Novel susceptibility loci for steroid-associated osteonecrosis of the femoral head in systemic lupus erythematosus.

Osteonecrosis of the femoral head (ONFH) involves necrosis of bone and bone marrow of the femoral head caused by ischemia with unknown etiology. Previous genetic studies on ONFH failed to produce consistent results, presumably because ONFH has various causes with different genetic backgrounds and the underlying diseases confounded the associations. Steroid-associated ONFH (S-ONFH) accounts for one-half of all ONFH, and systemic lupus erythematosus (SLE) is a representative disease underlying S-ONFH. We performed a genome-wide association study (GWAS) to identify genetic risk factors for S-ONFH in patients with SLE. We conducted a two-staged GWAS on 636 SLE patients with S-ONFH and 95 588 non-SLE controls. Among the novel loci identified, we determined S-ONFH-specific loci by comparing allele frequencies between SLE patients without S-ONFH and non-SLE controls. We also used Korean datasets comprising 148 S-ONFH cases and 37 015 controls to assess overall significance. We evaluated the functional annotations of significant variants by in silico analyses. The Japanese GWAS identified 4 significant loci together with 12 known SLE susceptibility loci. The four significant variants showed comparable effect sizes on S-ONFH compared with SLE controls and non-SLE controls. Three of the four loci, MIR4293/MIR1265 [odds ratio (OR) = 1.99, P-value = 1.1 × 10-9)], TRIM49/NAALAD2 (OR = 1.65, P-value = 4.8 × 10-8) and MYO16 (OR = 3.91, P-value = 4.9 × 10-10), showed significant associations in the meta-analysis with Korean datasets. Bioinformatics analyses identified MIR4293, NAALAD2 and MYO16 as candidate causal genes. MIR4293 regulates a PPARG-related adipogenesis pathway relevant to S-ONFH. We identified three novel susceptibility loci for S-ONFH in SLE.

Rigid fixation of pelvic tracker essential for accurate cup placement in CT-based navigation total hip arthroplasty.

Research is lacking on the effect of intraoperative pelvic tracker displacement relative to the pelvis on cup orientation accuracy in computed tomography (CT)-based navigation (CTN) or multivariable analysis to detect factors associated with CTN accuracy. Here, we asked: (1) how pelvic tracker displacement influences the CTN accuracy of cup orientation in total hip arthroplasty (THA)? and (2) what factors are associated with CTN accuracy on multivariable analysis? Regarding cup orientation in 446 THA procedures using CTN, we evaluated clinical error defined as the difference between postoperative measurement and preoperative planning and measurement error defined as the difference between postoperative and intraoperative measurements. Multivariable regression analyses detected the associated factors. Subjects with an intraoperative tracker displacement of < 2 mm were classified in the verified group. Mean absolute clinical and measurement errors were < 1.5° in the verified group, whereas the measurement error of 2.6° for cup inclination and 1.3° for anteversion was larger in the non-verified versus verified group. Tracker displacement and screw fixation were associated with larger clinical errors, while tracker displacement and surgeon inexperience were associated with larger measurement errors. Clinical and measurement accuracies were high for CTN cup placement with rigid pelvic tracker fixation.

Effects of Cerclage Cabling on Preventing Periprosthetic Femoral Fractures When Using Cementless Stems for Unstable Femoral Neck Fractures.

BACKGROUND: Periprosthetic femoral fractures (PFFs) are serious complications in hip arthroplasty for femoral neck fractures. The rates of intraoperative (iPFFs) and postoperative PFFs (pPFFs) are higher in cementless stem cases than in cemented cases. This study aimed to investigate the effects of cerclage cabling on PFF prevention in cementless arthroplasty for femoral neck fractures. METHODS: This retrospective study included 329 consecutive patients who underwent hip arthroplasty using a cementless stem for femoral neck fractures. A total of 159 and 170 patients were in the non-cabling and cabling groups, respectively. Patient characteristics were comparable in both groups. The PFF occurrence (iPFF and pPFF) rates, reoperation rates, operative time, and blood loss volume were compared between the groups. RESULTS: The iPFF rate was significantly higher in the noncabling group (6.3%) than in the cabling group (0%, P < .001). The rate of pPFF was significantly higher in the non-cabling group (5.1%) than in the cabling group (0.6%; P = .016). All patients in the non-cabling group required reoperation (5.1%), whereas the patient in the cabling group was an ambulatory case and required no reoperation (0%, P = .003). No significant difference in either operative time or blood loss volume was observed between the non-cabling (50 minutes, 133 mL) and cabling (52 minutes, P = .244; 149 mL, P = .212, respectively) groups. CONCLUSIONS: When a cementless stem is used to treat unstable femoral neck fractures, cerclage cabling effectively prevents iPPF and pPPF without increasing surgical time or blood loss volume.

Is There an Association Between Femoral Head Collapse and Acetabular Coverage in Patients With Osteonecrosis?

BACKGROUND: Osteonecrosis of the femoral head (ONFH) classification systems are based on the size, volume, and location of necrotic lesions. Often-but not always-ONFH results in femoral head collapse. Because acetabular coverage is associated with mechanical stress on the femoral head, it might also be associated with femoral head collapse in patients with ONFH. However, the association between acetabular coverage and femoral head collapse in these patients has not been established. QUESTIONS/PURPOSES: (1) Is femoral head collapse associated with acetabular coverage or pelvic incidence (PI) in patients with ONFH? (2) Are established predictors of femoral head collapse in ONFH classification systems associated with acetabular coverage? METHODS: Between 2008 and 2018, we evaluated 343 hips in 218 patients with ONFH. We considered all patients with ONFH except for those with a traumatic etiology, a history of surgical treatment before collapse, or those with collapse at initial presentation as potentially eligible for this study. Of those, 101 hips with ONFH (50% [50] were in males with a mean age of 44 ± 15 years) met our inclusion criteria. These patients were subsequently divided into two groups: those with femoral head collapse within 12 months (collapse group, 35 hips) and those without femoral head collapse (noncollapse group, 66 hips). No differences in patient demographics were observed between the two groups. CT images were used to measure the PI and acetabular coverage in three planes: the lateral center-edge angle (LCEA) in the coronal plane, the anterior and posterior center-edge angle in the sagittal plane, and the anterior and posterior acetabular sector angle in the axial plane; in addition, the difference between these parameters was investigated between the groups. The thresholds for femoral head collapse in the parameters that showed differences were investigated. Necrotic location and size were evaluated using the Japanese Investigation Committee (JIC) classification and the Steinberg grade classification, respectively. We examined the relationship between these parameters and classifications. RESULTS: The mean LCEA was slightly greater in the noncollapse group than in the collapse group (32° ± 6° versus 28° ± 7°; mean difference 4° [95% CI 1.15° to 6.46°]; p = 0.005); the clinical importance of this small difference is uncertain. There were no differences in PI between the two groups. After accounting for sex, age, BMI, and etiology as confounding factors, as well as acetabular coverage parameters and PI, we found a lower LCEA to be independently associated with increased odds of collapse, although the effect size is small and of questionable importance (OR 1.18 [95% CI 1.06 to 1.33]; p = 0.001). The threshold of LCEA for femoral head collapse was 28° (sensitivity = 0.79, specificity = 0.60, area under the curve = 0.73). The percentage of patients with an LCEA less than 28° was larger in JIC Type C1 (OR 6.52 [95% CI 1.64 to 43.83]; p = 0.006) and C2 (OR 9.84 [95% CI 2.34 to 68.38]; p = 0.001) than in patients with both Type A and Type B. The acetabular coverage data for the excluded patients did not differ from those of the patients included in the analysis. CONCLUSION: Our findings suggest that acetabular coverage appears to have little, if any, association with the likelihood of collapse in patients with ONFH. We found a small association between a lower LCEA and a higher odds of collapse, but the effect size may not be clinically important. Factors other than acetabular coverage need to be considered, and if our findings are verified by other investigators, osteotomy is unlikely to have a protective role. As the patients in our study were fairly homogeneous in terms of ethnicity and BMI, these factors need to be further investigated to determine whether they are associated with femoral head collapse in ONFH. LEVEL OF EVIDENCE: Level III, prognostic study.

What Changes in Pelvic Sagittal Tilt Occur 20 Years After THA?

BACKGROUND: Cup orientation in THA in the supine, standing, and sitting positions is affected by pelvic sagittal tilt (PT). Patterns of PT shift between these positions may increase the risk of dislocation and edge loading. The PT has also been reported to change during the aging process; however, there is limited research regarding long-term changes in PT and PT shifts after THA. QUESTIONS/PURPOSES: (1) What changes occur in PT in the supine, standing, and sitting positions during 20 years of follow-up after THA in patients who have not had revision or dislocation? (2) What factors are associated with the differences between preoperative supine PT and postoperative sitting or standing PT (Δ sitting and Δ standing, respectively) 20 years postoperatively? METHODS: Between January 1998 and December 1999, 101 consecutive patients underwent THA for appropriate indications. AP radiographs of the pelvis in the supine, standing, and sitting positions preoperatively and at 1, 10, and 20 years after THA were longitudinally performed to evaluate changes in PT. Fifty-nine percent (60 of 101) of patients were lost before 20 years of follow-up or had incomplete sets of imaging tests, leaving 41% (41 of 101) eligible for analysis here. There were no patients who had recurrent dislocation or underwent revision arthroplasty in the cohort; therefore, this analysis regarding postoperative changes in PT indicates the natural course of the change in PT during follow-up of THA. PT was measured based on the anterior pelvic plane. PT shifts with positional changes, Δ standing, and Δ sitting during the follow-up period were calculated. Posterior changes and shifts are represented by negative values. To analyze the factors associated with Δ standing and Δ sitting after 20 years, the correlations between these parameters and preoperative factors (including sex, age, pelvic incidence [PI], lumbar lordosis [LL], preoperative PT, and preoperative PT shift) and postoperative factors (including the occurrence of new lumbar vertebral fractures, lumbar spondylolisthesis, contralateral THA performed during follow-up, and PI-LL 20 years after THA) were determined. RESULTS: Median (IQR) supine and standing PTs changed (moved posteriorly) by -5° (-11° to -2°; p < 0.01) and -10° (-15° to -7°; p < 0.01), respectively. Sitting PT did not change during the 20-year follow-up period. Median (IQR) PT shift from standing to sitting changed from -34° preoperatively (-40° to -28°) to -23° after 20 years (-28° to -20°). There were posterior changes in median (range) Δ standing (median -12° at 20 years [-19° to -7°]); Δ sitting did not change during the follow-up period (median -36° at 20 years [-40° to -29°]). Patients with a large preoperative posterior PT shift from supine to standing demonstrated larger posterior tilt of Δ standing at 20 years. Patients with lumbar vertebral fractures during follow-up demonstrated larger posterior tilt of Δ standing at 20 years. CONCLUSION: Patients who demonstrate a large preoperative posterior shift from supine to standing deserve special consideration when undergoing THA. In such circumstances, we recommend that the anteversion of the cup not be excessive, given that there is a relatively high risk of further posterior tilt in PT, which may lead to anterior dislocation and edge loading. Further longitudinal study in a larger cohort of patients with complications including postoperative dislocation and revision, as well as older patients, is needed to verify these assumptions on the potential risk for dislocation and edge loading after THA. LEVEL OF EVIDENCE: Level III, therapeutic study.

Osteocompatibility of Si3N4-coated carbon fiber-reinforced polyetheretherketone (CFRP) and hydroxyapatite-coated CFRP with antibiotics and antithrombotic drugs.

This study used a rabbit model to investigate the osteocompatibility of Si3N4-coated carbon fiber-reinforced polyetheretherketone (CFRP) and hydroxyapatite (HA)-coated CFRP with antibiotics (vancomycin [VCM]) and antithrombotic drugs (polyvinylpyrrolidone [PVP]). HA-coated cylindrical CFRP implants were used as the controls (HA), and HA-coated implants treated with VCM and PVP were prepared (HA-VP) as the test groups; a cylindrical CFRP coated with Si3N4 was also prepared (SiN). Ten implants from each group were randomly inserted into the femoral diaphysis of rabbits. The pull-out test, radiological analysis using micro-computed tomography (µ-CT), and histological analysis were performed. The pull-out strength of the SiN group was lower than that of the HA group. µ-CT analysis revealed that the amount of bone formation around the implant in the SiN group was inferior to that in the HA group. Conversely, the HA-VP group had equivalent pull-out strength and bone formation as analyzed by µ-CT compared to the HA group. In conclusion, the additional surface treatment of the HA-coated CFRP with VCM and PVP provided sufficient bone fixation and formation.

Optimizing vancomycin release from novel carbon fiber-reinforced polymer implants with small holes: periprosthetic joint infection treatment.

Periprosthetic joint infection (PJI) is a catastrophic complication after total hip arthroplasty. A new drug-loaded carbon fiber-reinforced polymer (CFRP) prosthesis with a sustained drug-release mechanism is being developed for one-stage surgery. We aimed to examine the diffusion dynamics of vancomycin from vancomycin paste-loaded CFRP implants. The differences in the in vitro diffusion dynamics of vancomycin paste were investigated using the elution test by varying parameters. These included the mixing ratio of vancomycin and distilled water (1:0.8, 1:1.2, and 1:1.4) for vancomycin paste, and hole diameter (1 mm and 2 mm) on the container. The in vivo diffusion dynamics were investigated using a rabbit model with vancomycin-loaded CFRP implants placed subcutaneously. The in vitro experiments showed that the diffusion effect of vancomycin was highest in the parameters of vancomycin paste with distilled water mixed in a ratio of 1:1.4, and with a 2 mm hole diameter. The in vivo experiments revealed diffusion dynamics similar to those observed in the in vitro study. The drug diffusion effect tended to be high for vancomycin paste with a large water ratio, and a large diameter of holes. These results indicate that the drug diffusion dynamics from a CFRP implant with holes can be adjusted by varying the water ratio of the vancomycin paste, and the hole size on the CFRP implant.

Association between magnitude of femoral head collapse and quality of life in patients with osteonecrosis of the femoral head.

OBJECTIVES: The magnitude of femoral head collapse (MFHC) is one of the criteria for staging osteonecrosis of the femoral head (ONFH). The present study aimed to clarify the relationship between MFHC and hip pain or functional quality of life (QOL) scores in patients with ONFH. METHODS: Seventy patients with ONFH who had femoral head collapse without osteoarthritic changes were divided into four groups based on MFHC by 1 mm. Pain was assessed using the visual analogue scale (VAS). QOL was evaluated using patient-reported outcome measures such as the Japanese Orthopaedic Association Hip-Disease Evaluation Questionnaire (JHEQ), Oxford Hip Score (OHS), and Short Form-12 Health Survey, version 2 (SF-12v2). We also explored the relationship between MFHC and QOL. RESULTS: Pain score and satisfaction score in the VAS, JHEQ pain subscale, JHEQ movement subscale, and JHEQ total score were significantly associated with MFHC, and no significant differences were found between groups in any subscale or total score for OHS and SF-12v2. CONCLUSION: In patients with ONFH, differences in MFHC by 1 mm were associated with deterioration of some pain VAS and QOL outcomes.

Effect of hip flexion contracture on the pelvic sagittal tilt in the supine position: A retrospective case-series study.

OBJECTIVES: The functional pelvic plane, which adopts the natural pelvic sagittal tilt in the supine position, is a good reference for determining the cup angle in total hip arthroplasty. However, hip flexion contracture may change pelvic tilt postoperatively by the release of contracture. This study investigated the influence of hip flexion contracture on pelvic sagittal tilt in the supine position. METHODS: This study included 300 patients who underwent primary unilateral total hip arthroplasty. We divided the participants into two groups: with a preoperative hip extension angle of <0° (hip flexion contracture group) and without (non-contracture group). The pelvic sagittal tilt and femoral flexion angle were investigated using computed tomography or pelvic radiographs performed preoperatively and postoperatively. RESULTS: The femoral flexion angle had significantly reduced postoperatively in the hip flexion contracture group but remained unchanged in the non-contracture group. The preoperative and postoperative pelvic sagittal tilt showed no significant differences between the two groups up to 1 year postoperatively. CONCLUSIONS: The influence of hip flexion contracture on the pelvic sagittal tilt in the supine position was minimal. The functional pelvic plane in the supine position could be a good reference to ascertain the cup orientation, even in hip flexion contracture cases.

MRI screening for osteonecrosis of the femoral head after COVID-19.

OBJECTIVES: Systemic steroid administration has been suggested for the treatment of coronavirus disease 2019 (COVID-19), but the occurrence of osteonecrosis of the femoral head (ONFH) was one of the concerns for this treatment. This study aimed to use magnetic resonance imaging (MRI) to assess the incidence of ONFH after treatment COVID-19. METHODS: The study included 41 patients who were hospitalized and treated for pneumonia or other COVID-19-induced diseases. We conducted interviews with these patients regarding hip pain and performed MRI screenings for ONFH. The incidence and timing of ONFH after COVID-19 treatment were investigated. RESULTS: Of the 41 patients, one died of pneumonia, and the remaining patients did not complain of hip pain. MRI screening of 26 patients was performed, and asymptomatic ONFH was detected in one patient (3.8%) whose ONFH appeared 1 month after the COVID-19 infection. CONCLUSION: Our MRI screening of ONFH in post-COVID-19 patients revealed asymptomatic ONFH, which would not have been identified without active screening. Physicians should be aware that ONFH may occur in patients after treating COVID-19.

Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study.

OBJECTIVE: Genome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis. METHODS: We built gene expression predictive models in blood B cells, CD4+ and CD8+ T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches. RESULTS: TWAS identified 171 genes for SLE (p<1.0×10-5); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p<7.7×10-8). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10-9) around CD83. For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1, and that presence of the SLE risk allele decreased ACAP1 expression. CONCLUSIONS: Cell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.

The Effect of Region of Interest on Measurement of Bone Mineral Density of the Proximal Femur: Simulation Analysis Using CT Images.

While accurate measurement of bone mineral density (BMD) is essential in the diagnosis of osteoporosis and in evaluating the treatment of osteoporosis, it is unclear how region of interest (ROI) settings affect measurement of BMD at the total proximal femur region. In this study, we performed a simulation analysis to clarify the effect on BMD measurement of changing the ROI using hip computed tomography (CT) images of 75 females (mean age, 62.4 years). Digitally reconstructed radiographs of the proximal femur region were generated from CT images to calculate the change in BMD when the proximal boundary of the ROI was altered by 0-10 mm, and when the distal boundary of the ROI was altered by 0-30 mm. Further, changes in BMD were compared across BMD classification groups. A mean BMD increase of 0.62% was found for each 1-mm extension of the distal boundary. A mean BMD decrease of 0.18% was found for each 1-mm alteration of the proximal boundary. Comparing BMD classification groups, patients with osteoporosis and osteopenia demonstrated greater BMD changes than patients with normal BMD for the distal boundary (0.68%, 0.64%, and 0.54%, respectively) and patients with osteoporosis demonstrated greater BMD changes than patients with osteoporosis and normal BMD for the proximal boundary (0.37%, 0.13%, and 0.03%, respectively). In conclusion, our study found that a consistent ROI setting, especially on the distal boundary, is necessary for the accurate measurement of total proximal femur BMD. Based on the findings, we recommend confirming that the ROI setting shown on the BMD result form is consistent with changes in serial BMD.

Numerical analysis evaluation of artificial joints.

Artificial joints are exposed to loads on a daily basis. Loads on the bone through the artificial joint and the joint's sliding surface shear force may cause implant fixation failure, fatigue fractures, wear of the bearing and foreign body reactions. Artificial joints can experience sudden internal damage, which can be fatal if it occurs during activities performed at high altitudes or in water. The standard design hip prosthesis has a metal femoral stem. Most stem fractures are caused at the proximal one third of the stem by fatigue due to repetitive loading. Femoral stem neck fractures can also occur. To eliminate in vivo prosthesis failures, safety performance preclinical studies evaluate stem body and neck breakage. However, the development of new femoral stems via prototyping and fatigue test verification would require excessive time and money. Therefore, evaluation methods based on numerical analyses, such as finite element analysis (FEA), have been introduced to simulate tests on actual machines. Fatigue strength design verification using FEA can efficiently identify a design that can pass International Organization for Standardization fatigue tests. FEA may also aid with composite implant development by enabling efficient preclinical testing to prove safety using minimal actual fatigue testing. Once a biological safety study of a composite material is performed, a clinical trial can prove its clinical efficacy and safety and device regulatory approval can be requested. This review was created based on a translation of the Japanese review written in the Japanese Journal of Artificial Organs in 2020 (Vol. 49, No. 3, pp. 195-198), with adding some additional contents and references.

The 2021 Association Research Circulation Osseous Classification for Early-Stage Osteonecrosis of the Femoral Head to Computed Tomography-Based Study.

BACKGROUND: The Association Research Circulation Osseous developed a novel classification for early-stage (precollapse) osteonecrosis of the femoral head (ONFH). We hypothesized that the novel classification is more reliable and valid when compared to previous 3 classifications: Steinberg, modified Kerboul, and Japanese Investigation Committee classifications. METHODS: In the novel classification, necrotic lesions were classified into 3 types: type 1 is a small lesion, where the lateral necrotic margin is medial to the femoral head apex; type 2 is a medium-sized lesion, with the lateral necrotic margin being between the femoral head apex and the lateral acetabular edge; and type 3 is a large lesion, which extends outside the lateral acetabular edge. In a derivation cohort of 40 early-stage osteonecrotic hips based on computed tomography imaging, reliabilities were evaluated using kappa coefficients, and validities to predict future femoral head collapse by chi-squared tests and receiver operating characteristic curve analyses. The predictability for future collapse was also evaluated in a validation cohort of 104 early-stage ONFH. RESULTS: In the derivation cohort, interobserver reliability (k = 0.545) and intraobserver agreement (63%-100%) of the novel method were higher than the other 3 classifications. The novel classification system was best able to predict future collapse (P < .05) and had the best discrimination between non-progressors and progressors in both the derivation cohort (area under the curve = 0.692 [0.522-0.863], P < .05) and the validation cohort (area under the curve = 0.742 [0.644-0.841], P = 2.46 × 10-5). CONCLUSION: This novel classification is a highly reliable and valid method of those examined. Association Research Circulation Osseous recommends using this method as a unified classification for early-stage ONFH. LEVEL OF EVIDENCE: Level III, diagnostic study.

Geographical distribution of the associated factors of osteonecrosis of the femoral head, using the designated intractable disease database in Japan.

OBJECTIVES: Osteonecrosis of the femoral head (ONFH) is a designated intractable disease (DID) in Japan. The Ministry of Health, Labour, and Welfare launched an online registry system for DIDs. We aimed to investigate the epidemiological characteristics of patients with ONFH using the DID database. METHODS: Data of patients with ONFH registered in the DID database between January 2004 and December 2013 were extracted. The incidence of new cases and distributions of sex, age, and associated risk factors were investigated. The prevalence of the two categories, 'steroid-associated' and 'alcohol-associated' risk factors, was estimated for each prefecture. RESULTS: New 15,049 cases of ONFH were investigated. The mean registration rate-corrected annual ONFH incidence per 100,000 individuals was 1.77. The male-to-female ratio was 1.33. Age distribution peaked in the 40s and 50s for male and 60s for female. The prevalence of steroid-associated ONFH was lower in males (28.6%) than in females (49.8%), while that of alcohol-associated ONFH was higher in males (47.2%) than in females (9.3%). No clear region was identified for the steroids. The incidence of alcohol-associated ONFH was significantly higher in Tokyo and Okinawa, regardless of sex. CONCLUSIONS: Alcohol-associated ONFH incidence varies geographically across Japan, suggesting that it has regional characteristics.

Geographic distribution of the incidence of osteonecrosis of the femoral head in Japan and its relation to smoking prevalence.

OBJECTIVES: Alcohol intake and smoking are modifiable lifestyle-related risk factors for osteonecrosis of the femoral head (ONFH). We investigated geographic differences in ONFH incidence in Japan and the correlation with alcohol intake and smoking to develop prevention strategies for ONFH in Japan. METHODS: This ecological study was conducted in Japan primarily using the following data sources: nationwide epidemiological survey and national survey. We estimated the annual ONFH incidence and the prevalence of alcohol drinking and smoking in each prefecture. Prefectural incidence and prevalence were calculated by sex and age-standardization. RESULTS: The mean annual ONFH incidence per 100,000 population was 3.08 in men and 1.63 in women, respectively. There was no significant correlation between ONFH incidence and the prevalence of any levels of alcohol intake, while smoking ≥20 cigarettes/day showed a significant and moderate correlation in men (r = 0.47, p = .01). This correlation remained significant after adjustment for the prevalence of any levels of alcohol intake (standardized partial regression coefficient = 0.47-0.49, p = .009-.01). CONCLUSION: ONFH incidence is geographically variable in Japan, and this may be partly explained by the distribution of smoking prevalence. Smoking cessation may contribute to an effective decline in the overall ONFH incidence in Japan.

Epidemiological study of osteonecrosis of the femoral head using the national registry of designated intractable diseases in Japan.

OBJECTIVES: We aimed to investigate the epidemiological characteristics of osteonecrosis of the femoral head (ONFH) using the designated intractable diseases (DID) database in Japan. METHODS: Data on patients who had received public subsidies for medical costs due to ONFH from 2012 to 2013 were extracted from the DID database. The incidence and prevalence of ONFH, distribution of gender, age, and the prevalence of associated risk factors were assessed. These epidemiological characteristics were compared with those of another nationwide ONFH survey conducted during a similar period. RESULTS: Data on 3264 newly diagnosed patients (incident cases) and 20,042 patients registered until 2013 (prevalent cases) were evaluated. The corrected annual incidence and prevalence of ONFH per 100,000 were 3.0 and 18.2-19.2, respectively. The ratio of males to females was 1.4 in 2012 and 1.2 in 2013, respectively. Peak distribution was observed at ages 40s and 60s in males and females, respectively. The prevalence of the risk factors were steroid-associated: 39%, alcohol-associated: 30%, both: 4%, and none: 27%. CONCLUSIONS: The DID database data showed a similar distribution of gender and age to that in other nationwide surveys but lower incidence and prevalence of ONFH. Sampling bias may affect the epidemiological characteristics of ONFH.

Identification of CXCL12-abundant reticular cells in human adult bone marrow.

A population of mesenchymal stem cells, termed CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells or leptin receptor-expressing cells, are the major cellular component of niches for haematopoietic stem cells (HSCs) in murine bone marrow. CAR cells are characterized by several salient features, including much higher expression of CXCL12, stem cell factor (SCF), forkhead box C1 (FOXC1) and early B-cell factor 3 (EBF3), which are essential for HSC maintenance, than other cells. However, the human counterpart of CAR cells has not been fully described. Here, we show the presence of cells expressing much higher CXCL12 than other cells in human adult bone marrow using a flow cytometry-based in situ technique that enables high-throughput detection of mRNA at single-cell resolution. Most CXCL12hi cells expressed high levels of SCF, FOXC1 and EBF3 and had the potential to differentiate into adipocytes and osteoblasts. Histologically, the nuclei of CXCL12hi cells were identified and quantified by EBF3 expression in fixed marrow sections. CXCL12hi cells sorted from residual bone marrow aspirates of chronic myeloid leukaemia patients expressed reduced levels of CXCL12, SCF, FOXC1 and EBF3 in correlation with increased leukaemic burden. Together, we identified the human counterpart of CAR cells, enabling the evaluation of their alterations in various haematological disorders by flow cytometric and histological analyses.

Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations. METHODS: We newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations. RESULTS: We identified 113 genetic regions including 46 novel loci at genome-wide significance (p<5×10-8). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (rg=-0.242) and non-albumin protein (rg=0.238). CONCLUSION: This study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.

Gamma-Glutamyl Transferase: A Useful Marker of Habitual Drinking in Cases of Alcohol-Associated Osteonecrosis of the Femoral Head.

AIMS: Alcohol intake is one of the factors associated with the occurrence of osteonecrosis of the femoral head (ONFH), and its epidemiological information regarding alcohol intake depends on patients' self-reports. Therefore, we analysed the efficacy of laboratory tests as an objective diagnostic tool to indicate habitual drinking in patients with alcohol-associated ONFH. METHODS: This study included 109 consecutive patients diagnosed with ONFH who underwent primary hip surgery in our institution between 2010 and 2018. The patients were classified into group AL (alcohol-associated ONFH; n = 26) and group NO (alcohol-unassociated ONFH; n = 83), based on their self-reported information. Serum levels of gamma-glutamyl transferase (GGT), mean corpuscular volume (MCV), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol and triglycerides were compared between both groups. The sensitivities and specificities with the optimal cut-off values for detecting alcohol-associated ONFH were compared among these markers. RESULTS: The median serum levels of GGT, AST and ALT were significantly higher in the AL group than in the NO group. The receiver operating characteristic curve analysis demonstrated an area under the curve of 0.795 for GGT, 0.731 for AST and 0.709 for ALT. The optimal cut-off level of GGT as a marker for alcohol-associated ONFH was 36.5 units/L, with a sensitivity of 76% and specificity of 80%, and it was found to be the best marker among the other examined laboratory markers. CONCLUSION: Serum GGT level is a useful laboratory marker with moderate accuracy that indicates habitual drinking in patients with alcohol-associated ONFH.