Point-of-care testing, near-patient testing and patient self-testing: warning points.

Point-of-care testing (POCT), near-patient testing (NPT) and patient self-tests (PST) are diagnostic examinations performed at the time and place of patient care. While POCT and NPT are performed and analyzed by medical professionals, PST are based on samples and parameters directly collected and analyzed by lay users. These tests are spreading both in high income countries and in low to middle income countries as they are expected to improve healthcare efficiency and equity, by saving resources, releasing pressure from hospitals and reducing logistical barriers. However, accurate multidisciplinary assessment is mandatory to ensure that what they promise is real. We reviewed some important ethical aspects, international standards and regulations. The current risks associated with alternative ways of testing are explained by the principles of respect for patient autonomy and non-maleficence. Further evidence from multidisciplinary assessment is needed to evaluate pros and cons in light of the principles of beneficence and justice. Although POCT or NPT need common regulation and accurate provider training to ensure safe and appropriate interpretation of results, PST needs even more attention as they are subject to direct patient use. Randomized controlled trails including patient education should be conducted in order to provide reliable evidence on clinical outcomes, patient acceptance and cost-effectiveness. Mandatory regulation is needed to avoid harm and EU regulation should help different countries maintain a safe use of devices in a global population of producers and users.

Recent mortality rates due to complications of medical and surgical care in the US.

OBJECTIVES: Medical errors and complications pose a major threat to the safety of healthcare systems worldwide. This article was hence aimed at determining the current burden of complications of medical and surgical care in the US. METHODS: We searched the latest version of the US Centers for Disease Control and Prevention (CDC) WONDER online database (years 2018-2022) using ICD-10 codes Y40-Y84 (complications of medical and surgical care). RESULTS: The age-adjusted death rate for complications of medical and surgical care increased from 1.17 × 100,000 in 2018 to 1.49 × 100,000 in 2021, but then declined to 0.85 × 100,000 in 2022. The gender-specific analysis showed a similar trend, with the age-adjusted death rate values always being higher in men than in women. A clear age-dependent relationship was also found in the crude mortality rate for complications of medical and surgical care, as higher death rates were observed in older patients. CONCLUSIONS: This analysis reveals that the burden of complications of medical and surgical care has increased over time, especially during the COVID-19 pandemic, but has then considerably declined in 2022. However, root cause analysis and actions are still needed for preventing the still noticeable consequences of medical complications.

Dynamic mirroring: unveiling the role of digital twins, artificial intelligence and synthetic data for personalized medicine in laboratory medicine.

In recent years, the integration of technological advancements and digitalization into healthcare has brought about a remarkable transformation in care delivery and patient management. Among these advancements, the concept of digital twins (DTs) has recently gained attention as a tool with substantial transformative potential in different clinical contexts. DTs are virtual representations of a physical entity (e.g., a patient or an organ) or systems (e.g., hospital wards, including laboratories), continuously updated with real-time data to mirror its real-world counterpart. DTs can be utilized to monitor and customize health care by simulating an individual's health status based on information from wearables, medical devices, diagnostic tests, and electronic health records. In addition, DTs can be used to define personalized treatment plans. In this study, we focused on some possible applications of DTs in laboratory medicine when used with AI and synthetic data obtained by generative AI. The first point discussed how biological variation (BV) application could be tailored to individuals, considering population-derived BV data on laboratory parameters and circadian or ultradian variations. Another application could be enhancing the interpretation of tumor markers in advanced cancer therapy and treatments. Furthermore, DTs applications might derive personalized reference intervals, also considering BV data or they can be used to improve test results interpretation. DT's widespread adoption in healthcare is not imminent, but it is not far off. This technology will likely offer innovative and definitive solutions for dynamically evaluating treatments and more precise diagnoses for personalized medicine.

Evaluation of the Comparability of Wantai Wan200+ Instrument with Routine Laboratory Assays for 21 Different Analytes.

Background: We compared the performance of 21 different assays performed by the Wantai Wan200+ (Wantai BioPharm, Beijing, China) with respect to other methods in use at the University Hospital of Padova (AOPD), Italy. Methods: The plasma (P) or serum (S) of 5027 leftover samples, collected from May to Sept 2023, was either analyzed or frozen at -20 °C. Beckman DXI800 (DXI), Roche Cobas 8000 e801 (RC), Snibe Maglumi 4000 plus (SM), DiaSorin Liaison XL (DL) and Binding Site Optilite (BS) equipment were used at the AOPD. P-procalcitonin (PCT), DXI; P-Troponin I (TnI), DXI; S-CA125, DXI; S-free PSA (f-PSA), DXI; S-total PSA (t-PSA), DXI; S-IL6, SM; P-Troponin T (TnT), RC; P-NT-proBNP, RC; P-Neuron-Specific Enolase (NSE), RC; S-CA15-3, DL; S-CA19-9, DL; S-AFP, DL; and S-CEA, DL were tested in fresh samples. P-Myoglobin (Myo), DXI; P-Cyfra21-1, RC; S-ß2 microglobulin (B2MIC), BS; S-HE4, SM; S-PGI, SM; S-PGII, SM; S-CA72-4, SM; and S-CA50, SM were analyzed in frozen and thawed samples. Bland-Altman (BA), Passing-Bablok (PB) and Cohen's Kappa (CKa) metrics were used as statistics. Results: An excellent comparability profile was found for 11 analytes. For example, the t-PSA CKa was 0.94 (95%CI: 0.90 to 0.98), and the PB slope and intercept were 1.02 (95%CI: 0.99 to 1.03) and 0.02 (95%CI: 0.01 to 0.03), respectively; the BA bias was 2.25 (95%CI: -0.43 to 4.93). Ten tested measurands demonstrated a suboptimal comparability profile. Biological variation in EFLM (EuBIVAS) performance specifications was evaluated to assess the clinical relevance of measured biases. Conclusions: Evaluation of the Wantai Wan200+'s performance suggests that between-method differences did not exceed the calculated bias. Metrological traceability may influence the comparisons obtained for some measurands.

New reimbursement models to promote better patient outcomes and overall value in laboratory medicine and healthcare.

The most widespread healthcare reimbursement models, including diagnostic laboratory services, are Fee-for-Service, Reference Pricing and Diagnosis-Related Groups. Within these models healthcare providers are remunerated for each specific service or procedure they operate. Healthcare payers are increasingly exploring alternative models, such as bundled payments or value-based reimbursement to encourage value of patient care rather than the simple amount of delivered services. These alternative models are advised, as they are more efficient in promoting cost-effective, high-quality laboratory testing, thereby improving patient health outcomes. If outcomes-based evaluation is a pillar in a new vision of "Value-Based Healthcare", an active policy of Value-Based Reimbursement in laboratory medicine will assure both an efficiency-based sustainability and a high-quality effectiveness-based diagnostic activity. This review aims to evaluate current and alternative reimbursement models, to support a wider agenda in encouraging more Value-Based Healthcare and Value-Based Reimbursement in laboratory medicine.

High-Sensitivity Cardiac Troponin and the Management of Congenital Heart Disease in Newborns and Infants.

BACKGROUND: Early cardiac interventions in newborns and infants suspected for congenital heart disease (CHD) decrease morbidity and mortality. After updating current evidence on the use of cardiac troponins (cTn) in the context of CHD for risk stratification at early ages, we discuss relevant issues, starting from the evidence that only the measurement of the cTnT form is useful in this population. CONTENT: In newborns/infants with CHD, the cTnT concentration increase is correlated with: (a) cardiac stress and hemodynamic parameters, but not with the type of CHD; (b) volume overload/right ventricular pressure overload; (c) postoperative hypoperfusion injury and mortality; and (d) effects of cardioprotective strategies. For infants with CHD, high-sensitivity cTnT (hs-cTnT) concentrations >25 ng/L are an independent predictor of poor outcomes. Transitioning from cTnT to hs-cTnT in newborns/infants improves the identification of: (a) physiopathological mechanisms and factors that increased hs-cTnT early after birth; (b) myocardial injury, even when subclinical; (c) identification of patients requiring immediate therapeutic interventions; and (d) 99th percentile upper reference limits (URLs). However, no reliable URLs are currently available to allow the detection of myocardial injury associated with CHD in newborns/infants. SUMMARY: Additional data evaluating the clinical value of hs-cTnT in the risk stratification of newborns/infants with CHD who may suffer myocardial injury is needed. Validating the measurement, possibly in amniotic fluid samples, and improving the interpretation of hs-cTnT concentrations in the prenatal period, at birth and within 1 year of age are crucial to change CHD mortality/morbidity trends in the pediatric population.

Harmonizing the post-analytical phase: focus on the laboratory report.

The final, post-analytical, phase of laboratory testing is increasingly recognized as a fundamental step in maximizing quality and effectiveness of laboratory information. There is a need to close the loop of the total testing cycle by improving upon the laboratory report, and its notification to users. The harmonization of the post-analytical phase is somewhat complicated, mainly because it calls for communication that involves parties speaking different languages, including laboratorians, physicians, information technology specialists, and patients. Recently, increasing interest has been expressed in integrated diagnostics, defined as convergence of imaging, pathology, and laboratory tests with advanced information technology (IT). In particular, a common laboratory, radiology and pathology diagnostic reporting system that integrates text, sentinel images and molecular diagnostic data to an integrated, coherent interpretation enhances management decisions and improves quality of care.

Tubular phosphate transport: a comparison between different methods of urine sample collection in FGF23-dependent hypophosphatemic syndromes.

OBJECTIVES: Tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR) is used to evaluate renal phosphate reabsorption and it is a useful tool for the differential diagnosis of hypophosphatemic syndromes. TmP/GFR is typically calculated from fasting plasma and second morning void urine samples, obtained 2 h after the first void (TmP/GFR 2 h). The purpose of this study was to evaluate if TmP/GFR calculated from 24 h urine collection (TmP/GFR 24 h) can be used as an alternative for TmP/GFR 2 h in patients with urine phosphate wasting. METHODS: We enrolled adult patients with X-linked hypophosphatemia (XLH) or tumor-induced osteomalacia (TIO). All patients underwent blood and urine sample collections, to calculate TmP/GFR 24 h and TmP/GFR 2 h. RESULTS: Twenty patients (17 XLH and 3 TIO), aged 24-78 years, were included. All patients had low TmP/GFR 2 h (0.35 mmol/L, IQR 0.24-0.47 mmol/L) and TmP/GFR 24 h (0.31 mmol/L, IQR 0.22-0.43 mmol/L). The concordance correlation coefficient between TmP/GFR 2 h and TmP/GFR 24 h was 0.86 (95 % CI: 0.69-0.93), with a systematic bias of 0.05 mmol/L (95 % limits of agreement: -0.10 to 0.20). Furthermore, in 70 % (i.e., 14 patients out of 20) and 80 % (i.e., 16 patients out of 20) of cases the difference between TmP/GFR 2 h and TmP/GFR 24 h was within ±30 % and ±35 %, respectively. CONCLUSIONS: Despite TmP/GFR 2 and 24 h show a relatively suboptimal agreement, the difference between the two parameters appears to be small and not clinically significant in the setting of adult patients with FGF23-dependent urine phosphate wasting and secondary hypophosphatemia.

Real-world usage of Chronic Kidney Disease - Mineral Bone Disorder (CKD-MBD) biomarkers in nephrology practices.

Background: Chronic kidney disease mineral bone disorder (CKD-MBD) is a condition characterized by alterations of calcium, phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF-23) metabolism that in turn promote bone disorders, vascular calcifications, and increase cardiovascular (CV) risk. Nephrologists' awareness of diagnostic, prognostic, and therapeutic tools to manage CKD-MBD plays a primary role in adequately preventing and managing this condition in clinical practice. Methods: A national survey (composed of 15 closed questions) was launched to inquire about the use of bone biomarkers in the management of CKD-MBD patients by nephrologists and to gain knowledge about the implementation of guideline recommendations in clinical practice. Results: One hundred and six Italian nephrologists participated in the survey for an overall response rate of about 10%. Nephrologists indicated that the laboratories of their hospitals were able to satisfy request of ionized calcium levels, 105 (99.1%) of both PTH and alkaline phosphatase (ALP), 100 (94.3%) of 25(OH)D, and 61 (57.5%) of 1.25(OH)2D; while most laboratories did not support the requests of biomarkers such as FGF-23 (intact: 88.7% and c-terminal: 93.4%), Klotho (95.3%; soluble form: 97.2%), tartrate-resistant acid phosphatase 5b (TRAP-5b) (92.5%), C-terminal telopeptide (CTX) (71.7%), and pro-collagen type 1 N-terminal pro-peptide (P1NP) (88.7%). As interesting data regarding Italian nephrologists' behavior to start treatment of secondary hyperparathyroidism (sHPT), the majority of clinicians used KDOQI guidelines (n = 55, 51.9%). In contrast, only 40 nephrologists (37.7%) relied on KDIGO guidelines, which recommended referring to values of PTH between two and nine times the upper limit of the normal range. Conclusion: Results point out a marked heterogeneity in the management of CKD-MBD by clinicians as well as a suboptimal implementation of guidelines in Italian clinical practice.

Clinical and Analytical Performance of ELISA Salivary Serologic Assay to Detect SARS-CoV-2 IgG in Children and Adults.

Saliva is a promising matrix with several purposes. Our aim is to verify if salivary anti-SARS-CoV-2 antibody determination is suitable for monitoring immune responses. One hundred eighty-seven subjects were enrolled at University-Hospital Padova: 105 females (56.1%) and 82 males (43.9%), 95 (50.8%) children and 92 (49.2%) adults. Subjects self-collected saliva using Salivette; nineteen subjects collected three different samples within the day. A serum sample was obtained for all individuals. The N/S anti-SARS-CoV-2 salivary IgG (sal-IgG) and serum anti-SARS-CoV-2 S-RBD IgG (ser-IgG) were used for determining anti-SARS-CoV-2 antibodies. The mean (min-max) age was 9.0 (1-18) for children and 42.5 (20-61) for adults. Of 187 samples, 63 were negative for sal-IgG (33.7%), while 7 were negative for ser-IgG (3.7%). Spearman's correlation was 0.56 (p < 0.001). Sal-IgG and ser-IgG levels were correlated with age but not with gender, comorbidities, prolonged therapy, previous SARS-CoV-2 infection, or time from last COVID-19 infection/vaccination. The repeatability ranged from 23.8% (7.4 kAU/L) to 4.0% (3.77 kAU/L). The linearity of the assay was missed in 4/6 samples. No significant intrasubject differences were observed in sal-IgG across samples collected at different time points. Sal-IgG has good agreement with ser-IgG. Noninvasive saliva collection represents an alternative method for antibody measurement, especially in children.

Troponin T in spinal and bulbar muscular atrophy (SBMA).

Serum biomarkers that might detect clinical progression are currently lacking for Spinal and bulbar muscular atrophy (SBMA), thus limiting the effectiveness of possible future pharmacological trials. Elevation of cardiac troponin T (cTnT) unrelated to myocardial damage in a motor neuron (MN) disease as amyotrophic lateral sclerosis (ALS) was associated to disease severity. We enrolled 47 SBMA patients and 5 Spinal muscular atrophy (SMA) type 3 adult patients as control group; each SBMA patient was evaluated at baseline and at one-year follow-up visit. Demographic and clinical data including functional scores (SBMAFRS) were collected; serum was collected as standard of care and tested for cardiac troponins. Levels of cTnT but not cTnI were increased in SBMA with respect to reference values; unlike other neuromuscular diseases, SMA patients had overall normal cTnT values. Median cTnT concentrations did not change after one year and values were correlated to motor function, particularly with lower limb subdomain, at baseline only. Variations of cTnT and of SBMAFRS were unrelated. The cautiously promising results of cTnT as potential biomarker should undergo a more extensive clinical validation, including studies with longer follow-up period. When evaluating SBMA patients for a potential cardiac damage cTnI testing should be coupled or preferred to cTnT.

Analytical and clinical evaluations of SNIBE Maglumi chemiluminescent immunoassay for the detection of SARS-CoV-2 antigen in salivary samples.

OBJECTIVES: In this study, we describe the analytical and clinical performances of the SNIBE Maglumi SARS-CoV-2 antigen fully-automated chemiluminescent immunoassay (MAG-CLIA) on salivary samples. METHODS: Limit of detection (LOD), linearity and precision were tested for values close to or below the declared LOD. Clinical performance of MAG-CLIA was evaluated on leftover salivary samples from the healthcare workers (HCW) surveillance program, at the University-Hospital of Padova. Salivary samples were analyzed by Lumipulse G SARS-CoV-2 Ag, and in case where the values exceeded 0.41 ng/L, further testing was conducted using TaqPathTM COVID-19 RT-PCR (Applied Biosystems, Thermo Fisher Scientific). RESULTS: The estimated MAG-CLIA LOD was 3 ng/L, with repeatability of 7.5 %. Good linearity was demonstrated by diluting two samples at 52.7 ng/L and 211.4 ng/L. Of the 228 HCW samples, 59/228 (25.9 %) were positive, 169/228 (74.1 %) were negative. MAG-CLIA SARS-CoV-2 sAg median level (and interquartile range [IQR]) was 5.03 ng/L (<0.001-35.8 ng/L) for positive and <0.001 ng/L (<0.001 ng/L) for negative samples. MAG-CLIA AUC was 0.795 (95 % CI: 0.720-0.871). Using the best cut-off, 3.5 ng/L, sensitivity and specificity were 57.1 % (95 % CI: 42.2-71.2 %) and 97.0 % (95 % CI: 93.2-99.0 %), respectively. The agreement with the molecular assay was 88.1 % (Cohen's kappa 0.606 [SE=0.066, p<0.001]). CONCLUSIONS: The analytical performances of MAG-CLIA are satisfactory, also when values below LOD were tested. In saliva samples, although specificity was elevated, clinical performance was not comparable with that on nasopharyngeal swabs (NPS).

Rising adoption of artificial intelligence in scientific publishing: evaluating the role, risks, and ethical implications in paper drafting and review process.

BACKGROUND: In the rapid evolving landscape of artificial intelligence (AI), scientific publishing is experiencing significant transformations. AI tools, while offering unparalleled efficiencies in paper drafting and peer review, also introduce notable ethical concerns. CONTENT: This study delineates AI's dual role in scientific publishing: as a co-creator in the writing and review of scientific papers and as an ethical challenge. We first explore the potential of AI as an enhancer of efficiency, efficacy, and quality in creating scientific papers. A critical assessment follows, evaluating the risks vs. rewards for researchers, especially those early in their careers, emphasizing the need to maintain a balance between AI's capabilities and fostering independent reasoning and creativity. Subsequently, we delve into the ethical dilemmas of AI's involvement, particularly concerning originality, plagiarism, and preserving the genuine essence of scientific discourse. The evolving dynamics further highlight an overlooked aspect: the inadequate recognition of human reviewers in the academic community. With the increasing volume of scientific literature, tangible metrics and incentives for reviewers are proposed as essential to ensure a balanced academic environment. SUMMARY: AI's incorporation in scientific publishing is promising yet comes with significant ethical and operational challenges. The role of human reviewers is accentuated, ensuring authenticity in an AI-influenced environment. OUTLOOK: As the scientific community treads the path of AI integration, a balanced symbiosis between AI's efficiency and human discernment is pivotal. Emphasizing human expertise, while exploit artificial intelligence responsibly, will determine the trajectory of an ethically sound and efficient AI-augmented future in scientific publishing.

Machine learning-based nonlinear regression-adjusted real-time quality control modeling: a multi-center study.

OBJECTIVES: Patient-based real-time quality control (PBRTQC), a laboratory tool for monitoring the performance of the testing process, has gained increasing attention in recent years. It has been questioned for its generalizability among analytes, instruments, laboratories, and hospitals in real-world settings. Our purpose was to build a machine learning, nonlinear regression-adjusted, patient-based real-time quality control (mNL-PBRTQC) with wide application. METHODS: Using computer simulation, artificial biases were added to patient population data of 10 measurands. An mNL-PBRTQC was created using eight hospital laboratory databases as a training set and validated by three other hospitals' independent patient datasets. Three different Patient-based models were compared on these datasets, the IFCC PBRTQC model, linear regression-adjusted real-time quality control (L-RARTQC), and the mNL-PBRTQC model. RESULTS: Our study showed that in the three independent test data sets, mNL-PBRTQC outperformed the IFCC PBRTQC and L-RARTQC for all measurands and all biases. Using platelets as an example, it was found that for 20 % bias, both positive and negative, the uncertainty of error detection for mNL-PBRTQC was smallest at the median and maximum values. CONCLUSIONS: mNL-PBRTQC is a robust machine learning framework, allowing accurate error detection, especially for analytes that demonstrate instability and for detecting small biases.

Machine learning algorithms in sepsis.

Sepsis remains a significant global health challenge due to its high mortality and morbidity, compounded by the difficulty of early detection given its variable clinical manifestations. The integration of machine learning (ML) into laboratory medicine for timely sepsis identification and outcome forecasting is an emerging field of interest. This comprehensive review assesses the current body of research on ML applications for sepsis within the realm of laboratory diagnostics, detailing both their strengths and shortcomings. An extensive literature search was performed by two independent investigators across PubMed and Scopus databases, employing the keywords "Sepsis," "Machine Learning," and "Laboratory" without publication date limitations, culminating in January 2023. Each selected study was meticulously evaluated for various aspects, including its design, intent (diagnostic or prognostic), clinical environment, demographics, sepsis criteria, data gathering period, and the scope and nature of features, in addition to the ML methodologies and their validation procedures. Out of 135 articles reviewed, 39 fulfilled the criteria for inclusion. Among these, the majority (30 studies) were focused on devising ML algorithms for diagnosis, fewer (8 studies) on prognosis, and one study addressed both aspects. The dissemination of these studies across an array of journals reflects the interdisciplinary engagement in the development of ML algorithms for sepsis. This analysis highlights the promising role of ML in the early diagnosis of sepsis while drawing attention to the need for uniformity in validating models and defining features, crucial steps for ensuring the reliability and practicality of ML in clinical setting.

Evaluation of a new molecular test for the detection of SARS-CoV-2 nucleic acid in salivary samples.

Background: Molecular testing is considered the gold standard for the detection of SARS-CoV-2. This study aimed to compare the performance of the P742H SARS-CoV-2 Nucleic Acid Multiplex Detection Kit in salivary samples, with respect to the 732HF Novel Coronavirus (2019-nCoV) Nucleic Acid Detection Kit and the TaqPath COVID-19 CEIVD RT-PCR Kit, used at University-Hospital of Padova, Italy. Methods: One hundred twenty-four salivary samples selfcollected by healthcare workers (HCW) during the screening program at University-Hospital of Padova, Italy, from Oct to Nov 2022, were included in the study. RNA extraction was performed by Viral DNA and RNA Extraction Kit (Technogenetics, Lodi, Italy) and amplification by P742H and 732HF (Technogenetics, Lodi, Italy). RNA was extracted using MagNa Pure 96 DNA and Viral NA Small Volume Kit (Roche, Switzerland) for TaqPath analysis (Thermo Fisher Scientific, USA).

Measurement of Cardiac-Specific Biomarkers in the Emergency Department: New Insight in Risk Evaluation.

The aim of this article review is to analyze some models and clinical issues related to the implementation of accelerated diagnostic protocols based on specific cardiac biomarkers in patients admitted to the emergency department (ED) with symptoms compatible with acute cardiac disorders. Four specific clinical issues will be discussed in detail: (a) pathophysiological and clinical interpretations of circulating hs-cTnI and hs-cTnT levels; (b) the clinical relevance and estimation of the biological variation of biomarkers in patients admitted to the ED with acute and severe diseases; (c) the role and advantages of the point-of-care testing (POCT) methods for cardiac-specific biomarkers in pre-hospital and hospital clinical practice; and (d) the clinical role of specific cardiac biomarkers in patients with acute heart failure (AHF). In order to balance the risk between a hasty discharge versus the potential harms caused by a cardiac assessment in patients admitted to the ED with suspected acute cardiovascular disease, the measurement of specific cardiac biomarkers is essential for the early identification of the presence of myocardial dysfunction and/or injury and to significantly reduce the length and costs of hospitalization. Moreover, specific cardiac biomarkers (especially hs-cTnI and hs-cTnT) are useful predictors of mortality and major adverse cardiovascular events (MACE) in patients admitted to the ED with suspected acute cardiovascular disease. To guide the implementation of the most rapid algorithms for the diagnosis of Non-ST-Elevation Myocardial Infarction (NSTEMI) into routine clinical practice, clinical scientific societies and laboratory medicine societies should promote collaborative studies specifically designed for the evaluation of the analytical performance and, especially, the cost/benefit ratio resulting from the use of these clinical protocols and POCT methods in the ED clinical practice.