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COVID-19 has affected surgical practice globally. Treating neurosurgical patients with the restrictions imposed by the pandemic is challenging in institutions with shared patient areas. The present study was performed to assess the changing patterns of neurosurgical cases, the efficacy of repeated testing before surgery, and the prevalence of COVID-19 in asymptomatic neurosurgical inpatients.Cases of non-trauma-related neurosurgical patients treated at the Postgraduate Institute of Medical Education and Research (PGIMER) before and during the COVID-19 pandemic were reviewed. During the pandemic, all patients underwent a nasopharyngeal swab reverse transcription-polymerase chain reaction test to detect COVID-19 at admission. Patients who needed immediate intervention were surgically treated following a single COVID-19 test, while stable patients who initially tested negative for COVID-19 were subjected to repeated testing at least 5 days after the first test and within 48 hours prior to the planned surgery. The COVID-19 positivity rate was compared with the local period prevalence. The number of patients who tested positive at the second test, following a negative first test, was used to determine the probable number of people who could have become infected during the surgical procedure without second testing.Of the total 1769 non-trauma-related neurosurgical patients included in this study, a mean of 337.2 patients underwent surgery per month before COVID-19, while a mean of 184.2 patients (54.6% of pre-COVID-19 capacity) underwent surgery per month during the pandemic period, when COVID-19 cases were on the rise in India. There was a significant increase in the proportion of patients undergoing surgery for a ruptured aneurysm, stroke, hydrocephalus, and cerebellar tumors, while the number of patients seeking surgery for chronic benign diseases declined. At the first COVID-19 test, 4 patients (0.48%) tested were found to have the disease, a proportion 3.7 times greater than that found in the local community. An additional 5 patients tested positive at the time of the second COVID-19 test, resulting in an overall inpatient period prevalence of 1%, in contrast to a 0.2% national cumulative caseload. It is possible that COVID-19 was prevented in approximately 67.4 people every month by using double testing.COVID-19 has changed the pattern of neurosurgical procedures, with acute cases dominating the practice. Despite the fact that the pandemic has not yet reached its peak in India, COVID-19 has been detected 3.7 times more often in asymptomatic neurosurgical inpatients than in the local community, even with single testing. Double testing displays an incremental value by disclosing COVID-19 overall in 1 in 100 inpatients and thus averting its spread through neurosurgical services.

The COVID-19 pandemic has not only had a negative impact on people's health and life behavior, but also on economies around the world. At the same time, laboratories and institutions are working hard to obtain a COVID-19 vaccine, which we hope will be available soon. However, there has been no assessment of whether an individual and society value ​​a vaccine monetarily, and what factors determine this value. Therefore, the objective of this research was to estimate the individual's willingness to pay (WTP) for a hypothetical COVID-19 vaccine and, at the same time, find the main factors that determine this valuation. For this, we used the contingent valuation approach, in its single and double-bounded dichotomous choice format, which was based on a hypothetical market for a vaccine. The sample used was obtained through an online survey of n = 566 individuals from Chile. The main results showed that the WTP depends on the preexistence of chronic disease (p≤0.05), knowledge of COVID-19 (p≤0.05), being sick with COVID-19 (p≤0.05), perception of government performance (p≤0.01), employment status (p≤0.01), income (p≤0.01), health care (p≤0.05), adaptation to quarantine with children at home (p≤0.01) and whether the person has recovered from COVID-19 (p≤0.10). According to our discrete choice model in double-bounded dichotomous format, it was concluded that the individuals' WTP is US$184.72 (CI: 165.52-203.92; p 0.01). This implies a social valuation of approximately US$2232 million, corresponding to 1.09% of the GNP per capita.

Although metal-on-metal (MoM) bearing surfaces provide low rates of volumetric wear and increased stability, evidence suggests that certain MoM hip arthroplasties have high rates of complication and failure. Some evidence indicates that women have higher rates of failure compared with men; however, the orthopaedic literature as a whole has poorly reported such complications stratified by gender.This systematic review aimed to: (1) compare the rate of adverse local tissue reaction (ALTR); (2) dislocation; (3) aseptic loosening; and (4) revision between men and women undergoing primary MoM hip resurfacing arthroplasty (HRA).Systematic MEDLINE and EMBASE searches identified all level I to III articles published in peer-reviewed journals, reporting on the outcomes of interest, for MoM HRA. Articles were limited to those with 2-year followup that reported outcomes by gender. Ten articles met inclusion criteria. Study quality was evaluated using the Modified Coleman Methodology Score; the overall quality was poor. Heterogeneity and bias were analyzed using a Mantel-Haenszel statistical method.Women demonstrated an increased odds of developing ALTR (odds ratio [OR], 5.70 [2.71-11.98]; p0.001), dislocation (OR, 3.04 [1.2-7.5], p=0.02), aseptic loosening (OR, 3.18 [2.21-4.58], p0.001), and revision (OR, 2.50 [2.25-2.78], p0.001) after primary MoM HRA.A systematic review of the currently available literature reveals a higher rate of complications (ALTR, dislocation, aseptic loosening, and revision) after MoM HRA in women compared with men. Although femoral head size has been frequently implicated as a prime factor in the higher rate of complication in women, further research is necessary to specifically probe this relationship. Retrospective studies of data available (eg, registry data) should be undertaken, and moving forward studies should report outcomes by gender (particularly complications).Level III, therapeutic study.

W e thank Dr. Wyland and appreciate his interest in our study. We would like to respond to the concerns raised in his letter to the editor [2]. We agree with Dr. Wyland that reporting the outcome in five separate subscales (symptoms; pain; function, daily living; function, sports and recreational activities; quality of life), enhances interpretation. However, as stated by Roos and colleagues [7], even though it makes it impossible to closely monitor the stages of rehabilitation, the calculation of a total KOOS score can show an improvement. Due to the fact that our objective was to report the general patient-relevant outcome at a minimum of 6 months postoperatively (and not to optimize rehabilitation), we decided to report a single score in this initial retrospective case series. Dr. Wyland noted that ‘‘the grading system described by Mitsou et al. and previously by Tegner actually evaluated the success of ACL reconstruction, not knee osteoarthritis treatments.’’ Due to lack of a specific patient-reported outcome score for treatment evaluation of subchondral bone marrow edema lesions, we decided to use the Tegner-Lysholm Score which, as correctly stated by Dr. Wyland, was initially developed and validated for ACL injuries. The rationale behind our decision lies in the fact that in up to 80% of ACL-ruptured knees, bone marrow edema lesions are present [3, 4]. We also feel that the critique by Bengsston and colleagues [1] on the sensitivity of the Tegner Lysholm Score regarding ACL injuries and other lower extremity conditions corroborates as opposed to discredits our choice. The grading of the score allows a more critical analysis of the outcome [1]. Dr. Wyland also correctly noted that ‘‘... there was no discussion of surgical revisions in evaluating clinical failure or surgeon learning curve, which one would expect to influence failure rates.’’ Within the confines of manuscript length, we reported the followup data that was available for this retrospective study; none of the patients had revisions. However, three patients were lost to followup. Also, the minimum followup to be included in this (RE: Chatterjee D, McGee A, Strauss E, Youm T, Jazrawi L. Subchondral calcium phosphate is ineffective for bone marrow edema lesions in adults with advanced osteoarthritis. Clin Orthop Relat Res. 2015;473:2334–2342). Each author certifies that he or she, or a member of his or her immediate family, has no funding or commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research editors and board members are on file with the publication and can be viewed on request. The opinions expressed are those of the writers, and do not reflect the opinion or policy of CORR or The Association of Bone and Joint Surgeons. D. Chatterjee MD (&), A. McGee MD, E. Strauss MD, T. Youm MD, L. Jazrawi MD Orthopaedic Surgery, NYU Langone Medical Center, 333 East 38th Street 4th Floor, New York, NY 10016, USA e-mail: Dipal.Chatterjee@nyumc.org; dipal.chatterjee@gmail.com Reply to Letter to the Editor Published online: 24 September 2015 The Association of Bone and Joint Surgeons1 2015

CCAAT/enhancer binding protein alpha (CEBPA) mutations in AML are associated with favourable prognosis and are divided into N- and C-terminal mutations. The majority of AML patients have both types of mutations. We assessed the prognostic significance of single (n=7) and double (n=12) CEBPA mutations among 224 AML patients. Double CEBPA mutations conferred a decisively favourable overall (P=0.006) and disease-free survival (P=0.013). However, clinical outcome of patients with single CEBPA mutations was not different from CEBPA wild-type patients. In a multivariable analysis, only double -- but not single -- CEBPA mutations were identified as independent prognostic factors. These findings indicate heterogeneity within AML patients with CEBPA mutations.

Sir, We read with interest the article by Loupakis et al (2013) entitled ‘Histopathologic evaluation of liver metastases from colorectal cancer in patients treated with FOLFOXIRI plus bevacizumab' published in the June 2013 issue of the British Journal of Cancer. This paper clearly underlines the positive impact of FOLFOXIRI plus bevacizumab, on the extent of both tumour regression and necrosis, in resected liver metastases from colorectal cancer (CRC). The authors conclude that the addition of bevacizumab leads to a high ‘histopathologic activity' as compared to FOLFOXIRI or XELOXIRI alone. These data are important as pathologic response is considered as a new outcome end point by some authors, representing a prognostic parameter and a marker of sensitivity to preoperative treatments (Rubbia-Brandt et al, 2007; Blazer et al, 2008). Indeed, the higher the histopathologic response, the longer the survival (Rubbia-Brandt et al, 2007; Blazer et al, 2008). In this setting, we would like to mention several points that may be clinically relevant. First of all, pathologic complete response (pCR) was defined, in the study by Loupakis et al (2013), as the absence of tumour cells replaced by fibrosis and/or necrosis. This pCR definition corresponds to the grade 0 of the classification proposed by Blazer et al (2008), which is based exclusively on the percentage of residual tumour cells whatever the type of regression. However, in the Tumour Regression Grade (TRG) classification as proposed by Rubbia-Brandt et al (2007), fibrosis, but not necrosis, is considered as a characteristic feature of cellular response. According to these authors, the necrosis seen in CRC liver metastases is linked to spontaneous evolution of the tumour, involving insufficient vascular supply, and not to the treatment itself, thus excluding this characteristic from the TRG. In contrast, Li Chang et al (2012) recently showed a particular type of necrosis, so-called ‘infarct-like necrosis' (ILN), characterised by large confluent areas of eosinophilic cytoplasmic remnants, located centrally within a lesion and surrounded by a rim of fibrosis with foamy macrophages (Li Chang et al, 2012). This necrosis is morphologically different from the so-called ‘dirty necrosis', usually seen in CRC, containing nuclear debris in a patchy distribution. In this study, ILN was only seen in preoperatively treated CRC liver metastases and never observed in untreated patients who underwent primary resection of CRC liver metastases. In addition, Li Chang et al (2012) also noticed that ILN was significantly associated with chemotherapy plus bevacizumab treatment, although this feature was not specific and was also encountered with chemotherapy alone. Moreover, progression-free survival and overall survival were longer in patients with CRC whose liver metastases showed ILN as compared with CRC patients whose metastases lacked this feature. Besides the well-designed work by Loupakis et al (2013), several studies concerning preoperative treatment of liver metastases have already reported a higher percentage of necrotic areas in tumours treated with bevacizumab (Klinger et al, 2010; Wicherts et al, 2011). However, the precise type of necrosis involved in tumour response was not reported. Our team recently confirmed the previous findings of Li Chang et al (2012), but on a larger population of bevacizumab-treated patients and in the setting of first-line metastatic treatment. We retrospectively reviewed archival liver CRC metastases from 91 patients who underwent secondary resection after preoperative treatment. On the basis of tumour availability, three group of patients with liver metastases were identified: a control group of chemonaive metastases (n=29), a group with metastases treated with chemotherapy (CT) alone (n=31) and a group with metastases treated with CT and bevacizumab (n=31). The frequency of ILN was statistically different among the three groups (P

Reply: Comment on ‘Allergy and acute leukaemia in children with Down syndrome: a population study. Report from the Mexican Inter-Institutional Group for the Identification of the Causes of Childhood Leukaemia (MIGICCL)’ – A reality or myth or two viewpoints about the association between allergies and acute leukaemia in Down syndrome children

Vaccination coverage is a widely used indicator of programme performance, measured by registries, routine administrative reports or household surveys. Because the population denominator and the reported number of vaccinations used in administrative estimates are often inaccurate, survey data are often considered to be more reliable. Many countries obtain survey data on vaccination coverage every 3-5years from large-scale multi-purpose survey programs. Additional surveys may be needed to evaluate coverage in Supplemental Immunization Activities such as measles or polio campaigns, or after major changes have occurred in the vaccination programme or its context. When a coverage survey is undertaken, rigorous statistical principles and field protocols should be followed to avoid selection bias and information bias. This requires substantial time, expertise and resources hence the role of vaccination coverage surveys in programme monitoring needs to be carefully defined. At times, programmatic monitoring may be more appropriate and provides data to guide program improvement. Practical field methods such as health facility-based assessments can evaluate multiple aspects of service provision, costs, coverage (among clinic attendees) and data quality. Similarly, purposeful sampling or censuses of specific populations can help local health workers evaluate their own performance and understand community attitudes, without trying to claim that the results are representative of the entire population. Administrative reports enable programme managers to do real-time monitoring, investigate potential problems and take timely remedial action, thus improvement of administrative estimates is of high priority. Most importantly, investment in collecting data needs to be complemented by investment in acting on results to improve performance.

W e would like to support the interesting conclusions from a systematic review recently presented by Schlatterer and colleagues [1]. Their study addresses treatment for Grade IIIB tibial fractures and points to negative pressure wound therapy as an option that is changing the way many traumatologists think about the treatment of these difficult-to-manage wounds. As Schlatterer and colleagues point out, some clinicians support wound closure or stable muscle flap coverage within 72 hours to limit complications. The authors, however, found evidence to suggest that negative pressure wound therapy can be performed safely beyond 72 hours without increasing the risk of infection. These complex wounds can cause terrible morbidity and constitute a public health problem for many centers [2]. Through the years, researchers have devised a hierarchy of procedures within a hypothetical reconstructive ladder to guide the surgical treatment of wounds. This traditional reconstructive ladder, in its various iterations, subsequently has become a paradigm that helps to inform the choice of closure method across an array of defects. Currently, the increased availability of negative pressure wound therapy has illuminated its key benefits, including faster granulation tissue formation, less periwound edema, decreased closure time, less-frequent dressing changes, control of bacterial proliferation, and potential cost reduction. Although Janis et al. [3] have now incorporated negative pressure wound therapy as a new step in the traditional reconstructive ladder, we are advocating a different approach. In our experience, a descent in the usual reconstructive ladder (that is, from flaps to skin grafts or primary closure) is feasible if neoadjuvant negative pressure wound therapy is applied in the course of treating some complex wounds. This downscaled approach was taken in 106 patients with complex wounds seen between February 2011 and August 2014. All patients were initially subjected to negative pressure wound therapy via VAC system (Kinetic Concepts Inc, San Antonio, TX, USA). In 90 patients whose wounds were measured, the average wound area was 87 cm. (RE: Schlatterer DR, Hirschfeld AG, Webb LX. Negative pressure wound therapy in grade IIIB tibial fractures: Fewer infections and fewer flap procedures? Clin Orthop Relat Res. 2015;473:1802–1811). The authors certify that they, or any member of their immediate families, have no commercial associations (eg, consultancies, stock ownership, equity interest, patent/ licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research editors and board members are on file with the publication and can be viewed on request. The opinions expressed are those of the writers, and do not reflect the opinion or policy of CORR or The Association of Bone and Joint Surgeons. J. A. Farina Jr MD, PhD (&), C. E. F. de Almeida MD, PhD, E. G. S. C. Marques MD, J. L. G. Jorge MD, R. V. K. S. Lima MD Division of Plastic Surgery of Department of Surgery and Anatomy, Ribeirao Preto Medical School of University of Sao Paulo-Brazil, Av. Bandeirantes, 3900 Monte Alegre, Ribeirao Preto, Sao Paulo 14049-900, Brazil e-mail: jafarinajr@fmrp.usp.br Letter to the Editor Published online: 21 August 2015 The Association of Bone and Joint Surgeons1 2015

Sir, We thank you for the response and valuable comments (Dieckmann, 2014). We appreciate your contribution by pointing out that, besides experimental data (Nuver et al, 2010), there is growing clinical evidence of acute cardiovascular toxicity of chemotherapy in TC patients, which is most likely based on vascular wall damage. Previous studies have suggested not only chronic atherosclerotic effects of chemotherapy for TC, but also more acute effects of thrombo-embolic origin (Dieckmann et al, 2010). The increased von Willebrand factor found in patients directly after chemotherapy contributes to the idea of acute vascular toxicity of chemotherapy (Dieckmann et al, 2011). It is indeed important for clinicians treating patients with TC, to appreciate the acute as well as the more chronic vascular effects of cisplatin-based chemotherapy.

Reply: Comment on ‘A derived neutrophil to lymphocyte ratio predicts clinical outcome in stage II and III colon cancer patients’

On behalf of my coauthors, I thank Singh et al. for their comments regarding our study [2]. We agree they have raised valid questions. We believe that traction or tethering effect on the nerve roots due to spinal cord shift occurring after spinal canal decompression is the cause of postoperative C5 palsy [4]. The rationale for choosing this technique is to preserve ligamentous attachments and bony posterior elements as much as possible to control posterior shift of spinal cord after suitable decompression, instead of excessive decompression. The mean improvement ratio of neurologic function (Japanese Orthopaedic Association score) was 59% at last followup in this study. Because we did not have a control group for this study, it is unclear whether the suitable decompression of hemilaminectomy decreases the degree of cord function compared to excessive decompression of laminectomy. It is true that the hemilaminectomy approach may provide a relatively narrow exposure of the spinal canal, but does more decompression lead to a better clinical result? The surgical results for multilevel continuous/mixed cervical ossification of posterior longitudinal ligament involves various aspects, including neurological function and complications (especially C5 palsy and kyphosis) at short- and long-term followup. Previous studies [1, 3] reported that unilateral fixation had comparable efficacy to bilateral fixation in lumbar spinal fusion. Unilateral fixation is one of the remarkable novel ideas of this technique. We performed contralateral fixation because it was convenient to perform bone grafting on this side, and there was sufficient bone graft bed to afford adequate stabilization of the cervical spine. Because the cervical spine was not unstable, we tried unilateral fixation after multilevel hemilaminectomy and found it was enough for stabilization of the cervical spine. Our last followup indicated a spinal fusion rate of 100%. There were no instances of pseudoarthrosis, rod breakage, or pullout of screws. Fixation on both sides may be more rigid, but unilateral fixation can be acceptable if the approach stabilizes the cervical spine. Future research studying the long-term biomechanical outcomes of unilateral fixation is necessary. Thank you for highlighting some interesting issues relevant to this surgical technique.

Background: A phase III trial was conducted to determine whether neoadjuvant chemotherapy (NACT) before radical surgery (RS) improves overall survival. Methods: Patients with stage IB2, IIA2, or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7 mg days 1–5, vincristine 0.7 mg m−2 day 5, mitomycin 7 mg m−2 day 5, cisplatin 14 mg m−2 days 1–5, every 3 weeks for 2 to 4 cycles) plus RS (NACT group) or RS alone (RS group). Patients with pathological high-risk factors received postoperative radiotherapy (RT). The primary end point was overall survival. Results: A total of 134 patients were randomly assigned to treatment. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the RS group. Patients who received postoperative RT were significantly lower in the NACT group (58%) than in the RS group (80% P=0.015). The 5-year overall survival was 70.0% in the NACT group and 74.4% in the RS group (P=0.85). Conclusion: Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival, but reduced the number of patients who received postoperative RT.

To the Editor: We read the article “Intramedullary Nails Result in More Reoperations Than Sliding Hip Screws in Two-part Intertrochanteric Fractures” by Matre et al. [3] with great interest, and we congratulate the authors for their valuable contribution to the orthopaedic literature. A fracture registration system database including more than 17,000 primary operations for hip fractures is a golden opportunity. The choice of implant for stable AO 31A1 fractures is a sliding hip screw and this is textbook knowledge [1, 2] that was confirmed by this article [3]. Another generally accepted piece of textbook knowledge is that the two disadvantages of intramedullary nails are local pain and fracture about the implant [2]. Matre et al. also confirmed this by reporting the two major reasons for increased reoperations for intramedullary nails other than sliding hip screws were local pain from the implant and fracture around the implant (with p values of 0.043 and 0.027, respectively; Table 4 [3]). Another statistically significant difference was the risk of implant removal (p = 0.028), which was lower for sliding hip screws. In their article, Matre et al. discussed the limitations of their database, and stated that they did not have the radiographs of the patients in their register. However, we believe analyzing the reasons for reoperations by depending on the radiographic images and file records (at least the failures of osteosynthesis, nonunions, cutouts, fractures around implants, and pain) would be important. In Table 4 [3], it shows there were 249 reoperations, including 189 sliding hip screws and 60 intramedullary nails. If the authors are able to review the x-rays and file records of a reasonable number of patients, perhaps as the subject of a new article, they might discuss the tip apex distance, position of the lag screw, reasons for the observed failures, pain, infection, and other reasons leading to reoperations, which we believe would be valuable contributions to the literature, and in particular would help us to distinguish implant-related from surgeon-related causes of reoperations.

I appreciate and agree with the comments shared by Rohman and Boddice regarding the expanding library of useful orthopaedic applications. In fact, since the initial publication of “Smartphone apps for Orthopaedic Surgeons” in July 2011 [3], much has changed in the realm of available orthopaedic apps. A followup study specifically examining iPad apps [4] and another review of orthopaedic apps [1] were published. I and others are continuing to examine the role that mobile technology will play in the lives of orthopaedic surgeons and patients. Rohman and Boddice identified an important concept: that the world of apps is in a state of constant change. With this in mind I launched www.TopOrthoApps.com in December 2011 to serve as a continuously updated resource of orthopaedic mobile apps. The site currently includes more than 200 apps for iPhone, iPad, and Android devices, a substantial increase from the 74 apps identified for my original article just 18 months ago. The website includes a listing of peer-reviewed apps and current literature on the topic of orthopaedic applications. In addition, the recent release of the “Top Ortho” app from the iTunes App Store (https://itunes.apple.com/us/app/toportho/id553738826?mt=8) now allows users to read reviews and download apps directly from their mobile devices. I also appreciate the authors’ mention of many newer apps and general surgical and anatomy apps that were not included in the initial review. To expand on their list, it is worth mentioning new educational resource apps such as AAOS eBooks, a plethora of online journals (Spine, Journal of Hand Surgery, JBJS Image Quiz, Journal of Orthopaedic Trauma, etc), TraumaLine, and EBSS.Live from AO. There also exist new reference and decision-management apps, such as OrthoRef, Septic Hip, SLIC, and eSplint. Newer apps have been released that focus on patient information and education, including the “Decide” series (SpineDecide, HandDecide, FootDecide, KneeDecide, etc) and DrawMD Orthopedics. Some publications [5, 7, 8, 11–13, 15] have started validating particular apps, which to this point have focused mostly on goniometer-based devices for angular measurements (ie, simple gait or function analysis measures). Finally, the number of nonEnglish apps has been increasing and currently includes apps such as OmbroCotov, OrtoClas, and TumorOsseo (Portuguese). With the prevalence and use of clinical apps on the rise, concerns have increased regarding app validation [6, 10], the risk of decreased hand hygiene [2, 14], confidentiality [9], and physician distraction [16]. Ultimately it is the responsibility of the physician to make decisions based on appropriate medical information and to ensure the safety of his or her patients. I encourage all providers to consider how apps influence their own practice and to remain diligent about ensuring patient safety and care.

Sir, We read with interest the findings presented by Muller et al (2012) evaluating associations between second to fourth digit ratio (2D : 4D) and breast cancer risk in a cohort in Melbourne. They reported a modest positive association between left 2D : 4D and breast cancer risk. They also observed an inverse association for Δr−l, which is the difference between right and left 2D : 4D, particularly for poorly or undifferentiated tumours. We were concerned that the authors focused on the Δr−l marker in their interpretations, as this marker has a lower reliability than 2D : 4D. At the same time, the 2D : 4D ratio has lower reliability than finger lengths. This is understandable, as the ratio is a computed variable of two-digit lengths, and thus their associated uncertainty is propagated following a specific function of both variables. Therefore, Δr−l contains the error associated to both right and left 2D : 4D ratios. The authors showed results on their measurement reliability in respect to digit lengths and 2D : 4D ratios, but not for Δr−l, although they based their conclusions on this marker. We previously conducted a validation study of these traits in the framework of an ongoing case–control study with more than 10 000 recruited participants. We assessed the reliability of these measures using a physical direct method with calipers, and compared it with those determined using a computer-assisted analysis on scanned images in 50 subjects. We found similar results than Muller et al in regard to digit lengths and ratios reliability. However, intraclass correlation coefficients (ICCs) for Δr−l were lower than 0.50, and variability owing to individual differences was around 30%. These results were observed for both direct and scan method, being even lower for women. These observations mean that only 30% of the Δr−l variation was produced by real differences between subjects. Allaway et al (2009) showed that ratios using the scan method with computer-assisted analysis presented slightly higher ICCs than those using photocopies. Thereby, it is expectable that the results we observed for Δr−l could be obtained using photocopies, which is the method that was used in the Melbourne cohort. Same results have been described previously by Voracek et al (2007), who found ‘ICCs unacceptably low (mostly less than 0.5)' for Δr−l, and remarked that ‘the direction and magnitude of the sex effect changed erratically across investigators'. Hopefully, misclassification will be non-differential between cases and controls, what would reinforce Muller's findings as this situation usually produce bias towards the null. However, if the exposure variable has more than two levels, like it is the case, bias away from the null may be present (Rothman et al, 2008). In conclusion, based on the previous observations, we believe that detailed information on the reliability of these measurements is needed in studies reporting associations with cancer risk, in particular specifying the variance components for all the markers involved.

To the Editor We read with interest the article by Shi et al. [9] published in your journal that addresses the controversial topic of percutaneous vertebroplasty (PVP) using meta-analysis of selected literature. The authors’ conclusion [9] appears to contradict Recommendation 8 of the American Academy of Orthopaedic Surgeons (AAOS) “Clinical Practice Guideline (CPG) on the Treatment of Symptomatic Osteoporotic Spinal Compression Fractures” [2]. We would like to address the differences between their analysis and that done by the AAOS CPG Workgroup. Although the meta-analysis process was similar in both reviews, some methodologic aspects differ. AAOS established a priori content based inclusion and exclusion criteria for study selection [2]. It is unclear how Shi et al. determined which articles to include. The AAOS Workgroup excluded three studies that they included [1, 4, 8] for poor study design description and for not being the best available evidence. A study is not the best available evidence if there are at least two studies of higher quality that measure the same outcomes; high quality studies are unlikely to be overturned by future evidence. Three studies in the current review [5, 7, 11] were published after the AAOS CPG was completed, but would not have changed our recommendation. Only three studies were mutually included [3, 6, 10]. Both reviews show no difference between sham treatments and PVP [2, 9]. There is disagreement in outcomes between nonoperative therapy and PVP, a comparison not made in randomized controlled studies because of inherent bias. The AAOS considered the magnitude of treatment effects by using statistical significance in the context of minimal clinically important improvements (MCII). The MCII is the smallest change that is important to patients; it controls for statistically significant treatment effects that are too small to matter. Shi et al. appear to incorporate only statistics. They rely heavily on the results of PVP that measure subjective outcomes and, in their conclusion, diminish the validity of comparing PVP with nonoperative treatment [9]. The meta-analysis by Shi et al. offers a different conclusion on the benefits of PVP than does the AAOS guideline. The methodology used by the AAOS is substantially more rigorous and transparent. Additional studies used in the Shi et al. analysis either do not meet our inclusion criteria standards or their weakened quality would exclude them in the AAOS analysis. We believe the AAOS’s use of MCII is preferred over the use of straight statistical comparisons used by Shi et al. PVP versus sham surgery is the gold standard of comparisons, and these results are not contradicted. It is understandable that physicians would want to validate a procedure that they believe works. For this to occur, high-quality studies using appropriate outcome measures will have to show a difference greater than the MCII.

We appreciate the thoughtful comments of Dr. Berger regarding our recent publication [1]. He focused on the following methodologic points: randomization methods, concealment of allocations, and masking (blinding). Overall, we are in agreement with the position that every action should be taken to minimize susceptibility to bias by using the most appropriate methods for conducting randomized controlled trials. However, we are concerned that theoretical judgments were proposed by Dr. Berger without detailed review of the actual studies being evaluated. Specifically, he argues that “in point of fact, it is unlikely that any of the studies were properly randomized, or enjoyed the benefits of allocation concealment”. In addition, he stated “it is unlikely that even the one study [2] that claimed masking could have been truly masked”. We should start by examining the specific methods used in the excellent study by Brushoj et al. [2] as an example. With respect to randomization, each subject was randomly divided into a group performing the prevention training program or a group performing the placebo training program using a stochastic computer-generated method. With respect to allocation concealment, group assignment was performed (according to personal registration number) by the head nurse who maintained the allocation sequence and who otherwise did not participate in the study. With respect to masking, the subjects and program instructors did not know which of the training programs was being tested. All subjects with knee or shin pain were examined by one of the authors who was blinded to training group allocation. Data were entered in a blinded manner from coded collection forms. In light of these actual methods, we are interested in comments and direction from Dr. Berger on how to better design, conduct, and report randomization, allocation concealment, and masking in future orthopaedic prevention studies.

To the editor, We read the Level I study by Tarwala and colleagues [11] with great interest. The study compared the operative tourniquet group to cementation tourniquet group in patients undergoing TKA. The authors found no difference in surgical time, postoperative pain, motion of the knee, blood loss, and complications between the two groups. The authors also indicated in their conclusion that they prefer to use the tourniquet only during cementing in TKA. Although the authors mentioned that there were no previous studies comparing the effects of tourniquet used only during cementing, we found two studies on the same topic published before the current study [4, 7]. Kvederas and colleagues [4] compared three groups undergoing TKA in a Level II study. In the first group, the tourniquet was inflated before incision and deflated after hardening of the cement. In the second group, the tourniquet was inflated just prior to cementing and was released after its hardening. In the third group, it was inflated before incision and deflated after closure of the incision. In contrast to Tarwala et al., these authors found higher estimated blood loss with the second group (the group that used the tourniquet only during cementation). The second study by Mittal and colleagues [7] noted higher transfusion rates with the short tourniquet group (cementation tourniquet). The authors had to abandon the study due to unacceptably high transfusion rates in the cementation-only tourniquet group. As both of these studies were not cited by the authors, their findings, which are in contrast to the present study, were not compared in the Discussion section. The authors failed to perform a power analysis at the initiation of the study because similar studies were not available in literature. The timing of deflation of the tourniquet remains unclear in the current study. In the Methods section, it is stated that the tourniquet was released in all patients at the completion of cementation of the patella and the knee held in extension with compression of the patella for the subsequent 10 minutes it took for the cement polymerize. If the tourniquet was released after complete polymerization of the cement, the mean tourniquet time in the cementation tourniquet group of 9 minutes (range = 7 minutes to 14 minutes) is less than the time it took for the cement to polymerize completely. If the tourniquet was released just after implantation, but before complete curing of the cement, blood that would flow after the tourniquet’s deflation would be mixed with cement at the crucial phase of cement polymerization and weaken the interface for cementation. It has been shown that hyperemia following tourniquet deflation peaks at 5 minutes after deflation [5]. Therefore, it would not provide a bloodless bone for cementation, defeating the purpose of using tourniquet only during cementation. Additionally, certain discrepancies were found in the references cited in the text and their actual contribution. In the Introduction, the authors compared randomized controlled trials featuring patients undergoing TKA with or without tourniquet that show no statistical difference in blood loss or less blood loss when no tourniquet is used. The authors provided three additional studies [2, 6, 13] in their References section. However, none of these three papers have studied blood loss with or without tourniquet in TKA. Yang and colleagues [13] investigated the effectiveness and safety of tranexamic acid in reducing postoperative blood loss in TKA, but not of the tourniquet alone. A study by Vandenbussche and colleagues [12] has been quoted as showing no difference or less blood loss without tourniquet. However, the study reports higher blood loss without the use of a tourniquet. Similarly, a study by Kato et al. [3] has been cited as a reference for wound complications following tourniquet use. However, the original study purpose was to detect emboli during the tourniquet inflation phase and to identify the composition of the echogenic material. In the Discussion section, the authors cited two meta-analyses [1, 10] as references for the absence of differences in pain with or without the use of tourniquet. However, both of these articles failed to assess pain as a part of their meta-analysis. Also, no difference in swelling of the knee has been shown as a finding of both these meta-analysis when they have not assessed the same. In fact, both of these studies discussed increased swelling of the extremity with tourniquet use in their Introduction. Alcelik and colleagues used a reference by Silver et al. [8] to cite the increased swelling post-tourniquet use. A study by Tai and colleagues [9] has been mentioned as reference for a study showing that increased drainage has been correlated to tourniquet pressure more than 225-mm of Mercury. However, this study compared the tourniquet and non-tourniquet group with respect to blood loss, soft tissue damage, pain, swelling rehabilitation, and hospital stay. It does not address the correlation between tourniquet pressure and drainage. In fact, Tai et al. [9] did not use a drain in their study in order to avoid excessive blood loss.

Comment on ‘Prevalence of the metabolic syndrome and cardiovascular disease risk in chemotherapy-treated testicular germ cell tumour survivors’

Comment: childhood leukaemia and power lines – the Geocap study: is proximity an appropriate MF exposure surrogate?

Around 1 in 10 of all cancer cases occur in adults of reproductive age. Cancer and its treatments can cause long-term effects, such as loss of fertility, which can lead to poor emotional adjustment. Unmet information needs are associated with higher levels of anxiety. US research suggests that many oncologists do not discuss fertility. Very little research exists about fertility information provision in the United Kingdom. This study aimed to explore current knowledge, practice and attitudes among oncologists in the United Kingdom regarding fertility preservation in patients of child-bearing age.A national online survey of 100 oncologists conducted online via medeconnect, a company which has exclusive access to the doctors.net.uk membership of GMC registered doctors.Oncologists saw fertility preservation (FP) as mainly a women's issue, and yet only felt knowledgeable about sperm storage, not other methods of FP; 87% expressed a need for more information. Most reported discussing the impact of treatment on fertility with patients, but only 38% reported routinely providing patients with written information, and 1/3 reported they did not usually refer patients who had questions about fertility to a specialist fertility service. Twenty-three per cent had never consulted any FP guidelines. The main barriers to initiating discussions about FP were lack of time, lack of knowledge, perceived poor success rates of FP options, poor patient prognosis and, to a lesser extent, if the patient already had children, was single, or could not afford FP treatment.The findings from this study suggest a deficiency in UK oncologist's knowledge about FP options and highlights that the provision of information to patients about FP may be sub-optimal. Oncologists may benefit from further education, and further research is required to establish if patients perceive a need for further information about FP options.

Reply: Comment on 'Stage-dependent alterations of the serum cytokine pattern in colorectal carcinoma'

We read the letter from Tao et al. with great interest. We very much appreciate their comments. In our study [4], we highlighted the fact that surgical technique is the key to achieve ideal nail positioning, ensure stable fixation, and prevent major complications. We agree with the importance of keeping the instrument insertion line (guide wire, reamer, and the nail) coaxial to the femoral canal line. Following the surgical technique guidance is the safest way to achieve that. In our practice, we always try to use the recommended entry point for the PFNA II according to the manufacturer’s suggested surgical technique; the entry point recommended by Synthes is at the tip of the greater trochanter or slightly lateral to it [6]. The decreased mediolateral angle of the PFNA II (5° compared with 6° for the PFNA) and its flattened lateral surface allow for that slightly more lateral entry point. To date, in our department, the PFNA-II has been used in more than 300 cases of unstable intertrochanteric fractures and no varus reduction of the proximal head-neck fragment or a wedge opening effect between the head-neck fragment and the shaft fragment has occurred. It is true that there are numerous cases where defining the exact position of the awl at the tip of the greater trochanter is not reliable [1, 2]. We agree that potential problems such as a stiff spine, soft tissue mass about the hip, operative drapes, or laterally oriented operating trajectory of the side-standing surgeon could arise, as Tao et al. noted. We still consider the greater trochanter entry point to be adequate for those cases. There also are cases with extension of the fracture line around the tip of the greater trochanter or with substantial comminution at the suggested entry point. In the latter cases we suggest a deeper awl insertion bypassing the fracture line and introduction of the guide wire under careful fluoroscopy in the AP and lateral views. Tao et al., in their letter, are in accordance with Streubel et al. [5] who suggested that the trochanteric tip represents the ideal starting point in only the minority of cases and an entry point 3 mm medial to the tip is the most suitable for the majority of the trochanteric nails. Nevertheless, the above suggestions are contrary not only to the manufacturer’s surgical technique, but also to the pioneering studies that introduced the PFNA II for Asian patients [3, 7]. We do not argue with the experience of Tao et al., as we do not have a medial entry point experience. However, we do stress the fact that the suggested entry point is at the tip of the greater trochanter and this specific approach was used in our published series. We thank Tao et al. for adding their experience. Adherence to the suggested surgical techniques should not discourage surgeons from trying to improve on or question some of details.

The posterior tension band complex, as articulated so clearly by Dr. Yoshihara, in my opinion makes an important contribution to the etiology of proximal junctional kyphosis (PJK). However, my hesitation in attributing the posterior tension band as the most important risk factor is largely owing to the lack of supportive data in the current literature. This lack of data lies partially in the difficulty of measuring the preservation of the posterior structures and lack of consistency with which the data often are presented. For example, if the dissection of the posterior muscular attachments to transverse processes of the upper thoracic vertebrae plays a pivotal role in the development of PJK, studies should consistently show upper instrumented vertebrae of T1–T6 having a higher incidence of PJK [1]. More recent literature comparing PJK rates in those with upper thoracic (T1–T3) versus lower thoracic (T10–T12) instrumented vertebrae [4, 8] have determined that upper instrumented vertebrae in the lower thoracic spine had a higher PJK rate. In addition, some studies [4–8] have failed to show a difference in PJK rates between different upper instrumented vertebrae. The etiology of PJK is clearly multifactorial and therefore, studies should focus on conducting multivariate analyses when identifying risk factors associated with the development of PJK. We did not investigate the posterior soft tissue integrity. As mentioned by Dr. Yoshihara, the difficulty in including this as a risk factor lies in the inability to reliably quantify the extent of soft tissue dissection and facet capsule disruption at the time of the index operation. One point mentioned by Dr. Yoshihara is that pedicle screw instrumentation damages the supraadjacent facet capsule owing to the footprint of the screw head. Although I agree this is theoretically possible, this has not been supported consistently in the literature [2, 4, 7, 10]. If this were true, one would expect constructs using hooks at the upper instrumented vertebrae to have lower rates of PJK. In fact, reports are inconsistent when it comes to instrumentation type at the upper instrumented vertebrae and PJK, with one report [2] showing a difference and others [4, 7, 10] showing no difference whether a pedicle screw or a hook is used at the upper instrumented vertebrae. As our understanding of the etiology of PJK improves, the spectrum of pathologic features encompassing PJK is becoming more transparent. Earlier studies have described PJK to be a pure radiographic finding [1, 6] while more recent studies [4, 5] suggest differences in Scoliosis Research Society outcomes scores between those with and without PJK. In studies such as those referenced by Dr. Yoshihara [2, 3, 9], no differences in health-related quality of life questionnaires were noted between patients with and without PJK and therefore, the amount of increase in PJK angle noted may be of questionable clinical importance (if it is attributed solely to the posterior approach). This shows the necessity in distinguishing purely radiographic PJK versus progressive PJK causing pain versus catastrophic PJK which often can present with myelopathy and spinal cord impingement. Studies that focus on differences between these subsets of patients with PJK will be useful in determining clinically important risk factors since it is entirely plausible that the inclusion of less severe cases of PJK with more severe cases in a study cohort can have an umbrella effect and dilute otherwise important findings. At the recent Hibbs Society Meeting held during the 2012 Annual Scoliosis Research Society Meeting in Chicago, Illinois, USA, a group of surgeons met with interest on the topic of PJK. It is clear that our understanding of PJK has improved since it was first described [1] but much work remains in understanding the cause and optimal method for treating severe cases. I believe these questions will be answered in future studies and will help us tailor methods for the prevention of PJK.

Sir, In his letter, Dr O'Mahony (2012) makes two main points. The first of these relates to the number of alternatives explored during our assessment of colorectal cancer screening in Ireland (Sharp et al, 2012), and the second relates to the terminology used in the paper. Our paper reports findings from a health technology assessment (HTA) of colorectal cancer screening; the full report has been published (Health Information and Quality Authority, 2009a). The purpose of HTA is to inform decision makers about the relative efficacy and costs of possible health-care interventions in order that coherent policy decisions can be taken. In the case of our work, the question of interest was whether population screening for colorectal cancer in Ireland would be effective and cost-effective. The initial phase of an HTA involves scoping the assessment. During this process, the alternative screening strategies to be considered were identified. The selection of the screening scenarios that would be considered was informed by an Expert Group established by the commissioners, the Health Information and Quality Authority, to oversee the evaluation. In an ideal world, all possible interventions (an exhaustive and mutually exclusive list of alternative courses of action) would be considered. However, some options may be excluded because they are deemed infeasible to implement (e.g., due to insufficient endoscopy capacity) or unacceptable to the service providers (e.g., due to risk of death associated with the technology). It may also be impractical to detail all alternatives (e.g., every possible screening frequency or combination of tests). Specifically, in our HTA, whether to consider screening by colonoscopy or CT colonography was discussed at this stage; the former was considered to be associated with unacceptably high risks of death and the latter was considered as both unfeasible and to have an insufficient evidence base. Thus, after scoping, the actual number of alternatives to be investigated in the detailed modelling was fewer than the initial set examined. The second point made in the letter is that of terminology. The concept of ICERs and ACERs is discussed, and the received interpretation of them is highlighted. In our HTA, the results are provided in a disaggregated fashion (as is recommended by 5.7.6 of the NICE methods guidance, 2008) (National Institute for Health and Clinical Excellence, 2008). This allows a proper comparison to be made between the interventions, and ensures that the decision maker does not blindly adopt a course of action deemed to be ‘cost-effective' by reference to the ICER alone. It also permits other readers to calculate ICERs for many different comparisons should they so wish. Similarly, it is possible to evaluate any scenario vs no screening (which equates to an ACER, but also to the ICER when other options become infeasible). An additional consideration when carrying out an HTA is how uncertainty in model inputs will be treated. Our analysis included a full probabilistic sensitivity analysis (PSA). Doing this involves greater consideration of the details of each scenario, but provides better information for the decision maker. For similar strategies (such as limiting screening to particular age groups), the relative cost-effectiveness of each was indistinguishable in the PSA. That is, the uncertainty made it impossible to determine which was the most cost-effective. This provides another reason to include a limited number of scenarios and to provide results in a disaggregated manner. Since our HTA was conducted, additional work has been carried out by the Health Information and Quality Authority to establish how a screening programme, although cost-effective, might be funded at a national level (Health Information and Quality Authority, 2009b). Following this work, a decision was made to implement a population-based colorectal cancer screening programme in Ireland, based on biennial faecal immunochemical testing. Significant progress has been made towards this objective (National Cancer Screening Service, 2012). This process illustrates very effectively how the reality of limited resources means that HTA is of increasing importance for decision makers in prioritising health-care interventions.

We thank Dr. Moyad for his constructive criticism and service to the Haitian people. His positive experience providing care in the wake of this natural disaster is testament to the power of volunteerism in resource-poor countries. After the earthquake, many medical and surgical volunteers sacrificed to provide the highest quality care to disaster casualties. These stories and tremendous worldwide response should give all of us hope regarding our international capacity for relief. Nevertheless, the intention of the publication was to provide our readership with a perspective that has remained largely elusive. Although many publications regarding the orthopaedic response to the Haiti earthquake document the quantity of procedures performed and the personal stories of the volunteers, there are few systematic documentations of the failures. Our systematic method of data collection and analysis has many weaknesses highlighted in the publication, but it provides an important window into potential ways in which we can improve and devise measures of disaster care. Many of the anecdotes associated with poor-quality care, we believe, were preventable with training. From our interviews, for example, we discovered that ill-prepared physicians such as ophthalmologists and pediatricians were performing orthopaedic surgeries without adequate training. In addition, to address Dr. Moyad’s specific point regarding fasciotomies, there is documentation to suggest that this procedure should be reconsidered in the acute muscle-crush compartment syndromes commonly found in earthquake zones. The muscle in these limbs usually is already dead and in these resource-poor settings, when damage-control orthopaedics is necessary, there is limited time for repeated operations that risk limb-threatening infection [2]. Although we will never know the specific nature of every injury treated, there clearly is room for debate and greater need for better documentation and further study of disaster response. A substantial report from the Pan American Health Organization (PAHO) discusses the overall lack of organization and chaotic pattern of the relief effort [1]. The foreword of the report states that the response, “included a number of wholly unprepared or even incompetent health actors who bypassed the overburdened coordination mechanisms”. For these reasons, the PAHO report highlights the need for accreditation and training in disaster response, a matter about which we disagree with Dr. Moyad. Regardless of the outcome, training courses provide volunteers with the opportunity to share stories, exchange knowledge, build expert opinion, and prepare for a variety of patient-care possibilities. We hope that formal training courses are cultivated to continue to improve the care provided to patients most in need.

Reply: Comment on ‘Childhood leukaemia close to high-voltage power lines – the Geocap study, 2002–2007’ – Odds ratio and confidence interval

Sir, We congratulate Hashida et al (2013) on an interesting report that Merkel cell polyomavirus (MCV) is present in ∼18% of non-small cell lung carcinoma (NSCLC). An important clarification is needed; however, we have not yet discovered a naturally occurring mutation in the MCV large T retinoblastoma-binding motif (LFCDE). We engineered the sequence that the authors refer to as Appendix206 ({"type":"entrez-nucleotide","attrs":{"text":"JN038578","term_id":"354683949","term_text":"JN038578"}}JN038578) to have a lysine substitution mutation (LFCDK) to serve as a negative control for the wild-type appendix-derived LT deposited as {"type":"entrez-nucleotide","attrs":{"text":"JN038579","term_id":"354683952","term_text":"JN038579"}}JN038579, which possesses a wild-type LXCXE motif. Post-submission editing at NCBI obfuscated the description of {"type":"entrez-nucleotide","attrs":{"text":"JN038578","term_id":"354683949","term_text":"JN038578"}}JN038578, leading to the confusion described in this paper. Thus, all but one of the MCV sequences Hashida et al (2013) report are consistent with wild-type virus and do not have the tumour-specific mutations we described that eliminate MCV LT helicase activity (Shuda et al, 2008). The authors do describe one virus (AC43) with a terminally truncated LT consistent with a tumour-derived mutation. Together with its high viral copy number, this case represents a particularly intriguing tumor that deserves careful follow-up, such as Southern blotting for clonality and histopathological characterization with reliable biomarkers for NSCLC to investigate a potential MCV contribution to its tumorigenesis.

Reply: Comment on ‘Quiescence and yH2AX in neuroblastoma are regulated by ouabain/Na,K-ATPase’: ouabain and cancer

The pathogenesis of lymph node metastases in preinvasive breast cancer – ductal carcinoma in situ (DCIS) – remains controversial. The one-step nucleic acid amplification (OSNA) assay is a novel molecular method that can assess a whole node and detect clinically relevant metastases. In this retrospective cohort study, we determined the performance of the OSNA assay in DCIS and the pathogenesis of node-positive DCIS.The subjects consisted of 623 patients with DCIS who underwent sentinel lymph node (SN) biopsy. Of these, 2-mm-sectioned nodes were examined using frozen-section (FS) histology in 338 patients between 2007 and 2009, while 285 underwent OSNA whole node assays between 2009 and 2011. The SN-positivity rate was compared between cohorts, and the characteristics of OSNA-positive DCIS were investigated.The OSNA detected more cases of SN metastases than FS histology (12 out of 285, 4.2% vs 1 out of 338, 0.3%). Most of the metastases were micrometastases. The characteristics of high-risk DCIS (i.e., mass formation, size, grade, and comedo) and preoperative breast biopsy (i.e., methods or time to surgery) were not valid for OSNA assay–positive DCIS.The OSNA detects more SN metastases in DCIS than FS histology. Further examination of the primary tumours and follow-up of node-positive DCIS are needed to elucidate the pathogenesis.

Sir, In their interesting study Wong et al (2012) report a preclinical and clinical correlation between the number of CD45−CD31+ cells in the peripheral blood and the growth of prostate cancer. Using flow cytometry and microscopy, they suggest that the large majority of CD45−CD31+ cells are more likely immature platelets and not circulating endothelial cells (CECs). Considering the wide antigenic overlap between CECs and platelets, and the possible aggregation/adhesion of platelets with CECs, we and others feel that in multiparametric flow cytometry the use of a cell viability stain and of a DNA-specific staining are necessary to discriminate DNA-containing CECs from DNA-free, CEC-derived macroparticles and platelets (Bertolini et al, 2006; Mancuso and Bertolini, 2010; Mund et al, 2012). When Ning et al (2010) used a nucleic acid stain to enumerate CECs in prostate cancer patients receiving Bevacizumab, Docetaxel, Thalidomide and Predinisone, they reported a strong inverse correlation between changes in apoptotic CECs and PSA levels, suggesting that the drug combination may effectively inhibit tumour angiogenesis. Along this line, Strijbos et al (2010) used a nuclear stain to enumerate CECs in prostate cancer patients receiving Docetaxel. They reported that CECs' kinetics during treatment, alone or in combination with other biomarkers, predicted survival in this cancer population. Data from Wong et al (2012) suggest that immature platelets deserve further clinical investigation as possible biomarkers of disease status in metastatic prostate cancer. One of the unique features of multiparametric flow cytometry is the possibility to enumerate in the same test-tube several different populations of cells, such as DNA-containing CECs, DNA-free, CEC-derived macroparticles and platelets. Several previous clinical studies involving antiangiogenic therapeutics in cancer patients indicated that these different cell and platelet populations might serve as unique predictive and/or prognostic biomarkers. We, therefore, recommend investigating them all in parallel in one test-tube using multiparametric flow cytometry technique.

To the Editor We read with great interest the article, ‘‘The Withdrawn ASR™ THA and Hip Resurfacing Systems: How Have Our Patients Fared Over 1 to 6 Years?”, by Hug et al. [5]. We thank them for sharing their results and for their contribution to the knowledge related to the performance of The ASR™. However, in two instances in the Discussion section, Hug et al. state that metal-on-metal devices are flawed or poorly performing as a class. The scope of their study was limited to the ASR™ system and such statements cannot be derived from their results. If they were referring to other publications, references should have been inserted, but none was present. Such statements can be made only after demonstration that all devices from a class are outperformed by all devices from another and such a result is unlikely. In addition, there are at least five recent publications showing Kaplan-Meier survival estimates of metal-on-metal hip resurfacing devices ranging from 94.6% to 99% at 10 years in male patients [2, 4, 6, 7] or patients with large femoral components sizes [1]. If progress is going to be made in the field of hip arthroplasty, is it not time surgeons begin to treat patients as individual cases rather than with a “one device fits all” policy? The revision rates of metal-on-metal devices are design-dependent [3]. The high failure rate, elevated blood metal ion levels, and high prevalence of adverse local tissue reactions observed with the ASR™ prosthesis are unfortunate but do not allow inference to the performance of the bearing technology itself.

To the Editor With great interest we read the article by Johnson et al. regarding the presence of the ACL in patients with arthritic knees [1]. Limitations in function after TKA are common. Because of the increasing need for TKA, it is important to determine the cause of patients’ dissatisfaction. Johnson et al. concentrated on the kinematics of the knee, and more specifically the presence of the ACL preoperatively. They concluded the best way to determine if the ACL is present is to combine MRI with the Lachman test. However, we had some difficulties interpreting the results because Johnson et al. did not mention whether the researchers who performed the observation during the operation were blinded for the results of the Lachman test. If this is not the case, the results possibly are biased and the observed relationships may be overestimated. Furthermore, we question why the Lachman test was performed after induction of anesthesia. It seems more logical and clinically relevant to perform this test at the outpatient clinic before surgery so that the surgeon can choose the right implants and instruments in advance. Johnson et al. assessed preoperative MRIs from 100 of the 200 included patients. It is unclear why and on what basis the authors’ selection of 100 of the total of 200 included patients was made. Was this a representative selection? In the Results section, part of the answer to the 5th question (did ACL status depend on age or sex?) is missing. Does the ACL status depend on sex? Unfortunately it is only reported that patients with an intact ACL at the time of surgery were older. Finally, there are inconsistencies and missing data in Table 1. The number of patients with absent intraoperative ACL integrity is missing. In the same table we found that the 194 negative Lachman tests should be 184 to make a total of 100%. We would appreciate the authors’ responses to our questions.