Background
The diagnosis of periprosthetic joint infection (PJI) remains a serious clinical challenge. There is a pressing need for improved diagnostic testing methods; biomarkers offer one ...potentially promising approach.
Questions/purposes
We evaluated the diagnostic characteristics of 16 promising synovial fluid biomarkers for the diagnosis of PJI.
Methods
Synovial fluid was collected from 95 patients meeting the inclusion criteria of this prospective diagnostic study. All patients were being evaluated for a revision hip or knee arthroplasty, including patients with systemic inflammatory disease and those already receiving antibiotic treatment. The Musculoskeletal Infection Society (MSIS) definition was used to classify 29 PJIs and 66 aseptic joints. Synovial fluid samples were tested by immunoassay for 16 biomarkers optimized for use in synovial fluid. Sensitivity, specificity, and receiver operating characteristic curve analysis were performed to assess for diagnostic performance.
Results
Five biomarkers, including human α-defensin 1-3, neutrophil elastase 2, bactericidal/permeability-increasing protein, neutrophil gelatinase-associated lipocalin, and lactoferrin, correctly predicted the MSIS classification of all patients in this study, with 100% sensitivity and specificity for the diagnosis of PJI. An additional eight biomarkers demonstrated excellent diagnostic strength, with an area under the curve of greater than 0.9.
Conclusions
Synovial fluid biomarkers exhibit a high accuracy in diagnosing PJI, even when including patients with systemic inflammatory disease and those receiving antibiotic treatment. Considering that these biomarkers match the results of the more complex MSIS definition of PJI, we believe that synovial fluid biomarkers can be a valuable addition to the methods utilized for the diagnosis of infection.
Level of Evidence
Level II, diagnostic study. See Instructions for Authors for a complete description of levels of evidence.
The diagnosis of periprosthetic joint infection remains a challenge. The purpose of this study was to evaluate the combined measurement of the levels of two synovial fluid biomarkers, α-defensin and ...C-reactive protein (CRP), for the diagnosis of periprosthetic joint infection.
One hundred and forty-nine synovial fluid aspirates, including 112 from patients with an aseptic diagnosis and thirty-seven from patients with periprosthetic joint infection, met the inclusion criteria for this prospective study. Synovial fluid aspirates were tested for α-defensin and CRP levels with use of enzyme-linked immunosorbent assay (ELISA). The Musculoskeletal Infection Society (MSIS) definition of periprosthetic joint infection was utilized for the classification of cases as aseptic or infected. Comorbidities, such as inflammatory conditions, that could confound a test for periprosthetic joint infection were documented, but the patients with such comorbidities were included in the study.
The combination of synovial fluid α-defensin and CRP tests demonstrated a sensitivity of 97% and a specificity of 100% for the diagnosis of periprosthetic joint infection. Synovial fluid α-defensin tests alone demonstrated a sensitivity of 97% and a specificity of 96% for the diagnosis of periprosthetic joint infection. Synovial fluid CRP tests, with a low threshold of 3 mg/L, reversed all-false positive α-defensin results without affecting the sensitivity of the test. The diagnostic characteristics of these assays were achieved in a population of patients demonstrating a 23% rate of systemic inflammatory diseases (in the series as a whole) and a 27% rate of concurrent antibiotic treatment (in the infection group). The synovial fluid levels of α-defensin in the setting of periprosthetic joint infection were unchanged during concurrent antibiotic treatment.
The combined measurement of synovial fluid α-defensin and CRP levels correctly diagnosed 99% of the cases in this study as aseptic or infected. This was achieved despite the inclusion of patients with systemic inflammatory disease and those receiving treatment with antibiotics.
Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence.
Background
Synovial fluid biomarkers have demonstrated diagnostic accuracy surpassing the currently used diagnostic tests for periprosthetic joint infection (PJI).
Questions/purposes
The purpose of ...this study is to directly compare the sensitivity and specificity of the synovial fluid α-defensin immunoassay to the leukocyte esterase (LE) colorimetric test strip.
Methods
Synovial fluid was collected from 46 patients meeting the inclusion criteria of this prospective diagnostic study. Synovial fluid samples were tested with both a novel synovial-fluid-optimized immunoassay for α-defensin and the LE colorimetric test strip. The Musculoskeletal Infection Society (MSIS) definition was used to classify 23 periprosthetic infections and 23 aseptic failures; this classification was used as the standard against which the two diagnostic tests were compared.
Results
The synovial fluid α-defensin immunoassay correctly predicted the MSIS classification of all patients in the study, demonstrating a sensitivity and specificity of 100% for the diagnosis of PJI. The α-defensin assay could be read for all samples, including those with blood in the synovial fluid. The leukocyte esterase test strip could not be interpreted in eight of 46 samples (17%) as a result of blood interference. Analysis of the LE strips that could be interpreted yielded a sensitivity of 69% and a specificity of 100%.
Conclusions
The synovial fluid α-defensin immunoassay outperformed the LE colorimetric test strip in this study and provided reliable results even when the LE test strip failed as a result of blood interference. The simple analytic results provided by the α-defensin immunoassay, compared with the more complex and interpretive nature of both the MSIS criteria and LE colorimetric test strip, make it a highly attractive diagnostic tool.
Level of Evidence
Level II, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.
Biased G protein-coupled receptor ligands engage subsets of the receptor signals normally stimulated by unbiased agonists. However, it is unclear whether ligand bias can elicit differentiated ...pharmacology in vivo. Here, we describe the discovery of a potent, selective β-arrestin biased ligand of the angiotensin II type 1 receptor. TRV120027 (Sar-Arg-Val-Tyr-Ile-His-Pro-D-Ala-OH) competitively antagonizes angiotensin II-stimulated G protein signaling, but stimulates β-arrestin recruitment and activates several kinase pathways, including p42/44 mitogen-activated protein kinase, Src, and endothelial nitric-oxide synthase phosphorylation via β-arrestin coupling. Consistent with β-arrestin efficacy, and unlike unbiased antagonists, TRV120027 increased cardiomyocyte contractility in vitro. In rats, TRV120027 reduced mean arterial pressure, as did the unbiased antagonists losartan and telmisartan. However, unlike the unbiased antagonists, which decreased cardiac performance, TRV120027 increased cardiac performance and preserved cardiac stroke volume. These striking differences in vivo between unbiased and β-arrestin biased ligands validate the use of biased ligands to selectively target specific receptor functions in drug discovery.
Biogenic sources contribute to cloud condensation nuclei (CCN) in the clean marine atmosphere, but few measurements exist to constrain climate model simulations of their importance. The chemical ...composition of individual atmospheric aerosol particles showed two types of sulfate-containing particles in clean marine air masses in addition to mass-based Estimated Salt particles. Both types of sulfate particles lack combustion tracers and correlate, for some conditions, to atmospheric or seawater dimethyl sulfide (DMS) concentrations, which means their source was largely biogenic. The first type is identified as New Sulfate because their large sulfate mass fraction (63% sulfate) and association with entrainment conditions means they could have formed by nucleation in the free troposphere. The second type is Added Sulfate particles (38% sulfate), because they are preexisting particles onto which additional sulfate condensed. New Sulfate particles accounted for 31% (7 cm
) and 33% (36 cm
) CCN at 0.1% supersaturation in late-autumn and late-spring, respectively, whereas sea spray provided 55% (13 cm
) in late-autumn but only 4% (4 cm
) in late-spring. Our results show a clear seasonal difference in the marine CCN budget, which illustrates how important phytoplankton-produced DMS emissions are for CCN in the North Atlantic.
Researchers developing biomarkers for cancer prognosis from quantitative gene expression data are often faced with an odd methodological discrepancy: while Cox's proportional hazards model, the ...appropriate and popular technique, produces a continuous and relative risk score, it is hard to cast the estimate in clear clinical terms like median months of survival and percent of patients affected. To produce a familiar Kaplan-Meier plot, researchers commonly make the decision to dichotomize a continuous (often unimodal and symmetric) score. It is well known in the statistical literature that this procedure induces significant bias.
We illustrate the liabilities of common techniques for categorizing a risk score and discuss alternative approaches. We promote the use of the restricted mean survival (RMS) and the corresponding RMS curve that may be thought of as an analog to the best fit line from simple linear regression.
Continuous biomarker workflows should be modified to include the more rigorous statistical techniques and descriptive plots described in this article. All statistics discussed can be computed via standard functions in the Survival package of the R statistical programming language. Example R language code for the RMS curve is presented in the appendix.
Trends in Leadership at Spine Surgery Fellowships Donnally, 3rd, Chester J; Schiller, Nicholas C; Butler, Alexander J ...
Spine (Philadelphia, Pa. 1976),
2020-May-15, Volume:
45, Issue:
10
Journal Article
Peer reviewed
Cross-sectional study.
To illustrate demographic trends among spine fellowship leaders (FLs).
No previous study in the orthopedic literature has analyzed the demographic characteristics or past ...surgical training of FL in an orthopedic sub-specialty. We attempt to illustrate demographic trends among spine fellowship leadership including fellowship directors (FDs) and co-fellowship directors (co-FDs). We also highlight the institutions that have trained these leaders at various levels.
Our search for FDs was constructed from the 2018 to 2019 North American Spine Surgery (NASS) Fellowship Directory. Datapoints gathered included: age, sex, residency/fellowship training location, time since training completion until FD appointment, length in FD role, and personal research H-index.
We identified 103 FLs consisting of 67 FDs, 19 co-FDs, and another 16 individuals with a synonymous leadership title. 96.1% (99) of the leadership consisted of males while 3.9% (4) were female. The mean age was 52.9 years old and the mean h-index of the FLs was 23.8. FLs were trained in orthopedic surgery (n = 89), neurosurgery (n = 13), or combined orthopedic surgery and neurosurgery training (n = 1). The top fellowships programs producing future FLs were: Case Western Reserve University, Cleveland (n = 10), Washington University, St. Louis (n = 9), and Rothman Orthopaedic Institute, Thomas Jefferson University, Philadelphia (n = 7).
Spine surgery fellowship directors are more likely to have graduated from certain residency and fellowship programs. This finding could be a result of the training provided by these centers or the institution's predilection to select applicants that are more likely to later seek academic leadership roles post-training.
4.
Patients with multiple myeloma who have relapsed after or become refractory to lenalidomide in early treatment lines represent a clinically important population in need of effective therapies. The ...safety and efficacy of pomalidomide, low-dose dexamethasone, and daratumumab was evaluated in lenalidomide-pretreated patients with relapsed or refractory multiple myeloma (RRMM) after one to two prior treatment lines in the phase 2 MM-014 study. Patients received pomalidomide 4 mg daily from days 1-21 and dexamethasone 40 mg weekly (28-day cycles). Daratumumab 16 mg/kg was administered per label. Primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS) and safety. Per protocol, all patients (N = 112) had received lenalidomide in their most recent prior regimen (75.0% lenalidomide refractory). ORR was 77.7% (76.2% in lenalidomide-refractory patients); median follow-up was 17.2 months. Median PFS was not reached (1-year PFS rate 75.1%). The most common hematologic grade 3/4 treatment-emergent adverse event was neutropenia (62.5%). Grade 3/4 infections were reported in 31.3% of patients, including 13.4% with grade 3/4 pneumonia. These results demonstrate the safety and efficacy of pomalidomide-based therapy as early as second line in patients with RRMM, even immediately after lenalidomide failure, indicating that switching from the immunomodulatory agent class is not necessary.
Select patients with acute cholecystitis (AC) are not candidates for index cholecystectomy. We compared the influence of ERCP-guided transpapillary gallbladder drainage (ERGD) versus percutaneous ...cholecystostomy (PC) on delayed cholecystectomy outcomes.
Consecutive patients undergoing ERGD or PC for AC from January 2007 to October 2018 were included. Primary outcome was the rate of conversion to open cholecystectomy and perioperative complications in groups.
The study included 52 patients with ERGD and 140 with PC prior to cholecystectomy (median 68 days IQR: 47–105.5). Technical success was higher in the PC group (100% vs 91%; P = 0.0004). There was a nonsignificant trend to lower postoperative complications with ERGD (30.7% vs 43.5%; P = 0.07). No difference in conversion to open cholecystectomy OR: 1.5 (95% CI: 0.68–3.65; P = 0.28) or severity of complications (Clavien-Dindo grade >2) OR: 0.60, (95% CI: 0.19–1.87; P = 0.38) was noted between the ERGD and PC groups. PC was associated with higher rates of unplanned repeat intervention (16.4% vs 7.7%; P = 0.02).
ERGD is suitable for patients with AC who is candidates for delayed cholecystectomy and should be considered for gallbladder drainage in patients with concomitant choledocholithiasis or cholangitis who require ERCP.
Summary
Patients with relapsed/refractory multiple myeloma (RRMM) for whom the benefits of lenalidomide have been exhausted in early treatment lines need effective therapies. In cohort A of the phase ...2 MM‐014 trial, we examined the safety and efficacy of pomalidomide plus low‐dose dexamethasone immediately after lenalidomide‐based treatment failure in patients with RRMM and two prior lines of therapy. Pomalidomide 4 mg was given on days 1 to 21 of 28‐day cycles. Dexamethasone 40 mg (20 mg for patients aged >75 years) was given on days 1, 8, 15 and 22 of 28‐day cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression‐free survival (PFS), overall survival (OS) and safety. The intention‐to‐treat population comprised 56 patients; all received prior lenalidomide (87·5% lenalidomide refractory) and 39 (69·6%) received prior bortezomib. ORR was 32·1% (28·2% in the prior‐bortezomib subgroup). Median PFS was 12·2 months (7·9 months in the prior‐bortezomib subgroup). Median OS was 41·7 months (38·6 months in the prior‐bortezomib subgroup). The most common grade 3/4 treatment‐emergent adverse events were anaemia (25·0%), pneumonia (14·3%) and fatigue (14·3%). These findings support earlier sequencing of pomalidomide‐based therapy in lenalidomide‐pretreated patients with RRMM, including those who have become refractory to lenalidomide.
Trial registration: www.ClinicalTrials.gov identifier NCT01946477.
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