Testosterone and high‐sensitive C‐reactive protein in coronary artery disease patients awaiting coronary artery bypass graft

Natural androgens inhibit atherosclerosis in men. This study aimed to examine whether testosterone and high‐sensitive C‐reactive protein differ between patients with coronary artery disease and those without coronary artery disease and to determine the association with the severity of coronary artery disease. Two hundred and six male subjects were recruited. Serum total testosterone and high‐sensitive C‐reactive protein were estimated. Severity of coronary artery disease was assessed by angiographic scores. Total testosterone level in patients was significantly different from controls (11.4 ± 2.7 vs. 18.1 ± 7.2 nm P = 0.001) and high‐sensitive protein level in cases was significantly higher compared to controls (3.37 ± 1.62 mg l^?1 vs. 1.71 ± 0.60 mg l^?1, P = 0.001). Testosterone levels were not significantly different with vessel (P = 0.592), Leaman (P = 0.694) and Gensini (P = 0.329) score groups, but high‐sensitive C‐reactive protein showed significant positive correlation among the respective groups (P = 0.005, P = 0.028, P = 0.015). Testosterone was lower, while high‐sensitive C‐reactive protein was higher in patients compared to controls. Testosterone showed no correlation with the severity of atherosclerosis, but high‐sensitive C‐reactive protein showed significant positive correlation.     

Hypoxia‐induced apoptosis and mechanism of epididymal dysfunction in rats with left‐side varicocele

To investigate the relationship between hypoxia and epididymal dysfunction and the mechanism of epididymal dysfunction in rats with left‐side varicocele, a total of 45 male Wistar rats were randomly divided into three groups in average. The expression of hypoxia‐inducible factor‐1α (HIF‐1α) was detected by Western blot and immunohistochemical analysis respectively. HIF‐1α was expressed in the experimental group, and the positive rate was significantly higher than that of either the sham or the control group (P < 0.05). The apoptosis index (AI) of epididymal epithelium was higher in the experimental group (7.25 ± 2.56) than that in either the sham (0.52 ± 0.57, P < 0.01) or the control group (0.08 ± 0.13, P < 0.01). Additionally, the levels of sialic acid and carnitine were lower in the experimental group than that in either the sham or the control group (P < 0.05) and were significantly negatively correlated with HIF‐1α expression (r = ?0.620, P = 0.014, and r = ?0.610, P = 0.016 respectively). It is concluded that left‐side varicocele could cause epididymal hypoxia and epididymal dysfunction. Moreover, HIF‐1α maybe act as useful factor to predict germ cell apoptosis in varicocele.     

Program‐specific transplant rate ratios: Association with allocation priority at listing and posttransplant outcomes

The Scientific Registry of Transplant Recipients (SRTR) is considering more prominent reporting of program‐specific adjusted transplant rate ratios (TRRs). To enable more useful reporting of TRRs, SRTR updated the transplant rate models to adjust explicitly for components of allocation priority. We evaluated potential associations between TRRs and components of allocation priority that could indicate programs' ability to manipulate TRRs by denying or delaying access to low‐priority candidates. Despite a strong association with unadjusted TRRs, we found no candidate‐level association between the components of allocation priority and adjusted TRRs. We found a strong program‐level association between median laboratory Model for End‐stage Liver Disease (MELD) score at listing and program‐specific adjusted TRRs (r = .37; P < .001). The program‐level association was likely confounded by regional differences in donor supply/demand and listing practices. In kidney transplantation, higher program‐specific adjusted TRRs were weakly associated with better adjusted posttransplant outcomes (r = ?.14; P = .035) and lower adjusted waitlist mortality rate ratios (r = ?.15; P = .022), but these associations were absent in liver, lung, and heart transplantation. Program‐specific adjusted TRRs were unlikely to be improved by listing candidates with high allocation priority and can provide useful information for transplant candidates and programs.     

Impact of de novo donor‐specific HLA antibodies detected by Luminex solid‐phase assay after transplantation in a group of 88 consecutive living‐donor renal transplantations

De novo donor‐specific HLA antibodies (DSA) after renal transplantation are known to be correlated with poor graft outcome and the development of acute and chronic rejection. Currently, data for the influence of de novo DSA in patient cohorts including only living‐donor renal transplantations (LDRT) are limited. A consecutive cohort of 88 LDRT was tested for the occurrence of de novo DSA by utilizing the highly sensitive Luminex solid‐phase assay for antibody detection. Data were analyzed for risk factors for de novo DSA development and correlated with acute rejection (AR) and graft function. Patients with de novo DSA [31 (35%)] showed a trend for inferior graft function [mean creatinine change (mg/dL/year) after the first year: 0.15 DSA (+) vs. 0.02 DSA (?) (P = 0.10)] and a higher rate of AR episodes, especially in case of de novo DSA of both class I and II [6 (55%), (P = 0.05)]. Antibody‐mediated rejection (AMR) appeared in five patients and was significantly correlated with de novo DSA (P = 0.05). Monitoring for de novo DSA after LDRT may help to identify patients at risk of declining renal function. Especially patients with simultaneous presence of de novo DSA class I and class II are at a high risk to suffer AR episodes.     

Systematic review and meta‐analysis of post‐transplant lymphoproliferative disorder in lung transplant recipients

A systematic review of papers in English on post‐transplant lymphoproliferative disorder (PTLD) in lung transplant recipients (LTR) using MEDLINE, EMBASE, SCOPUS, and Cochrane databases was performed. The Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) recommendations were strictly adhered to. Pooled odds ratios (pOR) were calculated from a random‐effects model, and heterogeneity among studies was quantitated using I² values. Fourteen studies published from 2005 to 2015 were included in the meta‐analysis. One hundred and sixty‐four lung transplant recipients were included. LTRs who received single vs bilateral were associated with a 7.67‐fold risk of death after PTLD (6 studies with 64 LTRs; pOR 7.67 95% CI 1.98‐29.70; P = .003). pOR of death for early onset PTLD (<1 year post‐LT) vs late onset (> 1 year post‐LT) was not different (3 studies with 72 LTRS; pOR 0.62, 95% CI 0.20‐1.86, P = .39). Standardized mean difference (SMD) in time from transplant to PTLD onset between LTRs who died vs alive was not different (9 studies with 109 LTRs; SMD 0.03, 95% CI ?0.48‐0.53, P = .92). Survival in polymorphic vs monomorphic PTLD and extranodal vs nodal disease was similar (4 studies with 31 LTRs; pOR 0.44, 95% CI 0.08‐2.51; P = .36. 6 studies with 81 LTRs; pOR 1.05 95% CI 0.31‐3.52, P = .94). This meta‐analysis demonstrates that single LTRs are at a higher risk of death vs bilateral LTRs after the development of PTLD.     

Association of TNF‐α, TGF‐β1, IL‐10, IL‐6, and IFN‐γ gene polymorphism with acute rejection and infection in lung transplant recipients

Infection and rejection are common complications faced by lung transplant recipients (LTRs) and have become major impediments to long‐term survival. Cytokines may play an important role in the development of these complications. In this study, we explored the correlation between TNF‐α (?308 A/G), TGF‐β1 (+869 T/C, +915 G/C), IL‐10 (?592 C/A, ?819 T/C, ?1082 G/A), IL‐6 (?174 G/C), and IFN‐γ (+874 T/A) gene polymorphisms and the incidence of acute rejection and infection. Transplant outcomes were reviewed in a retrospective cohort of 113 LTRs from a single center between December 2004 and November 2012. Cytokine polymorphisms were measured using sequence‐specific primer‐based PCR. HLA typing was performed for the donors and recipients. We found that the LTRs with the IL‐10 ?819 CC and ?592 CC genotypes had a significantly decreased risk of infection (p = 0.017, OR = 0.177, 95% CI = 0.04–0.85). However, we found no significant association between cytokine polymorphisms and acute rejection. Furthermore, the data revealed that the occurrence of acute rejection was strongly associated with infection episodes (χ² = 8.5256, p < 0.01). These results suggest that LTRs possessing the IL‐10 ?819 CC and ?592 CC genotype may be protected from the occurrence of infection. Our results demonstrated that infection is an important cause of acute rejection for LTRs.     

The influence of CTLA‐4 single nucleotide polymorphisms on acute kidney allograft rejection in Turkish patients

Cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) is a cell surface protein, which down‐regulates the immune response at CTLA‐4/CD28/B7 pathway. We aimed to investigate the influence of the ?318C/T, +49A/G, ?1661A/G and CT60A/G, and CTLA‐4 gene polymorphisms on acute rejection of kidney allograft in Turkish patients. The study design was a case–control study that consists of three groups: Group 1 (n = 34) represented the kidney transplant (Ktx) recipients who experienced acute rejection, Group 2 (n = 47) was randomly assigned Ktx recipients without acute rejection, and Group 3 (n = 50) consisting of healthy volunteers to evaluate the normal genomic distribution. The polymerase chain reaction–restriction fragment length polymorphism technique was used to determine the polymorphisms. Genotype and allele frequencies among three groups denoted similar distributions for +49A/G, ?1661A/G, and CT60A/G. Conversely, ?318C/T genotype was three times more frequent in the acute rejection group than in the non‐rejection group (OR = 3.45; 95%CI = 1.18–10.1, p = 0.015) and two times more frequent than the healthy control group (OR = 2.45; 95% CI = 0.98 – 6.11, p = 0.047). Additionally, having a T allele at ?318 position was significantly associated with acute rejection (0.147 vs. 0.043, OR = 3.45; 95% CI = 1.13–10.56, p = 0.02). 318C/T gene polymorphism and T allelic variant were found to be associated with increased acute rejection risk in Turkish kidney allograft recipients.     

Seminal level of clusterin in infertile men as a significant biomarker reflecting spermatogenesis

The objective of this study was to assess the impact of seminal clusterin level on spermatogenesis in infertile men. This study included 89 men who visited our clinic due to infertility, consisting of 28, 33, and 28 diagnosed with normospermia, oligozoospermia and nonobstructive azoospermia (NOA) respectively. The seminal clusterin concentrations measured by enzyme‐linked immunosorbent assay were 47.9, 28.2 and 18.4 ng ml^?1 in men with normospermia, oligozoospermia and NOA, respectively, with significant differences among these three groups (P < 0.01). Microdissection testicular sperm extraction (MD‐TESE) was performed in the 28 men with NOA, and spermatozoon was successfully retrieved from 9. There was a significant correlation between seminal clusterin level and testicular clusterin protein expression evaluated by immunohistochemical staining in these men with NOA (P = 0.026). Of several parameters available before MD‐TESE, the univariate analysis identified serum follicle‐stimulating hormone (FSH) level <10 IU ml^?1 and seminal clusterin level ≥18 ng ml^?1 as significant predictors of sperm retrieval, and of these, only serum FSH level <10 IU ml^?1 was shown to be independently associated with sperm retrieval in the multivariate analysis. Accordingly, it might be worthy to further evaluate the significance of seminal clusterin level as a biomarker for the assessment of spermatogenic status in infertile men.     

Human leukocyte antigen matching in heart transplantation: systematic review and meta‐analysis

Allocation of donors with regard to human leukocyte antigen (HLA) is controversial in heart transplantation. This paper is a systematic review and meta‐analysis of the available evidence. PubMed, Embase, and the Cochrane Library were searched systematically for studies that addressed the effects of HLA matching on outcome after heart transplantation. Fifty‐seven studies met the eligibility criteria. 34 studies had graft rejection as outcome, with 26 of the studies reporting a significant reduction in graft rejection with increasing degree of HLA matching. Thirteen of 18 articles that reported on graft failure found that it decreased significantly with increasing HLA match. Two multicenter studies and nine single‐center studies provided sufficient data to provide summary estimates at 12 months. Pooled comparisons showed that graft survival increased with fewer HLA‐DR mismatches [0–1 vs. 2 mismatches: risk ratio (RR) = 1.09 (95% confidence interval (CI): 1.01–1.19; P = 0.04)]. Having fewer HLA‐DR mismatches (0–1 vs. 2) reduced the incidence of acute rejection [(RR = 0.81 (0.66–0.99; P = 0.04)]. Despite the considerable heterogeneity between studies, the short observation time, and older data, HLA matching improves graft survival in heart transplantation. Prospective HLA‐DR matching is clinically feasible and should be considered as a major selection criterion.     

Long‐term outcomes and transmission rates in hepatitis C virus‐positive donor to hepatitis C virus‐negative kidney transplant recipients: Analysis of United States national data

The use of kidneys from hepatitis C virus (HCV)‐positive (D+) deceased donors for HCV‐negative recipients (R?) might increase the donor pool. We analyzed the national Organ Procurement and Transplant Network (OPTN) registry from 1994 to 2014 to compare the outcomes of HCV D+/R? (n = 421) to propensity‐matched HCV‐negative donor (D?)/R? kidney transplants, as well as with waitlisted patients who never received a transplant, in a 1:5 ratio (n = 2105, per matched group). Both 5‐year graft survival (44% vs 66%; P < .001) and patient survival (57% vs 79%; P < .001) were inferior for D+/R? group compared to D?/R?. Nevertheless, 5‐year patient survival from the time of wait listing was superior for D+/R? when compared to waitlisted controls (68% vs 43%; P < .001). Of the 126 D+/R? with available post‐transplant HCV testing, HCV seroconversion was confirmed in 62 (49%), likely donor‐derived. Five‐year outcomes were similar between D+/R? that seroconverted vs D+/R? that did not (n = 64). Our analysis shows inferior outcomes for D+/R? patients although detailed data on pretransplant risk factors was not available. Limited data suggest that HCV transmission occurred in half of HCV D+/R? patients, although this might not have been the primary factor contributing to the poor observed outcomes.     

Association between seminal plasma zinc level and asthenozoospermia: a meta‐analysis study

Zinc is proposed to have an important role in the morphology, viability and motility of spermatozoa. There are inconsistent reports on the association between seminal plasma zinc concentration and male infertility. For this purpose, papers reporting the level of seminal zinc among asthenozoospermic groups were selected and used for further analysis. This meta‐analysis of previous published studies was performed to obtain more precise information on the association between seminal plasma zinc and asthenozoospermia. Relevant studies for inclusion were identified after preliminary investigation of research papers published on electronic databases up to February 2015. Eight reports and 475 subjects were finally included in the meta‐analysis. In the overall analysis, a statistically significant reduction in seminal plasma zinc concentrations was observed in asthenozoospermic infertile men. Random‐effects method was used to evaluate the summary effect size due to the presence of significant heterogeneity. The effect of zinc on asthenozoospermia was significant (Hedge's G effect size = ?0.506, 95% confidence interval (95% CI): ?0.998 to ?0.014, P = 0.044). Taken together, despite of significant statistical heterogeneity between studies, our findings were indicative of significant association between zinc concentration and asthenozoospermia. In conclusion, the meta‐analysis suggests that seminal plasma zinc concentration is negatively associated with male infertility.     

Associations between folate metabolism enzyme polymorphisms and breast cancer: A meta‐analysis

We performed this meta‐analysis to explore associations between folate metabolism enzyme polymorphisms and breast cancer (BC) in a larger pooled population. Systematic literature research was performed to identify eligible studies for pooled analyses. Totally 92 genetic association studies were included for analyses. The pooled analyses revealed significant findings for MTRR rs1801394 polymorphism in South Asians, for MTR rs1805087 polymorphism in Caucasians and East Asians, and for MTHFR rs1801133 polymorphism in East Asians. In conclusion, the present meta‐analysis indicated that MTRR rs1801394, MTR rs1805087, and MTHFR rs1801133 polymorphisms could be used to identify individuals at high risk of developing BC.     

Changes in bone microarchitecture following kidney transplantation—Beyond bone mineral density

Bone disease in kidney transplant recipients (KTRs) is characterized by bone mineral density (BMD) loss but bone microarchitecture changes are poorly defined. In this prospective cohort study, we evaluated bone microarchitecture using non‐invasive imaging modalities; high‐resolution magnetic resonance imaging (MRI), peripheral quantitative computed tomography (pQCT), dual energy X‐ray absorptiometry (DXA), and the trabecular bone score (TBS) following kidney transplantation. Eleven KTRs (48.3 ± 11.2 years) underwent MRI (tibia), pQCT (radius) and DXA at baseline and 12 months post–transplantation. Transiliac bone biopsies, performed at transplantation, showed 70% of patients with high/normal bone turnover. Compared with baseline, 12‐month MRI showed deterioration in indices of trabecular network integrity—surface to curve ratio (S/C; ?15%, P = 0.03) and erosion index (EI; +19%, P = 0.01). However, cortical area increased (+10.3%, P = 0.04), with a non‐significant increase in cortical thickness (CtTh; +7.8%, P = 0.06). At 12 months, parathyroid hormone values (median 10.7 pmol/L) correlated with improved S/C (r = 0.75, P = 0.009) and EI (r = ?0.71, P = 0.01) while osteocalcin correlated with CtTh (r = 0.72, P = 0.02) and area (r = 0.70, P = 0.02). TBS decreased from baseline (?5.1%, P = 0.01) with no significant changes in BMD or pQCT. These findings highlight a post–transplant deterioration in trabecular bone quality detected by MRI and TBS, independent of changes in BMD, underlining the potential utility of these modalities in evaluating bone microarchitecture in KTRs.     

Identification of IDUA and WNT16 Phosphorylation‐Related Non‐Synonymous Polymorphisms for Bone Mineral Density in Meta‐Analyses of Genome‐Wide Association Studies

Protein phosphorylation regulates a wide variety of cellular processes. Thus, we hypothesize that single‐nucleotide polymorphisms (SNPs) that may modulate protein phosphorylation could affect osteoporosis risk. Based on a previous conventional genome‐wide association (GWA) study, we conducted a three‐stage meta‐analysis targeting phosphorylation‐related SNPs (phosSNPs) for femoral neck (FN)‐bone mineral density (BMD), total hip (HIP)‐BMD, and lumbar spine (LS)‐BMD phenotypes. In stage 1, 9593 phosSNPs were meta‐analyzed in 11,140 individuals of various ancestries. Genome‐wide significance (GWS) and suggestive significance were defined by α = 5.21 × 10^–6 (0.05/9593) and 1.00 × 10^–4, respectively. In stage 2, nine stage 1–discovered phosSNPs (based on α = 1.00 × 10^–4) were in silico meta‐analyzed in Dutch, Korean, and Australian cohorts. In stage 3, four phosSNPs that replicated in stage 2 (based on α = 5.56 × 10^–3, 0.05/9) were de novo genotyped in two independent cohorts. IDUA rs3755955 and rs6831280, and WNT16 rs2707466 were associated with BMD phenotypes in each respective stage, and in three stages combined, achieving GWS for both FN‐BMD (p = 8.36 × 10^–10, p = 5.26 × 10^–10, and p = 3.01 × 10^–10, respectively) and HIP‐BMD (p = 3.26 × 10^–6, p = 1.97 × 10^–6, and p = 1.63 × 10^–12, respectively). Although in vitro studies demonstrated no differences in expressions of wild‐type and mutant forms of IDUA and WNT16B proteins, in silico analyses predicts that WNT16 rs2707466 directly abolishes a phosphorylation site, which could cause a deleterious effect on WNT16 protein, and that IDUA phosSNPs rs3755955 and rs6831280 could exert indirect effects on nearby phosphorylation sites. Further studies will be required to determine the detailed and specific molecular effects of these BMD‐associated non‐synonymous variants. © 2015 American Society for Bone and Mineral Research.     

CMV‐infected kidney grafts drive the expansion of blood‐borne CMV‐specific T cells restricted by shared class I HLA molecules via presentation on donor cells

We aimed to determine the role of cytomegalovirus (CMV)‐infected donor cells in the development of a CMV‐specific immune response in kidney transplant recipients. We assessed the CMV pp65‐specific immune response by using interferon‐? ELISPOT and dextramers in peripheral blood mononuclear cells from 115 recipients (D+R? 31, D+R + 44, D?R + 40) late after transplantation (mean 59 ± 42 months). Receiving a kidney from a D+ donor resulted in a higher number of IFN‐?‐producing anti‐CMV T cells (P = .004). This effect disappeared with the absence of shared HLA class I specificities between donors and recipients (P = .430). To confirm the role of donor cells in stimulating the expansion of newly developed CMV‐specific CD8⁺ T cells after transplantation, we compared the number of HLA‐A2–restricted CMV‐specific CD8⁺ T cells in primo‐infected recipients who received an HLA‐A2 or non–HLA‐A2 graft. The median of anti‐CMV pp65 T cells restricted by HLA‐A2 was very low for patients who received a non–HLA‐A2 graft vs an HLA‐A2 graft (300 [0‐14638] vs. 17972 [222‐85594] anti‐CMV pp65 CD8⁺ T cells/million CD8⁺ T cells, P = .001). This adds new evidence that CMV‐infected kidney donor cells present CMV peptides and drive an inflation of memory CMV‐specific CD8⁺ T cells, likely because of frequent CMV replications within the graft.     

Association Analysis of BMD‐associated SNPs with Knee Osteoarthritis

Osteoarthritis (OA) risk is widely recognized to be heritable but few loci have been identified. Observational studies have identified higher systemic bone mineral density (BMD) to be associated with an increased risk of radiographic knee osteoarthritis. With this in mind, we sought to evaluate whether well‐established genetic loci for variance in BMD are associated with risk for radiographic OA in the Osteoarthritis Initiative (OAI) and the Johnston County Osteoarthritis (JoCo) Project. Cases had at least one knee with definite radiographic OA, defined as the presence of definite osteophytes with or without joint space narrowing (Kellgren‐Lawrence [KL] grade ≥ 2) and controls were absent for definite radiographic OA in both knees (KL grade ≤ 1 bilaterally). There were 2014 and 658 Caucasian cases, respectively, in the OAI and JoCo Studies, and 953 and 823 controls. Single nucleotide polymorphisms (SNPs) were identified for association analysis from the literature. Genotyping was carried out on Illumina 2.5M and 1M arrays in Genetic Components of Knee OA (GeCKO) and JoCo, respectively and imputation was done. Association analyses were carried out separately in each cohort with adjustments for age, body mass index (BMI), and sex, and then parameter estimates were combined across the two cohorts by meta‐analysis. We identified four SNPs significantly associated with prevalent radiographic knee OA. The strongest signal (p = 0.0009; OR = 1.22; 95% CI, 1.08–1.37) maps to 12q3, which contains a gene coding for SP7. Additional loci map to 7p14.1 (TXNDC3), 11q13.2 (LRP5), and 11p14.1 (LIN7C). For all four loci the allele associated with higher BMD was associated with higher odds of OA. A BMD risk allele score was not significantly associated with OA risk. This meta‐analysis demonstrates that several genomewide association studies (GWAS)‐identified BMD SNPs are nominally associated with prevalent radiographic knee OA and further supports the hypothesis that BMD, or its determinants, may be a risk factor contributing to OA development. © 2014 American Society for Bone and Mineral Research.     

Effect of adjuvant drug therapy after varicocelectomy on fertility outcome in males with varicocele‐associated infertility: Systematic review and meta‐analysis

Varicocele is one of the common correctable causes of male infertility. Recent studies have demonstrated varicocelectomy in males with abnormal semen parameters was associated with better fertility outcome, but the effect of adjuvant drug therapy after varicocelectomy on fertility outcome in patients with varicocele‐associated infertility remains undefined. Hence, the present meta‐analysis was performed to assess the efficacy of adjuvant drug therapy after varicocelectomy. The protocol was registered with PROSPERO (No. CRD42018093749). Ten randomised controlled trails containing 533 patients with adjuvant drug therapy after varicocelectomy and 368 patients with no medical treatment after varicocelectomy were included. Our analysis revealed that the improvement in pregnancy rate after adjuvant drug therapy was insignificant. (OR = 1.70, 95%CI = 0.99–2.91), but resulted in significant improvements in sperm concentration (MD = 13.71, 95%CI = 5.80–21.63) and motility (MD = 4.77, 95%CI = 3.98–5.56) at 3 months, sperm DNA integrity (SMD = 3.13, 95%CI = 1.50–4.75) and serum FSH level (MD = ?1.02, 95%CI = ?1.79 to ‐0.24). Therefore, compared to no medical treatment, the adjuvant drug therapy, especially the use of antioxidants seems to be associated with better fertility outcome. However, more evidences with high‐quality studies are necessary to conform its benefits.     

Susceptibility genes for osteoporotic fracture in postmenopausal chinese women

To identify the susceptibility genes for osteoporotic fracture in postmenopausal Chinese women, a two‐stage case‐control association study using joint analysis was conducted in 1046 patients with nontraumatic vertebra, hip, or distal radius fractures and 2303 healthy controls. First, 113 single‐nucleotide polymorphisms (SNPs) in 16 potential osteoporosis candidate genes reported in recent genomewide association studies, meta‐analyses studies, large‐scale association studies, and functional studies were genotyped in a small‐sample‐size subgroup consisting of 541 patients with osteoporotic fractures and 554 healthy controls. Variants and haplotypes in SPTBN1, TNFRSF11B, CNR2, LRP4, and ESR1 that have been identified as being associated with osteoporotic fractures were further reanalyzed in the entire case‐control group. We identified one SNP in TNFRSF11B (rs3102734), three SNPs in ESR1 (rs9397448, rs2234693, and rs1643821), two SNPs in LRP4 (rs17790156 and rs898604), and four SNPs in SPTBN1 (rs2971886, rs2941583, rs2941584, and rs12475342) were associated with all of the broadly defined osteoporotic fractures. The most significant polymorphism was rs3102734, with increased risk of osteoporotic fractures (odds ratio, 1.35; 95% confidence interval [CI], 1.17–1.55, Bonferroni p = 2.6 × 10^?4). Furthermore, rs3102734, rs2941584, rs12475342, rs9397448, rs2234693, and rs898604 exhibited significant allelic, genotypic, and/or haplotypic associations with vertebral fractures. SNPs rs12475342, rs9397448, and rs2234693 showed significant genotypic associations with hip fractures, whereas rs3102734, rs2073617, rs1643821, rs12475342, and rs2971886 exhibited significant genotypic and/or haplotypic associations with distal radius fractures. Accordingly, we suggest that in addition to the clinical risk factors, the variants in TNFRSF11B, SPTBN1, ESR1, and LRP4 are susceptibility genetic loci for osteoporotic fracture in postmenopausal Chinese women. © 2012 American Society for Bone and Mineral Research © 2012 American Society for Bone and Mineral Research     

Risk factors for post‐transplant lymphoproliferative disorder after Thymoglobulin‐conditioned hematopoietic cell transplantation

Epstein‐Barr virus (EBV)‐induced post‐transplant lymphoproliferative disorder (PTLD) occurs frequently when rabbit antithymocyte globulin (ATG) is used in hematopoietic cell transplant (HCT) conditioning. We retrospectively studied 554 patients undergoing ATG‐conditioned myeloablative HCT. Strategies used to minimize mortality due to PTLD were either therapy of biopsy‐diagnosed PTLD in the absence of EBV DNAemia monitoring (n = 266) or prompt therapy of presumed PTLD (based on clinical/radiologic signs and high EBV DNAemia, in the setting of weekly EBV DNAemia monitoring) (n = 199). Both strategies resulted in similar mortality due to PTLD (0.7% vs 1% at 2 years, P = .43) and similar overall survival (63% vs 67% at 2 years, P = .23) even though there was a trend toward higher PTLD incidence with the prompt therapy. Donor positive with recipient negative EBV (D+R?) serostatus was a risk factor for developing PTLD. Older patient age, HLA‐mismatched donor, and graft‐versus‐host disease were not associated with increased risk of PTLD. In summary, in ATG‐conditioned HCT, D+R? serostatus, but not older age, mismatched donor or GVHD is a risk factor for developing PTLD. EBV DNAemia monitoring may be a weak risk factor for developing/diagnosing PTLD; the monitoring coupled with prompt therapy does not improve survival.     

Dynamics of anti‐human leukocyte antigen antibodies after renal transplantation and their impact on graft outcome

The purpose of this study was to sequentially monitor anti‐HLA antibodies and correlate the results with antibody‐mediated rejection (AMR), graft survival (GS), and graft function (GF). We collected sera from 111 kidney transplant recipients on transplant days 0, 7, 14, 30, 60, 90, 180, and 360 and analyzed PRA levels by ELISA. DSAs were analyzed by single‐antigen beads in rejecting kidneys. At pre‐transplant, 79.3% of the patients were non‐sensitized (PRA = 0%) and 20.7% were sensitized (PRA > 1%). After transplant, patients were grouped by PRA profile: no anti‐HLA antibodies pre‐ or post‐transplant (group HLApre?/post?; n = 80); de novo anti‐HLA antibodies post‐transplant (group HLApre?/post+; n = 8); sensitized pre‐transplant/increased PRA post‐transplant (group HLApre+/post↑; n = 9); and sensitized pre‐transplant/decreased PRA post‐transplant (group HLApre+/post↓; n = 14). De novo anti‐HLA antibodies were detected at 7–180 d. In sensitized patients, PRA levels changed within the first 30 d post‐transplant. Incidence of AMR was higher in HLApre?/post+ and HLApre+/post↑ than in HLApre?/post?, and HLApre+/post↓ (p < 0.001) groups. One‐yr death‐censored GS was 36% in group HLApre+/post↑, compared with 98%, 88% and 100% in groups HLApre?/post?, HLApre?/post+, and HLApre+/post↓, respectively (p < 0.001). Excluding first‐year graft losses, GF and GS were similar among the groups. In conclusion, post‐transplant antibody monitoring can identify recipients at higher risk of AMR.