10,000 boys born in 1999 (p<0.001)".
Moreover, by a remarkable coincidence if you make the traditional reckoning of 4 autistic boys to 1 autistic girl then the 2.5 boys in 1000 rate proposed by Taylor et al (1998-2001) yields an autism rate of 1 in 640 which is just one tenth of the 1 in 64 rate (157 in 10,000) proposed by Baron-Cohen, based of his Cambridgeshire survey conducted in the early part of the last decade . So, a fundamental point is that despite the many and often publicised studies using the GPRD to study rates of autism [2,3,5,6,7,8,9,10,11,12) it actually only collects fragmentary data on the topic, of little or no statistical use. It is quite likely that in loose way the data follows the actual trend but most of the cases are not there.
It is an anomaly that while Taylor et al focus on MMR as an issue they fail to consider important confounders like the introduction of the accelerated mercury containing DPT vaccine schedule in 1990 and HiB vaccine in 1992 (although both Taylor and Jick examined the DPT/mercury issue in other papers). My attempts to raise this with Prof Taylor have so far not been successful [13, 14].
Nevertheless, the present article has been reported in many places, notably on the BBC  and in The Times : once again the world has been reasured that autism has plateaued and it never had anything to do with vaccines. But on what basis?
 http://www.bmjopen.bmj.com/content/3/10/e003219.reviewer- comments.pdf
 Brent Taylor, Hershel Jick and Dean MacLaughlin 'Prevalence and incidence rates of autism in the UK: time trend from 2004-2010 in children aged 8 years'BMJ Open 2013 3:e003219; doi:10.1136/bmjopen-2013-003219
 Jick H, Kaye J. 'Epidemiology and possible causes of autism', Pharmocotherapy: 2003; http://www.medscape.com/viewarticle/465861_1
Baron-Cohen S, Scott FJ, Allison C, Williams J, Bolton P, Matthews FE, Brayne C, 'Prevalence of autism-spectrum conditions: UK school-based population study' http://www.ncbi.nlm.nih.gov/pubmed/19478287
 Nick Andrews, Elizabeth Miller, Andrew Grant, Julia Stowe, Velda Osborne and Brent Taylor, Thimerosal Exposure in Infants and Developmental Disorders: a retrospective cohort study in the United Kingdom does not support a causal association. Pediatrics 2004; http://pediatrics.aappublications.org/content/114/3/584
 Kaye JA, del Mar Melero-Montes M, Jick H, 'Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: a time trend analysis' http://www.bmj.com/content/322/7284/460
 Black C, Kaye JA, Jick H, 'Relation of childhood gastrointestinal disorders to autism: nested case-control study using data from the UK General Practice Research Database' BMJ. 2002 Aug 24;325(7361):419-21
 Jick H, Kaye JA, Black C, 'Changes in risk of autism in the U.K. for birth cohorts 1990-1998' Epidemiology. 2003 Sep;14(5):630-2
 Fombonne E, Heavey L, Smeeth L et al. Validation of the diagnosis of autism in general practitioners records. BMC Public Health 2004;4:5. http://www.biomedcentral.com/1471-2458/4/5
 Smeeth L, Hall AJ, Fombonne E et al. A case control study of autism and mumps measles rubella vaccination using the general practice research database. BMC Public Health 2001;1:2 http://www.biomedcentral.com/1471-2458/1/2
 Smeeth, L, Cook C, Fombonne E et al. MMR vaccination and pervasive development disorders: a case-control study. The Lancet 2004;364: 963-69
 Smeeth L, Cook C, Fombonne et al. Rate at first recorded diagnosis of pervasive developmental disorders in United Kingdom general practice, 1988-2001. BMC Medicine 2004;2:39. http://www.biomedcentral.com/1741-7015/2/39 Accessed Sept. 1, 2005
 John Stone, 'A missing confounder', 27 November 2006 http://adc.bmj.com/content/88/8/666.long/reply#archdischild_el_2773
 John Stone, 'Re: Side effects of mercury containing vaccines like influenza', 23 November 2006 http://www.bmj.com/rapid- response/2011/10/31/re-side-effects-mercury-containing-vaccines-influenza
 "UK autism cases have 'levelled off'" http://www.bbc.co.uk/news/health-24547956
 Chris Smyth, 'Autism rate steady after mystery peak', http://www.thetimes.co.uk/tto/health/news/article3896569.ece
Conflict of Interest:
UK study of SmPCs complements the findings of German study.
Summaries of Product Characteristics (SmPCs) are a cornerstone of the EU medicines licensing process, and could be a valuable information resource for doctors and other health professionals. We welcome the paper by Vromans et al, looking at how SmPCs could better support physicians, and are pleased to say that their findings with German doctors, are consistent with the findings from UK doctors which we published contemporaneously (1). As in Germany, we found that UK doctors did not value nor use SmPCs in their day-to-day practice.
Our methods similarly used both quantitative and qualitative methods, under the umbrella of 'user testing', the process widely used in the EU to test whether the information supplied as patient information leaflets (PILs) is clear and easy to use (these leaflets are based on the information in the SmPC, but should be written in a manner understandable to the public). This performance-based method of testing first determines whether people can find and understand key pieces of information. It then includes a short semi-structured interview to determine participants' general views on the document. Good practice in information writing and design is then used to improve the document and then it is tested again. It was recently used to test the European Public Assessment Report (EPAR) Summary produced by the European Medicines Agency to explain to the public how decisions to grant a licence for a medicine are made (2).
Our UK study of two SmPCs utilised this iterative 'user testing' approach to develop a revised format and content which, like the German study, included a 'synopsis' or 'key information summary at the beginning. Both studies will form part of the evidence used in the assessment report from the European Commission on the shortcomings of SmPCs and PILs and recommendations for improvement.
(1)Raynor DK, De Veene, P, Bryant D. The effectiveness of the SmPC and recommendations for improvement. Therapeutic Innovation and Regulatory Science 2013. DOI: 10.1177/2168479013501311 http://dij.sagepub.com/content/early/2013/09/23/2168479013501311.abstract
(2)Raynor DK, Bryant D. European Public Assessment Report (EPAR) summaries for the public: are they fit for purpose? A user-testing study. BMJ Open 2013. DOI: 10.1136/bmjopen-2013-003185 http://bmjopen.bmj.com/content/3/9/e003185.abstract
Conflict of Interest:
DKR is co-founder and academic advisor to Luto Research, which develops, refines and tests health information materials
Data owner and pollen allergens in Denmark
Dear Professor Ping Qin, Dear Editor
I have with interest read the article: Suicide risk in relation to air pollen counts: a study based on data from Danish registers. As the data producer and data owner I have identified a number of incorrect statements in this study, that I would like to see corrected or added. Due to these errors, the study is unacceptable both with respect to scientific practice as well as with respect to correctness of a number of statements. It is however straightforward to correct and I try to be as constructive as possible in this process.
The pollen data that has been used in the article is alone measured and produced by the Danish Asthma and Allergy Association. All use of the data must include proper credit to the data owner and producer: Danish Asthma and Allergy Association. We collaborate with DMI - the Danish Meteorological Institute. The pollen data is owned by both organizations and this should be addressed in the article; e.g. in the section on methods, data and acknowledgments. But it is not. I know that Professor Ping Qin has received pollen data from DMI, and that she has been given the information about data copyright in the correspondence with Alix Rasmussen (DMI) from May, 2008, where Professor Ping Qin discussed data format and received pollen data according to her wishes.
The phrase in the mail goes: "Following standard conditions on the use of data shall be followed: Please note that the Danish Asthma and Allergy Association (AAF) and the Danish Meteorological Institute (DMI) cannot be held responsible for the use of incorrect data or the interpretation and use of data in general. The data are property of AAF and DMI, and may not be sold, copied or handed over to third party. If data are published AAF and DMI has to be referred to as source of information".
I am aware that Professor Ping Qin also had a general contract with DMI on climate and weather data. Climate and weather data are solitary DMIs property. How this should be handled is reflected by the contract. And despite the formulation in the contract, then DMI can give access to pollen data too and these data can be used in scientific publications, if the authors follow the guideline for referencing and ownership.
Reading the article you could get the impression that Danish pollen data was only available in the format used in the study: Grand total and "daily counts". This is incorrect. Pollen concentrations in the air have been measured in Copenhagen from 1977- and from Viborg since 1980-. Denmark has a long, unique detailed 2-hour data base of pollen concentrations for 23 individual pollen taxa and one fungal spore taxon: Alternaria. Cladosporium data is also available, but only as a daily mean values. These data can all be aggregated to daily, weekly or annual totals. It is the authors that selected an atypical aggregation. It is not a limitation of the data. A number of studies on the same data set that have been published since 2007 have shown this very clearly. A more thorough literature review on studies that use this data set would easily have revealed this inconsistency. A recent study on the data from Copenhagen was recently published in Atmospheric Chemistry and Physics and later in February 2013 highlighted by the European Commission as one of the most important studies in relation to air quality, health and policy. The newsletter and the paper are both freely available and I will suggest that the authors use this as a starting point (e.g. http://ec.europa.eu/environment/integration/research/newsalert/pdf/317na4.pdf) for their literature review as they provides a good description of observational methods and links to related literature.
Concerning the methods, then the authors use "todays daily pollen count" and not the daily mean concentration. "Todays daily pollen count" is the average concentration in numbers of pollen grains per m3 of air from specific taxa measured from 1 p.m. the previous day to 1 p.m today for Copenhagen. For Viborg this is from 9 a.m. to 9a.m. These numbers are only used for forecasting and dissemination studies. These numbers have never been used in scientific research. All previous clinical and aerobiological studies on the Danish data set have used daily mean concentrations or similar. It will mean that a part of this study is not directly comparable to previous clinical studies on this data set. This issue is not discussed in either the methods or the discussion of the results. In aerobiological studies it is common to use bi-hourly data, daily mean (00 a.m. to 24 p.m.) or annual totals. Moreover pollen data and season expresses large variations from year to year. If annual data or seasonality is studied, especially in statistical studies, then data gabs must be taken into account. This is not done here.
A minor flaw is that the article states that ragweed is common allergenic pollen in Denmark. It is not. Ragweed is an invasive species that can become a problem over time. I assume that you mean mugwort = Artemisia vulgaris L. in Latin. Ragweed is Ambrosia artemisiifolia L. It should also be corrected. I will strongly recommend using Latin names in this article with respect to botany in order to avoid such misunderstandings.
Janne Sommer Aerobiologist at the Danish Asthma-Allergy Association. Head of pollen monitoring in Denmark from 2004 to October, 2013.
Referred reference: C. A. Skj?th, J. Sommer, L. Frederiksen, and U. Gosewinkel Karlson. Crop harvest in Denmark and Central Europe contributes to the local load of airborne Alternaria spore concentrations in Copenhagen. Atmos. Chem. Phys., 12, 11107-11123, 2012.
Conflict of Interest: