Medicine Correspondence Blog

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

Thursday, September 20, 2018

With great interest we read the article by Jang et al.1 They showed that 8/20 (40%) heart valves of patients with culture-negative infectious endocarditis (IE) were Coxiella burnetii PCR-positive. None of these patients received adequate treatment and their mortality was higher than in C. burnetii PCR-negative patients.


This study describes a high percentage of missed diagnoses of Q fever endocarditis with a high mortality rate and hopefully raises awareness among medical specialists in South Korea. All medical specialists that care for patients with IE should be educated on how to recognize and treat Q fever endocarditis. When culture-negative IE is suspected or diagnosed, serological testing for C. burnetii is indicated in line with the modified Duke criteria.2,3 It surprised us that testing for C. burnetii serology had not been performed in these patients with culture-negative IE reportedly because of "low clinical suspicion" due to the low incidence of Q fever endocarditis.


Q fever endocarditis can present as a chronic low-grade infection with few signs or symptoms, but can cause life-threatening complications.4,5 When C. burnetii PCR is positive on blood or tissue in patients with suspected or diagnosed IE, the diagnosis of Q fever endocarditis is considered proven. This criterion is described in the Dutch consensus guideline on chronic Q fever6 as well as in the French guidelines from Eldin et al.7 and also applies to countries with low incidence of Q fever endocarditis.


Even if the diagnosis of Q fever endocarditis is made in retrospect for research purposes, a positive C. burnetii PCR on heart valves should never be discarded and treatment should have been initiated. We were surprised that only two C. burnetii PCR-positive patients were serologically tested for C. burnetii after their heart valves were C. burnetii PCR-positive and none of them were treated for Q fever endocarditis. Without adequate therapy, the higher mortality rate in the C. burnetii PCR-positive patients is not surprising at all. Therefore, we strongly advise to inform C. burnetii PCR-positive patients about their diagnosis, examine them for ongoing endocarditis and start treatment.


To conclude that C. burnetii PCR on excised heart valves may increase the diagnostic yield and reduce the number of missed cases is important, but it should not result in waiting until IE progresses as far as needing heart valve replacement before diagnostic testing for C. burnetii is performed. We recommend serological testing for C. burnetii in all culture-negative IE patients, in line with the modified Duke criteria.2 This way, adequate treatment can be started early in the course of the disease and surgery may not be necessary.

Patients with (suspected) Q fever endocarditis should preferably be referred to a center with experience in this field or, if this is not possible, an expertise center should be consulted. The data presented by Jang et al. clearly indicate the necessity to consider Q fever endocarditis in all cases of culture-negative IE and will hopefully increase awareness in South Korea for this disease.  

Author Correspondence

 S.B. Buijs, MD 



[1] Jang YR, Song JS, Jin CE, et al. Molecular detection of Coxiella burnetii in heart valve tissue from patients with culture-negative infective endocarditis. Medicine (Baltimore). 2018;97(34):e11881.

[2] Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for diagnosis of infective endocarditis. CID. 2000;30:633-638.

[3] Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J. 2015;36(44):3075-3128.

[4] Kampschreur LM, Delsing CE, Groenwold RH, et al. Chronic Q fever in the Netherlands 5 years after the start of the Q fever epidemic: results from the Dutch chronic Q fever database. J Clin Microbiol. 2014;52(5):1637-1643.

[5] ​van Roeden SE, Wever PC, Kampschreur LM, et al. Chronic Q fever-related complications and mortality: data from a nationwide cohort. ECCMID 2017 eLibrary Material of the 27th European Congress of Clinical Microbiology and Infectious Diseases; 2017; Vienna, Austria.

[6] Wegdam-Blans MC, Kampschreur LM, Delsing CE, et al. Chronic Q fever: review of the literature and a proposal of new diagnostic criteria. J Infect. 2012;64(3):247-259.

[7] Eldin C, Melenotte C, Mediannikov O, et al. From Q Fever to Coxiella burnetii Infection: a Paradigm Change. Clin Microbiol Rev. 2017;30(1):115-190.


Thursday, September 13, 2018

I read with interest the article by Peng et al.[1] entitled: "The long-term efficacy of STN vs GPi deep brain stimulation for Parkinson disease: A meta-analysis". However, this meta-analysis includes several methodological mistakes that worth attention.

In systematic reviews and Meta-analyses, the authors should exclude duplicate reports and select unique studies for inclusion in the evidence synthesis process. This is a common practice in this journal "Medicine" and following the guidelines of Cochrane Handbook of Systematic Reviews and Meta-analysis of interventional studies and the preferred reporting items of systematic review and meta-analysis (PRISMA statement) [2, 3].

In this meta-analysis, the authors included five articles. However, three of these five articles described the same patients; Follet et al.[4], Weaver et al.[5], and Katz et al.[6], are three reports from the same study, Veterans Administration Cooperative Studies Program #468 multicentre study. Because of pooling three reports from the same RCT, the impact of this multicentre RCT in the analysis was augmented and has led to incorrect results.

For example, in Figure 5, the authors pooled the three duplicate reports from the Veterans Administration Cooperative Studies Program #468 multicentre study ( numbers, NCT00056563 and NCT01076452.). According to Figure 5, the differences in PDQ ADL in the 3 studies were as follows: Follet 2010 (MD -4.5 with 95% CI from -9.11 to 0.11), Katz 2015 (MD -1.6 with 95% CI from -6.63 to 3.43), and Weaver 2012 (MD -4.0 with 95% CI from -10.39 to 2.39). It deserves our notice that the MDs of the three reports were not statistically significant. However, when the three duplicate studies are pooled in the meta-analysis model, the pooled MD was statistically significant (MD -3.36 with 95% CI from -6.36 to -0.36, P=0.03).

Secondly, Rodriguez-Oroz et al.[7] published a long-term report from a non-randomized study (DBS study group 2000 [8]). There is a methodological concern in pooling randomized and non-randomized studies in meta-analysis. However, this is not the main problem; The authors assessed the risk of bias in Rodriguez-Oroz et al.[7] using the Cochrane ROB tool, a tool for evaluating the risk of bias in RCTs[2]. Alternatively, the authors should have assessed the Rodriguez-Oroz et al.[7] study using the ROBINS-I checklist for non-randomized studies [9]. A more serious mistake here is that the authors marked the allocation concealment as (yes +) and the blinding as (yes +) which seems impossible since the Rodriguez-Oroz et al.[7] study was not RCT and is no concealed allocation or blinding in non-RCT studies.

Another issue in the risk of bias assessment is that the study of Weaver et al.[5] was marked as (no -) in terms of the allocation concealment and (unclear ?) in terms of other source of bias while Follet 2010 [4] and Katz 2015 [6] were considered as (yes +) and (no -) in terms of allocation concealment and other bias, respectively. Given that the three reports are describing the same multicentre RCT (Veterans Administration Cooperative Studies Program #468), the risk of bias in these three reports should be similar as they represent the same clinical trial. However, the authors mistakenly judged the risk of bias scores of Weaver et al.[5] (4 out of 6) while both Follet 2010 [4] and Katz 2015 [6] scored 6.

(3) It is known that higher scores of UPDRS indicate worse PD symptoms while a decrease in UPDRS-III indicates the improvement in motor functions. Therefore, the mean change in UP​DRS scores in all included studies was calculated as MD=post–baseline, therefore, the changes in UPDRS scores after DBS include a minus sign highlighting a decrease in the UPDRS score. Unfortunately, the authors ignored the direction of the scale and therefore, the presented effect estimates of individual studies and the pooled effect estimate are in the opposite direction.

It is important to highlight that this meta-analysis was based on several methodological errors and if corrected by removing the duplicate studies, most of the provided plots will not be reliable statistically due to an insufficient number of included studies (one study in some outcomes). The evidence provided by this meta-analysis is not robust and is not conclusive; Further studies are still needed to evaluate the long-term efficacy of STN DBS and GPi DBS in patients with advanced PD.

Author Correspondence

Ahmed Negida; Faculty of Medicine, Zagazig University, Zagazig, El-Sharkia, Egypt



[1] Peng L, Fu J, Ming Y, et al. (2018) The long-term efficacy of STN vs GPi deep brain stimulation for Parkinson disease. Medicine (Baltimore) 97:e12153 . doi: 10.1097/MD.0000000000012153

[2] Higgins J, Green S (2011) Cochrane handbook for systematic reviews of interventions Version 5.1. 0. [updated March 2011]

[3] Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097 . doi: 10.1371/journal.pmed.1000097

[4] Follett KA, Weaver FM, Stern M, et al (2010) Pallidal versus Subthalamic Deep-Brain Stimulation for Parkinson's Disease. N Engl J Med 362:2077–2091 . doi: 10.1056/NEJMoa0907083

[5] Weaver FM, Follett KA, Stern M, et al (2012) Randomized trial of deep brain stimulation for Parkinson disease: thirty-six-month outcomes. Neurology 79:55–65 . doi: 10.1212/WNL.0b013e31825dcdc1

[6] Katz M, Luciano MS, Carlson K, et al (2015) Differential effects of deep brain stimulation target on motor subtypes in Parkinson's disease. Ann Neurol 77:710–719 . doi: 10.1002/ana.24374

[7] Rodriguez-Oroz MC, Obeso JA, Lang AE, et al (2005) Bilateral deep brain stimulation in Parkinson's disease: a multicentre study with 4 years follow-up. Brain 128:2240–9 . doi: 10.1093/brain/awh571

[8] Deep-Brain Stimulation for Parkinson's Disease Study Group, Obeso JA, Olanow CW, et al (2001) Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson's disease. N Engl J Med 345:956–63 . doi: 10.1056/NEJMoa000827

[9] Sterne JA, Hernán MA, Reeves BC, et al (2016) ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ i4919 . doi: 10.1136/bmj.i4919​

Friday, September 7, 2018

We have read with interest the paper by Zhu et al. on the management of a patient with testicular Leydig cell tumor.1

The Authors reported a patient with testicular neoplasm that histological and immunohistochemical analyses revealed to be a Leydig cell tumor. As stated by the Authors, the immunohistochemical analysis showed that the tumor cells stained positively for inhibin and negatively for pan-cytokeratin, cytokeratins 8/18, alpha-feto ptotein, human corionic gonadotropin, CD 30, CD 99 and S-100.

The Authors throughout the paper report the term inhibin but they should had reported inhibin B that is mainly produced within the testis.  To this regard it is well known that inhibin B is the main protein physiologically secreted by Sertoli cells located within the seminiferous tubule under the control of FSH.2,3 Leydig cells do not secrete inhibin B but produce other proteins such as INSL3, that has been utilized to characterize Leydig cells an also Leydig cells tumors by immunohistochemical analysis.4

In the case report of the Authors, if the immunohistochemical analysis revealed the expression of inhibin (possibly B), it could be the case of a mixed Sertoli-Leydig cell tumor, although this kind of tumor is exceptionally rare in the male being more frequent in the ovary.5


Author Correspondence:

Marco Rossato, MD, PhD

University of Padova, Padova, Italy.


Luca De Zorzi, MD,

Istituto Oncologico Veneto, Treviso, Italy




[1] Zhu JLuan YLi H. Management of testicular Leydig cell tumor: A case report. Medicine (Baltimore) 2018;97:25.

[2] de Kretser DM, Robertson DM. The isolation and physiology of inhibin and related proteins. Biol Reprod 1989;40:33-47.

[3] Foresta C, Bettella A, Petraglia F, Pistorello M, Luisi S, Rossato M. Inhibin B levels in azoospermic subjects with cytologically characterized testicular pathology. Clin Endocrinol 1999;50:695-701.

[4] Rossato M, Tavolini IM, Calcagno A, Gardiman M, Dal Moro F, Artibani W. The novel hormone INSL3 is expressed in human testicular Leydig cell tumors: a clinical and immunohistochemical study. Urol Oncol 2011;29:33-37.

[5] Young RH. Sex cord-stromal tumors of the ovary and testis: their similarities and differences with consideration of selected problems. Mod Pathol 2005;18 (Suppl 2):S81-S98.​

Tuesday, September 4, 2018

Dear Editor,
We have read with interest the article entitled "Association of vitamin D receptor BsmI rs1544410 and ApaI rs7975232 polymorphisms with susceptibility to adolescent idiopathic scoliosis: A systematic review and meta-analysis'' by Yin et al[1]. However, the meta-analysis has brought several questions to our minds that we would like to note to the authors:

  1. In the results, the authors declared that five case–control studies including 717 adolescents with AIS and 554 healthy controls were deemed eligible for inclusion for meta-analysis after they searched all the common databases. However, we believe that this process is not rigorous. In the five documents, two articles were belonged to the same institution and the same corresponding author, and the cases they included were repetitive. Among them, Chen's[2] study was conducted from April 2004 to October 2007 in 146 female patients at the Department of Spinal Surgery, Drum Tower Hospital, Nanjing University School of Medicine, with an average age of (13.50±1.43) years (10-18 years old) and an average Cobb angle of (32.03±10.34°) (15-65°). Xia's[3] study was conducted from January 2005 to July 2005 in 164 female patients at the Department of Spinal Surgery, Drum Tower Hospital, Nanjing University School of Medicine, with an average age of (14.4±2.0) years (9-20 years old) and an average Cobb angle of (31.26±13.45°) (10-105°). The population of these two studies must be have an overlap and therefore cannot be included in this study at the same time.
  2. Quality assessment of included studies was core component in a meta-analysis, so the authors should provide the detail of Newcastle–Ottawa Scale (NOS) for each included study in another table.
  3. In the sensitivity analysis and publication bias, the authors believed that the corresponding pooled results did not change dramatically when each study was removed. However, when removing the study conducted by Wang et al.[4]we find that the between-study heterogeneity was not
    significant (I2 = 23% after its removal). Thus, the study performed by Wang and coworkers was deemed as one potential source of heterogeneity across studies.
  4. Publication bias was an important aspect in the meta analysis. So the authors should present the detailed results of Begg's test and Egg's test. Moreover, the sample size was less than 10, so you should consider to use trim and fill analysis to conduct publication analysis.
  5. The author should verify that all the studies had genotype frequencies in control groups consist with HWE and show the result in Table 1.
  6. The literature searched for the ApaI polymorphism is quite limited, especially if there's repeated data between two literatures. Therefore, there is no strong statistical power to support this conclusion that the VDR ApaI polymorphism only played a key role in AIS etiology and development in Asian populations.

Thanks for authors' contribution in supplying us with a meta-analysis to explore the association between vitamin D receptor gene and adolescent idiopathic scoliosis. However, more studies with larger sample size and higher quality should be carried out in the future.

Author Correspondence

Lin Lu1, Jialang Hu1, Ying An1, Ming Chen1​




1.         Yin X, Wang H, Guo J, Zhang L, Zhang Y, Li L, Hou S. Association of vitamin D receptor BsmI rs1544410 and ApaI rs7975232 polymorphisms with susceptibility to adolescent idiopathic scoliosis: A systematic review and meta-analysis. Medicine (Baltimore). 2018; 97: e9627. doi: 10.1097/MD.0000000000009627

2.         Chen W, Qiu Y, Zhu F, Zhu Z, Sun X, Liu Z, Chen Z. [Vitamin D receptor gene polymorphisms: no association with low bone mineral density in adolescent idiopathic scoliosis girls]. Zhonghua Wai Ke Za Zhi. 2008; 46: 1183-6. doi: 10.3321/j.issn:0529-5815.2008.15.020

3.         Xia C, Qiu Y, Sun X, Qiu X, Wang S, Zhu Z, Zhu F. [Vitamin D receptor gene polymorphisms in female adolescent idiopathic scoliosis patients]. Zhonghua Yi Xue Za Zhi. 2007; 87: 1465-9. doi: 10.3760/j:issn:0376-2491.2007.21.007

4.         Wang Y, Cui ZQ, Luo TB, Liu L. Correlations of VDR and VDBP genetic polymorphisms with susceptibility to adolescent idiopathic scoliosis and efficacy of brace treatment. Genomics. 2016; 108: 194-200. doi: 10.1016/j.ygeno.2016.11.004.

Wednesday, August 8, 2018

​I read with great interest the Zeng, et al. paper presenting a patient with diabetic foot ulcer (DFU) who had been treated with placenta-derived mesenchymal stem cells hydrogel (1). However, I would like to express my disapproval for the accuracy of microbiologic analyse and for possibility of treatment of fungal infection with antibacterial agent, in which claimed Zeng's article.

Diabetic foot ulcer is a complex and severe clinical problem especially if it is complicated with infections (2). At present, although profound treatment options are in existence, patients with DFU are still bearing a high risk of infection, amputation and high cost of treatment and care (2,3). Nowadays, a growing number of DFUs are treated with stem cell applications. (4,5). Indeed, stem cell therapy is promising treatment option by the potential to promote foot wound healing in diabetic patients.

The authors indicated that Candida glabrata was isolated in culture of the patient's diabetic wound and it was sensitive to cefoperazone-sulbactam according to the sensitivity analysis of the microorganism. It is clear that the authors in either identification of microorganism or sensitivity tests did a serious mistake. They claim that C. glabrata was sensitive to cefoperazone-sulbactam and they treated the patient with cefoperazone-sulbactam, successfully. In fact, C. glabrata is a member of the Candida species and it is not possible to treat Candida spp. infections with antibacterial agents such as cefoperazone-sulbactam due to they don't susceptible to antibacterial agents (6).

Candida spp. are ubiquitous organism.  They have been considered a relatively nonpathogenic saprophyte of the normal flora of healthy individuals, rarely causing serious infections in humans (6). However, mucosal and systemic candida infections have increased significantly among patients with diabetes mellitus, especially in those with poorly controlled disease (7).  Most diabetic foot infections are known to have a polimicrobial etiology (8). The role of fungus in the etiology of diabetic foot infection is overlooked mainly due to the difficulty in distinguishing between colonization and infection (7,9). But recent studies revealed that fungal etiological agents, mainly Candida species, are responsible much more than estimated in diabetic foot infections (7,9,10,11).

As a result, Candida spp. are significant cause of diabetic wound infection and may require antifungal intervention for successful management of diabetic foot ulcers.


  1. Zeng X, Tang Y, Hu K, Jiao W, Ying L, Zhu L, Liu J, Xi J. Three-week topical treatment with placenta-derived mesenchymal stem cells hydrogel in a patient with diabetic foot ulser. A case report. Medicine 2017;96:51.
  2. Boulton AJ, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J. The global burden of diabetic foot disease. Lancet 2006;366:1719-1724.
  3. Prompers L, Schaper N, Apelqvist J, Edmonds M, Jude E, Mauricio D, et al. Prediction of outcome in individuals with diabetic foot ulcers: focus on the differences between individuals with and without peripheral arterial disease. The EURODIALE Study. Diabetologia 2008:51(5):747-55.
  4. Lu D, Chen B, Liang Z, Deng W, Jiang Y, Li S, at al. Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind, randomized, controlled trial. Diabetes Res Clin Pract 2011;92(1):26–36.
  5. Cau Y, Gang X, Sun C, Wang G. Mesenchymal stem cells improve healing of diabetic foot ulcer. J Diabetes Res 2017; 2017: 9328347.
  6. Fidel PL Jr, Vazquez JA, Sobel JD. Candida glabrata: review of epidemiology, pathogenesis, and clinical disease with comparison to C. albicans. Clin Microbiol Rev 1999;12(1):80-96.
  7. Chincholikar DA, Pal Rb. Study of fungal and bacterial infections of the diabetic foot. Indian J Pathol Microbiol 2002;45(1):15-22.
  8. Lipsky BA, Berendt AR, Deery HG, at al. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2004;39(7):885. 
  9. Heald AH, O'Halloran DJ, Richards K, at al. Fungal infection of the diabetic foot: two distinct syndromes. Diabet Med 2001;18(7):567-72.
  10. Mlinaric Missoni E, Vukelic M, de Soy D, Belicza M, at al. Fungal infection in diabetic foot ulcers. Diabet Med. 2005;22(8):1124-5.
  11. Gitau AM, Ng'ang'a ZW, Sigilai W, at al. Fungal infections among diabetic foot ulcer-patients attending clinic in Kenyatta National Hospital, Kenya. East Afr Med J 2011;88(1):9-17