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Background: We aimed to compare radiographic and digital tomosynthesis assessments of early biological fixation of a cementless stem in primary total hip arthroplasty and to investigate the factors associated with early biological fixation., Methods: Seventy-three patients underwent total hip arthroplasty using cementless short tapered-wedge stems. Both radiography and digital tomosynthesis were performed at 6 weeks and 3, 6, 12, and 24 months after surgery. The presence of spot welds (SW) was evaluated at each postoperative period to assess biological fixation between the stem and the femur. The area of contact between the femur and the stem was divided into seven zones based on Gruen's zone classification., Results: All 73 patients had no SW 6 weeks after surgery on radiography and digital tomosynthesis. Three months postoperatively, there was no SW on radiography; however, digital tomosynthesis revealed SW in 31 (42%) patients. Six months postoperatively, radiography showed 22 SW in 18 (24.7%) patients and digital tomosynthesis showed 94 SW in 48 patients (65.8%)., Conclusion: Digital tomosynthesis detected biological fixation between the stem and femur earlier than radiography; biological fixation may appear within 3 months after surgery., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aluminum hydroxide salts (alum) have been added to inactivated vaccines as safe and effective adjuvants to increase the effectiveness of vaccination. However, the exact cell types and immunological factors that initiate mucosal immune responses to alum adjuvants are unclear. In this study, the mechanism of action of alum adjuvant in nasal vaccination was investigated. Alum has been shown to act as a powerful and unique adjuvant when added to a nasal influenza split vaccine in mice. Alum is cytotoxic in the alveoli and stimulates the release of damage-associated molecular patterns, such as dsDNA, interleukin (IL)-1α, and IL-33. We found that Ag-specific IgA antibody (Ab) production was markedly reduced in IL-33-deficient mice. However, no decrease was observed in Ag-specific IgA Ab production with DNase I treatment, and no decrease was observed in IL-1α/β or IL-6 production in IL-33-deficient mice. From the experimental results of primary cultured cells and immunofluorescence staining, although IL-1α was secreted by alveolar macrophage necroptosis, IL-33 release was observed in alveolar epithelial cell necroptosis but not in alveolar macrophages. Alum- or IL-33-dependent Ag uptake enhancement and elevation of OX40L expression were not observed. By stimulating the release of IL-33, alum induced Th2 immunity via IL-5 and IL-13 production in group 2 innate lymphoid cells (ILC2s) and increased MHC class II expression in antigen-presenting cells (APCs) in the lung. Our results suggest that IL-33 secretion by epithelial cell necroptosis initiates APC- and ILC2-mediated T cell activation, which is important for the enhancement of Ag-specific IgA Ab production by alum., Competing Interests: The authors have declared that no competing interests exist.

Purpose: This study aimed to investigate the rate at which patients returned to sports after open wedge high tibial osteotomy and identify the continuity of sports activity post-operatively., Methods: Thirty-five patients (40 knees) who underwent open-wedge high tibial osteotomy (OW-HTO) in medial knee osteoarthritis were included in this study. The mean age of the patients who underwent surgery was 55.1 ± 10.7 years, and the mean follow-up period was 41.0 ± 24.7 months. Clinical results and radiographic parameters calculated in standing whole-leg radiographs preoperatively, post-operatively, and at the final follow-up were evaluated., Results: Thirty-one patients (88.6%) were able to return to preoperative sports activity; however, only 14 patients (40.0%) completely returned to preoperative sports activity levels. Of the 31 patients who returned to sports activity, 10 patients (32.3%) maintained post-operative sporting activity levels at the final follow-up. In radiographic parameters, the weight-bearing line ratio was considered loss of correction in the post-operative period leading to the final follow-up. Patients who completely returned to sports and maintained sporting activity levels at the final follow-up had significantly higher the Knee Injury and Osteoarthritis Outcome Score pain subscale values and lower visual analogue scale of knee pain at pre-surgery and final follow-up than other patients, including those who partially returned to sports., Conclusions: The proportion of patients who returned to sports after OW-HTO and were able to participate in competitions at the same activity level as before surgery was low and insufficient., Level of Evidence: Retrospective case series, IV., (© 2021. The Author(s).)

Background: This study compared the failure load of the femoral insertion site of the anterior cruciate ligament between different portions and knee flexion angles., Methods: In total, 87 fresh-frozen, porcine knees were used in this study. Three knees were used for histological evaluation; the remaining 84 knees were randomly divided into 4 groups: anterior anteromedial bundle, posterior anteromedial bundle, anterior posterolateral bundle, and posterior posterolateral bundle groups (n=21 per group). The anterior cruciate ligament femoral insertion site was divided into these four areas and excised, leaving a 3-mm square attachment in the center of each bundle. Tibia-anterior cruciate ligament-femur complexes were placed in a material testing machine at 30°, 120°, and 150° of knee flexion (n=7), and the failure load for each portion was measured under anterior tibial loading (0.33 mm/s)., Results: Histological study showed that the anterior cruciate ligament femoral insertion site consisted of direct and indirect insertions. Comparison of the failure load between the knee flexion angles revealed that all the failure loads decreased with knee flexion; significant decreases were observed in the failure load between 30 and 150° knee flexion in the posterior anteromedial bundle and posterior posterolateral bundle groups. Comparison of the failure load according to different portions revealed a significant difference between the anteromedial and posterolateral bundle groups at 150° of knee flexion, but no significant difference among the groups at 30° of flexion., Conclusions: Although the failure load of the posterior portion decreased significantly in the knee flexion position, it (mainly consisting of indirect insertion) plays a significant role against anterior tibial load in the knee extension position; this appears to be related to the characteristics of the insertion site. Reflecting the complex structure and function of the ACL, this study showed that the failure load of the femoral insertion site varies with differences in positions and knee flexion angles., (© 2021. The Author(s).)

Purpose: Knee pain is associated with osteoarthritis (OA) and increases during this condition; however, its correlation with central sensitization (CS) in arthritis patients requires greater understanding. The present cross-sectional cohort study to explore the prevalence of knee OA, nocturnal knee pain and disability in general population and to examine the association of CS with sleep quality in Japanese general population., Patients and Methods: From among 1056 community-dowelling volunteers, 942 were enrolled as participants in this study. Bilateral weight-bearing anterior-posterior knee radiographs were classified by the Kellgren-Lawrence grade. Nocturnal knee pain and disability were assessed with self-reported questionnaires. Using the CS inventory with nine items (CSI-9), CS was defined as 10 points or higher. Sleep quality was scored using the Pittsburgh Sleep Quality Index (PSQI). Linear regression analysis, adjusted by age, sex, body mass index, Kellgren-Lawrence grade, nocturnal knee pain, and lifestyle habits, was performed to investigate the association of CS with PSQI., Results: The prevalence of OA, nocturnal knee pain, and disability was 37.9%, 7.6%, and 6.2%, respectively. The mean CSI-9 score was 4.9 ± 4.4, with a CS prevalence of 14.0%. The mean PSQI score was 3.9 ± 2.4, which was correlated with the CSI-9 value. CS was not correlated with OA severity; however, nocturnal knee pain prevalence increased from 13.3% to 25.5% in knee OA patients with CS. The CSI-9 value correlated with PSQI total score and subscales., Conclusion: Knee OA severity correlated with nocturnal pain and disability; however, its association with CS was unproven. The combined effect of knee OA and CS elevated nocturnal pain and disability, resulting in diminished sleep quality., Competing Interests: The authors declare that they have no competing interests., (© 2021 Sasaki et al.)

Lycopene is a lipophilic unsaturated carotenoid and has a very strong singlet oxygen-quenching ability. Increased serum or plasma lycopene levels have been reported to be associated with a lower risk of metabolic syndrome. We aimed to investigate the effects of lycopene intake on blood HDL-cholesterol (HCL-c) and triglyceride (TG) levels, which are metabolic syndrome biomarkers, by systematic review and meta-analyses of human interventional trials. We searched 15 databases and included studies that assessed the effects of oral lycopene intake on blood HDL-c and TG levels of participants ≥18 years of age. Three reviewers independently selected applicable studies, then assessed study qualities. Data were pooled as standardized mean difference (SMD) and analyzed by random-effects model. Heterogeneity was assessed by I 2 statistics. Meta-analysis including 12 trial arms (n = 781) revealed a significantly increased HDL-c level in the lycopene group compared with that in the control group (SMD = 0.33 [95% CI: 0.12, 0.54], p = 0.002) and moderate heterogeneity (I 2  = 45%). Most subgroup meta-analyses (restricted to study design, test food type, intake period, and participants' characteristics) showed similar results for HDL-c level. On the other hand, meta-analysis including 11 studies (n = 854) revealed no significant difference in TG level between the lycopene and control groups. Most studies which met eligibility criteria had moderate risk of bias. Funnel plots for HDL-c and TG suggested an absence of publication bias. In conclusion, this systematic review and meta-analyses suggested that lycopene intake significantly improved blood HDL-c levels but not TG levels., (© 2021 Institute of Food Technologists®.)

We investigated the prevalence of magnetic resonance imaging (MRI) findings and their relationship with knee symptoms in women without radiographic evidence of knee osteoarthritis (KOA). This cross-sectional cohort study included 359 Japanese women without radiographic evidence of KOA (Kellgren‒Lawrence grade < 2). All participants underwent T2-weighted fat-suppressed MRI of their knees. Structural abnormalities (cartilage damage, bone marrow lesions [BMLs], subchondral cysts, bone attrition, osteophytes, meniscal lesions, and synovitis) were scored according to the whole-organ MRI score method. Knee symptoms were evaluated using the Knee Injury and Osteoarthritis Outcome Score. Participants were divided into early and non-KOA groups based on early KOA classification criteria. Logistic regression analysis was performed to evaluate the relationship between MRI abnormalities and knee symptoms. Cartilage damage was the most common abnormality (43.5%). The prevalences of cartilage damage, BMLs, subchondral cysts, bone attrition, meniscal lesions, and synovitis were higher in patients with early KOA than in those without. Synovitis (odds ratio [OR] 2.254, P = 0.002) and meniscal lesions (OR 1.479, P = 0.031) were positively associated with the presence of early KOA. Synovitis was most strongly associated with knee pain and might be a therapeutic target in patients with early KOA., (© 2021. The Author(s).)

Objective: The aim of this study was to demonstrate the non-inferiority of S-flurbiprofen plaster (SFPP) monotherapy for treating knee osteoarthritis compared with the combination of conventional oral and topical non-steroidal anti-inflammatory drugs (NSAIDs)., Methods: A total of 222 participants (114, SFPP group; 108, control group) were treated for 4 weeks. The primary endpoint was the change in the degree of pain felt while rising from a chair after 2 and 4 weeks of treatment as determined using the visual analog scale (VAS) . The secondary endpoint was the change in functional scores and test results. Safety was evaluated in terms of the adverse effects., Results: The VAS score significantly decreased in both groups after 2 and 4 weeks of treatment. Non-inferiority in the VAS score was established only at 2 weeks. There were no significant differences in the secondary endpoints between the groups. Skin disorders were more frequent in the SFPP group; however, there was no difference in gastrointestinal (GI) adverse effects., Conclusions: The therapeutic efficacy of SFPP monotherapy for knee OA, with respect to changes in the VAS, was not shown to be non-inferior to conventional treatment at 4 weeks; however, non-inferiority was established at 2 weeks. The functional improvement in the SFPP group was comparable to that of the control group. No severe GI adverse effects associated with SFPP administration were observed; however, it is necessary to pay more attention to the occurrence of skin disorders with SFPP than with conventional topical NSAIDs., Competing Interests: CONFLICTS OF INTEREST: Yasuyuki Ishibashi is on the speakers’ bureaus for Taisho Pharmaceutical Co., Ltd. and Teijin Pharma Ltd. The other authors declare that there are no conflicts of interest., (©2021 The Japanese Association of Rehabilitation Medicine.)

Background: Preoperative diagnosis of parotid tumor is mainly performed via imaging and cytology to avoid both facial nerve injury and tumor seeding. Synchronous resection of solitary parotid metastasis with esophagectomy for esophageal squamous cell carcinoma is rarely performed., Case Report: This is a case report of a 58-year-old male patient with a left preauricular tumor, which was cytologically diagnosed as squamous cell carcinoma. Esophageal squamous cell carcinoma was pathologically diagnosed following 18 F-fluorodeoxyglucose positron emission tomography with computed tomography. His diagnosis was cT2N0M0 esophageal squamous cell carcinoma with cT3N0M0 parotid carcinoma. Esophagectomy for esophageal cancer, as well as parotidectomy were performed. Pathological diagnosis of pT1bN1M1 (parotid) esophageal squamous cell carcinoma was based on exclusion diagnosis of no primary tumor from several specialists and pathological findings including immunohistochemical staining., Conclusion: Reporting of more cases of rare synchronous metastasectomy and esophagectomy is needed to clarify treatment strategies., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood., Methods: Genetic and clinical details of new and published individuals with pathogenic KDM6A variants were compiled and analyzed., Results: Sixty-one distinct pathogenic KDM6A variants (50 truncating, 11 missense) from 80 patients (34 males, 46 females) were identified. Missense variants clustered in the TRP 2, 3, 7 and Jmj-C domains. Truncating variants were significantly more likely to be de novo. Thirteen individuals had maternally inherited variants and one had a paternally inherited variant. Neonatal feeding difficulties, hypoglycemia, postnatal growth retardation, poor weight gain, motor delay, intellectual disability (ID), microcephaly, congenital heart anomalies, palate defects, renal malformations, strabismus, hearing loss, recurrent infections, hyperinsulinism, seizures, joint hypermobility, and gastroesophageal reflux were frequent clinical findings. Facial features of over a third of patients were not typical for KS. Males were significantly more likely to be born prematurely, have shorter stature, and severe developmental delay/ID., Conclusion: We expand the KDM6A variant spectrum and delineate the KS2 phenotype. We demonstrate that the variability of the KS2 phenotypic depends on sex and the variant type. We also highlight the overlaps and differences between the phenotypes of KS2 and KS1.

Background: Until the emergence of immune checkpoint inhibitors, the EXTREME regimen comprising platinum-based chemotherapy plus cetuximab was the standard of care for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Recent reports suggest the usefulness of regimens including taxanes in combination with cetuximab as treatment options for R/M HNSCC patients with contraindications for platinum. However, comparisons of weekly paclitaxel plus cetuximab (wPTX-Cmab) to the EXTREME regimen are limited., Materials and Methods: We compared the clinical impact of wPTX-Cmab to EXTREME as first line treatment for R/M HNSCC in Aichi Cancer Center Hospital. The primary outcome was overall survival (OS) and secondary outcomes were progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR). Propensity score-adjusted Cox proportional hazard models were used to determine hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: From 2012 to 2018, 77 patients, including 55 treated with EXTREME and 22 refractory or intolerant to platinum treated with wPTX-Cmab, were analyzed. wPTX-Cmab was comparable to EXTREME on OS [adjusted HR 0.82 (95% CI 0.39-1.48)], PFS [adjusted HR 0.90 (95% CI 0.49-1.65)], ORR [wPTX-Cmab 34.7% (12-43), EXTREME 30.9% (18-43), p = 0.877] and DCR [wPTX-Cmab 72.7% (52-92), EXTREME 65.4% (52-78), p = 0.337]. Survival trends remained similar after stratification by platinum-refractory or intolerance status. Disease control with wPTX-Cmab was significantly associated with better OS [adjusted HR 0.18 (0.05-0.57)]., Conclusion: wPTX-Cmab may be a suitable treatment option for R/M HNSCC patients with contraindications for platinum.

Cynomolgus macaque (Macaca fascicularis) and common marmoset (Callithrix jacchus) have been widely used in human biomedical research. Long-standing primate genome assemblies used the human genome as a reference for ordering and orienting the assembled fragments into chromosomes. Here we performed de novo genome assembly of these two species without any human genome-based bias observed in the genome assemblies released earlier. We assembled PacBio long reads, and the resultant contigs were scaffolded with Hi-C data, which were further refined based on Hi-C contact maps and alternate de novo assemblies. The assemblies achieved scaffold N50 lengths of 149 Mb and 137 Mb for cynomolgus macaque and common marmoset, respectively. The high fidelity of our assembly is also ascertained by BAC-end concordance in common marmoset. Our assembly of cynomolgus macaque outperformed all the available assemblies of this species in terms of contiguity. The chromosome-scale genome assemblies produced in this study are valuable resources for non-human primate models and provide an important baseline in human biomedical research.

The objective of our study was to clarify the clinical features of EGFR-mutated sinonasal squamous cell carcinoma (SNSCC) and human papilloma virus (HPV)-related SNSCC. Patients with SNSCC treated from April 2008 to June 2019 at our institution were retrospectively reviewed. We examined EGFR mutation and HPV status for all patients. Main outcomes were overall survival, recurrence, and outcome of each treatment modality. A total of 85 patients with SNSCC were enrolled in this study. EGFR mutations and HPV DNA were detected in 24 (28%) and 7 (8%) patients, respectively. Patients with EGFR-mutated SNSCC showed a worse overall survival (OS) than those with EGFR wild-type in the multivariate analysis (p = 0.037). No death was observed in HPV-positive SNSCC. The cumulative incidence of local recurrence was significantly higher in EGFR mutant than EGFR wild-type tumors (p = 0.03). In patients with EGFR mutations, treatment with induction chemotherapy significantly improved OS (p = 0.01). EGFR-mutated SNSCC have a high-risk feature for recurrence and requires intensive attention for treatment and observation. A new treatment approach, such as EGFR tyrosine kinase inhibitors, may be needed., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2021 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Clinical guidelines can help reduce the use of inappropriate therapeutics due to localism and individual clinician perspectives. Nevertheless, despite the intention of clinical guidelines to achieve survival benefit or desirable outcomes, they cannot ensure a robust outcome. This retrospective study aimed to investigate whether guideline-consistency, including adjuvant treatments after surgical resection (ATSR) and guideline-matched first-line treatment for recurrence (GMT-R), according to the genomic profiles and immune status, could influence overall survival (OS). From 2006 to 2017, the clinical data of 308 patients with stage III non-small cell lung cancer (NSCLC) after surgical resection were evaluated. ATSR and GMT-R were allowed in 164 (53.2%) and 129 (62.3%) patients cases after surgical pulmonary resection, among which 207 (67.2%) recurrences were identified. The 5-year OS in guideline-consistent cases was significantly better than that in guideline-inconsistent cases ( p < 0.01). Subgroup analyses further showed that the 5-year OS after propensity adjustment was significantly better in guideline-consistent than in guideline-inconsistent cases ( p < 0.01), but not in either ATSR or GMT-R ( p = 0.24). These data suggest that the guideline-consistent alternatives, which comprise ATSR or GMT-R, can contribute to survival benefits in pathological stage III NSCLC. However, only either ATSR or GMT-R has a potential survival benefit in these patients.

Purpose: The purpose of this study was to examine the effect of simple core muscle training (CMT) program on trunk muscle strength and neuromuscular control among pediatric athletes., Methods: Forty-nine male soccer players (mean age, 10.8 years) participated. The CMT program had three components (bench, side bench, and Nordic hamstrings) and was performed at least three times weekly for a year. Trunk flexion/extension muscle strength and the K/H ratio (determined by dividing knee separation distance by hip separation distance during drop-jump test and used as an index of lower limb valgus alignment) were measured, and the Y balance test (YBT) was performed before and after intervention. This study did not include the pure control group among the same team. To consider the effect of CMT on trunk muscle strength due to physical growth, we used the data of trunk muscle strength from the local cohort study previously conducted in our institution. One hundred participants who matched the age, height, body weight, and body mass index of the training group was designated as a control group., Results: In the training group, the trunk flexion/extension strength significantly increased at 6 months (p < 0.001, p < 0.001, respectively) and 12 months (p < 0.001, p < 0.001, respectively) compared to initial value. The K/H ratio at initial contact and maximum knee flexion phase significantly increased at 6 months (p < 0.001 and p < 0.001, respectively); however, it did not increase at 12 months (p = 0.384 and p = 0.070, respectively) compared to the initial value. In the YBT, the maximized reach distance in each direction significantly increased after intervention on both the dominant and non-dominant sides, except in the posteromedial direction on the non-dominant foot. Compared to the control group, although there was no significant difference in trunk flexion/extension strength at baseline (p = 0.141 and p = 0.390, respectively), the training group showed significantly higher trunk flexion/extension muscle strength at 12 months (p < 0.001 and p < 0.001, respectively)., Conclusion: The CMT program increased trunk muscle strength and improved dynamic balance among pediatric male athletes., Level of Evidence: Level II.

Triple-negative breast cancer (TNBC) lacks an effective treatment target and is usually treated with chemotherapy. Treatment of older patients with TNBC, however, should be decided carefully because of the side effects of chemotherapy in this population. Some forms of TNBC are associated with a favorable prognosis and do not require chemotherapy. To optimize the treatment of older patients with TNBC, it is important to know the clinicopathological characteristics and a prognostic marker. In this study, classic clinicopathological factors, immunohistochemical characteristics (androgen receptor [AR], cytokeratin 5/6 [CK5/6], epidermal growth factor receptor), tumor-infiltrating lymphocytes (TILs), and the clinical outcome based on the status of each biomarker were compared among a consecutive series of female patients with TNBC aged ≥75 years (n = 75) and among those aged 55-64 years matched for the pathological stage (n = 47) who underwent surgery without neoadjuvant therapy. TNBC with special histology (particularly apocrine carcinoma, pleomorphic invasive lobular carcinoma, and metaplastic carcinoma) was more frequent in the older group than in the younger group (35/75, 57% versus 11/47, 23%, P = 0.010). The AR positivity rate was higher in older patients than in younger patients, whereas TILs and CK5/6 exhibited the opposite results. In multivariate analyses, AR positivity was an independent predictor of a favorable outcome in older patients (lower recurrence rate), whereas the high level of TILs was favorable in younger patients (lower recurrence and mortality rates). AR positivity or apocrine morphology was frequent and predicts a favorable clinical outcome in older patients with TNBC, suggesting the importance of AR examination in this population., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Pluripotent stem cells (PSCs), embryonic stem cells (ESCs), and induced PSCs (iPSCs) are excellent tools for studying embryonic development in organisms and classified into naïve and primed states. ESC-derived germline chimera individuals can be produced by injecting naïve ESCs/iPSCs into preimplantation embryos, and conversion of primed human ESCs/iPSCs into a naïve state provides insights into epiblast cell features. Non-human ESCs/iPSCs are alternatives to human naïve ESCs/iPSCs, which elicit ethical issues. In this study, we used the common marmoset (Callithrix jacchus) as an animal model. Since 1996, 16 marmoset ESC lines have been established. Because most of these ESC lines are female and were derived >10 years ago, new ESCs, particularly male marmoset ESC lines, are needed. Here, we successfully established 17 novel marmoset ESC lines, including six male ESC lines from in vitro-fertilized (IVF) embryos and 12 ESC lines under feeder-free conditions. This report is the first to establish ESC lines using feeder-free conditions and IVF preimplantation blastocysts in marmosets, and these novel ESC lines could potentially facilitate future non-human primate ESC studies., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

POU class 5 homeobox 1 (POU5F1, also known as OCT4) is critical for maintenance of pluripotency, germ cell fate, reprogramming into a pluripotent state, and early embryogenesis. We generated an embryonic stem cell (ESC) line of the common marmoset (Callithrix jacchus) harboring a heterozygous knock-in allele of OCT4-P2A-mCerulean-T2A-pac. The ESC line (CMES40-OC) will be valuable for investigation of primed/naïve pluripotency and germ cell fate. Homozygous OCT4 knock-in clones were generated but could not be sustained in an undifferentiated state in long-term culture. The OCT4 knock-in system facilitated simultaneous knock-in of a reporter construct at another locus, DDX4 (VASA)., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The objectives of this study were to assess radiolucent lines around a highly porous titanium cup (Tritanium) using digital tomosynthesis and to investigate the clinical and radiographic factors associated with radiolucent lines on tomosynthesis., Methods: Fifty-five patients underwent total hip arthroplasty using a Tritanium cup, and digital tomosynthesis and plain radiography were performed at 1 week, 6 months, 1 year, and 2 years after surgery. The radiolucent lines around the cup were measured on both DTS and plain radiography at each postoperative period. Clinical evaluations were performed by the Japanese Orthopaedic Association hip disease evaluation questionnaire (JHEQ), and revision surgeries were examined. Based on the presence of radiolucent lines on digital tomosynthesis at 2 years postoperatively, patients were divided into RL (+) and RL (-) groups and investigated for related factors., Results: There were 20 cases in the RL (+) group and 35 cases in the RL (-) group, and no revision surgeries were required. Statistically, there were more cases with radiolucent lines on digital tomosynthesis (45.4% at 1 week and 36.3% at 2 years) than on plain radiography (9.1% at 1 week and 9.1% at 2 years) at each postoperative point. Logistic analysis showed no significant associations between the presence of radiolucent lines at 2 years on digital tomosynthesis, and the JHEQ parameters of pain (p = 0.937), movement (p = 0.266), or mental status (p = 0.404)., Conclusion: In a short-term evaluation up to 2 years, digital tomosynthesis detected more radiolucent lines around the titanium cups than plain radiography. The occurrence of radiolucent lines was not related to the postoperative clinical evaluation.

Induced pluripotent stem cells (iPSCs) are capable of providing an unlimited source of cells from all three germ layers and germ cells. The derivation and usage of iPSCs from various animal models may facilitate stem cell-based therapy, gene-modified animal production, and evolutionary studies assessing interspecies differences. However, there is a lack of species-wide methods for deriving iPSCs, in particular by means of non-viral and non-transgene-integrating (NTI) approaches. Here, we demonstrate the iPSC derivation from somatic fibroblasts of multiple mammalian species from three different taxonomic orders, including the common marmoset (Callithrix jacchus) in Primates, the dog (Canis lupus familiaris) in Carnivora, and the pig (Sus scrofa) in Cetartiodactyla, by combinatorial usage of chemical compounds and NTI episomal vectors. Interestingly, the fibroblasts temporarily acquired a neural stem cell-like state during the reprogramming. Collectively, our method, robustly applicable to various species, holds a great potential for facilitating stem cell-based research using various animals in Mammalia., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

In malaria, chemical genetics is a powerful method for assigning function to uncharacterized genes. MMV085203 and GNF-Pf-3600 are two structurally related napthoquinone phenotypic screening hits that kill both blood- and sexual-stage P. falciparum parasites in the low nanomolar to low micromolar range. In order to understand their mechanism of action, parasites from two different genetic backgrounds were exposed to sublethal concentrations of MMV085203 and GNF-Pf-3600 until resistance emerged. Whole genome sequencing revealed all 17 resistant clones acquired nonsynonymous mutations in the gene encoding the orphan apicomplexan transporter PF3D7&#95;0312500 ( pfmfr3 ) predicted to encode a member of the major facilitator superfamily (MFS). Disruption of pfmfr3 and testing against a panel of antimalarial compounds showed decreased sensitivity to MMV085203 and GNF-Pf-3600 as well as other compounds that have a mitochondrial mechanism of action. In contrast, mutations in pfmfr3 provided no protection against compounds that act in the food vacuole or the cytosol. A dihydroorotate dehydrogenase rescue assay using transgenic parasite lines, however, indicated a different mechanism of action for both MMV085203 and GNF-Pf-3600 than the direct inhibition of cytochrome bc1. Green fluorescent protein (GFP) tagging of PfMFR3 revealed that it localizes to the parasite mitochondrion. Our data are consistent with PfMFR3 playing roles in mitochondrial transport as well as drug resistance for clinically relevant antimalarials that target the mitochondria. Furthermore, given that pfmfr3 is naturally polymorphic, naturally occurring mutations may lead to differential sensitivity to clinically relevant compounds such as atovaquone.

Background: Osteochondritis dissecans (OCD) of the humeral capitellum occurs in adolescent overhead athletes, and medial epicondyle (ME) lesions are also common in this population., Purpose: To evaluate the association between elbow OCD and ME lesions in adolescent baseball players., Study Design: Cross-sectional study; Level of evidence, 3., Methods: This study retrospectively evaluated adolescent baseball players with unstable elbow OCD who underwent surgery between January 2000 and February 2020. Patients were excluded if they had osteoarthritis of the elbow. A total of 139 elbows were included in this study (138 male and 1 female athlete; mean ± SD age, 13.6 ± 1.5 years). The patients were first divided into 2 groups based on OCD location: a central lesion group (72 elbows) and a lateral group (67 elbows). Next, patients were divided according to OCD size into a localized group (56 elbows) and a widespread group (83 elbows). Finally, OCD lesions that were both lateral and widespread were defined as lateral-widespread (60 elbows), resulting in 5 groups. ME apophyseal fragmentation and elongation were evaluated and defined as ME lesions. We then compared the relationship between OCD and ME lesions., Results: Of the 139 elbows, 63 (45.3%) had ME lesions. The prevalence of ME lesion was higher in the lateral group than the central group (56.7% vs 34.7%; P = .009) and higher in the widespread group than the localized group (55.4% vs 30.4%; P = .004). Furthermore, the prevalence ratio of ME lesion was significantly higher in the lateral-widespread group than for other lesions (58.3% vs 35.4%; P = .007)., Conclusion: In patients undergoing surgery for capitellar OCD, the presence of ME lesions was more commonly associated with lateral and widespread capitellar lesions when compared with central and localized lesions., Competing Interests: The authors have declared that there are no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2021.)

Objective: The Japan Clinical Oncology Group 1505 trial is a single-arm multicentre prospective study that examined the possibility of non-surgical follow-up with endocrine therapy for patients with low-grade ductal carcinoma in situ. In that study, the eligible criteria included histopathological findings comprising low to intermediate nuclear grade and absence of comedo necrosis, and cases were entered according to the local histopathological diagnosis. Nuclear grade is largely based on the Consensus Conference criteria (1997), whereas comedo necrosis is judged according to the Rosen's criteria (2017). The purpose of this study was to standardize and examine the interobserver agreement levels of these histopathological criteria amongst the participating pathologists., Methods: We held slide conferences, where photomicrographs of haematoxylin-eosin-stained slides from 68 patients with ductal carcinoma in situ were presented using PowerPoint. The nuclear grade and comedo necrosis statuses individually judged by the pathologists were analysed using κ statistics., Results: In the first and second sessions, where 22 cases each were presented, the interobserver agreement levels of nuclear grade whether low/intermediate grade or high grade were moderate amongst 29 and 24 participating pathologists, respectively (κ = 0.595 and 0.519, respectively). In the third session where 24 cases were presented, interobserver agreement levels of comedo necrosis or non-comedo necrosis were substantial amongst 25 participating pathologists (κ = 0.753)., Conclusion: Although the concordance rates in nuclear grade or comedo necrosis were not high in a few of the cases, we believe that these results could provide a rationale for employing the present criteria of nuclear grade and comedo necrosis in the clinical study of ductal carcinoma in situ., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A recent epidemiological study revealed that the highest prevalence of early knee osteoarthritis (OA) was observed in females aged ≥ 50 years. The major causal factor of early knee OA was sex. Despite the relevance of estrogen in evaluating chondral and bone metabolism in OA, it is not easily clinically monitored because irregular menstrual cycles induce unstable female hormone patterns during menopausal transitions. Anti-Mullerian hormone (AMH) has been found to be a new stable biomarker to predict menopause. This study aimed to investigate the association between menopausal transition and early knee OA by using serum biomarkers, with special focus on AMH. A total of 518 female volunteers who participated in the Iwaki cohort study were enrolled and divided into pre-menopause and post-menopause groups. Weight-bearing anterior-posterior knee radiographs were classified by Kellgren-Lawrence (KL) grade, and grade ≥ 2 was defined as radiographic knee OA. In participants with KL grades 0 and 1, early knee OA was defined by Luyten's criteria. AMH, luteinizing hormone, follicle-stimulating hormone, estradiol (pg/ml), prolactin, and testosterone were measured on the female hormones. Bone mineral density at a distal radius was measured. The predictive power of female hormones for early knee OA was estimated by ROC analysis (comparison of area under curve, AUC) and regression analysis. Fifty-two participants (10.0%) were diagnosed with early knee OA and 204 (39.4%) with radiographic knee OA. In 393 (75.9%) females, menopause began. From the ROC analysis in pre-menopausal females, cutoff value of AMH for detecting early knee OA was 0.08 ng/ml (area under curve (AUC), 0.712; 95% CI, 0.527-0.897; p value, 0.025; odds ratio, 8.28). AUCs of other female hormones did not reach the level of AMH (range, 0.513 of prolactine to 0.636 of estradiol). Logistic regression analysis focusing on AMH reduction at menopausal transition showed that the related AMH below 0.08 ng/ml was significantly related to the presence of early knee OA (p = 0.035; odds ratio, 5.55). Reduced serum levels of AMH in middle-aged females were correlated with the presence of early knee OA, which might be a useful serum biomarker.

We previously reported the efficient targeted introduction of transgenes into the genomic DNA of the common marmoset (Callithrix jacchus) using CRISPR-Cas9. In this study, we generated a marmoset embryonic stem cell (ESC) line that ubiquitously expresses the tamoxifen-inducible Cre-driver ERT2CreERT2. We validated the pluripotency of the ESC line and also successfully demonstrated the temporal control of the Cre-driver in a tamoxifen-dependent manner in the ESCs. This ESC line, named ActiCre-B1, will be a valuable resource for in vitro investigation of phenotypes related to embryonic lethality by targeted knockout of functionally important genes., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: The purposes of this study are to clarify the details of the ALK tyrosine kinase inhibitor (TKI) resistance mechanism in rebiopsy cases and to predict novel resistance gene alterations using molecular dynamics simulation., Methods: A total of 21 patients with ALK-positive NSCLC who underwent a rebiopsy after ALK TKI failure were included in this analysis. ALK fluorescence in situ hybridization and reverse transcription polymerase chain reaction were performed with paired initial and rebiopsy tumor specimens., Results: Nine patients had no known ALK resistance mechanisms. Four had ALK amplification. L1196M, I1171N, and G1269A, mutations that are known to indicate resistance to ALK TKIs, were detected in one patient each. Small cell carcinoma and sarcomatoid transition were found in one case each. L1196Q, P1094H, and exon 24 76-base pair insertion were detected after the second-generation ALK TKIs., Conclusions: The combination of a genetic analysis and a computational simulation model may make a prediction of resistance mechanisms for overcoming ALK TKI resistance, and the construction of a genomic and simulation fused database is important for the development of personalized medicine in this field., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background/aim: The Archer FusionPlex platform is widely used for comprehensive fusion-gene detection in cancer tissues. This platform separately displays results for strong-evidence and weak-evidence fusion candidates (WEFCs). Distinctive fusion patterns are frequently found in the weak-evidence category and information about the patterns is clinically essential., Patients and Methods: We describe the type and frequency of WEFCs observed using the FusionPlex Sarcoma Panel (S Panel) and the FusionPlex ALK, RET, and ROS1 ver2 Panel (ARR Panel)., Results: A total of 97 specimens were examined and 620 candidates were detected and categorized as WEFCs. A median of five WEFCs were detected per sample. In the S Panel group, there were 13 WEFCs with a frequency of more than 1%. In the ARR Panel group, a total of 16 WEFCs were detected with a frequency of more than 1%., Conclusion: Specific WEFCs were detected according to the panel selected., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The factors predicting hand osteoarthritis (HOA) in patients remain unknown. We aimed to investigate the usefulness of serum hyaluronic acid (sHA) levels in predicting HOA progression from a 6-year longitudinal epidemiological study. A total of 417 participants in the Iwaki cohort were followed-up over 6 years. Hand and knee radiographs taken at baseline and follow-up were scored according to Kellgren-Lawrence grades and Kallman score. Participants were classified into the HOA group and the non-HOA group. sHA levels at baseline were determined by ELISA. Correlations between sHA levels, the number of involved joints, and Kallman score were estimated. Factors related to the incidence or progression of HOA over 6 years were analyzed. The prevalence of HOA was 19.9% at baseline, and 3.6 ± 2.1 joints were involved. sHA levels in the HOA group at baseline were significantly higher than in the non-HOA group (p < 0.001) and correlated with the number of involved joints (r = 0.399, p < 0.001) and Kallman score (r = 0.540, p < 0.001). The incidence rate was 14.5%, and the progression rate was 46.1% over 6 years. Higher sHA levels at baseline were the risk factor of HOA incidence. Thus, sHA levels predicted the incidence of HOA over 6 years.

Osteochondritis dissecans (OCD) of the knee is a subchondral bone abnormality that results in the separation of the articular cartilage and bone with subsequent progression to osteoarthritis. Unstable OCD lesions should undergo fixation to preserve the natural contour of the articular surface. Although several fixation procedures have been reported, the appropriate procedure remains unknown. Because the bony portion of the OCD lesion is usually thin, it is difficult to fix firmly with conventional methods. We began fixing OCD lesions with knotless PushLock anchors and sutures and have obtained satisfactory results. This report describes this fixation method that uses the PushLock suture anchor to treat unstable OCD lesions. This procedure also can be applied for traumatic osteochondral fractures., (© 2020 by the Arthroscopy Association of North America. Published by Elsevier.)

Background: Various biomarkers are being developed for the early diagnosis of cancer and for predicting its prognosis. The aim of this study is to evaluate the diagnostic significance of serum CD109 in head and neck squamous cell carcinoma (HNSCC)., Methods: The serum CD109 levels in a total of 112 serum samples collected before and after surgery from 56 HNSCC patients were analyzed with an enzyme-linked immunosorbent assay (ELISA). The clinical factor that showed a statistically significant association with both the preoperative serum CD109 level, and the CD109 index: which was defined as the ratio of the preoperative serum CD109 level to the postoperative serum CD109 level, were assessed. The correlations between the serum CD109 levels and lymph node density (LND), pathological features such as lymphatic invasion, and serum SCC antigen levels were also assessed., Results: The ELISA measurement revealed that preoperative serum CD109 levels were elevated in patients with node metastasis-positive and stage IV disease, in comparison to those with node metastasis-negative and Stage I+II+III disease, respectively. A multiple regression analysis indicated that serum CD109 level was significantly associated with the node metastasis status. A Spearman's rank correlation analysis also revealed a positive correlation between the preoperative serum CD109 level and LND. Furthermore, the probabilities of the overall and relapse-free survival were significantly lower in patients with a preoperative serum CD109 level of ≥38.0 ng/ml and a CD109 index of ≥1.6, respectively, than in others. There was no significant correlation between the serum CD109 and SCC antigen levels., Conclusions: The serum CD109 levels were elevated in patients with advanced stage disease, reflecting the node metastasis status. CD109 in sera could be a novel prognostic marker for HNSCC involving lymph node metastasis., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Growing evidence indicates that whether critical and hostile behavior harms relationships depends on how partners respond. The current studies test a key behavioral indicator of partners' responsiveness by examining whether partners' withdrawal when actors exhibit negative-direct behavior predicts within-person and longitudinal declines in perceived partner responsiveness and relationship satisfaction. Test of Actors' negative-direct × Partners' withdrawal interactions indicated that partners' withdrawal in the context of actors' negative-direct behavior when targeted for change during conflict discussions (Study 1, N = 162 dyads) and during daily interactions (Study 2, N = 151 dyads) predicted lower perceived partner responsiveness and relationship satisfaction. This Actor × Partner effect did not emerge when actors were pushing for change during conflict (Study 1) and was more consistent predicting perceived partner responsiveness. These results illustrate the importance of Actor × Partner effects and indicate that actors' own destructive behavior provides an important context to diagnose partners' responsiveness.

We describe an X-linked syndrome in 13 male patients from a single family with three generations affected. Patients presented prenatally or during the neonatal period with intrauterine growth retardation, ventriculomegaly, hydrocephalus, hypotonia, congenital heart defects, hypospadias, and severe neurodevelopmental delay. The disease is typically fatal during infancy, mainly due to sepsis (pneumonias). Female carriers are asymptomatic. We performed genome sequencing in four individuals and identified a unique candidate variant in the OTUD5 gene (NM&#95;017602.3:c.598G > A, p.Glu200Lys). The variant cosegregated with the disease in 10 tested individuals. OTUD5 was considered as a candidate gene based on two previous missense variants detected in patients with intellectual disability. In conclusion, we define a syndrome associated with OTUD5 defects and add compelling evidence of genotype-phenotype association. This finding ended the long diagnostic odyssey of this family., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Therapeutic strategies based on antisense oligonucleotides and therapeutic genes are being extensively investigated for the treatment of hereditary muscle diseases and hold great promise. However, the cellular uptake of these polyanions to the muscle cells is inefficient. Therefore, it is necessary to develop more effective methods of gene delivery into the muscle tissue. The A2G80 peptide (VQLRNGFPYFSY) from the laminin α2 chain has high affinity for α-dystroglycan (α-DG) which is expressed on the membrane of muscle cells. In this study, we designed a peptide-modified A2G80 with oligoarginine and oligohistidine (A2G80-R9-H8), and prepared peptide/plasmid DNA (pDNA) complex, to develop an efficient gene delivery system for the muscle tissue. The peptide/pDNA complex showed α-DG-dependent cellular uptake of the A2G80 sequence and significantly improved gene transfection efficiency mediated by the oligohistidine sequence in C2C12 myoblast cells. Further, the peptide/pDNA complex promoted efficient and sustained gene expression in the Duchenne muscular dystrophy mouse models. The A2G80-R9-H8 peptide has the potential for use as a specific carrier for targeting muscle in gene therapy in muscular dystrophy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Safe and efficient gene therapy for the treatment of Duchenne muscular dystrophy (DMD), a genetic disorder, is required. For this, the muscle-targeting delivery system of genes and nucleic acids is ideal. In this study, we focused on the A2G80 peptide, which has an affinity for α-dystroglycan expressed on muscle cell membranes, as a muscle targeted nanocarrier for DMD and developed A2G80-modified liposomes. We also prepared A2G80-modified liposomes coated with long- and short-chain PEG, called A2G80-LSP-Lip, to improve the blood circulation of liposomes using microfluidics. The liposomes had a particle size of approximately 80 nm. A2G80-LSP-Lip showed an affinity for the muscle tissue section of mice by overlay assay. When the liposomes were administered to DMD model mice (mdx mice) via the tail vein, A2G80-LSP-Lip accumulated efficiently in muscle tissue compared to control liposomes. These results suggest that A2G80-LSP-Lip can function as a muscle-targeting liposome for DMD via systemic administration, and may be a useful tool for DMD treatment., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Glandular papilloma (GP) and mixed squamous cell and glandular papilloma (MP) are rare benign pulmonary tumors occurring in the bronchi. Bronchiolar adenoma (BA) was recently characterized as a pulmonary tumor exhibiting alveolar spread. Both GP/MP and BA are composed of a mixture of glandular, ciliated, squamous, and basal cells. We aimed to clarify whether GP/MP and BA represent the same tumor. We evaluated the detailed histologic characteristics of 11 cases involving pulmonary peripheral tumors that exhibited histologic features of GP/MP or BA, and performed genetic analyses using targeted panel sequencing, allele-specific polymerase chain reaction, and digital polymerase chain reaction. Histologically, 4 and 7 tumors were classified as GP/MP and BA, respectively. GP/MP showed endobronchiolar papillary growth with a pseudostratified or stratified epithelium. In contrast, 5 BAs showed a predominant flat structure with a bilayered or pseudostratified epithelium, whereas 2 BAs showed a GP/MP-like papillary architecture. The mean epithelial thickness in each tumor was significantly larger in GP/MPs and BAs with a GP/MP-like morphology (103 to 242 μm) than in flat-predominant BA (23 to 47 μm, P=0.0010). AKT1 E17K mutations were detected in all GP/MPs and BAs with GP/MP-like morphology but were absent in the 5 flat-predominant BAs. AKT1 mutations were always concurrent with BRAF or HRAS mutations, and the variant allele frequency or percentage of mutant copies of AKT1 mutations was equal to those of BRAF or HRAS mutations. GP/MPs are characterized by AKT1 mutations concurrent with BRAF or HRAS mutations. Peribronchiolar papillary tumors with AKT1 mutations may also be classified as GP/MP.

Ossification of the posterior longitudinal ligament (OPLL) within the spinal canal sometimes leads to severe myelopathy. Teriparatide (TPD) is a recombinant human parathyroid hormone (PTH) (1-34), which promotes osteogenesis of mesenchymal stem cells (MSCs) via PTH 1 receptor (PTH1R). Although ligamentum flavum (LF)-MSCs from patients with OPLL have a high osteogenic potency, the effect of TPD on them remains unknown. In this study, we determined PTH1R expression in LF-MSCs from patients with OPLL and investigated whether TPD promotes osteogenic differentiation in them. First, LF-MSCs were isolated from patients with OPLL and cervical spondylotic myelopathy (CSM) (controls). Cultured LF-MSCs were treated with different concentrations of TPD on days 0, 7, and 14. On day 21, osteogenic gene expression was quantified. Mineralization was measured based on optical density after Alizarin Red S staining. LF-MSCs from both groups expressed PTH1R at the same level. TPD did not enhance osteogenic gene expression and mineralization in LF-MSCs from both groups. TPD did not promote the osteogenic differentiation of LF-MSCs from patients with OPLL. Thus, it may be safe for patients with OPLL. However, further confirmation of our results with in vivo studies is necessary., Competing Interests: Declaration of competing interest The authors indicated no potential conflicts of interest., (Copyright © 2020 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

C-X-C motif chemokine 10 (CXCL10) is an inflammatory chemokine and a key molecule in the pathogenesis of rheumatoid arthritis (RA). Melanoma differentiation-associated gene 5 (MDA5) is an RNA helicase that plays a role in innate immune and inflammatory reactions. The details of the regulatory mechanisms of CXCL10 production and the precise role of MDA5 in RA synovitis have not been fully elucidated. The aim of this study was to examine the role of MDA5 in regulating CXCL10 expression in cultured human rheumatoid fibroblast-like synoviocytes (RFLS). RFLS was stimulated with Toll-like receptor 3 (TLR3) ligand polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA mimetic. Expression of interferon beta (IFN-β), MDA5, and CXCL10 was measured by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting, and enzyme-linked immunosorbent assay. A neutralizing antibody of IFN-β and siRNA-mediated MDA5 knockdown were used to determine the role of these molecules in regulating CXCL10 expression downstream of TLR3 signaling in RFLS. Poly I:C induced IFN-β, MDA5, and CXCL10 expression in a concentration- and time-dependent manner. IFN-β neutralizing antibody suppressed the expression of MDA5 and CXCL10, and knockdown of MDA5 decreased a part of CXCL10 expression (p < 0.001). The TLR3/IFN-β/CXCL10 axis may play a crucial role in the inflammatory responses in RA synovium, and MDA5 may be partially involved in this axis.

Genetic modification of nonhuman primate (NHP) zygotes is a useful method for the development of NHP models of human diseases. This review summarizes the recent advances in the development of assisted reproductive and genetic manipulation techniques in NHP, providing the basis for the generation of genetically modified NHP disease models. In this study, we review assisted reproductive techniques, including ovarian stimulation, in vitro maturation of oocytes, in vitro fertilization, embryo culture, embryo transfer, and intracytoplasmic sperm injection protocols in marmosets. Furthermore, we review genetic manipulation techniques, including transgenic strategies, target gene knock-out and knock-in using gene editing protocols, and newly developed gene-editing approaches that may potentially impact the production of genetically manipulated NHP models. We further discuss the progress of assisted reproductive and genetic manipulation techniques in NHP; future prospects on genetically modified NHP models for biomedical research are also highlighted., (© The Author(s) 2021. Published by Oxford University Press on behalf of the National Academies of Sciences, Engineering, and Medicine. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Mice, both wild and laboratory strains, emit ultrasound to communicate. The sex differences between male to female (male-female) and female to female (female-female) ultrasonic vocalizations (USVs) have been discussed for decades. In the present study, we compared the number of USVs emitted to familiar and unfamiliar females by both males (male-female USVs) and females (female-female USVs). We found that females vocalized more to unfamiliar than to familiar females. By contrast, males exhibited more USVs to familiar partners. This sexually dimorphic behaviour suggests that mice change their vocal behaviour in response to the social context, and their perception of the context is based on social cognition and memory. In addition, because males vocalized more to familiar females, USVs appear to be not only a response to novel objects or individuals, but also a social response., Competing Interests: We declare we have no competing interests., (© 2020 The Authors.)

The number of anterior cruciate ligament (ACL) reconstructions in skeletally immature patients has been gradually increasing in recent years owing to the poor outcomes of conservative treatment. However, ACL reconstruction in children is a challenging procedure and may lead to severe complications, such as growth disturbance. Although double-bundle (DB) ACL reconstructions are preferable because of their superior clinical outcomes, there are few reports of DB ACL reconstruction in children with open epiphyses. In this Technical Note, an all-epiphyseal sparing DB ACL reconstruction technique, which is considered to help avoid growth disturbance, is described. This procedure does not create a thick tunnel and may facilitate subsequent revision surgery., (© 2020 by the Arthroscopy Association of North America. Published by Elsevier.)

Background: Repetitive mechanical stress on the elbow joint during throwing is a cause of ulnar collateral ligament dysfunction that may increase the compressive force on the humeral capitellum. This study aimed to examine the effects of ulnar collateral ligament material properties on the humeral capitellum under valgus stress using the finite element method., Methods: Computed tomography data of the dominant elbow of five healthy adults were used to create finite element models. The elbows were kept at 90° of flexion with the forearm in the neutral position, and the ulnar collateral ligament was reproduced using truss elements. The proximal humeral shaft was restrained, and valgus torque of 40 N·m was applied to the forearm. The ulnar collateral ligament condition was changed to simulate ulnar collateral ligament dysfunction. Ulnar collateral ligament stiffness values were changed to 72.3 N/mm, 63.3 N/mm, 54.2 N/mm, 45.2 N/mm, and 36.1 N/mm to simulate ulnar collateral ligament laxity. The ulnar collateral ligament toe region width was changed in increments of 0.5 mm from 0.0 to 2.5 mm to simulate ulnar collateral ligament loosening. We assessed the maximum equivalent stress and stress distribution on the humeral capitellum under these conditions., Results: As ulnar collateral ligament stiffness decreased, the maximum equivalent stress on the humeral capitellum gradually increased under elbow valgus stress ( P < .001). Regarding the change in the ulnar collateral ligament toe region width, as the toe region elongated, the maximum equivalent stress of the humeral capitellum increased significantly under elbow valgus stress ( P < .001). On the capitellum, the equivalent stress on the most lateral part was significantly higher than that on other parts ( P < .01 for all)., Conclusion: Under elbow valgus stress with elbow flexion of 90° and the forearm in the neutral position, ulnar collateral ligament dysfunction increased equivalent stress on the humeral capitellum during the finite element analysis. The highest equivalent stress was noted on the lateral part of the capitellum., (© 2020 The Author(s).)

GPR56, a member of the adhesion G protein-coupled receptor family, is abundantly expressed in cells of the developing cerebral cortex, including neural progenitor cells and developing neurons. The human GPR56 gene has multiple presumptive promoters that drive the expression of the GPR56 protein in distinct patterns. Similar to coding mutations of the human GPR56 gene that may cause GPR56 dysfunction, a 15-bp homozygous deletion in the cis-regulatory element upstream of the noncoding exon 1 of GPR56 (e1m) leads to the cerebral cortex malformation and epilepsy. To clarify the expression profile of the e1m promoter-driven GPR56 in primate brain, we generated a transgenic marmoset line in which EGFP is expressed under the control of the human minimal e1m promoter. In contrast to the endogenous GPR56 protein, which is highly enriched in the ventricular zone of the cerebral cortex, EGFP is mostly expressed in developing neurons in the transgenic fetal brain. Furthermore, EGFP is predominantly expressed in GABAergic neurons, whereas the total GPR56 protein is evenly expressed in both GABAergic and glutamatergic neurons, suggesting the GABAergic neuron-preferential activity of the minimal e1m promoter. These results indicate a possible pathogenic role for GABAergic neuron in the cerebral cortex of patients with GPR56 mutations.

An adult blue-fronted Amazon parrot (Amazona aestiva) was presented for a 6-wk history of ataxia and weight loss. Complete blood count, plasma chemistry panel, bile acids, and radiographic imaging were considered normal or unremarkable. The patient was hospitalized and supported with subcutaneous fluids, vitamin B complex, meloxicam, enrofloxacin, gavage feeding, and fenbendazole. While hospitalized, the ataxia significantly improved, and the bird began eating on its own and gaining weight. The bird was discharged from the hospital and prescribed enrofloxacin, meloxicam, and fenbendazole to be administered by the owner with recommendations for routine follow-up care. Medications were discontinued before emergent representation; at the time of reevaluation, the patient's condition had deteriorated severely. Given the poor prognosis, the owners elected for euthanasia. No gross abnormalities were noted on postmortem examination. Liver tissue zinc levels measured 125 ppm; normal limit is less than or equal to 25 ppm. Histopathologic changes to the brain were consistent with severe zinc toxicosis demonstrated by vasculopathy of the cerebral arteries and arterioles with multifocal areas of hemorrhage and astrocyte swelling. These findings have been reported in humans and other mammals but not birds. Although the source of this bird's heavy metal exposure is unknown, the high tissue zinc concentrations imply chronic exposure. This case presentation and unusual pathologic findings will be beneficial to the further understanding of avian zinc toxicosis.

Cystic fibrosis (CF) is the most common life-limiting autosomal recessive disease in the Republic of Ireland (ROI), with a previously quoted incidence of 1 in 1353 and carrier rate of 1 in 19. The National Newborn Screening (NBS) for CF was incorporated in July 2011 in the ROI. A cut-off point of the top 1% Immunoreactive Trypsinogen (IRT) was taken as an indication for 38 CFTR variant panel to maximise identification of affected CF cases and to minimise detection of carriers. All neonates from July 2011 to Dec 2017 with an elevated IRT on NBS were tested with 38 CFTR mutation panel and included. Clinical and laboratory database were analysed. In the first 6.5 years a total of 5,053 newborns (1.16% of total births) were screened with 38 CFTR panel. 170 CF affected cases, 320 unaffected carriers, 32 CF Screening Positive Inconclusive Diagnosis (CFSPID) were identified. There was one missed diagnosis. The most common disease-causing variant was c.1521&#95;1523delCTT (p.(Phe508del)) followed by c.1652G>A (p.(Gly551Asp)). 95 out of 170 (55%) affected newborns were homozygous for c.1521&#95;1523delCTT (p.(Phe08del)) and 25 (15%) carried at least one copy of c.1652G>A (p.(Gly551Asp)). Hence, 70% of affected newborns were eligible for CFTR modulator treatment. The NBS programme has identified almost triple the number of affected newborn with c.1652G>A (p.(Gly551Asp)) than previously quoted figures and identified less than 50% of carriers than predicted. The revised incidence and carrier frequency of CF in the ROI is 1 in 2570 and 1 in 25, respectively.

Introduction: The smaller cross-sectional areas of the dural sacs in patients without C5 palsy after posterior cervical spine surgery may lead to less neurological improvement., Objectives: The aim of this retrospective study was to clarify the differences in the cross-sectional area of the dural sac in the cervical spine and neurological improvement in patients with and without C5 palsy after posterior cervical spinal surgery., Methods: We retrospectively evaluated the postoperative cross-sectional areas of the dural sacs and neurological outcomes in patients with and without C5 palsy after posterior cervical spine surgery. We compared the postoperative cross-sectional areas of the dural sac at C4/5 and C5/6 on magnetic resonance images between the C5 palsy group (n = 19) and the no-C5 palsy group (n = 84) after posterior cervical spinal surgery 1 year postoperatively. Performance tests, namely, the 10-s grip-and-release test and the 10-s single-foot-tapping (FT) test, were compared between the two groups., Results: Postoperative cross-sectional areas of the dural sac at C4/5 and C5/6 (233.3 mm 2 and 226.6 mm 2 , respectively) in the C5 palsy group were significantly larger (P = 0.0036 and P = 0.0039, respectively) than those (195.0 mm 2 and 193.8 mm 2 , respectively) in the no-C5 palsy group. Postoperative gain in the grip-and-release test was similar between the two groups. Postoperative gain in the FT test (4.9 times) in the C5 palsy group was significantly larger (P = 0.0060) than that (1.8 times) in the no-C5 palsy group., Conclusions: In the C5 palsy group 1 year after posterior cervical spine surgery, the cross-sectional areas of the dural sac were larger, and the 10-s single FT test improved noticeably.

Background: One of the goals of anterior cruciate ligament (ACL) reconstruction is a meniscal protective effect on the knee. Despite the advancement of ACL reconstruction techniques, subsequent meniscal tears after ACL reconstruction remain a problem, and the risk factors for recurring lesions are still unclear., Purpose: To investigate the incidence of subsequent meniscal surgery after primary ACL reconstruction without revision ACL surgery and to determine the risk factors associated with this reoperation., Study Design: Case series; Level of evidence, 4., Methods: Overall, 518 patients who underwent primary ACL reconstruction between 2004 and 2012 at one instution participated in this study. Data on body mass index, graft type and femoral tunnel-drilling technique of ACL reconstruction, and location and type of meniscal injury and its treatment at ACL reconstruction were collected from medical records. Clinical outcomes were investigated, including side-to-side difference of anterior laxity, pivot-shift grade, and subsequent meniscal surgery without ACL insufficiency (at minimum 2-year follow-up)., Results: The prevalence of tears to the medial meniscus (MM) at the primary ACL reconstruction was 43.6% (226/518), 140 of which were repaired; on the contrary, tears of the lateral meniscus (LM) had a prevalence of 55.8% (289/518), 42 of which were repaired. At a mean 30.3 months (range, 8-124 months) after ACL reconstruction, 20 patients (3.9%; 14 MM tears, 3 LM tears, 3 MM + LM tears) required meniscal surgery without ACL reinjury or recurrence of instability. Of these, 14 MMs and 3 LMs had been repaired at primary ACL reconstruction. The failure rates of repaired MM and LM were 10.0% (14/140) and 7.1% (3/42), respectively. The failure rate of MM repair using the all-inside technique (6/36) was significantly higher compared with no treatment, inside-out repair, or partial resection ( P = .045). In multiple regression analysis, the presence of MM injury at the time of ACL reconstruction (odds ratio [OR], 7.81; P = .003), the side-to-side difference of postoperative anterior tibial translation (OR, 1.91; P = .032), and follow-up period after ACL reconstruction (OR, 1.02; P = .003) were risk factors of subsequent meniscal surgery after ACL reconstruction., Conclusion: Incidence of subsequent meniscal surgery after successful ACL reconstruction was <5%. Presence of MM tear at the time of ACL reconsturuction, small amount of increased anterior laxity, and long-term period after ACL reconstruction were predictive of subsequent meniscal surgery.