Leg length discrepancy should be assessed based on the whole length of the lower limb in patients with osteoarthritis secondary to developmental dysplasia of the hip.

Aims: This study aimed to investigate the incidence of ≥ 5 mm asymmetry in lower and whole leg lengths (LLs) in patients with unilateral osteoarthritis (OA) secondary to developmental dysplasia of the hip (DDH-OA) and primary hip osteoarthritis (PHOA), and the relationship between lower and whole LL asymmetries and femoral length asymmetry. Methods: In total, 116 patients who underwent unilateral total hip arthroplasty were included in this study. Of these, 93 had DDH-OA and 23 had PHOA. Patients with DDH-OA were categorized into three groups: Crowe grade I, II/III, and IV. Anatomical femoral length, femoral length greater trochanter (GT), femoral length lesser trochanter (LT), tibial length, foot height, lower LL, and whole LL were evaluated using preoperative CT data of the whole leg in the supine position. Asymmetry was evaluated in the Crowe I, II/III, IV, and PHOA groups. Results: The incidences of whole and lower LL asymmetries were 40%, 62.5%, 66.7%, and 26.1%, and 21.7%, 20.8%, 55.6%, and 8.7% in the Crowe I, II/III, and IV, and PHOA groups, respectively. The incidence of tibial length asymmetry was significantly higher in the Crowe IV group (44.4%) than that in the PHOA group (4.4%). In all, 50% of patients with DDH-OA with femoral length GT and LT asymmetries had lower LL asymmetry, and 75% had whole LL asymmetry. The incidences of lower and whole LL asymmetries were 20% and 42.9%, respectively, even in the absence of femoral length GT and LT asymmetries. Conclusion: Overall, 43% of patients with unilateral DDH-OA without femoral length asymmetry had whole LL asymmetry of ≥ 5 mm. Thus, both the femur length and whole LL should be measured to accurately assess LL discrepancy in patients with unilateral DDH-OA.

Successful treatment with tirabrutinib for relapsed lymphoplasmacytic lymphoma complicated by Bing-Neel syndrome.

A 53-year-old woman was diagnosed with lymphoplasmacytic lymphoma (LPL)/Waldenström's macroglobulinemia (WM) in 2008. Six courses of R-COP (rituximab, cyclophosphamide, vincristine, and prednisolone) resulted in complete remission, but LPL/WM relapsed in 2015. After six courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone), the M-peak disappeared, but the patient presented with muscle weakness and sensory disturbance in the lower extremities. No lesions were apparent in the brain parenchyma, but T2-weighted magnetic resonance imaging (MRI) showed a signal-hyperintense area with contrast enhancement in the spinal cord at the C2-4 and Th2-3 levels, and cerebrospinal fluid (CSF) examination showed only a few mononuclear cells. In 2020, the patient started to require walking assistance, and MRI findings worsened. Neurologically, lower limb muscle strength was reduced (manual muscle test score 3), and sensations of touch and pain were about 30% of normal. Vibratory sensation was absent at the knees and medial malleoli, accompanied by dysuria due to neurogenic bladder. CSF cell count was 15/µl (all mononuclear cells). Bing-Neel syndrome (BNS) was diagnosed and tirabrutinib was started. Within 2 months of treatment, lower extremity muscle strength had normalized and MRI findings had improved. Tirabrutinib may offer a promising therapeutic option for BNS.

Detection of novel and recurrent conjoined genes in non-Hodgkin B-cell lymphoma.

For this study, we investigated comprehensive expression of conjoined genes (CGs) in non-Hodgkin B-cell lymphoma (B-NHL) cell line KPUM-UH1 by using paired-end RNA sequencing. Furthermore, we analyzed the expression of these transcripts in an additional 21 cell lines, 37 primary samples of various malignancies and peripheral blood mononuclear cells of four normal individuals. Seventeen CGs were detected in KPUM-UH1: CTBS-GNG5, SRP9-EPHX1, RMND5A-ANAPC, OTX1-EHBP1, ATF2-CHN1, PRKAA1-TTC33, LARP1-MRPL22, LOC105379697-BAK1, TIAM2-SCAF8, SPAG1-VPS13B, WBP1L-CNNM2, NARS2-GAB2, CTSC-RAB38, VAMP1-CD27-AS1, LRRC37A2-NSF, UBA2-WTIP and ZNF600-ZNF611. To our knowledge, 10 of these genes have not been previously reported. The various characteristics of the CGs included in- and out-of-frame fusions, chimeras involving non-coding RNA and transcript variants. A finding of note was that LARP1-MRPL2 was characterized as in-frame fusion and was recurrently expressed in B-NHL samples. In this study, variety of CGs was expressed both in malignant and normal cells, some of which might be specific to lymphoma.

Differences in knee joint degeneration between primary hip osteoarthritis and hip osteoarthritis secondary to hip developmental dysplasia: A propensity score-based analysis.

OBJECTIVES: This study aimed to investigate differences in lower limb alignment and the prevalence of knee osteoarthritis (OA) among patients with primary hip osteoarthritis (PHOA) versus those with hip osteoarthritis secondary to developmental dysplasia of the hip (DDH-OA). METHODS: We compared 83 patients who underwent primary total hip arthroplasty for unilateral PHOA or DDH-OA after performing propensity score matching. The prevalence of knee OA and lower limb alignment were evaluated on preoperative plain radiographs. RESULTS: The prevalence of knee OA on the ipsilateral side was significantly higher in the PHOA group than in the DDH-OA group (p =.019), whereas there was no difference between the groups on the contralateral side (p = .631). Lower-limb alignment was more valgus on the ipsilateral side in the DDH-OA group than the PHOA group, whereas it was not significantly different on the contralateral side between groups. CONCLUSION: The prevalence of knee OA and lower-limb malalignment on the ipsilateral side of hip OA were different for PHOA and DDH-OA patients. Shifting the mechanical axis of lower limbs might be associated with the prevalence of knee OA and lower limb malalignment in the presence of unilateral hip OA.

What is the most cost-effective strategy for nasal screening and Staphylococcus aureus decolonization in patients undergoing total hip arthroplasty?

BACKGROUND: To reduce periprosthetic joint infection after total hip arthroplasty (THA), several nasal screening and decolonization strategies for methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA) have been performed. These include universal decolonization (UD; i.e., no screening and decolonization for all patients), universal screening and target decolonization (US; i.e., screening for all patients and decolonization for bacterial positive patients), and target screening and decolonization (TS; i.e., screening and decolonization for high-risk populations only). Although TS is the most cost-effective strategy, useful risk factors must be identified. The purpose of this study was to evaluate the presence of predictive factors that enable the TS strategy to be successfully implemented and to compare the costs of each strategy. METHODS: A total of 1654 patients scheduled for primary or revision THA (1464 female, 190 male; mean age 64 years) were screened prior to surgery for bacterial colonization of the nasal mucosa. Risk factors for positive MRSA and S. aureus (including both MRSA and MSSA) tests were analyzed according to the following parameters: sex, age ≥ 80 years, body mass index ≥ 30 kg/m2, antibiotic use within 3 years, corticosteroid use, serum albumin < 3.5 g/dL, glomerular filtration rate < 50 mL/min, presence of brain, thyroid, cardiac, or pulmonary disease, diabetes, asthma, smoking status, and whether revision surgery was performed. The average cost of each strategy was calculated. RESULTS: In total, 29 patients (1.8 %) tested positive for MRSA and 445 (26.9 %) tested positive for S. aureus. No parameters were identified as independent risk factors for MRSA and only female sex was identified as a risk factor for S. aureus (p = 0.003; odds ratio: 1.790; 95 % confidence interval: 1.210-2.640). The average cost of each strategy was 1928.3 yen for UD, 717.6 yen for US, and 717.6 yen for TS (for eradicating MRSA), and 1928.3 yen for UD, 1201.6 yen for US, and 1160.4 yen for TS (for eradicating S. aureus). CONCLUSIONS: No useful predictive parameters for implementing the TS strategy were identified. Based on cost implications, US is the most cost-effective strategy for THA patients.

Improving MiniHip femoral prosthesis positioning using a cross-laser projection system in total hip arthroplasty by an anterolateral supine approach.

BACKGROUND: The authors developed a cross-laser projection system (CLP) to place a femoral neck-sparing short stem using the minimally invasive anterolateral supine approach in total hip arthroplasty. This study aimed to verify the utility of CLP. METHODS: Thirty joints were assessed with the MiniHip (Corin). The authors compared femoral component implantation with a patient-specific femoral osteotomy guide (PSG) for the femoral neck-cut (PSG group), with the CLP attached to the rasp handle to irradiate the cross-laser to the target of PSG (CLP group), and without PSG or CLP (control group). RESULTS: In the CLP group, the positional deviation of anteversion, anterior/posterior tilt and varus/valgus placement of the stem postoperatively were 1.8° ± 0.2°, 2.0° ± 2.0° and 2.0° ± 0.1°, respectively. The positional deviation of anteversion (p < 0.001) and anterior/posterior tilt (p = 0.036) were significantly smaller than those in the other groups. CONCLUSIONS: CLP improves the accuracy of MiniHip femoral prosthesis placement.

Can sterility of stripped iodophor-impregnated plastic adhesive drape be maintained at the time of incision closure in total hip arthroplasty?

OBJECTIVE: The aim of this study was to analyze the contamination rates of the skin under the iodophor-impregnated plastic adhesive drape (IOD) at the time of incision closure in total hip arthroplasty (THA). METHODS: A total of 225 patients undergoing primary THA (28 men, 197 women; mean age=65 years; age range=30-85) were included in this study. After asepsis using a solution of 1% chlorhexidine with 83% alcohol by volume, the surgical site was painted with a 10% povidone-iodine solution, and IOD was attached tautly at the start of surgery. Swabs of the surgical site were collected as follows: swab A from the skin before IOD application, swab B from the surface of the IOD at the time of incision closure, and swab C from the skin after peeling back the IOD. The obtained samples were promptly sent for microbiological analysis. The contamination rate was determined for swabs A, B, and C, and the contamination rate of swab C was compared with that of swabs A and B, and the bacterial species were identified. RESULTS: Positive cultures were seen in 8 cases (3.6%) for swab A, 10 cases (4.4%) for swab B, and 22 cases (9.8%) for swab C. The contamination rate of swab C was significantly higher than that of swabs A (p=0.008) and B (p=0.028). Coagulase-negative Staphylococcus (n=10) and Cutibacterium acnes (n=7) were the most frequently cultured microorganisms from swab C. CONCLUSION: In THA, the contamination rate of the skin after peeling off the IOD before incision closure was higher than that of the skin immediately after sterilization with povidone-iodine and higher than that on the IOD at the time of incision closure. The detected bacterial species were considered clinically significant pathogens. Preventive measures against infection, such as minimizing stripping of the IOD or re-sterilizing bare skin after IOD stripping, should be instituted in consideration of these findings when performing THA using IOD.

BRD4-Regulated Molecular Targets in Mantle Cell Lymphoma: Insights into Targeted Therapeutic Approach.

BACKGROUND: Since bromodomain-containing protein 4 (BRD4) facilitates the transcription of genes important for neoplastic cells in a cancer-type specific manner, BRD4-regulated molecules may also include therapeutic targets for mantle cell lymphoma (MCL), a treatment-refractory subtype of malignant lymphoma. MATERIALS AND METHODS: In order to uncover direct BRD4-regulated targets in MCL, we performed integrated analysis using the pathway database and the results of both gene-expression profiling and chromatin immunoprecipitation with parallel sequencing for BRD4. RESULTS: Treatment with BRD4 inhibitor I-BET151 exerted a dose-dependent inhibitory effect on cell proliferation in MCL cell lines. BRD4 was found to directly regulate series of genes involved in the B-cell receptor (BCR) signaling pathway, including B-cell linker (BLNK), paired box 5 (PAX5), and IKAROS family zinc finger 3 (IKZF3), and several oncogenes, such as MYB. Indeed, the combinatory inhibition of BCR pathway and IKZF showed an additive antitumor effect. CONCLUSION: Concomitant targeting multiple BRD4-regulated molecules may constitute a rational therapeutic strategy for MCL.

Differential expression of individual transcript variants of PD-1 and PD-L2 genes on Th-1/Th-2 status is guaranteed for prognosis prediction in PCNSL.

In current molecular medicine, next-generation sequencing (NGS) for transcript variant detection and multivariable analyses are valid methods for evaluating gene expression, cancer mechanisms, and prognoses of patients. We conducted RNA-sequencing on samples from patients with primary central nervous system lymphoma (PCNSL) using NGS and performed multivariable analysis on gene expression data and correlations focused on Th-1/Th-2 helper T cell balance and immune checkpoint to identify diagnosis/prognosis markers and cancer immune pathways in PCNSL. We selected 84 transcript variants to limit the analysis range for Th-1/Th-2 balance and stimulatory and inhibitory checkpoints in 31 PCNSLs. Of these, 21 highly-expressed transcript variants were composed of the formulas for prognoses based on Th-1/Th-2 status and checkpoint activities. Using formulas, Th-1low, Th-2high, and stimulatory checkpointhigh resulted in poor prognoses. Further, Th-1highTh-2low was associated with good prognoses. On the other hand, CD40-001high and CD70-001high as stimulatory genes, and LAG3-001high, PDCD1 (PD-1)-001/002/003high, and PDCD1LG2 (PD-L2)-201low as inhibitory genes were associated with poor prognoses. Interestingly, Th-1highTh-2low and Th-1lowTh-2high were correlated with stimulatory checkpointlow as CD70-001low and inhibitory checkpointlow as HAVCR2 (TIM-3)-001low and PDCD1LG2-001/201low, respectively. Focused on the inhibitory checkpoint, specific variants of CD274 (PD-L1)-001 and PDCD1-002 served severe hazard ratios. In particular, PDCD1-002high by a cut off score was associated with poor prognoses, in addition to PDCD1-001/003high, PDCD1LG2-201low, and LAG3-001high. These results mainly suggest that expression of transcript variants of PDCD1 and PDCD1LG2 on the Th-1/Th-2 balance enable prognostic prediction in PCNSL. This study provides insights for development of molecular target therapies and identification of diagnosis/prognosis markers in PCNSL.

C/EBPß is a critical mediator of IFN-α-induced exhaustion of chronic myeloid leukemia stem cells.

Even in the era of ABL tyrosine kinase inhibitors, eradication of chronic myeloid leukemia (CML) stem cells is necessary for complete cure of the disease. Interferon-α (IFN-α) has long been used for the treatment of chronic-phase CML, but its mechanisms of action against CML stem cells remain unclear. We found that IFN-α upregulated CCAAT/enhancer binding protein ß (C/EBPß) in BCR-ABL-expressing mouse cells by activating STAT1 and STAT5, which were recruited to a newly identified 3' distal enhancer of Cebpb that contains tandemly aligned IFN-γ-activated site elements. Suppression or deletion of the IFN-γ-activated site elements abrogated IFN-α-dependent upregulation of C/EBPß. IFN-α induced differentiation and exhaustion of CML stem cells, both in vitro and in vivo, in a C/EBPß-dependent manner. In addition, IFN-α upregulated C/EBPß and induced exhaustion of lineage- CD34+ cells from CML patients. Collectively, these results clearly indicate that C/EBPß is a critical mediator of IFN-α-induced differentiation and exhaustion of CML stem cells.

Clinical accuracy and precision of hip resurfacing arthroplasty using computed tomography-based navigation.

PURPOSE: To avoid malalignment of components during hip resurfacing arthroplasty (HRA), we used a computed tomography (CT)-based navigation system for guidance. This study aimed to evaluate the clinical accuracy and precision of HRA performed using the CT-based navigation systems. METHODS: HRA was performed on 17 hips guided by the CT-based navigation systems. We measured cup alignment deviation, deviation of the stem position, and alignment from the plan by image matching between pre-operative and post-operative CT images. RESULTS: Cup anteversion was within 5° of that in the plan in all cases. Cup inclination was within 5° of that in the plan in 82.4% and within 10° in all cases. The angular difference of the stem was within 5° in all cases, and the entry point of the stem was within 4 mm in all cases. CONCLUSION: The CT-based navigation system for HRA guided accurate component placement according to the plan.

High-risk follicular lymphomas harbour more somatic mutations including those in the AID-motif.

We investigated clinical and genetic characteristics of high-risk follicular lymphoma (FL), that lacked evidence of large cell transformation at diagnosis, in the rituximab era. First, we retrospectively analysed the clinical features of 100 patients with non-transformed FL that were consecutively treated with rituximab-containing therapies in a discovery cohort. The presence of either peripheral blood and/or bone involvement was associated with short progression-free survival. This was confirmed in a validation cohort of 66 FL patients. Then, whole exome sequencing was performed on randomly selected 5 high- and 9 standard-risk FL tumours. The most common mutational signature was a CG > TG substitution-enriched signature associated with spontaneous deamination of 5-methylcytosine at CpG, but mutations in WA and WRC(Y) motifs (so-called activation-induced cytidine deaminase (AID) motifs) were also enriched throughout the whole exome. We found clustered mutations in target sequences of AID in the IG and BCL2 loci. Importantly, high-risk FLs harboured more somatic mutations (mean 190 vs. 138, P = 0.04), including mutations in WA (33 vs. 22, P = 0.038), WRC (34 vs. 22, P = 0.016) and WRCY motifs (17 vs. 11, P = 0.004). These results suggest that genomic instability that allows for emergence of distinct mutations through AID activity underlies development of the high-risk FL phenotype.

Novel common variants and susceptible haplotype for exfoliation glaucoma specific to Asian population.

The common variants in lysyl oxidase-like 1 gene (LOXL1) are associated with exfoliation glaucoma (XFG) patients developed through exfoliation syndrome (XFS). However, the risk allele of a variant in LOXL1 has been found to be inverted between Asian and Caucasian populations. Therefore, we newly performed a genome-wide association study using 201 XFS/XFG and 697 controls in Japanese, and identified 34 genome-wide significant single-nucleotide polymorphisms (SNPs) distributing in not only LOXL1 but also TBC1D21 and PML at the 15q24.1 locus. These SNPs were confirmed by an independent population consisted of 121 XFS/XFG and 263 controls in Japanese. Moreover, further analyses revealed a unique haplotype structure only from the combination of TBC1D21 and LOXL1 variants showing a high XFS/XFG susceptibility specific for the Asian population. Although there still should be other gene(s) in the other region(s) contributing to the disease process, these results suggested that the combination of newly discovered variants in these genes might be useful for precise XFG risk assessment, as well as for elucidating the molecular mechanism of XFG pathogenesis through XFS.