Periacetabular osteotomy with or without arthroscopic management in patients with hip dysplasia: Study protocol for a multicenter randomized controlled trial

BACKGROUND: Hip dysplasia is one of the most common causes of hip arthritis. Its incidence is estimated to be between 3.6 and 12.8% (Canadian Institute for Health Information, Hip and knee replacements in Canada, 2017-2018: Canadian joint replacement registry annual report, 2019; Jacobsen and Sonne-Holm, Rheumatology 44:211-8, 2004). The Periacetabular Osteotomy (PAO) has been used successfully for over 30 years (Gosvig et al., J Bone Joint Surg Am 92:1162-9, 2010), but some patients continue to exhibit symptoms post-surgery (Wyles et al., Clin Orthop Relat Res 475:336-50, 2017). A hip arthroscopy, performed using a small camera, allows surgeons to address torn cartilage inside the hip joint. Although both procedures are considered standard of care treatment options, it is unknown whether the addition of hip arthroscopy improves patient outcomes compared to a PAO alone. To delay or prevent future joint replacement surgeries, joint preservation surgery is recommended for eligible patients. While previous studies found an added cost to perform hip arthroscopies, the cost-effectiveness to Canadian Health care system is not known. METHODS: Patients randomized to the experimental group will undergo central compartment hip arthroscopy prior to completion of the PAO. Patients randomized to the control group will undergo isolated PAO. Patient-reported quality of life will be the primary outcome used for comparison between the two treatment groups as measured by The International Hip Outcome Tool (iHOT-33) (Saberi Hosnijeh et al., Arthritis Rheum 69:86-93, 2017). Secondary outcomes will include the four-square step test and sit-to-stand (validated in patients with pre-arthritic hip pain) and hip-specific symptoms and impairment using the HOOS; global health assessment will be compared using the PROMIS Global 10 Score; health status will be assessed using the EQ-5D-5L and EQ VAS questionnaires (Ganz et al., Clin Orthop Relat Res 466:264-72, 2008) pre- and post-operatively. In addition, operative time, hospital length of stay, adverse events, and health services utilization will be collected. A sub-group of patients (26 in each group) will receive a T1rho MRI before and after surgery to study changes in cartilage quality over time. A cost-utility analysis will be performed to compare costs and quality-adjusted life years (QALYs) associated with the intervention. DISCUSSION: We hypothesize that (1) concomitant hip arthroscopy at the time of PAO to address central compartment pathology will result in clinically important improvements in patient-reported outcome measures (PROMs) versus PAO alone, that (2) additional costs associated with hip arthroscopy will be offset by greater clinical improvements in this group, and that (3) combined hip arthroscopy and PAO will prove to be a cost-effective procedure. TRIAL REGISTRATION: ClinicalTrials.gov NCT03481010 . Registered on 6 March 2020. Protocol version: version 3

On the averaging of cardiac diffusion tensor MRI data: the effect of distance function selection

Diffusion tensor magnetic resonance imaging (DT-MRI) allows a unique insight into the microstructure of highly-directional tissues. The selection of the most proper distance function for the space of diffusion tensors is crucial in enhancing the clinical application of this imaging modality. Both linear and nonlinear metrics have been proposed in the literature over the years. The debate on the most appropriate DT-MRI distance function is still ongoing. In this paper, we presented a framework to compare the Euclidean, affine-invariant Riemannian and log-Euclidean metrics using actual high-resolution DT-MRI rat heart data. We employed temporal averaging at the diffusion tensor level of three consecutive and identically-acquired DT-MRI datasets from each of five rat hearts as a means to rectify the background noise-induced loss of myocyte directional regularity. This procedure is applied here for the first time in the context of tensor distance function selection. When compared with previous studies that used a different concrete application to juxtapose the various DT-MRI distance functions, this work is unique in that it combined the following: (i) Metrics were judged by quantitative - rather than qualitative – criteria, (ii) the comparison tools were non-biased, (iii) a longitudinal comparison operation was used on a same-voxel basis. The statistical analyses of the comparison showed that the three DT-MRI distance functions tend to provide equivalent results. Hence, we came to the conclusion that the tensor manifold for cardiac DT-MRI studies is a curved space of almost zero curvature. The signal to noise ratio dependence of the operations was investigated through simulations. Finally, the “swelling effect” occurrence following Euclidean averaging was found to be too unimportant to be worth consideration

Lentiviral Vector Delivery of Human Interleukin-7 (hIL-7) to Human Immune System (HIS) Mice Expands T Lymphocyte Populations

Genetically modified mice carrying engrafted human tissues provide useful models to study human cell biology in physiologically relevant contexts. However, there remain several obstacles limiting the compatibility of human cells within their mouse hosts. Among these is inadequate cross-reactvitiy between certain mouse cytokines and human cellular receptors, depriving the graft of important survival and growth signals. To circumvent this problem, we utilized a lentivirus-based delivery system to express physiologically relevant levels of human interleukin-7 (hIL-7) in Rag2-/-γc-/- mice following a single intravenous injection. hIL-7 promoted homeostatic proliferation of both adoptively transferred and endogenously generated T-cells in Rag2-/-γc-/- Human Immune System (HIS) mice. Interestingly, we found that hIL-7 increased T lymphocyte numbers in the spleens of HIV infected HIS mice without affecting viral load. Taken together, our study unveils a versatile approach to deliver human cytokines to HIS mice, to both improve engraftment and determine the impact of cytokines on human diseases

The family partners for health study: a cluster randomized controlled trial for child and parent weight management

Objective:The purpose of this study was to test a two-phased nutrition and exercise education, coping skills training, and exercise intervention program for overweight or obese low-income ethnic minority 2nd to 4th grade children and their parents in rural North Carolina, USA.Methods:A cluster randomized controlled trial was carried out with 358 children (7–10 years) and a parent for each child (n=358). General linear mixed models were used to determine the effects of the intervention on weight, adiposity, health behaviors, and eating and exercise self-efficacy by examining changes in children and parents from baseline to completion of the study (18 months).Results:At 18 months, children in the experimental group did not have a significantly decreased body mass index (BMI) percentile (P=0.470); however, they showed a reduction in the growth rate of their triceps (P=0.001) and subscapular skinfolds (P<0.001) and an improvement in dietary knowledge (P=0.018) and drank less than one glass of soda per day (P=0.052) compared with the control group. Parents in the experimental group had decreased BMI (P=0.001), triceps (P<0.001) and subscapular skinfolds (P<0.001) and increased nutrition (P=0.003) and exercise (P<0.001) knowledge and more often drank water or unsweetened drinks (P=0.029). At 18 months, children in the experimental group did not show significant improvement in eating (P=0.956) or exercise self-efficacy (P=0.976). Experimental parents demonstrated improved socially acceptable eating self-efficacy (P=0.013); however, they did not show significant improvement in self-efficacy pertaining to emotional eating (P=0.155) and exercise (P=0.680).Conclusion:The results suggest that inclusion of children and parents in the same intervention program is an effective way to decrease adiposity and improve nutrition behaviors in both children and parents and improve weight and eating self-efficacy in parents

Novel approaches for immune reconstitution and adaptive immune modeling with human pluripotent stem cells

Pluripotent stem cells have the capacity to generate all cell lineages, and substantial progress has been made in realizing this potential. One fascinating but as yet unrealized possibility is the differentiation of pluripotent stem cells into thymic epithelial cells. The thymus is a primary lymphoid organ essential for naïve T-cell generation. T cells play an important role in adaptive immunity, and their loss or dysfunction underlies in a wide range of autoimmune and infectious diseases. T cells are generated and selected through interaction with thymic epithelial cells, the functionally essential element of thymus. The ability to generate functional thymic epithelial cells from pluripotent stem cells would have applications in modeling human immune responses in mice, in tissue transplantation, and in modulating autoimmune and infectious disease

Oral Pre-Exposure Prophylaxis by Anti-Retrovirals Raltegravir and Maraviroc Protects against HIV-1 Vaginal Transmission in a Humanized Mouse Model

Sexual HIV-1 transmission by vaginal route is the most predominant mode of viral transmission, resulting in millions of new infections every year. In the absence of an effective vaccine, there is an urgent need to develop other alternative methods of pre-exposure prophylaxis (PrEP). Many novel drugs that are currently approved for clinical use also show great potential to prevent viral sexual transmission when administered systemically. A small animal model that permits rapid preclinical evaluation of potential candidates for their systemic PrEP efficacy will greatly enhance progress in this area of investigation. We have previously shown that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and displays CD4 T cell loss typical to that seen in the human. Thus far systemic PrEP studies have been primarily limited to RT inhibitors exemplified by tenofovir and emtricitabine. In these proof-of-concept studies we evaluated two new classes of clinically approved drugs with different modes of action namely, an integrase inhibitor raltegravir and a CCR5 inhibitor maraviroc as potential systemically administered chemo-prophylactics. Our results showed that oral administration of either of these drugs fully protects against vaginal HIV-1 challenge in the RAG-hu mouse model. Based on these results both these drugs show great promise for further development as orally administered PrEPs

Dengue Virus Infection and Virus-Specific HLA-A2 Restricted Immune Responses in Humanized NOD-scid IL2rγnull Mice

BACKGROUND:The lack of a suitable animal model to study viral and immunological mechanisms of human dengue disease has been a deterrent to dengue research. METHODOLOGY/PRINCIPAL FINDINGS:We sought to establish an animal model for dengue virus (DENV) infection and immunity using non-obese diabetic/severe combined immunodeficiency interleukin-2 receptor gamma-chain knockout (NOD-scid IL2rgamma(null)) mice engrafted with human hematopoietic stem cells. Human CD45(+) cells in the bone marrow of engrafted mice were susceptible to in vitro infection using low passage clinical and established strains of DENV. Engrafted mice were infected with DENV type 2 by different routes and at multiple time points post infection, we detected DENV antigen and RNA in the sera, bone marrow, spleen and liver of infected engrafted mice. Anti-dengue IgM antibodies directed against the envelope protein of DENV peaked in the sera of mice at 1 week post infection. Human T cells that developed following engraftment of HLA-A2 transgenic NOD-scid IL2rgamma(null) mice with HLA-A2(+) human cord blood hematopoietic stem cells, were able to secrete IFN-gamma, IL-2 and TNF-alpha in response to stimulation with three previously identified A2 restricted dengue peptides NS4b 2353((111-119)), NS4b 2423((181-189)), and NS4a 2148((56-64)). CONCLUSIONS/SIGNIFICANCE:This is the first study to demonstrate infection of human cells and functional DENV-specific T cell responses in DENV-infected humanized mice. Overall, these mice should be a valuable tool to study the role of prior immunity on subsequent DENV infections

Humanized Rag1−/−γc−/− Mice Support Multilineage Hematopoiesis and Are Susceptible to HIV-1 Infection via Systemic and Vaginal Routes

Several new immunodeficient mouse models for human cell engraftment have recently been introduced that include the Rag2−/−γc−/−, NOD/SCID, NOD/SCIDγc−/− and NOD/SCIDβ2m−/− strains. Transplantation of these mice with CD34+ human hematopoietic stem cells leads to prolonged engraftment, multilineage hematopoiesis and the capacity to generate human immune responses against a variety of antigens. However, the various mouse strains used and different methods of engrafting human cells are beginning to illustrate strain specific variations in engraftment levels, duration and longevity of mouse life span. In these proof-of-concept studies we evaluated the Balb/c-Rag1−/−γ−/− strain for engraftment by human fetal liver derived CD34+ hematopoietic cells using the same protocol found to be effective for Balb/c-Rag2−/−γc−/− mice. We demonstrate that these mice can be efficiently engrafted and show multilineage human hematopoiesis with human cells populating different lymphoid organs. Generation of human cells continues beyond a year and production of human immunoglobulins is noted. Infection with HIV-1 leads to chronic viremia with a resultant CD4 T cell loss. To mimic the predominant sexual viral transmission, we challenged humanized Rag1−/−γc−/− mice with HIV-1 via vaginal route which also resulted in chronic viremia and helper T cell loss. Thus these mice can be further exploited for studying human pathogens that infect the human hematopoietic system in an in vivo setting

Human Breast Milk and Antiretrovirals Dramatically Reduce Oral HIV-1 Transmission in BLT Humanized Mice

Currently, over 15% of new HIV infections occur in children. Breastfeeding is a major contributor to HIV infections in infants. This represents a major paradox in the field because in vitro, breast milk has been shown to have a strong inhibitory effect on HIV infectivity. However, this inhibitory effect has never been demonstrated in vivo. Here, we address this important paradox using the first humanized mouse model of oral HIV transmission. We established that reconstitution of the oral cavity and upper gastrointestinal (GI) tract of humanized bone marrow/liver/thymus (BLT) mice with human leukocytes, including the human cell types important for mucosal HIV transmission (i.e. dendritic cells, macrophages and CD4+ T cells), renders them susceptible to oral transmission of cell-free and cell-associated HIV. Oral transmission of HIV resulted in systemic infection of lymphoid and non-lymphoid tissues that is characterized by the presence of HIV RNA in plasma and a gradual decline of CD4+ T cells in peripheral blood. Consistent with infection of the oral cavity, we observed virus shedding into saliva. We then evaluated the role of human breast milk on oral HIV transmission. Our in vivo results demonstrate that breast milk has a strong inhibitory effect on oral transmission of both cell-free and cell-associated HIV. Finally, we evaluated the effect of antiretrovirals on oral transmission of HIV. Our results show that systemic antiretrovirals administered prior to exposure can efficiently prevent oral HIV transmission in BLT mice

Murine Gamma-herpesvirus Immortalization of Fetal Liver-Derived B Cells Requires both the Viral Cyclin D Homolog and Latency-Associated Nuclear Antigen

Human gammaherpesviruses are associated with the development of lymphoproliferative diseases and B cell lymphomas, particularly in immunosuppressed hosts. Understanding the molecular mechanisms by which human gammaherpesviruses cause disease is hampered by the lack of convenient small animal models to study them. However, infection of laboratory strains of mice with the rodent virus murine gammaherpesvirus 68 (MHV68) has been useful in gaining insights into how gammaherpesviruses contribute to the genesis and progression of lymphoproliferative lesions. In this report we make the novel observation that MHV68 infection of murine day 15 fetal liver cells results in their immortalization and differentiation into B plasmablasts that can be propagated indefinitely in vitro, and can establish metastasizing lymphomas in mice lacking normal immune competence. The phenotype of the MHV68 immortalized B cell lines is similar to that observed in lymphomas caused by KSHV and resembles the favored phenotype observed during MHV68 infection in vivo. All established cell lines maintained the MHV68 genome, with limited viral gene expression and little or no detectable virus production - although virus reactivation could be induced upon crosslinking surface Ig. Notably, transcription of the genes encoding the MHV68 viral cyclin D homolog (v-cyclin) and the homolog of the KSHV latency-associated nuclear antigen (LANA), both of which are conserved among characterized γ2-herpesviruses, could consistently be detected in the established B cell lines. Furthermore, we show that the v-cyclin and LANA homologs are required for MHV68 immortalization of murine B cells. In contrast the M2 gene, which is unique to MHV68 and plays a role in latency and virus reactivation in vivo, was dispensable for B cell immortalization. This new model of gammaherpesvirus-driven B cell immortalization and differentiation in a small animal model establishes an experimental system for detailed investigation of the role of gammaherpesvirus gene products and host responses in the genesis and progression of gammaherpesvirus-associated lymphomas, and presents a convenient system to evaluate therapeutic modalities