Startseite The CCR5-Delta32 genetic polymorphism and HIV-1 infection susceptibility: a meta-analysis
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The CCR5-Delta32 genetic polymorphism and HIV-1 infection susceptibility: a meta-analysis

  • Jun Ni , Dan Wang und Sheng Wang EMAIL logo
Veröffentlicht/Copyright: 16. Oktober 2018
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Open Medicine
Aus der Zeitschrift Open Medicine Band 13 Heft 1

Abstract

The CC chemokine receptor 5 (CCR5) is a chemokine receptor which is widely expressed in several immune cells involved in the inflammatory responses. Previous published studies revealed the relation of the CCR5 gene (CCR5-delta32) with the risk of HIV-1 infection, but the results are debatable and inconclusive. Here by meta-analysis, we have systematically evaluated the relation between the CCR5-delta32 polymorphism and the risk of HIV-1 infection. A comprehensive search in PubMed, EMBASE, CNKI, Cochrane Library, and WanFang database was performed up to April 15, 2018. The pooled odds ratio (ORs) along with its 95% credible interval (95%CI) was used to evaluate the relation between the CCR5-delta32 polymorphism and HIV-1 infection risk. The study included 24 case-control studies involving 4,786 HIV-1 infection patients and 6,283 controls. Compared with the wild-type homozygous genotypes, the results showed that the CCR5-delta32 heterozygotes (OR=1.16, 95%CI=1.02-1.32) had an increased susceptibility to HIV-1 and the delta32 homozygous (OR=0.25, 95%CI=0.09-0.68) had significantly reduced the susceptibility to HIV-1 for healthy controls. Moreover, we have found the delta32 allele carriers (OR=0.71, 95%CI=0.54-0.94) had significantly cut down the HIV-1 infection susceptibility when using exposed uninfected (EU) as controls. We also conducted the stratified analysis by ethnicity, and there significant association was detected in Caucasian in delta32 allele carrier genotype. To summarize, our meta-analysis suggests that the CCR5-delta32 homozygous genotype (delta32/delta32) confer possible protection against HIV-1, especially the exposed uninfected groups.

Keywords: CCR5-Delta32; Polymorphism; HIV-1; Susceptibility; Meta-analysis

1 Introduction

Human Immunodeficiency Virus-1 (HIV-1)/Acquired Immunodeficiency Syndrome (AIDS), the world major infectious killer remains one of the most important public health challenges in the world. It was estimated that about 36.7 (34.0-39.8) million people were living with HIV in 2016, and 1.8 million people have died from HIV/AIDS every year. Therefore, HIV prevalence can be considered as the greatest issue in contemporary society, including economic and health crisis [1]. However, many basic questions about the HIV-1 infection pathogenesis have not been answered. Several studies demonstrated that they have a significant difference in susceptibility and progression of HIV-1 infection [2, 3, 4]. Host genetic diversity has an important role in either disease susceptibility or resistance [4, 5]. However, the positive role of different genes in HIV/AIDS progression has still remained controversial [6, 7].

Its chemokines and their natural receptors act a key part in HIV-1 binding and entry [8]. Chemokine receptors act on CD4 as a relevant receptor for HIV-1 to regulate the first step in the entry of HIV-1 virus. CCR5, a chemokine receptor of gene product, is expressed on macrophages, monocytes, T and dendritic cells. This is a specific receptor for the CC ligand 3 (CCL3), CCL4, and CCL5 chemokine and a key part in the transferring of immune cells to inflammatory sites [9]. The CCR5Δ32 variant is characterized by a 32 base-pair (bp) deletion of the CCR5’s gene coding region; the deletion of CCR5-delta32 was initially discovered and gained the greatest interest in the relation to infection with the HIV-1. This lack of homozygosity is associated with preventing the risk of HIV-1 infection [10]. Liu et al performed a meta-analysis and demonstrated that there was no statistical correlation between the CCR5-delta32 polymorphism and the risk of HIV-1 infection. For adults, the CCR5-delta32 polymorphism was investigated for their association with the risk of HIV-1 infection, but the results from the previous published researches remains conflicting and inconclusive [11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34]. Thus, we conducted the present meta-analysis by pooling all available publications to evaluate the possible role of CCR5-delta32 polymorphism and HIV-1 infection susceptibility.

2 Methods

2.1 Literature search

From inception to April 2018, we conducted electronic searches using the terms “CCR5-delta32”, “polymorphism*” or “variant*” or “mutation”, “HIV” through PubMed, EMBASE, China National Knowledge Internet (CNKI), WanFang, and the Cochrane Library for relevant studies. No language restriction was applied.

2.2 Selection criteria

Articles must satisfy the following criteria: (a) evaluated the relation between CCR5-delta32 and the risk of HIV-1 infection; (b) case-control studies on human beings, no language restriction was applied; (c) sufficient data to evaluate the odds ratios (ORs) and 95% credible interval (CI), and P values; and (e) genotype distribution in controls must be in Hardy-Weinberg equilibrium (HWE) (P < 0.001). Review articles, conference abstracts, case reports and insufficient data to evaluate ORs and 95%CI were excluded.

2.3 Data extraction

Data extraction was done by two authors through a standardized form independently, such as first author, year of publication, country, ethnicity, source of the controls, genotype distribution of cases and controls, and P values for HWE in controls. Discrepancies were settled by discussion, with disagreements resolved by consensus.

2.4 Statistical analyses

The pooled odds ratio (ORs) along with 95% credible interval (95%CI) was utilized to access the strength of relation between the CCR5-delta32 and HIV-1 infection risk. We also conducted stratified analyses by ethnicity and sources of controls. The I2 and Cochran’s Q-test statistics were used to quantify the statistical heterogeneity, and the random-effect model was conducted if heterogeneity was significant (P < 0.05) [35]; otherwise, the fixed-effect model was conducted[36]; P < 0.05 was considered as a significant difference in the value between the two groups. Sensitivity analysis was performed by sequentially excluding studies to assess the stability of the pooled results. Begg’s funnel plot and the Egger’s tests was performed to evaluate the potential publication bias of the researches (P < 0.05 was considered significant) [37, 38]. The present meta-analysis was carried out by STATA 12.0 (Stata Corp LP, College Station, TX, USA).

3 Results

3.1 Characteristics of included studies

In this meta-analysis, the selection of eligible researches included is shown in Figure 1, 517 potentially relevant researches were initially obtained from the PubMed, EMBASE, China National Knowledge Internet (CNKI), WanFang, and the Cochrane Library. After the exclusion of irrelevant studies, a total of 24 published researches were identified to be eligible for the current study. The flow diagram describing selected studies inclusion or exclusion is in Figure 1. The baseline features of the selected researches are recorded in Table 1.

Figure 1 Flow diagram of the publication selection process.
Figure 1

Flow diagram of the publication selection process.

Table 1

Main characteristics of studies included in the meta-analysis

AuthorYearCountryEthnicityGenotyping methodsSample size CaseControlHWE
Tan2010ChinaAsiansPCR2512380.1899
Desgranges2001SantiagoMixedPCR63620.8452
Rathore2008IndiaAsiansPCR1903700.8656
Xu2009ChinaAsiansPCR-RFLP78700.9035
Shrestha2006AmericanCaucasianPCR2665320.7247
Liu2004AmericanCaucasianPCR3165190.8926
Veloso2010SpanishCaucasianPCR-RFLP1842360.3255
Munerato2003BrazilianCaucasianPCR1831150.4544
Adojaan2007EstoniaCaucasianPCR30004880.0026
Alvarez1998SpanishCaucasianPCR1502500.6120
Zimmerman1997AmericanCaucasianPCR74510960.8830
Mandl1998AustriaCaucasianPCR2254510.4286
Wang2008ChinaAsiansPCR-RFLP1041550.9863
Tiensiwakul2004ThailandAsiansPCR-RFLP1166220.9610
Rigato2008BrazilCaucasianPCR-RFLP200820.5990
Roman2014LuxembourgMixedPCR-RFLP2881550.7356
Wang2003ChinaAsiansPCR-RFLP3304740.9817
Deng2004ChinaAsiansPCR881190.9263
Balotta1997ItalyCaucasianPCR1521220.3977
Ellwanger2018BrazilCaucasianPCR3002740.4210
Heydarifard2017IranAsiansPCR1403000.7920
Zapata2013ColombiaMixedPCR571120.8091
Li2003ChinaAsianPCR-RFLP24460.9406
Rugeles2002ColombiaMixedPCR36500.0381

  1. HWE, Hardy-Weinberg equilibrium; AA, CCR5 homozygotes; AB, CCR5-delta32 heterozygotes; BB, delta32 homozygotes.

3.2 Meta-analysis results

A total of 24 case-control studies were included in the present work to estimate the relation between the CCR5-delta32 polymorphism and the HIV-1 infection risk. To sum up, pooled risk evaluations shows a statistically significant relation between the CCR5-delta32 polymorphism and increased HIV-1 infection risk in the CCR5-delta32 heterozygotes genotype (OR=1.16, 95%CI=1.02-1.32, P=0.024) for healthy controls (Figure 2 and Table 3). Meanwhile, we found the risk of HIV-1 infection was significantly reduced in the delta32 homozygous genotype (OR=0.25, 95%CI=0.09-0.68, P=0.006) for healthy controls (Table 3). When we conducted stratified analysis by sources of control, we also detected a significantly risk decline of HIV-1 infection in the delta32 allele carriers (OR=0.71, 95%CI=0.54-0.94, P=0.015) among exposed uninfected populations (Figure 3 and Table 3). We also performed the stratified analysis by ethnicity, there was significant association in Caucasian with delta32 allele carrier genotype.

Figure 2 Forest plots demonstrating the association between CCR5-delta32 polymorphism and HIV-1 infection susceptibility in the CCR5-delta32 heterozygote model.
Figure 2

Forest plots demonstrating the association between CCR5-delta32 polymorphism and HIV-1 infection susceptibility in the CCR5-delta32 heterozygote model.

Figure 3 Forest plots demonstrating the association between CCR5-delta32 polymorphism and HIV-1 infection susceptibility in the delta32 homozygote model.
Figure 3

Forest plots demonstrating the association between CCR5-delta32 polymorphism and HIV-1 infection susceptibility in the delta32 homozygote model.

Table 2

The distribution of CCR5-delta32 genotype of included studies.

AuthorEthnicityHIV-1 infectedHealthy ControlsExposed uninfected
AAABBBAAABBBAAABBB
TanAsians226241222151
DesgrangesMixed60305930
RathoreAsians19000314605000
XuAsians74406820
ShresthaCaucasian25880516160
LiuCaucasian26155035468369223
VelosoCaucasian1444001742603150
MuneratoCaucasian162210100150
AdojaanCaucasian2307003711170
AlvarezCaucasian138120205423
ZimmermanCaucasian6011440846121494265
MandlCaucasian182430367786
WangAsians10400104005100
TiensiwakulAsians116004320019000
RigatoCaucasian1851507390
RomanMixed226620127271
WangAsians3291047310
DengAsians880011720
BalottaCaucasian136151108131
EllwangerCaucasian265350240322
HeydarifardAsians1391029190
ZapataMixed5160107506370
LiAsian23104510
RugelesMixed33304721

  1. AA, CCR5 homozygotes; AB, CCR5-delta32 heterozygotes; BB, delta32 homozygotes.

Table 3

Meta-analysis of the association between CCR5-delta32 polymorphism and HIV-1 infection susceptibility

ComparisonSubgroupStudiesHeterogeneity testAssociation testModelPublication bias
P ValueI2(%)OR(95%CI) P ValueEgger
B vs. AOverall240.03739.41.08(0.96-1.22)0.222F0.125
Mixed30.00001.26(0.83-1.92)0.277R
Caucasian110.07056.80.99(0.79-1.23)0.918R
Asian60.26724.20.90(0.39-2.06)0.803R
EUs60.3559.50.71(0.54-0.94)0.015F
AB vs. AAOverall200.03539.81.16(1.02-1.32)0.024F0.078
Mixed30.56401.38(0.88-2.16)0.157R
Caucasian110.01057.01.05(0.83-1.33)0.665R
Asian60.22827.50.89(0.37-2.13)0.791R
EUs60.54900.91(0.66-1.25)0.568F
BB vs. AAOverall80.96500.25(0.09-0.68)0.006F0.058
Caucasian60.96600.22(0.07-0.69)0.009F
EUs30.27422.80.06(0.01-0.32)0.001F
AB+BB vs. AAOverall200.02841.31.12(0.99-1.28)0.071F0.096
Mixed30.54101.34(0.86-2.09)0.196R
Caucasian110.00758.51.02(0.81-1.29)0.871R
Asian60.23526.60.89(0.38-2.10)0.791R
EUs Overall60.44100.80(0.59-1.08)0.141F
BB vs. AA+ABCaucasian80.96300.25(0.09-0.67)0.006F0.058
EUs60.96200.21(0.07-0.68)0.009F
30.29218.80.06(0.01-0.32)0.001F

  1. OR, odds ratio; CI, confidence interval; F, fixed-effects model; R, random-effects model; EUs, exposed uninfected.

3.3 Sensitivity analysis and publication bias

Sensitivity analysis was conducted by sequentially excluding individual studies to assess the impact of each study on the summarized findings. This revealed that the findings were statistically robust and credible (data not shown) (Figure 4). Begg’s and Egger’s test (Table 3) was utilized to examine the potential bias of the publication [37, 38]. The shape of the funnel plot was symmetrical as shown in Figure 5 suggesting there was no obvious publication bias.

Figure 4 Sensitivity analysis for the influences of CCR5-delta32 polymorphism and HIV-1 infection susceptibility under the allele model.
Figure 4

Sensitivity analysis for the influences of CCR5-delta32 polymorphism and HIV-1 infection susceptibility under the allele model.

Figure 5 Funnel plot of publication biases on the association between CCR5-delta32 polymorphism and HIV-1 infection susceptibility.
Figure 5

Funnel plot of publication biases on the association between CCR5-delta32 polymorphism and HIV-1 infection susceptibility.

4 Discussion

AIDS remains one of the biggest public health challenges of the world, as we all know, it is a complex infectious disease, including HIV-1 infection, host immune response, and gene-environment interactions. Several studies have already found that both viral genetics and host genetic factors are important determinants of HIV-1 infection [4, 5, 10]. Chemokines and chemokine receptors are critical for immune response in HIV-1 infection. Although many researches demonstrated the association between chemokine and chemokine receptor gene polymorphisms, and host’s susceptibility to HIV-1 infection, the conclusions are still controversial [11, 12, 13].

Meta-analysis, a useful statistical tool through integrating and comparing the results of many related researches and taking into consideration of variations in characteristics that can affect overall estimate of the outcome of interest, which is used to evaluate the literature in both quantitative and qualitative ways. So it is especially worthy when previous researches could not provide significant differences among treatments because of sample sizes limitations, or when there is no consensus [39]. Despina et al. performed a meta-analysis and demonstrated that perinatal infection is not determined by heterozygosity for CCR5-delta32 in the children [40]. In addition, Liu et al. performed a meta-analysis suggested that no statistical relation was detected between the CCR5-delta32 polymorphism and HIV-1 infection risk in any genetic model [41].

Considering that many researches have produced conflicting results, we conducted the present meta-analysis involving 24 eligible researches with 4,786 cases and 6,283 controls. The present researches showed there is a significant relation between CCR5-delta32 polymorphism and the risk of HIV-1 infection in the total population. In CCR5-delta32 heterozygotes genetic model, we have detected a statistically significant increased susceptibility to HIV-1 infection (OR=1.16, 95%CI=1.02-1.32, P=0.024) for healthy control. Meanwhile, we have found significantly reduced the risk of HIV-1 infection in the delta32 homozygous genetic model (OR=0.25, 95%CI=0.09-0.68, P=0.006). In healthy subjects, CCR5-delta polymorphism may be protective effects against HIV-1 infection only in the delta32 homozygous individuals (OR=0.25, 95%CI=0.09-0.68, P=0.006). Stratified analysis by EU population, the results demonstrated that CCR5-delta32 polymorphism may be protect effects against HIV-1 infection susceptibility in the delta32 allele carriers (OR=0.71, 95%CI=0.54-0.94, P=0.015), which was in accordance with that in the healthy subjects. Meanwhile, we also conducted the stratified analyses by ethnicity, we have detected significant relation between the CCR5-delta32 polymorphism and HIV-1 infection susceptibility in Caucasian subjects.

There are several limitations in the current study. Firstly, suitable English or Chinese-language studies were only enrolled in current meta-analysis, which means related researches published in other languages may have been overlooked, which may also lead to selection bias. Secondly, the number as well as the sample size of some included studies was limited and the results should be interpreted with caution. Finally, the influences of other relevant components such as age, gender, life style as well as their interactions with CCR5-delta32 polymorphism on HIV-1 infection susceptibility were not analyzed due to the lack of original data.

5 Conclusion

In conclusion, our findings indicated that the CCR5-delta32 homozygous genotype (delta32/delta32) confer possible protection against HIV-1 infection, especially in exposed uninfected population. However, this conclusion should be confirmed by multi-center and large-scale studies based on multiple ethnic groups.

  1. Conflict of interest

    Interest conflict: The authors claim no conflict of interest.

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Received: 2018-07-12
Accepted: 2018-09-08
Published Online: 2018-10-16

© 2018 Jun Ni et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

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https://doi.org/10.1515/med-2018-0062
Schlagwörter für diesen Artikel
CCR5-Delta32; Polymorphism; HIV-1; Susceptibility; Meta-analysis
Creative Commons
BY-NC-ND 4.0

Artikel in diesem Heft

  1. Regular Articles
  2. Cleidocranial dysplasia-dental disorder treatment and audiology diagnosis
  3. A hybrid neural network – world cup optimization algorithm for melanoma detection
  4. Early administration of venovenous extracorporeal life support for status asthmaticus during anaesthetic induction: case report and literature review
  5. Assessment of maximal isometric hand grip strength in school-aged children
  6. Evaluation of a neurokinin-1 antagonist in preventing multiple-day cisplatin-induced nausea and vomiting
  7. Value of continuous video EEG and EEG responses to thermesthesia stimulation in prognosis evaluation of comatose patients after cardiopulmonary resuscitation
  8. Platelet-rich plasma protects HUVECs against oX-LDL-induced injury
  9. Pharmacoeconomics of three therapeutic schemes for anti-tuberculosis therapy induced liver injury in China
  10. Small-cell lung cancer presenting as fatal pulmonary hemorrhage
  11. Correlation of retinopathy of prematurity with bronchopulmonary dysplasia
  12. Prognosis of treatment outcomes by cognitive and physical scales
  13. The efficacy of radiofrequency hyperthermia combined with chemotherapy in the treatment of advanced ovarian cancer
  14. Arcuate Fasciculus in Autism Spectrum Disorder Toddlers with Language Regression
  15. Aesthetic dental procedures: legal and medico-legal implications
  16. Blood transfusion in children: the refusal of Jehovah’s Witness parents’
  17. Burnout among anesthetists and intensive care physicians
  18. Relationship of HS CRP and sacroiliac joint inflammation in undifferentiated spondyloarthritis
  19. Ethical and legal issues in gestational surrogacy
  20. Effects of arginine vasopressin on migration and respiratory burst activity in human leukocytes
  21. Associations of diabetic retinopathy with retinal neurodegeneration on the background of diabetes mellitus. Overview of recent medical studies with an assessment of the impact on healthcare systems
  22. Pituitary dysfunction from an unruptured ophthalmic internal carotid artery aneurysm with improved 2-year follow-up results: A case report
  23. Effectiveness of treatment with endostatin in combination with emcitabine, carboplatin, and gemcitabine in patients with advanced non-small cell lung cancer: a retrospective study
  24. Piercing and tattoos in adolescents: legal and medico-legal implications
  25. The central importance of information in cosmetic surgery and treatments
  26. Penile calciphylaxis in a patient with end-stage renal disease: a case report and review of the literature
  27. Serum CA72-4 as a biomarker in the diagnosis of colorectal cancer: A meta-analysis
  28. Association between uric acid and metabolic syndrome in elderly women
  29. Distinct expression and prognostic value of MS4A in gastric cancer
  30. MAPK pathway involved in epidermal terminal differentiation of normal human epidermal keratinocytes
  31. Association of central obesity with sex hormonebinding globulin: a cross-sectional study of 1166 Chinese men
  32. Successful endovascular therapy in an elderly patient with severe hemorrhage caused by traumatic injury
  33. Inflammatory biomarkers and risk of atherosclerotic cardiovascular disease
  34. Related factors of early mortality in young adults with cerebral hemorrhage
  35. Growth suppression of glioma cells using HDAC6 inhibitor, tubacin
  36. Post-stroke upper limb spasticity incidence for different cerebral infarction site
  37. The esophageal manometry with gas-perfused catheters
  38. MMP-2 and TIMP-2 in patients with heart failure and chronic kidney disease
  39. Genetic testing: ethical aspects
  40. Intervention for physician burnout: A systematic review
  41. The melanin-concentrating hormone system in human, rodent and avian brain
  42. Clinical effects of piribedil in adjuvant treatment of Parkinson’s Disease: A meta-analysis
  43. Identification of a novel BRAF Thr599dup mutation in lung adenocarcinoma
  44. Adrenal incidentaloma – diagnostic and treating problem – own experience
  45. Common illnesses in tropical Asia and significance of medical volunteering
  46. Genetic risk in insurance field
  47. Genetic testing and professional responsibility: the italian experience
  48. The mechanism of mitral regurgitant jets identified by 3-dimensional transesophageal echocardiography
  49. Control of blood pressure and cardiovascular outcomes in type 2 diabetes
  50. Pseudomesotheliomatous primary squamous cell lung carcinoma: The first case reported in Turkey and a review of the literature
  51. Diagnostic efficacy of serum 1,3-β-D-glucan for invasive fungal infection: An update meta-analysis based on 37 case or cohort studies
  52. GPER was associated with hypertension in post-menopausal women
  53. Metabolic activity of sulfate-reducing bacteria from rodents with colitis
  54. Association of miRNA122 & ADAM17 with lipids among hypertensives in Nigeria
  55. The efficacy and safety of enoxaparin: a meta-analysis
  56. Cuffed versus uncuffed endotracheal tubes in pediatrics: a meta-analysis
  57. Thresholding for medical image segmentation for cancer using fuzzy entropy with level set algorithm
  58. Sleep deprivation in Intensive Care Unit – systematic review
  59. Benefits of computed tomography in reducing mortality in emergency medicine
  60. Ipragliflozin ameliorates liver damage in non-alcoholic fatty liver disease
  61. Limits of professional competency in nurses working in Nicu
  62. MDA-19 suppresses progression of melanoma via inhibiting the PI3K/Akt pathway
  63. The effect of smoking on posttraumatic pseudoarthrosis healing after internal stabilization, treated with platelet rich plasma (PRP)
  64. Partial deletion of the long arm of chromosome 7: a case report
  65. Meta-analysis of PET/CT detect lymph nodes metastases of cervical cancer
  66. High Expression of NLRC5 is associated with prognosis of gastric cancer
  67. Is monitoring mean platelet volume necessary in breast cancer patients?
  68. Resectable single hepatic epithelioid hemangioendothelioma in the left lobe of the liver: a case report
  69. Epidemiological study of carbapenem-resistant Klebsiella pneumoniae
  70. The CCR5-Delta32 genetic polymorphism and HIV-1 infection susceptibility: a meta-analysis
  71. Phenotypic and molecular characterisation of Staphylococcus aureus with reduced vancomycin susceptibility derivated in vitro
  72. Preliminary results of Highly Injectable Bi-Phasic Bone Substitute (CERAMENT) in the treatment of benign bone tumors and tumor-like lesions
  73. Analysis of patient satisfaction with emergency medical services
  74. Guillain-Barré syndrome and Low back pain: two cases and literature review
  75. HELLP syndrome complicated by pulmonary edema: a case report
  76. Pharmacokinetics of vancomycin in patients with different renal function levels
  77. Recurrent chronic subdural hematoma: Report of 13 cases
  78. Is awareness enough to bring patients to colorectal screening?
  79. Serum tumor marker carbohydrate antigen 125 levels and carotid atherosclerosis in patients with coronary artery disease
  80. Plastic treatment for giant pseudocyst after incisional hernia mesh repair: a case report and comprehensive literature review
  81. High expression levels of fascin-1 protein in human gliomas and its clinical relevance
  82. Thromboembolic complications following tissue plasminogen activator therapy in patients of acute ischemic stroke - Case report and possibility for detection of cardiac thrombi
  83. The effects of gastrointestinal function on the incidence of ventilator-associated pneumonia in critically ill patients
  84. A report of chronic intestinal pseudo-obstruction related to systemic lupus erythematosus
  85. Risk model in women with ovarian cancer without mutations
  86. Direct oral anticoagulants and travel-related venous thromboembolism
  87. How bispectral index compares to spectral entropy of the EEG and A-line ARX index in the same patient
  88. Henoch-schonlein purpura nephritis with renal interstitial lesions
  89. Cardiovascular risk estimated by UKPDS risk engine algorithm in diabetes
  90. CD5 and CD43 expression are associate with poor prognosis in DLBCL patients
  91. Combination of novoseven and feiba in hemophiliac patients with inhibitors
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