The present study aimed to investigate whether patients with inflammatory bowel disease (IBD) undergoing joint arthroplasty have a higher incidence of adverse outcomes than those without IBD. A comprehensive literature search was conducted to identify eligible studies reporting postoperative outcomes in IBD patients undergoing joint arthroplasty. The primary outcomes included postoperative complications, while the secondary outcomes included unplanned readmission, length of stay (LOS), joint reoperation/implant revision, and cost of care. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model when heterogeneity was substantial.Aims
Methods
Osteoarthritis (OA) is prevalent among the elderly and incurable. Intra-articular parathyroid hormone (PTH) ameliorated OA in papain-induced and anterior cruciate ligament transection-induced OA models; therefore, we hypothesized that PTH improved OA in a preclinical age-related OA model. Guinea pigs aged between six and seven months of age were randomized into control or treatment groups. Three- or four-month-old guinea pigs served as the young control group. The knees were administered 40 μl intra-articular injections of 10 nM PTH or vehicle once a week for three months. Their endurance as determined from time on the treadmill was evaluated before kill. Their tibial plateaus were analyzed using microcalculated tomography (μCT) and histological studies.Aims
Methods
Bone is a connective tissue that undergoes constant remodeling. Any disturbances during this process may result in undesired pathological conditions. A single nucleotide substitution (596T-A) in exon eight which leads to a M199K mutation in human RANKL was found to cause osteoclast-poor autosomal recessive osteopetrosis (ARO). Patients with ARO cannot be cured by hematopoietic stem cell transplantation and, without proper treatments, will die in their early age. To date, how this mutation alters RANKL function has not been characterized. We thus hypothesized that hRANKL M199 residue is a structural determinant for normal RANKL-RANK interaction and osteoclast differentiation. By sharing our findings, we aim to achieve an improved clinical outcome in treating bone-related diseases such as osteoporosis, ARO and osteoarthritis. Site-directed mutagenesis was employed to create three rat RANKL mutants, replacing the methionine 200 (human M199 equivalent residue) with either lysine (M200K), alanine (M200A) or glutamic acid (M200E). Recombinant proteins were subsequently purified through affinity chromatography and visualized by Coomassie blue staining and western blot. MTS was carried out before osteoclastogenesis assay in vitro to measure the cellular toxicity. Bone resorption pit assay, immuno-fluorescent staining, luciferase reporter assay, RT-PCR, western blot and calcium oscillation detection were also conducted to explore the biological effect of rRANKL mutants. Computational modeling, thermal Shift Assay, western blot and protein binding affinity experiments were later carried out for structural analyses. rRANKL mutants M200K/A/E showed a drastically reduced ability to induce osteoclast formation and did not demonstrate features of competitive inhibition against wild-type rRANKL. These mutants are all incapable of supporting osteoclastic polarization and bone resorption or activating RANKL-induced osteoclast marker gene transcription. Consistently, they were unable to induce calcium flux, and also showed a diminished induction of IκBa degradation and activation of NF-kB and NFATc1 transcriptional activity. Furthermore, the transcriptional activation of the antioxidant response element (ARE) crucial in modulating oxidative stress and providing cytoprotection was also unresponsive to stimulation with rM200s. Structural analyses showed that rM200 is located in a hydrophobic pocket critical for protein folding. Thermal shift and western blot assays suggested that rM200 mutants formed unstructured proteins, with disturbed trimerisation and the loss of affinity to its intrinsic receptors RANK and OPG. Taken together, we first demonstrates the underlying cause of M199-meidated ARO in a cellular and molecular level by establishing a phenotype in BMMs similar to observed in human samples. Further investigation hints the structural significance of a hydrophobic pocket within the TNF-like region. Combined with pharmaceutical studies on small-molecule drugs, this finding may represent a therapeutic target motif for future development of anti-resorptive treatments.
Total Hip Arthroplasty has been shown to have excellent long term outcomes, yet early reoperation remains a risk. The current study assesses the incidence, causes, and cost associated with early revision following elective primary THA in the US Medicare population. The study used the Limited Data Set (LDS) from the Centers for Medicate and Medicaid Services (CMS) to identify all primary THA (DRG 469/470) performed in the US (excluding Maryland) during 2016. All cases were followed for one year after the original date of operation to create a database of readmissions after surgery. These data allowed for the determination of the 1-year incidence and type of reoperation, the timing of reoperation, the admitting diagnosis, hospital utilization, and total cost.Introduction
Methods
The practice of alternating operating theatres has long been used to reduce surgeon idle time between cases. However, concerns have been raised as to the safety of this practice. We assessed the payments and outcomes of total knee arthroplasty (TKA) performed during overlapping and nonoverlapping days, also comparing the total number of the surgeon’s cases and the total time spent in the operating theatre per day. A retrospective analysis was performed on the Centers for Medicare & Medicaid Services (CMS) Limited Data Set (LDS) on all primary elective TKAs performed at the New England Baptist Hospital between January 2013 and June 2016. Using theatre records, episodes were categorized into days where a surgeon performed overlapping and nonoverlapping lists. Clinical outcomes, economic outcomes, and demographic factors were calculated. A regression model controlling for the patient-specific factors was used to compare groups. Total orthopaedic cases and aggregate time spent operating (time between skin incision and closure) were also compared.Aims
Materials and Methods
In the United States, the Centers for Medicare and Medicaid Services consider rates of unplanned hospital readmissions to be indicators of provider quality. Understanding the common reasons for readmission following total joint arthroplasty will allow for improved standards of care and better outcomes for patients. The current study seeks to evaluate the rates, reasons, and Medicare costs for readmission after total hip and total knee arthroplasty. This study used the Limited Data Set (LDS) from the Centers for Medicare and Medicaid Services (CMS) to identify all primary, elective Total Knee Arthroplasties (TKA) and Total Hip Arthroplasties (THA) performed from January 2013 through June 2016. The data were limited to Diagnosis-Related Group (DRG) 470, which is comprised of major joint replacements without major complications or comorbidities. Readmissions were classified by corresponding DRG. Readmission rates, causes, and associated Medicare Part A payments were aggregated over a ninety-day post-discharge period for 804,448 TKA and 409,844 THA.INTRODUCTION
METHODS
Patient demand for hip and knee arthroplasty continues to rise. Information sources providing data on the volume and cost of Medicare total joint arthroplasty by hospital are of use to patients and healthcare professionals. Data have demonstrated that higher volume surgeons are associated with lower cost, morbidity, and mortality. The current study assesses if the same is true for hospitals. The Limited Data Set (LDS) from the Centers for Medicare and Medicaid (CMS) were used for this study. All elective, DRG 470 Total Hip Arthroplasties (THA) reported by CMS from the first quarter of 2013 through the second quarter of 2016 were included. Volume and part A Medicare payments over a 90-day period for the 20 highest volume hospitals in the US were analyzed. Cost associated with initial hospital stay and post discharge skilled nursing, home health, long term acute care, inpatient rehabilitation facilities, and readmission was aggregated and analyzed. For each episode, demographic information (age, sex, and race), geographic location, and Elixhauser comorbidities were calculated to control for major confounding factors in the regression.Introduction
Methods
Surgeons face a substantial risk of infection because of the occupational exposure to blood-borne pathogens (BBPs) from patients undergoing high-risk orthopaedic procedures. This study aimed to determine the seroprevalence of four BBPs among patients undergoing joint arthroplasty in Shanghai, China. In addition, we evaluated the significance of pre-operative screening by calculating a cost-to-benefit ratio. A retrospective observational study of pre-operative screening for BBPs, including hepatitis B and C viruses (HBV and HCV), human immunodeficiency virus (HIV) and Treponema pallidum (TP), was conducted for sequential patients in the orthopaedic department of a large urban teaching hospital between 01 January 2009 and 30 May 2016. Medical records were analysed to verify the seroprevalence of these BBPs among the patients stratified by age, gender, local origin, type of surgery, history of previous transfusion and marital status.Objectives
Methods
Osteoclastic bone resorption is a highly dynamic process that requires the tight ordering of intracellular trafficking events in order to maintain the structural and functional polarization of the ruffled border and basolateral domains. Rab3 proteins are a subfamily of GTPases, known to mediate membrane transport in eukaryotic cells and play a role in exocytosis. Our recent data indicates that Rab3D modulates a post-TGN trafficking step that is required for osteoclastic bone resorption (1). Here, to identify down-stream regulatory molecules of Rab3D, we have performed a yeast two-hybrid screen. Amongst several candidate Rab3D-interacting proteins identified, Rab3D was found to associate with calmodulin, an established regulator of osteoclastic bone resorption. As an initial effort to better define the interaction between Rab3D and calmodulin, we generated several mutants of Rab3D which interfere with the GDP/GTP nucleotide exchange (Rab3DQ81L, Rab3DN135I) and/or membrane attachment of Rab3D (Rab3D-CXC). By in vivo bioluminescence resonance energy transfer (BRET) assay, Calmodulin was found to associate equivalently with wild type Rab3D as well as Rab3DN135I and Rab-3DCXC variants. Over expression of constitutively active Rab3D (Rab3DQ81L) enhanced this interaction suggesting that the active form of Rab3D (i.e. GTP-bound) might recruit additional effector molecules which further potentiate it’s binding to calmodulin. In an attempt to address the impact of calmodulin activity on Rab3D-calmodulin interaction and osteoclastic bone resorption, we performed complementary BRET and in vitro bone resorption assays in the presence of the calmodulin inhibitor, calmidazolium chloride. Interestingly, we show that suppression of calmodulin activity via calmidazolium chloride impairs the association of Rab3D with calmodulin, an affect that correlates with a disruption in osteoclastic bone resorption. We propose that the recruitment of calmodulin by Rab3D might be an important requirement for osteoclast-mediated bone resorption.
Vacuolar adenosine triphosphatase (V-ATPase) proton pumps play an essential role in the acidification of the bone matrix during osteoclast-mediated bone resorption. Recently, mice lacking the V-ATPase d2 subunit have been shown to be osteopetrotic due to defective osteoclasts (Lee et al., Nature Med, 2006). Here, to investigate the transcriptional regulation of the d2 gene during RANKL-induced osteoclastogenesis, we have cloned and characterized its promoter region. By semi-quantitative RT-PCR, expression of d2 and NFATc1 was found to be strongly up-regulated by RANKL but not by other pro-osteoclastic factors including TNF, LPS and M-CSF. Bioinformatic analysis of the cloned 3 kb d2 promoter region revealed several candidate transcription factor binding sites including NFATc1, a key transcription factor for osteoclastogenesis. To explore the influence of RANKL on d2 transcription, we generated a series of d2 promoter constructs using the pGL-3 reporter plasmid. Using luciferase assays, the d2 promoter was found to be induced by RANKL stimulation. Chromatin immunoprecipitation (ChIP) assays demonstrate that NFATc1 forms a complex with the d2 promoter. Using EMSA assays, we have defined a specific NFATc1 biding site between nucleotide − 555 to −561 upstream from the translation start site of d2 gene. Furthermore, targeted mutagenesis of the putative NFAT transcription binding site was found to significantly reduce the luciferase activity as induced by NFATc1 over expression. Addition of the NFAT inhibitor cyclosporin A was found to blunt the mRNA expression of d2 induced by RANKL in RAW264.7 cells. We propose that NFATc1 is an important regulator of d2 transcription during RANKL-induced osteoclastogenesis.
