What Are the Relative Associations of Surgeon Performance and Prosthesis Quality With THA Revision Rates?

BACKGROUND: Many factors, including some related to the patient, implant selection, and the surgeon's skill and expertise, likely contribute to the risk of THA revision. However, surgeon factors have not been extensively analyzed in national joint replacement registries, and there is limited insight into their potential as a confounding variable for revision outcomes; for example, if surgeons with higher revision rates choose more successful prostheses, would this alone reduce their revision rate? QUESTIONS/PURPOSES: This study used Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) data for patients receiving primary THA for a diagnosis of osteoarthritis to answer the following questions: (1) Will the difference in revision rates among surgeons change or disappear when only procedures performed with the best prostheses or prostheses that have been identified as having higher revision rates are considered? (2) Is the benefit associated with using the best-performing prostheses different among surgeons with different revision rates? (3) Do the reasons for revision differ between surgeons with higher rates of revision compared with surgeons with lower rates of revision? METHODS: All primary THA procedures performed and recorded in the AOANJRR for osteoarthritis from September 1, 1999, to December 31, 2022, were considered for inclusion. Each THA prosthesis used was categorized per the AOANJRR as superior-performing, middle-performing, or identified as having a higher rate of revision by the AOANJRR benchmarking process. Surgeons who had performed at least 50 procedures and had a recorded 2-year cumulative percent revision (CPR) were included. After applying these restrictions, the study consisted of 302,066 procedures performed by 476 known surgeons. For the primary outcome measure of all-cause revision, we examined the variation in all-cause revision rates across individual surgeons when different classes of devices were used to assess whether differences between surgeons persisted when accounting for prosthesis selection. For the purposes of descriptively comparing reasons for revision between surgeons with higher-than-average or lower-than-average risk of revision, surgeons were classified into quartiles and outcomes compared when these surgeons used the same class of prosthesis. RESULTS: The difference in rates of revision among surgeons remained even after accounting for the effects of the prosthesis used. For any given surgeon, identified prostheses were associated with higher revision rates compared with both superior-performing prostheses (HR 1.73 [95% CI 1.57 to 1.92]; p < 0.01) and medium-performing prostheses (HR 1.31 [95% CI 1.20 to 1.43]; p < 0.01). All surgeons demonstrated a lower revision rate when using a superior-performing prosthesis, but the difference was greatest for surgeons with the highest rates of revision. Surgeons with the lowest rates of revision had a 19-year CPR of 3.9% (95% CI 3.0% to 5.0%) when using a superior-performing prosthesis compared with 5.4% (95% CI 4.0% to 7.3%) for procedures in which an identified prosthesis was used. Surgeons with the highest rates of revision had a 19-year CPR of 10.9% (95% CI 8.6% to 13.8%) when using a superior-performing prosthesis, and this increased to 20.4% (95% CI 18.0% to 23.1%) for procedures in which an identified prosthesis was used. The reasons for revision differ between surgeons, with causes of revision likely preventable and not related to the prosthesis choice being apparent for surgeons with high revision rates. CONCLUSION: The choice of implant and the surgeon performing the index procedure both affected the risk of revision as well as the reasons for revision. Surgeons could improve the survivorship of the arthroplasties they perform by choosing implants identified by registries as having lower revision rates. Acceptance of the fact that surgeons have different revision rates is needed, and detailed analysis is required to explain why surgeons with high revision rates have increased rates of likely preventable revisions, and outside of prosthesis choice, how revision rates can be lowered. The influence of training, fellowship completion, ongoing education, patient selection, indications for surgery, and factors underlying prosthesis decision-making should be assessed. The surgeon performing THA is an important confounder that should be considered in future registry analyses. LEVEL OF EVIDENCE: Level III, therapeutic study.

Factors associated with an inconclusive result from commercial homologous recombination deficiency testing in ovarian cancer.

INTRODUCTION: Homologous recombination deficiency (HRD) testing is used to determine the appropriateness of poly ADP-ribose polymerase inhibitors for patients with epithelial ovarian cancer and no germline/somatic BRCA1/2 alterations. Myriad MyChoice CDx reports a genomic instability score (GIS) to quantify the level of HRD, with a positive score defined as ≥42. The authors sought to define factors associated with obtaining an inconclusive HRD test result. METHODS: GIS was retrieved for patients at their institution with epithelial ovarian cancer without germline/somatic BRCA1/2 deleterious alterations who underwent HRD testing from April 2020-August 2023. Clinical data were abstracted from the medical record. RESULTS: Of 477 HRD test results identified, 57 (12%) were inconclusive. High-grade serous ovarian cancers had higher GIS than other histologic types (median 29 vs. 21, p < .001). Most HRD cases were of high-grade serous histology; no cases with clear cell or endometrioid histology were HRD-positive. On univariate analysis, interval versus primary cytoreductive surgery, other specimen sources versus surgical specimens, and chemotherapy exposure were risk factors for inconclusive HRD testing. On multivariable analysis, chemotherapy exposure, and tissue source were associated with an inconclusive test result, with surgical specimens more likely to yield a conclusive result than other sources (biopsy, cytology, other). Age, stage, self-reported race, and histology were not associated with an inconclusive result. CONCLUSIONS: Surgical tissue was more likely to yield a conclusive HRD test result versus other sources of epithelial ovarian cancer tissue acquisition. When feasible, laparoscopic biopsy before initiation of neoadjuvant chemotherapy may increase the likelihood of obtaining interpretable HRD test results.

Acute Q fever in patients with an influenza-like illness in regional New South Wales, Australia.

INTRODUCTION: Query (Q) fever is a zoonosis caused by the bacterium Coxiella burnetii typically presenting as an influenza-like illness (ILI) with or without hepatitis. The infection may be missed by clinicians in settings of low endemicity, as the presentation is clinically not specific, and there are many more common differential diagnoses for ILI including SARS-CoV-2 infection. METHODS: Residual serum samples were retrospectively tested for Phase 1 and 2 Q fever-specific IgM, IgG, IgA antibodies by indirect immunofluorescence and C. burnetii DNA by polymerase chain reaction. They had not been previously tested for Q fever, originating from undiagnosed patients with probable ILI, aged 10-70 years and living in regional New South Wales, Australia. The results were compared with contemperaneous data on acute Q fever diagnostic tests which had been performed based on clinicians requests from a geographically similar population. RESULTS: Only one (0.2%) instance of missed acute Q fever was identified after testing samples from 542 eligible patients who had probable ILI between 2016-2023. Laboratory data showed that during the same period, 731 samples were tested for acute Q fever for clinician-initiated requests and of those 70 (9.6%) were positive. Probability of being diagnosed with Q fever after a clinician initiated request was similar regardless of the patients sex, age and the calendar year of sampling. CONCLUSION: In this sample, Q fever was most likely to be diagnosed via clinician requested testing rather than by testing of undiagnosed patients with an influenza like illness.

Molecular analysis of human tick-bitten skin yields signatures associated with distinct spatial and temporal trajectories - A proof-of-concept study.

Tick-associated diseases present challenges due to tridirectional interactions among host-specific responses, tick toxins and salivary proteins as well as microbes. We aimed to uncover molecular mechanisms in tick-bitten skin samples (cases) and contralateral skin samples (controls) collected simultaneously from the same participants, using spatial transcriptomics. Cases and controls analysed using NanoString GeoMx Digital Spatial Profiler identified 274 upregulated and 840 downregulated differentially expressed genes (DEGs), revealing perturbations in keratinization and immune system regulation. Samples of skin biopsies taken within 72 h post tick-bite DEGs had changes in protein metabolism and viral infection pathways as compared to samples taken 3 months post tick-bite, which instead displayed significant perturbations in several epigenetic regulatory pathways, highlighting the temporal nature of the host response following tick bites. Within-individual signatures distinguished tick-bitten samples from controls and identified between-individual signatures, offering promise for future biomarker discovery to guide prognosis and therapy.

Seroprevalence of Rickettsia Spp. and Orientia tsutsugamushi in Indigenous Populations from the Sierra Nevada de Santa Marta, Colombia.

Background: Rickettsia spp. are vector-borne zoonotic pathogens that cause febrile illness in humans. Rickettsioses is not included in the Colombian national surveillance system and is subsequently expected to be underreported. This cross-sectional study aimed to determine the seroprevalence of Rickettsia spp. and the closely related Orientia tsutsugamushi in two indigenous populations residing in the Sierra Nevada de Santa Marta, Colombia. Materials and Methods: Serum samples (n = 539) were collected from the Wiwa and Koguis people between 2021 and 2022. Serum samples were screened for spotted fever group (SFG) and typhus group (TG) Rickettsia spp. using the Fuller laboratories Rickettsia IgG IFA kit and for O. tsutsugamushi with the Scrub Typhus Detect™ IgG ELISA. Results: We observed an overall seroprevalence of 26.2% (95% confidence interval [CI] 22.5-30.1] for Rickettsia spp. of the SFG, 5.4% (95% CI 3.6-7.6) for Rickettsia spp. of the TG and 4.3% (95% CI 2.7-6.3) for O. tsutsugamushi. Common risk factors for zoonotic disease infections were assessed for 147 of the Wiwa participants. Increased odds of seropositivity for SFG Rickettsia spp. were observed for Wiwa participants who cared for livestock, including assisting with the birth of cattle (odds ratio [OR] = 8.85; 95% CI 1.54-50.90; p = 0.015) and goats (OR = 7.60; 95% CI 1.70-33.90; p = 0.008). Conclusions: These results highlight a notable exposure to Rickettsia spp., especially the SFG, in rural Colombia. Together with recent reports of high mortality for Rocky Mountain Spotted Fever in nearby regions of South America, more detailed investigations focusing on improving knowledge and awareness as well as "One Health" and "causes-of-fever" studies are needed. The characterization of Rickettsia spp. infections in humans, livestock, and tick vectors with their potential transmission routes could make a high impact on these easily treatable diseases.

Lumbar and Thoracic Vertebrae Segmentation in CT Scans Using a 3D Multi-Object Localization and Segmentation CNN.

Radiation treatment of cancers like prostate or cervix cancer requires considering nearby bone structures like vertebrae. In this work, we present and validate a novel automated method for the 3D segmentation of individual lumbar and thoracic vertebra in computed tomography (CT) scans. It is based on a single, low-complexity convolutional neural network (CNN) architecture which works well even if little application-specific training data are available. It is based on volume patch-based processing, enabling the handling of arbitrary scan sizes. For each patch, it performs segmentation and an estimation of up to three vertebrae center locations in one step, which enables utilizing an advanced post-processing scheme to achieve high segmentation accuracy, as required for clinical use. Overall, 1763 vertebrae were used for the performance assessment. On 26 CT scans acquired for standard radiation treatment planning, a Dice coefficient of 0.921 ± 0.047 (mean ± standard deviation) and a signed distance error of 0.271 ± 0.748 mm was achieved. On the large-sized publicly available VerSe2020 data set with 129 CT scans depicting lumbar and thoracic vertebrae, the overall Dice coefficient was 0.940 ± 0.065 and the signed distance error was 0.109 ± 0.301 mm. A comparison to other methods that have been validated on VerSe data showed that our approach achieved a better overall segmentation performance.

A re-activation model for 169Yb intensity modulated brachytherapy sources accounting for spatiotemporal isotopic composition.

BACKGROUND: Intensity modulated brachytherapy based on partially shielded intracavitary and interstitial applicators is possible with a cost-effective 169Yb production method. 169Yb is a traditionally expensive isotope suitable for this purpose, with an average γ-ray energy of 93 keV. Re-activating a single 169Yb source multiple times in a nuclear reactor between clinical uses was shown to theoretically reduce cost by approximately 75% relative to conventional single-activation sources. With re-activation, substantial spatiotemporal variation in isotopic source composition is expected between activations via 168Yb burnup and 169Yb decay, resulting in time dependent neutron transmission, precursor usage, and reactor time needed per re-activation. PURPOSE: To introduce a generalized model of radioactive source production that accounts for spatiotemporal variation in isotopic source composition to improve the efficiency estimate of the 169Yb production process, with and without re-activation. METHODS AND MATERIALS: A time-dependent thermal neutron transport, isotope transmutation, and decay model was developed. Thermal neutron flux within partitioned sub-volumes of a cylindrical active source was calculated by raytracing through the spatiotemporal dependent isotopic composition throughout the source, accounting for thermal neutron attenuation along each ray. The model was benchmarked, generalized, and applied to a variety of active source dimensions with radii ranging from 0.4 to 1.0 mm, lengths from 2.5 to 10.5 mm, and volumes from 0.31 to 7.85 mm3, at thermal neutron fluxes from 1 × 1014 to 1 × 1015 n cm-2 s-1. The 168Yb-Yb2O3 density was 8.5 g cm-3 with 82% 168Yb-enrichment. As an example, a reference re-activatable 169Yb active source (RRS) constructed of 82%-enriched 168Yb-Yb2O3 precursor was modeled, with 0.6 mm diameter, 10.5 mm length, 3 mm3 volume, 8.5 g cm-3 density, and a thermal neutron activation flux of 4 × 1014 neutrons cm-2 s-1. RESULTS: The average clinical 169Yb activity for a 0.99 versus 0.31 mm3 source dropped from 20.1 to 7.5 Ci for a 4 × 1014 n cm-2 s-1 activation flux and from 20.9 to 8.7 Ci for a 1 × 1015 n cm-2 s-1 activation flux. For thermal neutron fluxes ≥2 × 1014 n cm-2 s-1, total precursor and reactor time per clinic-year were maximized at a source volume of 0.99 mm3 and reached a near minimum at 3 mm3. When the spatiotemporal isotopic composition effect was accounted for, average thermal neutron transmission increased over RRS lifetime from 23.6% to 55.9%. A 28% reduction (42.5 days to 30.6 days) in the reactor time needed per clinic-year for the RRS is predicted relative to a model that does not account for spatiotemporal isotopic composition effects. CONCLUSIONS: Accounting for spatiotemporal isotopic composition effects within the RRS results in a 28% reduction in the reactor time per clinic-year relative to the case in which such changes are not accounted for. Smaller volume sources had a disadvantage in that average clinical 169Yb activity decreased substantially below 20 Ci for source volumes under 1 mm3. Increasing source volume above 3 mm3 adds little value in precursor and reactor time savings and has a geometric disadvantage.

Supervised machine learning for the prediction of post-operative clinical outcomes of hip and knee replacements: a review.

Prediction models are being increasingly used in the medical field to identify risk factors and possible outcomes. Some of these are presently being used to develop guidelines for improving clinical practice. The application of machine learning (ML), comprising a powerful set of computational tools for analysing data, has been clearly expanding in the role of predictive modelling. This paper reviews the latest developments of supervised ML techniques that have been used to analyse data related to post-operative total hip and knee replacements. The aim was to review the most recent findings of relevant published studies by outlining the methodologies employed (most-widely used supervised ML techniques), data sources, domains, limitations of predictive analytics and the quality of predictions.

What Is the Most Appropriate Comparator to Use in Assessing the Comparative Performance of Primary Total Knee Prostheses? A Registry-Based Study.

Background: The Australian Orthopedic Association National Joint Replacement Registry has developed a standardized multi-stage approach to identify prostheses with a higher-than-anticipated rate of revision when comparing a prosthesis of interest to all other prostheses within the same broad class. However, the approach does not adequately differentiate between the conventional and complex design prostheses, and the comparator classes need to be re-evaluated. This study aimed to identify a more relevant comparator to better reflect conventional and complex surgical practices according to the stability design and also explore how the rate of revision estimated in the comparator groups affects the identification of "prosthesis outliers." Methods: The cumulative percent revision (CPR) was calculated for 640,045 primary total knee replacements (TKRs) undertaken for Osteoarthritis from 1 January 2003 to 31 December 2019. At first, survivorship analyses were undertaken to calculate the rate of revision for primary TKR by stability design. A modified TKR comparator group was developed by excluding the "complex" group of prostheses with fully stabilized and hinged designs. The effectiveness of the modified comparator groups, including cruciate retaining and posterior stabilized designs, was evaluated based on the ability to detect additional prostheses by performing the Australian Orthopedic Association National Joint Replacement Registry standardized method for identifying prosthesis outliers. Results: The modified comparator to include only conventional designs had a 10-year CPR of 5.2% (5.1, 5.3). When the fully stabilized and hinged design groups were combined as a comparator group of complex devices to reflect devices used only for specific purposes in primary TKR, the CPR at 10 year was 10.3% (8.6, 12.0). Conclusions: The use of modified comparator groups led to identifying additional conventional prostheses but fewer complex designs as being at risk and has the potential to improve the early assessment of TKR prostheses.

A comparison of cemented femoral fixation via anterior versus posterior approach total hip arthroplasty: an analysis of 60,739 total hip arthroplasties.

BACKGROUND: Anterior approach total hip arthroplasty (THA) decreases the rate of dislocation but increases femoral-sided complications in the way of periprosthetic fractures and component loosening. A cemented prosthesis may reduce femoral-sided complications and improve the risk:benefit profile of anterior approach THA. METHODS: Data from the Australian National Joint Replacement Registry were analysed for patients undergoing primary THA via the anterior or posterior approach using a cemented polished femoral stem from January 2015 to December 2021. The primary outcome measure was the cumulative percent revision (CPR) for all causes and CPR for femoral component loosening and fracture. The CPR for the primary outcome measures were compared between the anterior and posterior approach and adjusted for age, sex, ASA score, BMI and femoral head size. RESULTS: The study included 60,739 THAs with cemented stems (10,742 anterior, 49,997 posterior). The rate of revision of the anterior versus the posterior approach did not significantly differ (HR 0.87 (95% CI, 0.74-1.03), p = 0.100). Anterior approach THA had a significantly higher rate of revision for femoral component loosening (HR 5.06 [95% CI, 3.08-8.30], p < 0.001); and a decreased rate of revision for infection (HR 0.59 [95% CI, 0.43-0.81], p = 0.001) and dislocation/instability (HR 0-3 months 0.48 [95% CI, 0.27-0.83], p = 0.008; HR >3 months 0.30 [95% CI, 0.15-0.61], p < 0.001). There was no difference in the rate of revision surgery for fracture between the 2 approaches (HR 1.01 [95% CI, 0.71-1.43]), p = 0.975). CONCLUSIONS: There is no significant difference in overall revision rates with cemented femoral fixation performed with an anterior or posterior approach. Cemented fixation performed with the anterior approach partly mitigates femoral complications with no difference in the revision rate for fracture but an increased rate of femoral component loosening.

Gaps and inconsistencies in the current knowledge and implementation of biosafety and biosecurity practices for rickettsial pathogens.

INTRODUCTION: Rickettsia spp. and Orientia spp. are the causes of neglected infections that can lead to severe febrile and systemic illnesses in humans. Implementing proper biosafety practices when handling these pathogens is crucial to ensure a safe and sustainable work environment. It is essential to assess the current knowledge and identify any potential gaps to develop effective measures that minimise the risk of exposure to these pathogens. By doing so, we can establish a comprehensive framework that promotes safety, mitigates hazards, and safeguards the well-being of personnel and the surrounding community. METHODS AND RESULTS: This review aimed to synthesise and determine the evidence base for biosafety precautions for Rickettsia spp. and Orientia spp. pathogens. Enhancing our understanding of the relative infectious risk associated with different strains of Rickettsia and Orientia spp. requires identifying the infectious dose of these pathogens that can cause human disease. The application of risk groups for Rickettsia and Orientia spp. is inconsistent across jurisdictions. There is also incomplete evidence regarding decontamination methods for these pathogens. With regards to Orientia spp. most of the available information is derived from experiments conducted with Rickettsia spp. CONCLUSIONS: Rickettsia and Orientia spp. are neglected diseases, as demonstrated by the lack of evidence-based and specific biosafety information about these pathogens. In the case of Orientia spp., most of the available information is derived from Rickettsia spp., which may not be appropriate and overstate the risks of working with this pathogen. The advent of effective antibiotic therapy and a better understanding of the true hazards and risks associated with pathogen manipulation should inform decisions, allowing a sustainable and safe work environment.

Synthetic Particulate Subunit Vaccines for the Prevention of Q Fever.

Coxiella burnetti is an intracellular bacterium that causes Q fever, a disease of worldwide importance. Q-VAX® , the approved human Q fever vaccine, is a whole cell vaccine associated with safety concerns. Here a safe particulate subunit vaccine candidate is developed that is ambient-temperature stable and can be cost-effectively manufactured. Endotoxin-free Escherichia coli is bioengineered to efficiently self-assemble biopolymer particles (BPs) that are densely coated with either strings of 18 T-cell epitopes (COX-BP) or two full-length immunodominant antigens (YbgF-BP-Com1) all derived from C. burnetii. BP vaccine candidates are ambient-temperature stable. Safety and immunogenicity are confirmed in mice and guinea pig (GP) models. YbgF-BP-Com1 elicits specific and strong humoral immune responses in GPs with IgG titers that are at least 1 000 times higher than those induced by Q-VAX® . BP vaccine candidates are not reactogenic. After challenge with C. burnetii, YbgF-BP-Com1 vaccine leads to reduced fever responses and pathogen burden in the liver and the induction of proinflammatory cytokines IL-12 and IFN-γ inducible protein (IP-10) when compared to negative control groups. These data suggest that YbgF-BP-Com1 induces functional immune responses reducing infection by C. burnetii. Collectively, these findings illustrate the potential of BPs as effective antigen carrier for Q fever vaccine development.

AAPM Medical Physics Practice Guideline 14.a: Yttrium-90 microsphere radioembolization.

Radioembolization using Yttrium-90 (90 Y) microspheres is widely used to treat primary and metastatic liver tumors. The present work provides minimum practice guidelines for establishing and supporting such a program. Medical physicists play a key role in patient and staff safety during these procedures. Products currently available are identified and their properties and suppliers summarized. Appropriateness for use is the domain of the treating physician. Patient work up starts with pre-treatment imaging. First, a mapping study using Technetium-99m (Tc-99m ) is carried out to quantify the lung shunt fraction (LSF) and to characterize the vascular supply of the liver. An MRI, CT, or a PET-CT scan is used to obtain information on the tumor burden. The tumor volume, LSF, tumor histology, and other pertinent patient characteristics are used to decide the type and quantity of 90 Y to be ordered. On the day of treatment, the appropriate dose is assayed using a dose calibrator with a calibration traceable to a national standard. In the treatment suite, the care team led by an interventional radiologist delivers the dose using real-time image guidance. The treatment suite is posted as a radioactive area during the procedure and staff wear radiation dosimeters. The treatment room, patient, and staff are surveyed post-procedure. The dose delivered to the patient is determined from the ratio of pre-treatment and residual waste exposure rate measurements. Establishing such a treatment modality is a major undertaking requiring an institutional radioactive materials license amendment complying with appropriate federal and state radiation regulations and appropriate staff training commensurate with their respective role and function in the planning and delivery of the procedure. Training, documentation, and areas for potential failure modes are identified and guidance is provided to ameliorate them.

Pre-clinical evaluation of biomarkers for the early detection of nephrotoxicity following alpha-particle radioligand therapy.

PURPOSE: Cancer treatment with alpha-emitter-based radioligand therapies (α-RLTs) demonstrates promising tumor responses. Radiolabeled peptides are filtered through glomeruli, followed by potential reabsorption of a fraction by proximal tubules, which may cause acute kidney injury (AKI) and chronic kidney disease (CKD). Because tubular cells are considered the primary site of radiopeptides' renal reabsorption and potential injury, the current use of kidney biomarkers of glomerular functional loss limits the evaluation of possible nephrotoxicity and its early detection. This study aimed to investigate whether urinary secretion of tubular injury biomarkers could be used as an additional non-invasive sensitive diagnostic tool to identify unrecognizable tubular damage and risk of long-term α-RLT nephrotoxicity. METHODS: A bifunctional cyclic peptide, melanocortin 1 ligand (MC1L), labeled with [203Pb]Pb-MC1L, was used for [212Pb]Pb-MC1L biodistribution and absorbed dose measurements in CD-1 Elite mice. Mice were treated with [212Pb]Pb-MC1L in a dose-escalation study up to levels of radioactivity intended to induce kidney injury. The approach enabled prospective kidney functional and injury biomarker evaluation and late kidney histological analysis to validate these biomarkers. RESULTS: Biodistribution analysis identified [212Pb]Pb-MC1L reabsorption in kidneys with a dose deposition of 2.8, 8.9, and 20 Gy for 0.9, 3.0, and 6.7 MBq injected [212Pb]Pb-MC1L doses, respectively. As expected, mice receiving 6.7 MBq had significant weight loss and CKD evidence based on serum creatinine, cystatin C, and kidney histological alterations 28 weeks after treatment. A dose-dependent urinary neutrophil gelatinase-associated lipocalin (NGAL, tubular injury biomarker) urinary excretion the day after [212Pb]Pb-MC1L treatment highly correlated with the severity of late tubulointerstitial injury and histological findings. CONCLUSION: Urine NGAL secretion could be a potential early diagnostic tool to identify unrecognized tubular damage and predict long-term α-RLT-related nephrotoxicity.

A serological assay using Tropheryma whipplei antigens for the presumptive exclusion of Whipple disease.

Whipple disease (WD) is a rare infection in genetically susceptible people caused by the bacterium Tropheryma whipplei. An indirect immunofluorescence serological assay (IFA), detecting patient antibodies to the bacterium, was developed using T. whipplei as antigen. We hypothesised that this assay could be used to rule out WD in patients in whom the diagnosis was being considered, based on high immunoglobulin (Ig) G titres to T. whipplei. In this study, 16 confirmed WD patients and 156 age-matched controls from across Australia were compared serologically. WD patients mostly underproduced IgG antibody to T. whipplei, with titres of ≤1:32 being common. While at an antibody titre of <1:64 the assay sensitivity for WD was only 69% [95% confidence interval (CI) 41-89%], its specificity for excluding WD was 91% (95% CI 85-95%). This specificity increased to 95% (95% CI 90-98%) at an antibody titre of <1:16. Patients with antibody titres of >1:64 were unlikely to have WD. At this titre, the seroprevalence of T. whipplei IgG antibody was 92% (223/242) in Australian blood donors. Unlike other serological assays, which are used to confirm a specific infection, this novel assay is designed to rule out WD infection with a specificity in Australia of 91%. Further validation of this assay, by trialling in other countries, should now be undertaken, as its usefulness is dependent on there being a high background seropositivity to T. whipplei in the general population at the location in which the assay is being used.

Seroprevalence of Coxiella burnetii in an Indigenous Population from the Sierra Nevada De Santa Marta, Colombia.

Coxiella burnetii is an underreported zoonotic pathogen in many rural regions globally. We investigated C. burnetii exposure in a remote indigenous tribe residing in the Sierra Nevada de Santa Marta, Colombia. The high seroprevalence of 35% (95% CI, 27-43%) demonstrates the need for One Health studies to identify risk factors, clinical impact, and potential medical, veterinary, and environmental interventions.

Chemokine Receptor CXCR4 Radioligand Targeted Therapy Using 177Lutetium-pentixather for Pulmonary Neuroendocrine Cancers.

Intermediate to high-grade lung neuroendocrine tumors (NETs; i.e., atypical carcinoid tumors) and neuroendocrine carcinomas (NECs) are currently difficult to cure. These tumors were found to express the CXCR4 G-protein coupled receptor that can be targeted with radioligands. PCR and flow cytometric analysis of lung NET and NEC cell lines using an anti-CXCR4 antibody demonstrated that all cell lines tested expressed CXCR4. PET/CT imaging with 68Galium-pentixafor in mouse xenografts of NETs and NECs verified tumor targeting that was blocked by a CXCR4 agonist. Clonogenic survival analysis demonstrated a more than additive enhancement of killing when 1 µM auranofin (a thioredoxin reductase inhibitor) was used as a radiosensitizer in combination with 177Lu-pentixather (10 µCi). DMS273 small cell lung cancer xenografts in female nude mice treated with 25 µCi/g 177Lu-pentixather induced inhibition of tumor growth and resulted in an increase in overall survival without causing unacceptable normal tissue toxicities. Immunohistochemical staining of 95 retrospective human samples (containing 90 small cell lung carcinomas) demonstrated 84% CXCR4 positivity. In a multivariable analysis of this cohort that included age, gender, stage, primary site, SSTR2 status, and CXCR4 status, Cox regression models determined that only distant metastasis at presentation (P < 0.01) and a CXCR4 H-score >30 (P = 0.04) were significantly associated with reduced survival. Prospective clinical testing of patient tumors identified CXCR4-positivity in 76% of 21 NECs, 67% of 15 lung NETs (including 8 of 10 atypical carcinoids), and 0% of 25 non-lung NETs (including 5 NETS G3s). These data support the hypothesis that CXCR4-targeted theranostics can be utilized effectively for select NETs and NECs.

What is the most appropriate comparator group to use in assessing the performance of primary total hip prostheses within the community?

BACKGROUND: There are variations in the performance of individual prostheses used in hip replacements. Some of which have unexpectedly higher revision rates - outliers. The Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) has established a standardised multi-stage approach for identifying these devices. This is done by comparing the revision rates of individual prostheses to all other prostheses in class, with the exception of large head metal-on-metal (LHMoM) prostheses. However, improvements in device design and performance over time have required a need to reconsider the comparator group. This study aimed to identify a more specific comparator to better reflect contemporary surgical practice. METHODS: The time to first revision was estimated on the data of 413,417 primary total conventional hip replacements undertaken for osteoarthritis (OA) from 01 January 2003 to 31 December 2019. Survivorship analyses with stepwise exclusions were undertaken. The first exclusion was LHMoM, followed by other non-modern bearing surfaces (defined as all the bearing couples except metal or ceramic heads on cross-linked polyethylene and mixed ceramic-on-ceramic), and then devices with modular neck-stem design or used for specific purposes (incl. constrained, dual-mobility, and head size <28 mm). Lastly, all remaining prostheses previously identified as having a higher than anticipated rate of revision (HTARR) were also excluded. RESULTS: These exclusions progressively reduced the cumulative percent revision (CPR) rate. The final comparator, which only includes satisfactory-performed prostheses of contemporary design and use, has a 10-year CPR of 4.30% (95% CI, 4.2-4.41) which is lower than 4.93% (95% CI, 4.84-5.02) for the current comparator used by the AOANJRR (all prostheses excluding LHMOM). Over the study period, 13 additional components were identified utilising the modified comparator. CONCLUSIONS: The calculation of the comparator revision rate should be re-evaluated to include only modern prosthesis constructs to ensure that poorly performing prostheses are identified early.

Q fever - immune responses and novel vaccine strategies.

Q fever is a zoonotic disease caused by the bacterium Coxiella burnetii. It is an occupational risk for employees of animal industries and is associated with contact with wildlife and domestic animals. Although Q fever infection may be asymptomatic, chronic sequelae such as endocarditis occur in 5% of symptomatic individuals. Disease outcomes may be predicted through measurement of immune correlates. Vaccination is the most efficient method to prevent Q fever. Currently, Q-VAX is the only licenced human vaccine. Q-VAX is highly effective; however, individuals previously exposed to C. burnetii are at risk of adverse reactions. This review examines the immunological responses of acute and chronic Q fever and the efforts to provide a safer and cost-effective Q fever vaccine.

Q fever is a disease that is spread by some animals, such as sheep and cattle, to humans. Although most people will recover if they get Q fever, some become very ill. There is a vaccine for Q fever (Q-VAX), but it can cause a reaction when given to some people. Research is ongoing into how the human immune system reacts to the bacteria that causes Q fever. A small number of people who get Q fever will develop a prolonged disease that can be serious and affect the heart, which is why there is also research into developing new vaccines for this disease. This research will look at those parts of the germ that causes Q fever that can be used for a new vaccine.

Pre-clinical Evaluation of Biomarkers for Early Detection of Nephrotoxicity Following Alpha-particle Radioligand Therapy.

Purpose: Cancer treatment with alpha-emitter-based radioligand therapies (α-RLTs) demonstrates promising tumor responses. Radiolabeled peptides are filtered through glomeruli, followed by potential reabsorption of a fraction by proximal tubules, which may cause acute kidney injury (AKI) and chronic kidney disease (CKD). Because tubular cells are considered the primary site of radiopeptides' renal reabsorption and potential injury, the current use of kidney biomarkers of glomerular functional loss limits the evaluation of possible nephrotoxicity and its early detection. This study aimed to investigate whether urinary secretion of tubular injury biomarkers could be used as additional non-invasive sensitive diagnostic tool to identify unrecognizable tubular damage and risk of long-term α-RLTs nephrotoxicity. Methods: A bifunctional cyclic peptide, melanocortin ligand-1(MC1L), labeled with [ 203 Pb]Pb-MC1L, was used for [ 212 Pb]Pb-MC1L biodistribution and absorbed dose measurements in CD-1 Elite mice. Mice were treated with [ 212 Pb]Pb-MC1L in a dose escalation study up to levels of radioactivity intended to induce kidney injury. The approach enabled prospective kidney functional and injury biomarker evaluation and late kidney histological analysis to validate these biomarkers. Results: Biodistribution analysis identified [ 212 Pb]Pb-MC1L reabsorption in kidneys with a dose deposition of 2.8, 8.9, and 20 Gy for 0.9, 3.0, and 6.7 MBq injected [ 212 Pb]Pb-MC1L doses, respectively. As expected, mice receiving 6.7 MBq had significant weight loss and CKD evidence based on serum creatinine, cystatin C, and kidney histological alterations 28 weeks after treatment. A dose-dependent urinary Neutrophil gelatinase-associated lipocalin (NGAL, tubular injury biomarker) urinary excretion the day after [ 212 Pb]Pb-MC1L treatment highly correlated with the severity of late tubulointerstitial injury and histological findings. Conclusion: urine NGAL secretion could be a potential early diagnostic tool to identify unrecognized tubular damage and predict long-term α-RLT-related nephrotoxicity.