Utility of Plasma Protein Biomarkers and Mid-Infrared Spectroscopy for Diagnosing Fracture-Related Infections: A Pilot Study.

OBJECTIVES: To compare a large panel of plasma protein inflammatory biomarkers and mid-infrared (MIR) spectral patterns between patients with confirmed fracture related infections (FRIs) and controls without infection. DESIGN: Prospective case-control. SETTING: Academic, level 1 trauma center. PATIENTS: Thirteen patients meeting confirmatory FRI criteria were matched to 13 controls based on age, time after surgery, and fracture region. INTERVENTION: Plasma levels of 49 proteins were measured using enzyme-linked immunosorbent assay (ELISA) techniques. Fourier transform infrared (FTIR) spectroscopy of dried films was used to obtain MIR spectra of plasma samples. MAIN OUTCOME MEASUREMENTS: Plasma protein levels and MIR spectra of samples. RESULTS: Multivariate analysis-based predictive model developed utilizing ELISA-based biomarkers had sensitivity, specificity, and accuracy of 69.2±0.0%, 99.9±1.0%, and 84.5±0.6%, respectively, with PDGF-AB/BB, CRP, and MIG selected as the minimum number of variables explaining group differences (P CONCLUSIONS: This pilot study demonstrates the feasibility of using a select panel of plasma proteins and FTIR spectroscopy to diagnose FRI. The preliminary data suggest that measurement of these select proteins and MIR spectra may be potential clinical tools to detect FRI. Further investigation of these biomarkers in a larger cohort of patients is warranted. LEVEL OF EVIDENCE: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence

Methodology, selection, and integration of fracture healing assessments in mice

Long bone fractures are one of the most common and costly medical conditions encountered after trauma. Characterization of the biology of fracture healing and development of potential medical interventions generally involves animal models of fracture healing using varying genetic or treatment groups, then analyzing relative repair success via the synthesis of diverse assessment methodologies. Murine models are some of the most widely used given their low cost, wide variety of genetic variants, and rapid breeding and maturation. This review addresses key concerns regarding fracture repair investigations in mice and may serve as a guide in conducting and interpreting such studies. Specifically, this review details the procedures, highlights relevant parameters, and discusses special considerations for the selection and integration of the major modalities used for quantifying fracture repair in such studies, including X-ray, microcomputed tomography, histomorphometric, biomechanical, gene expression and biomarker analyses

A Comprehensive Review of Mouse Diaphyseal Femur Fracture Models

Complications related to treatment of long bone fractures still stand as a major challenge for orthopaedic surgeons. Elucidation of the mechanisms of bone healing and development, and the subsequent alteration of these mechanisms to improve outcomes, typically requires animal models as an intermediary between in vitro and human clinical studies. Murine models are some of the most commonly used in translational research, and mouse fracture models are particularly diverse, offering a wide variety of customization with distinct benefits and limitations depending on the study. This review critically examines three common femur fracture models in the mouse, namely cortical hole, 3-point fracture (Einhorn), and segmental bone defect. We lay out the general procedure for execution of each model, evaluate the practical implications and important advantages/disadvantages of each and describe recent innovations. Furthermore, we explore the applications that each model is best adapted for in the context of the current state of murine orthopaedic research

Single-cell RNA sequencing of intramedullary canal tissue to improve methods for studying fracture repair biology

The ability to study the bone microenvironment of failed fracture healing may lead to biomarkers for fracture nonunion. Herein the authors describe a technique for isolating individual cells suitable for single-cell RNA sequencing analyses from intramedullary canal tissue collected by reaming during surgery. The purpose was to detail challenges and solutions inherent to the collection and processing of intramedullary canal tissue samples. The authors then examined single-cell RNA sequencing data from fresh and reanimated samples to demonstrate the feasibility of this approach for prospective studies

Polytraumatized patient lower extremity nonunion development: Raw data

In this article we report data collected to evaluate the pathomechanistic effect of acute anaerobic metabolism in the polytraumatized patient and its subsequent effect on fracture nonunion; see "Base Deficit ≥6 within 24 Hours of Injury is a Risk Factor for Fracture Nonunion in the Polytraumatized Patient" (Sardesai et al., 2021) [1]. Data was collected on patients age ≥16 with an Injury Severity Score (ISS) >16 that presented between 2013-2018 who sustained a fracture of the tibia or femur distal to the femoral neck. Patients presenting to our institution greater than 24 hours post-injury and those with less than three months follow-up were excluded. Medical charts were reviewed to collect patient demographic information and known nonunion risk-factors, including smoking, alcohol use, and diabetes. In addition, detailed injury characteristics to quantify injury magnitude including ISS, Glasgow Coma Scale (GCS) at admission, and ICU length of stay were recorded. ISS values were obtained from our institutional trauma database where they are entered by individuals trained in ISS calculations. Associated fracture-related features including fracture location, soft-tissue injury (open vs. closed fracture), vascular injury, and compartment syndrome were recorded. Finally, vital signs, base deficit (BD), and blood transfusions over 24 hours from admission were recorded. We routinely measure BD and less consistently measure serum lactate in trauma patients at the time of presentation or during resuscitation. BD values are automatically produced by our laboratory with any arterial blood gas order, and we recorded BD values from the medical record. Clinical notes and radiographs were reviewed to confirm fracture union versus nonunion and assess for deep infection at the fracture site. Patients were categorized as having a deep infection if they were treated operatively for the infection prior to fracture healing or classification as a nonunion. Nonunion was defined by failure of progressive healing on sequential radiographs and/or surgical treatment for nonunion repair at least six months post-injury

Planck intermediate results. VIII. Filaments between interacting clusters

About half of the baryons of the Universe are expected to be in the form of filaments of hot and low density intergalactic medium. Most of these baryons remain undetected even by the most advanced X-ray observatories which are limited in sensitivity to the diffuse low density medium. The Planck satellite has provided hundreds of detections of the hot gas in clusters of galaxies via the thermal Sunyaev-Zel'dovich (tSZ) effect and is an ideal instrument for studying extended low density media through the tSZ effect. In this paper we use the Planck data to search for signatures of a fraction of these missing baryons between pairs of galaxy clusters. Cluster pairs are good candidates for searching for the hotter and denser phase of the intergalactic medium (which is more easily observed through the SZ effect). Using an X-ray catalogue of clusters and the Planck data, we select physical pairs of clusters as candidates. Using the Planck data we construct a local map of the tSZ effect centered on each pair of galaxy clusters. ROSAT data is used to construct X-ray maps of these pairs. After having modelled and subtracted the tSZ effect and X-ray emission for each cluster in the pair we study the residuals on both the SZ and X-ray maps. For the merging cluster pair A399-A401 we observe a significant tSZ effect signal in the intercluster region beyond the virial radii of the clusters. A joint X-ray SZ analysis allows us to constrain the temperature and density of this intercluster medium. We obtain a temperature of kT = 7.1 +- 0.9, keV (consistent with previous estimates) and a baryon density of (3.7 +- 0.2)x10^-4, cm^-3. The Planck satellite mission has provided the first SZ detection of the hot and diffuse intercluster gas.Comment: Accepted by A&

Exploring cosmic origins with CORE: Gravitational lensing of the CMB

Lensing of the CMB is now a well-developed probe of large-scale clustering over a broad range of redshifts. By exploiting the non-Gaussian imprints of lensing in the polarization of the CMB, the CORE mission can produce a clean map of the lensing deflections over nearly the full-sky. The number of high-S/N modes in this map will exceed current CMB lensing maps by a factor of 40, and the measurement will be sample-variance limited on all scales where linear theory is valid. Here, we summarise this mission product and discuss the science that it will enable. For example, the summed mass of neutrinos will be determined to an accuracy of 17 meV combining CORE lensing and CMB two-point information with contemporaneous BAO measurements, three times smaller than the minimum total mass allowed by neutrino oscillations. In the search for B-mode polarization from primordial gravitational waves with CORE, lens-induced B-modes will dominate over instrument noise, limiting constraints on the gravitational wave power spectrum amplitude. With lensing reconstructed by CORE, one can "delens" the observed polarization internally, reducing the lensing B-mode power by 60%. This improves to 70% by combining lensing and CIB measurements from CORE, reducing the error on the gravitational wave amplitude by 2.5 compared to no delensing (in the null hypothesis). Lensing measurements from CORE will allow calibration of the halo masses of the 40000 galaxy clusters that it will find, with constraints dominated by the clean polarization-based estimators. CORE can accurately remove Galactic emission from CMB maps with its 19 frequency channels. We present initial findings that show that residual Galactic foreground contamination will not be a significant source of bias for lensing power spectrum measurements with CORE. [abridged

Planck intermediate results XIII : Constraints on peculiar velocities

Peer reviewe

Exploring Cosmic Origins with CORE: Cluster Science

We examine the cosmological constraints that can be achieved with a galaxycluster survey with the future CORE space mission. Using realistic simulationsof the millimeter sky, produced with the latest version of the Planck SkyModel, we characterize the CORE cluster catalogues as a function of the mainmission performance parameters. We pay particular attention to telescope size,key to improved angular resolution, and discuss the comparison and thecomplementarity of CORE with ambitious future ground-based CMB experiments thatcould be deployed in the next decade. A possible CORE mission concept with a150 cm diameter primary mirror can detect of the order of 50,000 clustersthrough the thermal Sunyaev-Zeldovich effect (SZE). The total yield increases(decreases) by 25% when increasing (decreasing) the mirror diameter by 30 cm.The 150 cm telescope configuration will detect the most massive clusters($>10^{14}\, M_\odot$) at redshift $z>1.5$ over the whole sky, although theexact number above this redshift is tied to the uncertain evolution of thecluster SZE flux-mass relation; assuming self-similar evolution, CORE willdetect $\sim 500$ clusters at redshift $z>1.5$. This changes to 800 (200) whenincreasing (decreasing) the mirror size by 30 cm. CORE will be able to measureindividual cluster halo masses through lensing of the cosmic microwavebackground anisotropies with a 1-$\sigma$ sensitivity of $4\times10^{14}M_\odot$, for a 120 cm aperture telescope, and $10^{14} M_\odot$ for a 180 cmone. [abridged

Exploring cosmic origins with CORE : Effects of observer peculiar motion

We discuss the effects on the cosmic microwave background (CMB), cosmic infrared background (CIB), and thermal Sunyaev-Zeldovich effect due to the peculiar motion of an observer with respect to the CMB rest frame, which induces boosting effects. After a brief review of the current observational and theoretical status, we investigate the scientific perspectives opened by future CMB space missions, focussing on the Cosmic Origins Explorer (CORE) proposal. The improvements in sensitivity offered by a mission like CORE, together with its high resolution over a wide frequency range, will provide a more accurate estimate of the CMB dipole. The extension of boosting effects to polarization and cross-correlations will enable a more robust determination of purely velocity-driven effects that are not degenerate with the intrinsic CMB dipole, allowing us to achieve an overall signal-to-noise ratio of 13; this improves on the Planck detection and essentially equals that of an ideal cosmic variance-limited experiment up to a multipole l similar or equal to 2000. Precise inter-frequency calibration will offer the opportunity to constrain or even detect CMB spectral distortions, particularly from the cosmological reionization epoch, because of the frequency dependence of the dipole spectrum, without resorting to precise absolute calibration. The expected improvement with respect to COBE-FIRAS in the recovery of distortion parameters (which could in principle be a factor of several hundred for an ideal experiment with the CORE configuration) ranges from a factor of several up to about 50, depending on the quality of foreground removal and relative calibration. Even in the case of similar or equal to 1% accuracy in both foreground removal and relative calibration at an angular scale of 1 degrees, we find that dipole analyses for a mission like CORE will be able to improve the recovery of the CIB spectrum amplitude by a factor similar or equal to 17 in comparison with current results based on COBE-FIRAS. In addition to the scientific potential of a mission like CORE for these analyses, synergies with other planned and ongoing projects are also discussed.Peer reviewe