Anti-IL-5/5Ra biologics improve work productivity and activity in severe asthma: a RAPSODI registry-based cohort study.

INTRODUCTION: Severe asthma is associated with a serious disease burden, partially caused by limitations in activity and work impairment. AIMS AND OBJECTIVES: This study aims to relate treatment with biologics targeting IL-5/5Ra to work productivity and activity in the long term in a real-world context. MATERIAL AND METHODS: This is a registry-based multi-center cohort study evaluating data from adults with severe eosinophilic asthma included in the Dutch Register of Adult Patients with Severe Asthma for Optimal DIsease management (RAPSODI). Patients that started with anti-IL-5/5Ra biologics and completed the work productivity and activity improvement questionnaire, were included. Study and patient characteristics were compared between the employed and unemployed patients. Work productivity and activity impairment are related to accompanying improvements in clinical outcomes. RESULTS: At baseline, 91 of 137 patients (66%) were employed which remained stable throughout the follow-up period. Patients in the working age category were younger and had significantly better asthma control (p = 0.02). Mean overall work impairment due to health decreased significantly from 25.5% (SD2.6) to 17.6% (SD 2.8) during 12 months anti-IL-5/5Ra biologics treatment (P = 0.010). There was a significant association between ACQ6 and overall work improvement after targeted therapy (ß = 8.7, CI 2.1-15.4, P = 0.01). The improvement of asthma control of 0.5 points on the asthma Control Questionnaire was associated with an overall work impairment of -9%. CONCLUSIONS: Work productivity and activity in severe eosinophilic asthma improved after starting anti-IL-5/5Ra biologics. Clinically relevant improvement in asthma control was associated with an overall work impairment score of -9% in this study.

Empowering rice seedling growth by endophytic Bradyrhizobium sp. SUTN9-2.

Bradyrhizobium sp. strain SUTN9-2 was confirmed as rice endophytic bacteria and also as rice growth promotion agent. SUTN9-2 showed the capability of plant growth promotion characteristics, such as indole-3-acetic acid (IAA) and 1-amino-cyclopropane-1-carboxylic acid (ACC) deaminase productions and nitrogen fixation. In this study, the ability of SUTN9-2 to stimulate rice growth was investigated at different stages with N-free and NH4 NO3 under in vivo condition. The rice dry weight and chlorophyll content could be enhanced when SUTN9-2 was inoculated in N-free, especially at seedling stage (7 and 14 dai). The rice dry weight was also increased when SUTN9-2 was inoculated with NH4 NO3 at 7 and14 dai. The results of quantitative analysis of IAA and ACC deaminase were inconsistent with the expression of genes involved in IAA (nit) and ACC deaminase (acdS) productions. This inconsistently could implied that IAA and ACC deaminase produced from SUTN9-2 do not directly affect rice growth, but other factors resulting from the production of IAA and ACC deaminase could be involved. Moreover, the expression of genes involved in nitrogen fixation (nifH and nifV) of SUTN9-2 was also induced in rice tissues. This finding suggested that rice growth promotion may be supported by NH4 NO3 together with nitrogen fixation by SUTN9-2. SIGNIFICANCE AND IMPACT OF THE STUDY: Indole-3-acetic acid, 1-amino-cyclopropane-1-carboxylic acid deaminase productions and nitrogen fixation may play important roles in rice growth promotion by endophytic SUTN9-2, especially at early rice seedling growth stage, which has the potential to be used as rice seedling growth promoter in the system of rice intensification.

Preceding haemorrhagic shock as a detrimental risk factor for respiratory distress after excessive allogeneic blood transfusion.

BACKGROUND AND OBJECTIVES: Whether transfusion-associated circulatory overload arises as a simple result of over-transfusion or requires another trigger remains unclear. Here, we examined whether respiratory distress could be reproduced by massive transfusion alone in an animal model. MATERIALS AND METHODS: A total of 20 anaesthetized swine were equipped with monitors. Allogeneic blood was obtained from 10 donor swine. A 4-stage loading protocol with each stage equivalent to 25% of the blood volume (BV) in the recipient swine was then used to infuse crystalloid (CR), hydroxyethyl starch (HES) or allogeneic blood (TR) (n = 5 each). The five remaining animals were subjected to a haemorrhagic shock (HS) prior to an allogeneic blood transfusion (TRS). RESULTS: The PaO2 /FiO2 (P/F) ratio did not decrease to the level of respiratory distress in either the CR group or the HES group after loading with a volume corresponding to 100% of the recipient BV. However, the TRS and TR groups exhibited significant reductions in the P/F ratio after fluid overloading (227 ± 29 and 267 ± 133, respectively). Blood transfusion after HS expanded the blood volume, but over-transfusion alone did not. HS was accompanied by an increase in the white blood cell count. CONCLUSION: The lung and the heart can tolerate volume overloads with HES, CR and even transfused blood. However, a preceding HS may induce an inflammatory response, making the lung vulnerable to subsequent blood overloads. In this study, a preceding haemorrhagic shock mediated respiratory distress following massive transfusion in a swine model. (247 words).

Perioperative respiratory complications: current evidence and strategy discussed in 2017 JA symposium.

Respiratory management during general anesthesia aims to safely secure the airway and maintain adequate ventilation to deliver oxygen to the vital organs, maintaining homeostasis even during surgery. Despite its clinical importance, anesthesiologists often encounter difficulties in properly managing respiration during the perioperative period, leading to severe respiratory complications. In this year's JA symposium, 5 editorial board members of Journal of Anesthesia (JA) who are experts in the field of respiratory management in anesthesia discussed the following topics: quitting smoking before surgery: exposure to passive smoke is damaging to children, ventilator-associated pneumonia, high inspiratory oxygen concentration and lung injury, aspiration pneumonia, and postoperative respiratory management strategy in patients with obstructive sleep apnea. We hope that this special article regarding this year's JA symposium may be useful for JA readers to manage clinical anesthesia on a daily basis.

Selective release of miRNAs via extracellular vesicles is associated with house-dust mite allergen-induced airway inflammation.

BACKGROUND: MicroRNAs (miRNAs) may facilitate cell-to-cell communication via extracellular vesicles (EVs). The biological roles of miRNAs in EVs on allergic airway inflammation are unclear. METHODS: Airway-secreted EVs (AEVs) were isolated from bronchoalveolar lavage fluid (BALF) of control and house-dust mite (HDM) allergen-exposed HDM-sensitized mice. The expression of miRNAs in AEVs or miRNAs and mRNAs in lung tissue was analysed using miRNA microarray. RESULTS: The amount of AEV increased 8.9-fold in BALF from HDM-exposed mice compared with that from sham-control mice. HDM exposure resulted in significant changes in the expression of 139 miRNAs in EVs and 175 miRNAs in lung tissues, with 54 miRNAs being common in both samples. Expression changes of these 54 miRNAs between miRNAs in AEVs and lung tissues after HDM exposure were inversely correlated. Computational analysis revealed that 31 genes, including IL-13 and IL-5Ra, are putative targets of the miRNAs up-regulated in AEVs but down-regulated in lung tissues after HDM exposure. The amount of AEV in BALF after HDM exposure was diminished by treatment with the sphingomyelinase inhibitor GW4869. The treatment with GW4869 also decreased Th2 cytokines and eosinophil counts in BALFs and reduced eosinophil accumulation in airway walls and mucosa. CONCLUSION: These results indicate that selective sorting of miRNA including Th2 inhibitory miRNAs into AEVs and increase release to the airway after HDM exposure would be involved in the pathogenesis of allergic airway inflammation.

Changes in esophageal motility after endoscopic submucosal dissection for superficial esophageal cancer: a high-resolution manometry study.

The effect of endoscopic submucosal dissection (ESD) on esophageal motility remains unknown. Therefore, the aim of this study is to elucidate changes in esophageal motility after ESD along with the cause of dysphagia using high-resolution manometry (HRM). This is a before-and-after trial of the effect of ESD on the esophageal motility. Twenty patients who underwent ESD for superficial esophageal carcinoma were enrolled in this study. Patients filled out a questionnaire about dysphagia and underwent HRM before and after ESD. Results before and after ESD were compared. Data were obtained from 19 patients. The number of patients who complained of dysphagia before and after ESD was 1/19 (5.3%) and 6/19 (31.6%), respectively (P = 0.131). Scores from the five-point Likert scale before and after ESD were 0.1 ± 0.5 and 1.0 ± 1.6, respectively (P = 0.043). The distal contractile integral (DCI) before and after ESD and the number of failed, weak, or fragmented contractions were not significantly different. However, in five patients with circumferential ESD, DCI was remarkably decreased and the frequency of fail, weak, or fragmented contractions increased. Univariate regression analysis showed a relatively strong inverse correlation of ΔDCI with the circumferential mucosal defect ratio {P < 0.01, standardized regression coefficient (r) = -0.65}, the number of stricture preventions (P < 0.01, r = -0.601), and the number of stricture resolutions (P < 0.01, r = -0.77). This HRM study showed that impairment of esophageal motility could be caused by ESD. The impairment of esophageal motility was conspicuous, especially in patients with circumferential ESD and subsequent procedures such as endoscopic triamcinolone injection and endoscopic balloon dilatation. Impaired esophageal motility after ESD might explain dysphagia.

Utility of serum periostin and free IgE levels in evaluating responsiveness to omalizumab in patients with severe asthma.

BACKGROUND: Omalizumab, a humanized anti-IgE monoclonal antibody, has demonstrated efficacy in patients with severe allergic asthma. However, treatment responses vary widely among individuals. Despite a lack of data, free serum IgE levels following omalizumab treatment have been proposed as a marker of treatment responsiveness. METHODS: In this prospective, observational study, we assessed the utility of biomarkers of type 2 inflammation in predicting omalizumab treatment responses, as determined by the absence of asthma exacerbation during the first year of treatment. Free serum IgE levels were monitored for 2 years to examine their association with baseline biomarker levels and the number of exacerbations. RESULTS: We enrolled thirty patients who had been treated with omalizumab for at least 1 year, of whom 27 were treated for 2 years. Baseline serum periostin levels and blood eosinophil counts were significantly higher in patients without exacerbations during the first year of treatment than in patients with exacerbations. Baseline serum periostin levels, but not eosinophil counts, were negatively associated with free serum IgE levels after 16 or 32 weeks of treatment. Reduced free serum IgE levels during treatment from those at baseline were associated with reduced exacerbation numbers at 2 years. In 14 patients who continued to have exacerbations during the first year of treatment, exacerbation numbers gradually and significantly decreased over the 2-year study period, with concurrent significant reductions in free serum IgE levels. CONCLUSION: Baseline serum periostin levels and serum free IgE levels during treatment follow-up may be useful in evaluating responses to omalizumab treatment.

Mitochondrial dynamics and their intracellular traffic in porcine oocytes.

Meiotic maturation of oocytes requires a variety of ATP-dependent reactions, such as germinal vesicle breakdown, spindle formation, and rearrangement of plasma membrane structure, which is required for fertilization. Mitochondria are accordingly expected be localized to subcellular sites of energy utilization. Although microtubule-dependent cellular traffic for mitochondria has been studied extensively in cultured neuronal (and some other somatic) cells, the molecular mechanism of their dynamics in mammalian oocytes at different stages of maturation remains obscure. The present work describes dynamic aspects of mitochondria in porcine oocytes at the germinal vesicle stage. After incubation of oocytes with MitoTracker Orange followed by centrifugation, mitochondria-enriched ooplasm was obtained using a glass needle and transferred into a recipient oocyte. The intracellular distribution of the fluorescent mitochondria was then observed over time using a laser scanning confocal microscopy equipped with an incubator. Kinetic analysis revealed that fluorescent mitochondria moved from central to subcortical areas of oocytes and were dispersed along plasma membranes. Such movement of mitochondria was inhibited by either cytochalasin B or cytochalasin D but not by colcemid, suggesting the involvement of microfilaments. This method of visualizing mitochondrial dynamics in live cells permits study of the pathophysiology of cytoskeleton-dependent intracellular traffic of mitochondria and associated energy metabolism during meiotic maturation of oocytes.

NFκB2 Gene as a Novel Candidate that Epigenetically Responds to Interval Walking Training.

Physical fitness has been reported to decrease the risk of lifestyle-related diseases. The present study evaluated genome-wide methylation under the hypothesis that interval walking training (IWT) imparted beneficial effects on health, particularly by epigenetically ameliorating susceptibility to inflammation. We screened DNA from peripheral blood samples via genome-wide microarray for genes whose methylation was affected by IWT, paying special attention to promoter regions, and identified over 40 hyper- or hypo-methylated genes following IWT that were not witnessed in controls. We next selected genes in which the degree of methylation change in the promoter region was correlated with energy consumption following IWT. In this way, we found the NFκB2 gene to have increased methylation in multiple regions of its promoter sequence following participation in an exercise regimen. Next, IWT-induced NFκB2 hyper-methylation was confirmed by a quantitative PyroSequencing assessment of methylation in samples obtained from independent subjects who also underwent IWT. The increase in NFκB2 gene promoter methylation by IWT indicates that this regimen may suppress pro-inflammatory cytokines. Thus, these results provide an additional line of evidence that IWT is advantageous in promoting health from an epigenetic perspective by ameliorating susceptibility to inflammation.

Effectiveness of third-line chemotherapy in recurrent ovarian cancer patients.

OBJECTIVE: Despite recent advances in the treatment of recurrent ovarian cancer, little evidence exists describing the benefit of third- line chemotherapy. The present authors previously reported that the treatment-free interval (TFI) after second-line chemotherapy may predict a survival benefit of third-line chemotherapy, however the length of TFI was uncertain due to limited cases. In this study, the authors evaluated the length of TFI, which is correlated with the effectiveness of third-line chemotherapy and a prognostic factor of third-line chemotherapy. MATERIALS AND METHODS: The authors reviewed the medical records of 85 women with recurrent ovarian cancer who received third-line chemotherapy after a paclitaxel/carboplatin (PC) regimen as first-line chemotherapy. RESULTS: The response rate [complete response (CR) + partial response (PR)] and clinical benefit rate [(CBR): CR + PR + stable disease (SD)] during the TFI after second-line chemotherapy for 0-3 months, 3-6 months, and 6-12 months and ≥ 12 months were 9.8%, 0%, 0%, 43.8% and 15.7%, 50%, 66.7%, and 93.8%, respectively. The median overall survival (OS) from the onset of third-line chemotherapy was longer for TFI ≥ 3 months than for TFI 0-3 months (795 days vs. 281 days, p < 0.001). Finally, according to univariate (HR = 0.256; p < 0.001) and multivariate (HR = 0.264; p < 0.001) analyses, TFI was the independent significant prognostic factor for OS. CONCLUSIONS: TFI less than three months after second-line chemotherapy may predict little survival benefit of third-line chemotherapy.

Anatomy of the larynx and pharynx: effects of age, gender and height revealed by multidetector computed tomography.

Although oropharyngeal and laryngeal structures are essential for swallowing, the three-dimensional (3D) anatomy is not well understood, due in part to limitations of available measuring techniques. This study uses 3D images acquired by 320-row area detector computed tomography ('320-ADCT'), to measure the pharynx and larynx and to investigate the effects of age, gender and height. Fifty-four healthy volunteers (30 male, 24 female, 23-77 years) underwent one single-phase volume scan (0.35 s) with 320-ADCT during resting tidal breathing. Six measurements of the pharynx and two of larynx were performed. Bivariate statistical methods were used to analyse the effects of gender, age and height on these measurements. Length and volume were significantly larger for men than for women for every measurement (P < 0.05) and increased with height (P < 0.05). Multiple regression analysis was performed to understand the interactions of gender, height and age. Gender, height and age each had significant effects on certain values. The volume of the larynx and hypopharynx was significantly affected by height and age. The length of pharynx was associated with gender and age. Length of the vocal folds and distance from the valleculae to the vocal folds were significantly affected by gender (P < 0.05). These results suggest that age, gender and height have independent and interacting effects on the morphology of the pharynx and larynx. Three-dimensional imaging and morphometrics using 320-ADCT are powerful tools for efficiently and reliably observing and measuring the pharynx and larynx.

Anticancer effects of gemcitabine are enhanced by co-administered iRGD peptide in murine pancreatic cancer models that overexpressed neuropilin-1.

BACKGROUND: Impaired drug transport is an important factor that reduces the efficacy of anticancer agents against pancreatic cancer. Here, we report a novel combination chemotherapy using gemcitabine (GEM) and internalised-RGD (iRGD) peptide, which enhances tumour-specific drug penetration by binding neuropilin-1 (NRP1) receptor. METHODS: A total of five pancreatic cancer murine models (two cell line-based xenografts (CXs) and three tumour grafts (TGs)) were treated with either GEM (100 mg kg(-1), q3d × 4) alone or GEM plus iRGD peptide (8 µmol kg(-1)). Evaluation of NRP1 expression in xenografts and 48 clinical cancer specimens was performed by immunohistochemistry (IHC). RESULTS: We identified a subset of pancreatic cancer models that showed NRP1 overexpression sensitive to iRGD co-administration. Treatment with GEM plus iRGD peptide resulted in a significant tumour reduction compared with GEM monotherapy in CXs, but not remarkable in TGs. Potential targets of iRGD were characterised as cases showing NRP1 overexpression (IHC-2+/3+), and these accounted for 45.8% of the clinical specimens. CONCLUSIONS: Internalised RGD peptide enhances the effects of co-administered drugs in pancreatic cancer models, its efficacy is however only appreciable in those employing cell lines. Therefore, the clinical application needs to be given careful consideration.

Squamous-lined cyst of the pancreas: Radiological-pathological correlation.

Pancreatic cystic lesions are increasingly being detected incidentally because of the increased use of cross-sectional imaging. Squamous-lined cysts of the pancreas (lymphoepithelial cyst, epidermoid cyst, and dermoid cyst) are rare cystic lesions lined with squamous epithelium. Distinguishing squamous-lined cysts from other cystic lesions of the pancreas is important to avoid unnecessary surgery, because squamous-lined cysts of the pancreas have no malignant potential. The purpose of this review is to describe findings on computed tomography and magnetic resonance imaging and the histopathological characteristics of squamous-lined cysts, and to summarize the key points of differential diagnosis for pancreatic cystic lesions.

Possible selection of viable human blastocysts after vitrification by monitoring morphological changes.

PURPOSE: Morphological assessment of human blastocysts has been effective for selecting embryos with high potential. However, they often show repeated shrinkage and expansion toward their hatching. Here we assessed whether capturing morphological changes over time of vitrified-warmed blastocysts could lead to a better selection of viable embryos from shrunken blastocysts. METHODS: The implantation rates of vitrified-warmed blastocysts that were shrunken or expanded (developing) at the time of loading for transfer were compared among 2,729 cycles that were subjected to single blastocyst transfer. Vitrified (107) and fresh blastocysts (17) were donated for the experimental study. To assess the relationship between morphology (expanded vs. shrunken) and the mitochondrial respiration of blastocysts, the oxygen consumption rate (OCR) was analyzed for 55 specimens using an uncoupler of oxidative phosphorylation. The remaining 69 blastocysts were used for recording morphological changes every 15 min for 48 h after warming. RESULTS: Because there were no surplus embryos, 7 % of the vitrified-warmed blastocysts were shrunken and transferred. The shrunken embryos had sufficient implantation ability (40 %). The OCR of the shrunken embryos was significantly lower than that of their expanded counterparts. Upon exposure to the uncoupler, the OCR of some shrunken embryos increased to levels similar to the expanded specimens. Time-lapse images revealed some shrunken embryos which formed blastocoel by 5 h following warming exhibited developmental competence to the hatched stage. CONCLUSIONS: Data of the present study suggest a group of shrunken blastocysts contains many viable and clinically available embryos and time-lapse observation of vitrified-warmed blastocysts is a potential method to distinguish viable embryos from shrunken blastocysts.

Impact of immunoreactive substances contained in apheresis platelet concentrate on postoperative respiratory function in surgical patients receiving platelet transfusion: a prospective cohort study.

OBJECTIVES: To construct an alternative policy for the donor selection of platelet concentrate (PC), a clinical study exploring the features of lung injury following PC administration is needed. BACKGROUND: Although a male-donor-only policy for plasma products appears to have efficiently reduced transfusion-related acute lung injury (TRALI), this policy may not be applied to PC because of supply shortages. METHODS AND MATERIALS: We prospectively examined pulmonary function after the transfusion of PC in informed surgical patients treated at a tertiary university hospital in Japan. The contributions of immunoreactive substances contained in the PC to respiratory function after PC transfusion was then statistically examined. RESULTS: Eighty-six patients (56 men, 30 women) were enrolled in the analysis. Fifty-four cases experienced respiratory failure (PaO2 /FiO2 <300 mmHg) after transfusion. Five cases were diagnosed as possible TRALI based on permeability pulmonary oedema, while 23 cases were diagnosed as transfusion-associated circulatory overload (TACO) based on chest radiograph findings. A multivariate logistic regression analysis identified the presence of anti-granulocyte antibody as a significant predictor of possible TRALI [P = 0.023; odds ratio (OR), 13.0; 95% confidence interval (CI), 1.4-118.3]. Meanwhile, anti-leukocyte antibody class II was identified as a significant independent predictor of TACO (P = 0.010; OR, 18.4; 95% CI, 2.0-170.1). CONCLUSIONS: Our data suggest that antibodies contained in PC may contribute to the deterioration of respiratory function after PC transfusion, although the diagnoses of TACO and TRALI may have overlapped among the patients with pulmonary distress in this cohort.

A full genome search in multiple sclerosis.

The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold over the general population. Twin studies have shown monozygotic concordance rates of 25-30% compared to 4% for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of lambda>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (non-significant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 chi2 = 10.8, adjusted P < 0.01)(DS2 and DS3 chi2 = 10.9, P < 0.0005), suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.

Current treatment of severe asthma.

Severe asthma is considered a heterogeneous disease in which a variety of clinical, physiological and inflammatory markers determine disease severity. Pivotal studies in the last 5 years have led to substantial progress in many areas, ranging from a more accurate definition of truly severe, refractory asthma, to classification of the disease into distinct clinical phenotypes, and introduction of new therapies. This review focuses on three common clinical phenotypes of severe asthma in adults (early onset severe allergic asthma, late onset non-atopic eosinophilic asthma, late onset non-eosinophilic asthma with obesity), and provides an overview of recent developments regarding treatment options that are best suited for each of these phenotypes.

Cartilage and bone changes during development of post-traumatic osteoarthritis in selected LGXSM recombinant inbred mice.

INTRODUCTION: Little evidence is available on the natural course of osteoarthritis (OA) development and the genes that protect and predispose individuals to it. This study was designed to compare strain-dependent development of OA and its association with tissue regeneration in mice. Two recombinant inbred lines LGXSM-6 and LGXSM-33 generated from LG/J and SM/J intercross were used. Previous studies indicated that LGXSM-6 can regenerate both articular cartilage and ear hole punch while LGXSM-33 cannot. METHODS: Transection of the medial meniscotibial ligament was performed on 10-week-old male mice to induce OA. Cartilage damage was analyzed by histology and bone morphology was evaluated using micro-computed tomography (CT). Ear punches were performed and evaluated by measurement of residual hole diameter. RESULTS: Cartilage analysis showed that LGXSM-33 developed a significantly higher grade of OA than LGXSM-6. Bone analysis showed that LGXSM-33 had substantial subchondral bone and trabecular bone thickening 8 weeks post-surgery, while LGXSM-6 showed bone loss over time. We also confirmed that LGXSM-6 can heal ear tissues significantly better than LGXSM-33. CONCLUSIONS: OA was found to be negatively correlated with the degree of tissue regeneration. LGXSM-33, a poor healer of ear tissues (and articular cartilage), developed more OA compared to LGXSM-6, which had better regenerative ability for ear tissues and articular cartilage. The phenotypic differences observed here are due to genetic differences further suggesting that similar sets of physiological processes and gene variants may mediate variation in OA development and tissue regeneration.