A Novel Digital Templating Method for Total Hip Arthroplasty in Patients With Unilateral Hip Arthrosis.

BACKGROUND: Identification of the hip center of rotation (HCOR) before total hip arthroplasty (THA) is crucial for achieving optimal implant position and size, and for restoring native biomechanics around the hip joint. Current techniques for determining the HCOR in cases of abnormal hip anatomy are limited and unreliable. This study presents a novel technique using open-access software for preoperative THA templating for patients with significantly abnormal hip anatomy due to unilateral hip arthrosis. The aim is to reliably predict the HCOR and acetabular implant size compared with a traditional intraoperative method. MATERIALS AND METHODS: This retrospective study involved 20 patients with unilateral hip arthrosis who underwent THA. Preoperative templating was performed using the experimental technique, and the position of the HCOR was measured on preoperative and postoperative radiographs. The positions of the predicted and actual HCOR were compared, along with the inclination and size of the acetabular component. RESULTS: The difference between the predicted and actual HCOR positions was insignificant (0.43±0.22 mm vertically and 0.18±0.20 mm horizontally), and there was a positive correlation between them (r=0.78, P<.005; r=0.72, P<.005). The agreement between the predicted and actual acetabular implant sizes was 85%, with near-perfect interobserver agreement (Cohen's kappa=0.827). CONCLUSION: This novel technique provides a reliable method for predicting HCOR and acetabular implant size for THA in cases of unilateral hip arthrosis. This technique may help optimize biomechanics and improve outcomes in challenging cases. Further research and validation are warranted to establish its broader applicability. [Orthopedics. 2024;47(3):e139-e145.].

Total Hip Arthroplasty in the Ultrayoung.

Background: Total hip arthroplasty (THA) procedures provide a surgical option for "ultrayoung" patients ≤30 years old with end-stage hip arthropathy. This has historically been coupled with concerns over early component failure and challenging surgical technique leading to increased risk of overall morbidity. The purpose of this study is to better elucidate the poorly defined indications and outcomes for THA in ultrayoung patients with end-stage hip disease. Methods: A total of 40 THAs in 35 patients ≤30 years old performed at our institution from 2009 to 2016 were retrospectively followed for an average of 2 years (median 11 months, interquartile range 1-31.25). Primary outcome measure was THA revision. Patient demographics were compared against outcomes. The effects on revision rate of hip joint pathology and type of bearing surface were investigated. T-test, chi-square test, and bivariate correlation were performed to determine statistical significance (P < .05). Machine learning was used to determine the normalized important factor leading to THA revision. Results: Fifteen male and 25 female patients were included. Median patient age was 23 (interquartile range 19-27) years, with an average body mass index of 27.0 ± 7.9. A majority of THAs were indicated for osteonecrosis (32) and bearing surface type was predominantly metal-on-highly cross-linked polyethylene (36). The overall revision rate was 7.5%, without a correlation between revision and demographic characteristics. Revision surgery was significantly correlated with bearing surface type (P = .028). Important factors for revision were age (100%), bearing surface type (84.7%), and body mass index (52.1%). Conclusions: In patients ≤30 years old, THAs performed with the use of modern implants and surgical methods show satisfactory survivorship and functional outcomes with short-term follow-up.

Cannabis use disorder is associated with shorter length of stay and increased home discharge after primary total joint arthroplasty: a propensity-weighted analysis.

INTRODUCTION: Increased legalization of cannabis use across the United States has been correlated with increased cannabis use in the clinical setting. However, little is known regarding the characteristics and postoperative outcomes after primary joint arthroplasty (TJA) for patients with cannabis use disorder (CUD). METHODS: This retrospective cohort study used data from the National Inpatient Sample of patients undergoing primary TJA between 2006 to 2015. Patients were grouped based on presence of concomitant CUD. Patient demographic characteristics and outcome data between groups were analyzed. Propensity score methodology was used to compare immediate in-hospital complications and economic outcomes. RESULTS: A total of 8,740,798 TJAs were included. The prevalence of CUD increased nearly five-fold from 0.05% to 0.26% during this time (P < 0.0001). CUD patients were significantly younger, more likely to be male, most frequently of non-Hispanic Black race, and had higher rates of Medicaid insurance. Patients with CUD had a significantly shorter length of hospital stay (3.04 vs. 3.24 days, P = 0.0297), while incurring significantly higher daily ($22,614 vs. $17,955, P < 0.0001) and total charges during admission ($58,507 vs. $50,924, P < 0.0001), compared to patients without CUD. When compared with the control group, CUD was associated with significantly greater odds of home discharge (odds ratio (OR): 1.45, P = 0.0007), and significantly lower odds of rehab discharge (OR: 0.70, P = 0.0013). There were no differences in overall complication profile or in the vast majority of individual in-hospital complications between groups. CONCLUSION: While CUD is correlated to shorter length of stay and increased home discharge after TJA, it does not show a strong effect on complications in an inpatient postoperative setting. It is important for clinicians to appreciate the demographic profile and expected clinical and economic outcomes for patients with CUD undergoing TJA, particularly in the context of evolving laws surrounding cannabis use.

Surgical outcomes of periprosthetic distal femur fractures after total knee arthroplasty classified by Su et al. system.

Background: Periprosthetic fractures of the distal femur remain a challenge to treat due to variations in both patient- and fracture-specific factors. This study was designed to analyze the outcomes of different subtypes of periprosthetic distal femur fractures based on the Su et al. classification system. Methods: Thirty-six patients were classified with Su et al. system. All Type I and II fractures were managed with a locking plate. Most Type III fractures were managed with locking plate, while two were managed with long-stem revision arthroplasty due to evidence of implant loosening. Outcomes were measured and analyzed based on healing time, revision rate, and complication rate. Results: Of the 36 patients, 30 (83.3%) achieved acceptable fracture union, while the remaining 6 (16.7%) experienced either delayed union or non-union. Type I fractures showed a significantly lower healing time than Type II and III fractures managed by locking plate. Delayed union was present in the Type II group, while non-union was recorded for two Type III fractures. Need for revision was more prevalent in fracture Types II and III. Conclusion: The Su et al. system of classification for periprosthetic fractures of the distal femur matches the clinical outcomes of this study and would seem to be useful in the approach to the treatment of these fractures. The majority of these fractures can be managed with locking plate with reasonable results. However, if the implant is loosened in Type III fractures, revision arthroplasty is suggested.

Cannabis Use Disorder in the Setting of Primary Total Hip Arthroplasty: Understanding the Epidemiology, Demographic Characteristics, and Inpatient Postoperative Outcomes.

INTRODUCTION: Cannabis use is expected to increase in the context of its decriminalization and legalization in several states. The purpose of this study was to report on the epidemiologic and demographic characteristics and inpatient postoperative outcomes of patients with cannabis use disorder (CUD) undergoing primary total hip arthroplasty (THA). METHODS: The National Inpatient Sample registry was used to identify patients undergoing THA between 2006 and 2015. Patients were stratified into groups with and without CUD. Epidemiology, comorbidity, and outcomes data were comparatively analyzed between these two groups. RESULTS: A total of 2,838,742 THAs were performed during the study period. The prevalence of CUD significantly increased from 0.10% in 2006 to 0.39% in 2015 (P < 0.0001). Patients with CUD were significantly younger, more likely to be male, had higher rates of Medicaid insurance and were more likely to be non-Hispanic Black and less likely to be non-Hispanic White when compared with the control group. When comparing patients with and without CUD, there was no significant difference in the composite any complication variable and no significant difference in seven of eight individual in-hospital complications assessed, with the exception being higher genitourinary complications in the CUD group. There were no significant differences in discharge disposition or length of stay. DISCUSSION: Although CUD is significantly associated with various demographic, comorbidity, and hospital characteristics, it is not significantly associated with in-hospital complications, discharge disposition, and length of stay outcomes in the immediate in-hospital, postoperative period. It is critical for clinicians and public health professionals to understand the characteristics and expected inpatient outcomes of this evolving population of patients with CUD undergoing THA, particularly in the context of widespread legalization. LEVEL OF EVIDENCE: Level III.

The Role of Sperm Centrioles in Human Reproduction - The Known and the Unknown.

Each human spermatozoon contains two remodeled centrioles that it contributes to the zygote. There, the centrioles reconstitute a centrosome that assembles the sperm aster and participate in pronuclei migration and cleavage. Thus, centriole abnormalities may be a cause of male factor infertility and failure to carry pregnancy to term. However, the precise mechanisms by which sperm centrioles contribute to embryonic development in humans are still unclear, making the search for a link between centriole abnormalities and impaired male fecundity particularly difficult. Most previous investigations into the role of mammalian centrioles during fertilization have been completed in murine models; however, because mouse sperm and zygotes appear to lack centrioles, these studies provide information that is limited in its applicability to humans. Here, we review studies that examine the role of the sperm centrioles in the early embryo, with particular emphasis on humans. Available literature includes case studies and case-control studies, with a few retrospective studies and no prospective studies reported. This literature has provided some insight into the morphological characteristics of sperm centrioles in the zygote and has allowed identification of some centriole abnormalities in rare cases. Many of these studies suggest centriole involvement in early embryogenesis based on phenotypes of the embryo with only indirect evidence for centriole abnormality. Overall, these studies suggest that centriole abnormalities are present in some cases of sperm with asthenoteratozoospermia and unexplained infertility. Yet, most previously published studies have been restricted by the laborious techniques (like electron microscopy) and the limited availability of centriolar markers, resulting in small-scale studies and the lack of solid causational evidence. With recent progress in sperm centriole biology, such as the identification of the unique composition of sperm centrioles and the discovery of the atypical centriole, it is now possible to begin to fill the gaps in sperm centriole epidemiology and to identify the etiology of sperm centriole dysfunction in humans.

Prospective Review of Mesenchymal Stem Cells Differentiation into Osteoblasts.

Stem cell research has been a popular topic in the past few decades. This review aims to discuss factors that help regulate, induce, and enhance mesenchymal stem cell (MSC) differentiation into osteoblasts for bone regeneration. The factors analyzed include bone morphogenic protein (BMP), transforming growth factor ß (TGF-ß), stromal cell-derived factor 1 (SDF-1), insulin-like growth factor type 1 (IGF-1), histone demethylase JMJD3, cyclin dependent kinase 1 (CDK1), fucoidan, Runx2 transcription factor, and TAZ transcriptional coactivator. Methods promoting bone healing are also evaluated in this review that have shown promise in previous studies. Methods tested using animal models include low intensity pulsed ultrasound (LIPUS) with MSC, micro motion, AMD3100 injections, BMP delivery, MSC transplantation, tissue engineering utilizing scaffolds, anti-IL-20 monoclonal antibody, low dose photodynamic therapy, and bone marrow stromal cell transplants. Human clinical trial methods analyzed include osteoblast injections, bone marrow grafts, bone marrow and platelet rich plasma transplantation, tissue engineering using scaffolds, and recombinant human BMP-2. These methods have been shown to promote and accelerate new bone formation. These various methods for enhanced bone regeneration have the potential to be used, following further research, in clinical practice.

Diabetes and bone health: latest evidence and clinical implications.

As the prevalence of diabetes is increasing worldwide, research on some of the lesser-known effects, including impaired bone health, are gaining a lot of attention. The two most common forms of diabetes are type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). These two differ in their physiology, with T1DM stemming from an inability to produce insulin, and T2DM involving an insufficient response to the insulin that is produced. This review aims to highlight the most current information regarding diabetes as it relates to bone health. It looks at biochemical changes that characterize diabetic bone; notably increased adiposity, altered bone metabolism, and variations in bone mineral density (BMD). Then several hypotheses are analyzed, concerning how these changes may be detrimental to the highly orchestrated processes that are involved in bone formation and turnover, and ultimately result in the distinguishing features of diabetic bone. The review proceeds by explaining the effects of antidiabetes medications on bone health, then highlighting several ways that diabetes can play a part in other clinical treatment outcomes. With diabetes negatively affecting bone health and creating other clinical problems, and its treatment options potentiating these effects, physicians should consider the use of anti-osteoporotic drugs to supplement standard anti-diabetes medications in patients suffering with diabetic bone loss.

High Resolution Discovery Proteomics Reveals Candidate Disease Progression Markers of Alzheimer's Disease in Human Cerebrospinal Fluid.

Disease modifying treatments for Alzheimer's disease (AD) constitute a major goal in medicine. Current trends suggest that biomarkers reflective of AD neuropathology and modifiable by treatment would provide supportive evidence for disease modification. Nevertheless, a lack of quantitative tools to assess disease modifying treatment effects remains a major hurdle. Cerebrospinal fluid (CSF) biochemical markers such as total tau, p-tau and Ab42 are well established markers of AD; however, global quantitative biochemical changes in CSF in AD disease progression remain largely uncharacterized. Here we applied a high resolution open discovery platform, dMS, to profile a cross-sectional cohort of lumbar CSF from post-mortem diagnosed AD patients versus those from non-AD/non-demented (control) patients. Multiple markers were identified to be statistically significant in the cohort tested. We selected two markers SME-1 (p<0.0001) and SME-2 (p = 0.0004) for evaluation in a second independent longitudinal cohort of human CSF from post-mortem diagnosed AD patients and age-matched and case-matched control patients. In cohort-2, SME-1, identified as neuronal secretory protein VGF, and SME-2, identified as neuronal pentraxin receptor-1 (NPTXR), in AD were 21% (p = 0.039) and 17% (p = 0.026) lower, at baseline, respectively, than in controls. Linear mixed model analysis in the longitudinal cohort estimate a decrease in the levels of VGF and NPTXR at the rate of 10.9% and 6.9% per year in the AD patients, whereas both markers increased in controls. Because these markers are detected by mass spectrometry without the need for antibody reagents, targeted MS based assays provide a clear translation path for evaluating selected AD disease-progression markers with high analytical precision in the clinic.

Quantitative analysis of apolipoproteins in human HDL by top-down differential mass spectrometry.

The field of quantitative, label-free proteomics has evolved significantly over time, with most experiments performed "bottom-up" using proteolyzed protein mixtures. In these experiments, statistically significant peptide abundance differences between two or more experimental conditions are determined, and their corresponding proteins later identified. Recently, the rationale for extending this experimental design to mixtures of intact proteins has become clear, as analysis at the protein level allows for the independent detection of each protein form present, including those modified posttranslationally. This provides a level of specificity lost in bottom-up experiments. As such, the application of label-free top-down differential mass spectrometry has provided a means for understanding the subtle protein changes that define a particular phenotype. Described here is an approach for the top-down label-free quantitative analysis of the proteins which constitute human high-density lipoprotein particles. The methodology is conceptually very straightforward; however, it does require a level of rigor and consistency typically not addressed by more conventional proteomics experiments.

A platform for characterizing therapeutic monoclonal antibody breakdown products by 2D chromatography and top-down mass spectrometry.

With the growing commercialization of therapeutic monoclonal antibodies developed for the treatment of various diseases comes the need for increased analytical scrutiny of the impurity components contained within such drug products. Traditionally, relatively low performance and throughput analytical techniques were employed for elucidating the product-related breakdown components derived from the original molecule, including N-terminal Edman sequencing and matrix-assisted laser desorption time-of-flight (MALDI-TOF) mass spectrometry. Although N-terminal sequencing provides a definitive starting point of an unknown breakdown product, the resolution and mass accuracy of MALDI-TOF instruments are often insufficient for unambiguous sequence characterization. Described here is the implementation of existing advanced analytical technologies, including high-performance mass spectrometry (LTQ-Orbitrap XL-ETD) and a chip-based nanoelectrospray autosampling robot (TriVersa NanoMate), for the thorough identification and characterization of breakdown products derived from a force-degraded monoclonal antibody. Many anticipated breakdown products were identified, including Fab fragment (48,325 Da) and heavy chain polypeptide hydrolysis product (15,521 Da). Using high-resolution collisionally induced and electron transfer dissociation methods, additional identifications were made with specific localization of unpredicted modifications. As examples, a modified Fab fragment (N- and C-terminal cyclization, 47,902 Da) and a hydrolyzed free light chain impurity components (23,191 Da) were identified with a high degree of confidence (E value, <1e-5). This work describes the approach for top-down characterization of breakdown products and is readily applicable to additional monoclonal antibodies (mAb) characterization experiments, including charge isoform characterization and aggregate analysis, for a more thorough understanding of therapeutic mAb drug products.

An algorithm for identifying multiply modified endogenous proteins using both full-scan and high-resolution tandem mass spectrometric data.

Mass spectrometry based proteomic experiments have advanced considerably over the past decade with high-resolution and mass accuracy tandem mass spectrometry (MS/MS) capabilities now allowing routine interrogation of large peptides and proteins. Often a major bottleneck to 'top-down' proteomics, however, is the ability to identify and characterize the complex peptides or proteins based on the acquired high-resolution MS/MS spectra. For biological samples containing proteins with multiple unpredicted processing events, unsupervised identifications can be particularly challenging. Described here is a newly created search algorithm (MAR) designed for the identification of experimentally detected peptides or proteins. This algorithm relies only on predefined list of 'differential' modifications (e.g. phosphorylation) and a FASTA-formatted protein database, and is not constrained to full-length proteins for identification. The algorithm is further powered by the ability to leverage identified mass differences between chromatographically separated ions within full-scan MS spectra to automatically generate a list of likely 'differential' modifications to be searched. The utility of the algorithm is demonstrated with the identification of 54 unique polypeptides from human apolipoprotein enriched from the high-density lipoprotein particle (HDL), and searching time benchmarks demonstrate scalability (12 high-resolution MS/MS scans searched per minute with modifications considered). This parallelizable algorithm provides an additional solution for converting high-quality MS/MS data of multiply processed proteins into reliable identifications.

Quantitative analysis of intact apolipoproteins in human HDL by top-down differential mass spectrometry.

Top-down mass spectrometry holds tremendous potential for the characterization and quantification of intact proteins, including individual protein isoforms and specific posttranslationally modified forms. This technique does not require antibody reagents and thus offers a rapid path for assay development with increased specificity based on the amino acid sequence. Top-down MS is efficient whereby intact protein mass measurement, purification by mass separation, dissociation, and measurement of product ions with ppm mass accuracy occurs on the seconds to minutes time scale. Moreover, as the analysis is based on the accurate measurement of an intact protein, top-down mass spectrometry opens a research paradigm to perform quantitative analysis of "unknown" proteins that differ in accurate mass. As a proof of concept, we have applied differential mass spectrometry (dMS) to the top-down analysis of apolipoproteins isolated from human HDL(3). The protein species at 9415.45 Da demonstrates an average fold change of 4.7 (p-value 0.017) and was identified as an O-glycosylated form of apolipoprotein C-III [NANA-(2 --> 3)-Gal-beta(1 --> 3)-GalNAc, +656.2037 Da], a protein associated with coronary artery disease. This work demonstrates the utility of top-down dMS for quantitative analysis of intact protein mixtures and holds potential for facilitating a better understanding of HDL biology and complex biological systems at the protein level.

Quantitative analysis of complex peptide mixtures using FTMS and differential mass spectrometry.

Label-free LC-MS profiling is a powerful quantitative proteomic method to study relative peptide abundances between two or more biological samples. Here we demonstrate the use of a previously described comparative LC-MS method, differential mass spectrometry (dMS), to analyze high-resolution Fourier transform mass spectrometry (FTMS) data for detection and quantification of known peptide differences between two sets of complex mixtures. Six standard peptides were spiked into a processed plasma background at fixed ratios from 1.25:1 to 4:1 to make two sets of samples. The resulting mixtures were analyzed by microcapillary LC-FTMS and dMS. dMS successfully identified five out of the six peptides as statistically significant differences (p

Parallel interrogation of covalent intermediates in the biosynthesis of gramicidin S using high-resolution mass spectrometry.

For determination of multiple covalent intermediates bound to the ultra-large enzymes responsible for biosynthesis via nonribosomal peptide synthesis, mass spectrometry (MS) is a promising method to provide new mechanistic insight. Application of a quadrupole-Fourier-transform instrument (Q-FTMS) for direct analysis of aminoacyl intermediates is demonstrated for the first two modules (127 and 120 kDa) involved in the nonribosomal synthesis of gramicidin S. Cyanogen bromide digestions of recombinant proteins afforded detection of two active site peptides (both ~13 kDa) that provided direct evidence for modules copurifying with their preferred amino acid substrates. Given the ability to detect multiple covalent intermediates in tandem, a competition experiment among several nonnatural substrates in parallel was performed using the first module. This defined mixture of acyl-enzyme intermediates was used to probe the selectivity of the condensation step producing a diversity of noncognate dipeptides on the second module.

Chemoenzymatic approaches for streamlined detection of active site modifications on thiotemplate assembly lines using mass spectrometry.

For the direct interrogation of peptides harboring covalently modified serines in nonribosomal peptide synthetases, streamlined methodologies described here employ proteolysis and reporter-coenzyme A analogues of four types. The chromophoric and fluorescent coenzyme A analogues pyrene-maleimidyl-S-CoA and BODIPY-FL-N-(2-aminoethyl)maleimidyl-S-CoA were enzymatically loaded onto the active site serines harbored in the ArCP, PCP1, and PCP2 thiolation domains of PchE and PchF, the nonribosomal peptide synthetases responsible for the biosynthesis of the siderophore pyochelin. During the chromatographic separation of cyanogen bromide digests, observation of the absorbance (at 338 and 504 nm) or fluorescence (after irradiation at 365 nm) enabled the selective detection of peptides containing each active site serine. This resulted in quick detection of each active site peptide by Fourier transform mass spectrometry in the fully reconstituted pyochelin system. The loading of short acyl chain reporters in equimolar quantities permitted further insights into digestion heterogeneity and side reactions by virtue of a mass shift signature on each active site peptide. The chromatographic shift of the reporter-loaded peptides relative to peptides carrying on pathway intermediates was 2 min at 7 kDa, providing a general strategy for efficient localization of "carrier" peptides in complex digests of thiotemplate enzymes. Also, the use of the affinity reporter, biotin-maleimidyl-S-coenzyme A, permitted the isolation of intact synthetases at high purity via removal of contaminating Escherichia coli proteins.

The role of doctor's opinion in shared decision making: what does shared decision making really mean when considering invasive medical procedures?

OBJECTIVE: The goal of this study was to gain understanding about patients' perspectives on decision making in the context of invasive medical interventions and whether patients' decision-making preferences influenced the type of information they desired to be provided by physicians. DESIGN: Questionnaire study of consecutive patients in a university-based general medicine clinic. INTERVENTIONS: Patients were presented with a randomized list of three types of information that physicians could provide (risk, benefit and physician's opinion on whether they should undergo the procedure). Patients were asked whether they preferred patient-based, physician-based, or shared decision making and then were asked to select which one or combination of these three information types was most important to them in their own decision making. Patients were also asked to self-report on how many invasive procedures they had undergone in their own lives. PARTICIPANTS: A total of 202 consecutive patients (mean age = 65.1 years, SD = 12.3, range 28-88; mean education 13.3 years, SD 2.9, range 2-23). MAIN OUTCOME MEASURES: Patient reports. RESULTS: Of the 202 patients, two patients reported no decision-making preference. These two patients were excluded from the analysis. Of the 200 remaining patients, 62.5% (125/200) preferred shared, 22.5%(45/200) preferred physician-based, and 15.5% (31/200) preferred patient-based decision making. More than half of all subjects chose physician opinion as the most important type of information for decision making. Older patients (odds ratio 1.028; confidence interval 1.003-1.053) were more likely to have ranked the doctor's opinion as the most important in their decision making for invasive medical interventions. CONCLUSIONS: Although most patients want to share decision making with their physicians regarding invasive procedures, the majority of these patients report relying on the doctor's opinion on whether to undergo the procedure as the most important information in their own decision making.

Mass spectrometric interrogation of thioester-bound intermediates in the initial stages of epothilone biosynthesis.

Direct detection of thioester intermediate mixtures bound to EpoC, a 195 kDa polyketide synthase, has been achieved using limited proteolysis and Fourier-transform mass spectrometry (FTMS). Incubation with various N-acetylcysteamine thioester (S-NAC) substrate mimics produced mass shifts on the EpoC ACP domain consistent with their condensation with an enzyme-bound carbanion produced by the decarboxylation of methylmalonyl-S-EpoC. Reconstitution of EpoA-ACP, EpoB, and EpoC gave a +165.0 Da mass shift consistent with the formation of the methylthiazolyl-methacrylyl product by incorporation of acetyl-CoA, cysteine, and methylmalonyl-CoA. Thioester-templated reaction intermediates and products are typically characterized by quantifying radioactive substrates, either enzyme bound or chemically hydrolyzed. In contrast, the MS-based methodology described here provides semiquantifiable ratios of free enzyme, intermediate, and product occupancy and reveals that certain substrates result in a >50% formation of nonproductive intermediates.