Over the past decade, there have been a rising number of clinically used tests that combine 2 or more biochemical or molecular assays, demographics, and clinical information into an algorithm to generate diagnostic, prognostic, or predictive information for a specific disease. The concept of multianalyte analyses is relatively new in the field of laboratory medicine. Dating back to the 1980s, prenatal screening for fetal abnormalities, such as Down syndrome, by use of maternal biomarkers is among the pioneer tests that use algorithmic analyses for risk assessment. Yet, the number of multianalyte algorithms used clinically remains modest. The American Medical Association provides current procedural terminology (CPT)8 codes for 20 multianalyte assays with algorithmic analyses (MAAAs.) Among these, 9 consist of biochemical markers detected by immunoassay or mass spectrometry, with or without other clinical information; 11 use molecular genetics markers; and 1 is for generic use. In this Q&A, we refer to multivariable tests with risk scores as MAAAs, although not all of them have an associated MAAA CPT code.
Generally speaking, MAAAs aim at improving diagnostics for diseases in which single biomarkers have limited clinical validity. The Prostate Health Index (Beckman Coulter) and the 4Kscore® (GenPath) exemplify some of these strategies for prostate cancer detection. Likewise, multianalyte analyses such as the Risk of Ovarian Malignancy Algorithm (ROMA®) and OVA1® and its second-generation OVERATM (Vermillion Inc.) improve upon the suboptimal performance of the tumor marker CA125 in the differential diagnosis and likelihood of ovarian carcinoma in women presenting with a pelvic mass. While both have Food and Drug Administration (FDA) clearance, ROMA is a nonproprietary algorithm cleared on various commercial immunoassays (Fujirebio Diagnostics, Inc.; Abbott Laboratories; Roche Diagnostics). Early identification of acute kidney injury is another area in which an FDA-approved multianalyte test, Nephrocheck® (Astute Medical), …
Abstract Background Demand on hospital emergency departments for paediatric problems is increasing. However, the volume and nature of paediatric health demands placed on other parts of the urgent care system have not been explored. This understanding is an important first step in developing and improving out-of-hospital care. We aimed to describe the volume, nature, and outcomes of paediatric contacts with out-of-hours general practice (OOH GP). We performed a retrospective service evaluation using data from 12 months of paediatric patient contacts with the Oxfordshire OOH GP service. Methods A database of contacts with the Oxfordshire OOH GP service was created for a 12 month period from December 2014 to November 2015. Descriptive statistics were calculated using SPSS Version 25. Results 27,455 contacts were made by 18,987 individuals during a 12 month period. The majority of these were for children aged under 5. Over 70% of contacts were at the weekend. The peak contact period was between 18:30 and 21:30. Over 40% of contacts resulted in advice only (no onward referral, requirement for GP follow up, or prescription). 19.7% of contacts resulted in an antibiotic prescription, most commonly those linked with ear, chest, and throat infections. Discussion Paediatric contacts with the Oxfordshire OOH GP service were predominantly in younger age groups and in the evening, with 19.7% resulting in an antibiotic prescription. Almost half of the contacts had no follow up or prescription, suggesting non-prescribing health care professionals could be involved in providing care in OOH GP. Further research should consider how children and their parents can be best supported to optimise OOH consulting.
COVID-19 presented unique challenges in preparing our stand-alone children’s emergency department for the pandemic and has demonstrated well the paediatric adage, ‘children aren’t little adults’.
The expanded availability of adalimumab products continues to widen patient access and reduce costs with substantial benefit to healthcare systems. However, the long-term success of these medicines is highly dependent on maintaining consistency in quality, safety and efficacy while minimizing any risk of divergence during life-cycle management. In recognition of this need and demand from global manufacturers, the World Health Organization (WHO) Expert Committee on Biological standardization established the WHO 1 st International standard (IS) for Adalimumab (coded 17/236) in October 2019 with a defined unitage ascribed to each of the individual bioactivities evaluated in the study namely, TNF-α binding, TNF-α neutralization, complement dependent cytotoxicity and antibody-dependent cellular cytotoxicity. For development of the IS, two candidate standards were manufactured as per WHO recommendations. Analysis of extensive datasets generated by testing of a common set of samples including the candidate standards by multiple stakeholders including regulatory agencies using their own qualified assays in a large international collaborative study showed comparable biological activity for the tested candidates for the different activities. Use of a common standard significantly decreased the variability of bioassays and improved agreement in potency estimates. Data from this study clearly supports the utility of the IS as an important tool for assuring analytical assay performance, for bioassay calibration and validation, for identifying and controlling changes in bioactivity during life-cycle management and for global harmonization of adalimumab products. In addition, in a separate multi-center study which included involvement of hospital and clinical diagnostic laboratories, the suitability of the adalimumab IS for therapeutic drug monitoring assays was examined by analysis of data from testing of a common blind coded panel of adalimumab spiked serum samples representative of the clinical scenario along with the IS and in-house standards in diverse immunoassays/platforms. Both commercially available and in-house assays that are routinely used for assessing adalimumab trough levels were included. Excellent agreement in estimates for adalimumab content in the spiked samples was observed regardless of the standard or the method with inter-laboratory variability also similar regardless of the standard employed. This data, for the first time, provides support for the extended applicability of the IS in assays in use for therapeutic drug monitoring based on the mass content of the IS. The adalimumab IS, in fulfilling clinical demand, can help toward standardizing and harmonizing clinical monitoring assays for informed clinical decisions and/or personalized treatment strategies for better patient outcomes. Collectively, a significant role for the adalimumab IS in assuring the quality, safety and efficacy of adalimumab products globally is envisaged.
Abstract The CD28-specific mAb TGN1412 rapidly caused a life-threatening “cytokine storm” in all six healthy volunteers in the Phase I clinical trial of this superagonist, signaling a failure of preclinical safety testing. We report novel in vitro procedures in which TGN1412, immobilized in various ways, is presented to human white blood cells in a manner that stimulates the striking release of cytokines and profound lymphocyte proliferation that occurred in vivo in humans. The novel procedures would have predicted the toxicity of this superagonist and are now being applied to emerging immunotherapeutics and to other therapeutics that have the potential to act upon the immune system. Data from these novel procedures, along with data from in vitro and in vivo studies in nonhuman primates, suggest that the dose of TGN1412 given to human volunteers was close to the maximum immunostimulatory dose and that TGN1412 is not a superagonist in nonhuman primates.
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