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Clinical short-read exome and genome sequencing approaches have positively impacted diagnostic testing for rare diseases. Yet, technical limitations associated with short reads challenge their use for the detection of disease-associated variation in complex regions of the genome. Long-read sequencing (LRS) technologies may overcome these challenges, potentially qualifying as a first-tier test for all rare diseases. To test this hypothesis, we performed LRS (30× high-fidelity [HiFi] genomes) for 100 samples with 145 known clinically relevant germline variants that are challenging to detect using short-read sequencing and necessitate a broad range of complementary test modalities in diagnostic laboratories. We show that relevant variant callers readily re-identified the majority of variants (120/145, 83%), including ∼90% of structural variants, SNVs/insertions or deletions (indels) in homologous sequences, and expansions of short tandem repeats. Another 10% (n = 14) was visually apparent in the data but not automatically detected. Our analyses also identified systematic challenges for the remaining 7% (n = 11) of variants, such as the detection of AG-rich repeat expansions. Titration analysis showed that 90% of all automatically called variants could also be identified using 15-fold coverage. Long-read genomes thus identified 93% of challenging pathogenic variants from our dataset. Even with reduced coverage, the vast majority of variants remained detectable, possibly enhancing cost-effective diagnostic implementation. Most importantly, we show the potential to use a single technology to accurately identify all types of clinically relevant variants. Detecting pathogenic germline variants in the clinic remains technically challenging. We analyzed 145 previously identified, hard-to-detect variants in 100 samples using HiFi long-read sequencing (LRS). 93% of these variants could be recovered in the data, highlighting LRS as a promising single technology for the diagnosis of rare diseases. [ABSTRACT FROM AUTHOR]

The Chilean degu (Octodon degus) is a medium sized, long-lived rodent with traits that make them a natural model for neuroscience research. Their social behaviors, diurnality, and extended developmental time course, when compared to other rodents, make them useful for social behavioral, chronobiology, and developmental research. Lab-kept degus have a long lifespan (5–8 years) and may naturally develop age-related diseases that resemble Alzheimer's disease. While there is significant interest in using the Octodon degus for neuroscience research, including aging and Alzheimer's disease studies, laboratory management and methods for degus research are currently not standardized. This lack of standardization potentially impacts study reproducibility and makes it difficult to compare results between different laboratories. Degus require species-specific housing and handling methods that reflect their ecology, life history, and group-living characteristics. Here we introduce major principles and ethological considerations of colony management and husbandry. We provide clear instructions on laboratory practices necessary for maintaining a healthy and robust colony of degus for Alzheimer's disease neuroscience research towards conducting reproducible studies. We also report detailed procedures and methodical information for degu Apoe genotyping and ethologically relevant burrowing behavioral tasks in laboratory settings. [ABSTRACT FROM AUTHOR]

Lab testing is a high-volume activity that is often overused, leading to wasted resources and inappropriate care. Improving test ordering practices in tertiary care involves deciding where to focus scarce intervention resources, but clear guidance on how to optimize these resources is lacking. We aimed to explore context-sensitive factors and processes that inform individual decisions about laboratory stewardship interventions by speaking to key interest holders in this area. We conducted semi-structured interviews with test-ordering intervention development experts and authors of test-ordering guidance documents to explore five broad topics: 1) processes used to prioritize tests for intervention; 2) factors considered when deciding which tests to target; 3) measurement of these factors; 4) interventions selected; 5) suggestions for a framework to support these decisions. Transcripts were double coded using directed-content and thematic analysis. We interviewed 14 intervention development experts. Experts noted they frequently consider test volume, test value, and patient care when deciding on a test to target. Experts indicated that quantifying many relevant factors was challenging. Processes to support these decisions often involved examining local data, obtaining buy-in, and relying on an existing guideline. Suggestions for building a framework emphasized the importance of collaboration, consideration of context and resources, and starting with "easy wins" to gain support and experience. Our study provides insight into the factors and processes experts consider when deciding which tests to target for intervention and can inform the development of a framework to guide the selection of tests for intervention and guideline development. [ABSTRACT FROM AUTHOR]

This opinion article highlights the critical role of laboratory medicine and emerging technologies in cardiovascular risk reduction through exposome analysis. The exposome encompasses all external and internal exposures an individual faces throughout their life, influencing the onset and progression of cardiovascular diseases (CVD). Integrating exposome data with genetic information allows for a comprehensive understanding of the multifactorial causes of CVD, facilitating targeted preventive interventions. Laboratory medicine, enhanced by advanced technologies such as metabolomics and artificial intelligence (AI), plays a pivotal role in identifying and mitigating these exposures. Metabolomics provides detailed insights into metabolic changes triggered by environmental factors, while AI efficiently processes complex datasets to uncover patterns and associations. This integration fosters a proactive approach in public health and personalized medicine, enabling earlier detection and intervention. The article calls for global implementation of exposome technologies to improve population health, emphasizing the need for robust technological platforms and policy-driven initiatives to seamlessly integrate environmental data with clinical diagnostics. By harnessing these innovative technologies, laboratory medicine can significantly contribute to reducing the global burden of cardiovascular diseases through precise and personalized risk mitigation strategies. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) represent a diverse class of nanoscale membrane vesicles actively released by cells. These EVs can be further subdivided into categories like exosomes and microvesicles, based on their origins, sizes, and physical attributes. Significantly, disease-derived EVs have been detected in virtually all types of body fluids, providing a comprehensive molecular profile of their cellular origins. As a result, EVs are emerging as a valuable addition to liquid biopsy techniques. In this collective statement, the authors share their current perspectives on EV-related research and product development, with a shared commitment to translating this newfound knowledge into clinical applications for cancer and other diseases, particularly as disease biomarkers. The consensus within this document revolves around the overarching recognition of the merits, unresolved questions, and existing challenges surrounding EVs. This consensus manuscript is a collaborative effort led by the Committee of Exosomes, Society of Tumor Markers, Chinese anti-Cancer Association, aimed at expediting the cultivation of robust scientific and clinically applicable breakthroughs and propelling the field forward with greater swiftness and efficacy. [ABSTRACT FROM AUTHOR]

Introduction: The emergence of high-efficacy disease-modifying therapies (HE DMT) for multiple sclerosis (MS) may pose challenges to the administration and monitoring burden of the therapies. This article presents the results of the Delphi consensus method to generate insights from experts on the administration and monitoring burden of HE DMT in Saudi Arabia with a special focus on cladribine. Methods: Between January and March 2023, a two-round modified Delphi method was used to establish consensus regarding the administration and monitoring burden of HE DMTs used for MS. Through a questionnaire, the advisors evaluated 17 properties of six individual HE DMTs on the basis of their clinical experience. Advisors were required to rank each property on a scale of 1–5, with 1 being the lowest burden and 5 being the highest burden. Results: Experts ranked cladribine as having the lowest monitoring burden, followed by ofatumumab and ocrelizumab. Natalizumab and fingolimod were ranked fourth, and alemtuzumab had the highest burden. During the first round, experts agreed on the scores of the administration burden properties, except for hospital visit time and facility use during administration for ofatumumab, route of administration for fingolimod, monitoring of specific side effects and frequency of lab tests at follow-up, and the washout period for natalizumab. During the second round, there was agreement on all properties. Conclusion: In the absence of alternative scientific data, recommendations from experts and their consensus provide useful insights into the administration and monitoring burden of HE DMTs used for MS in Saudi Arabia. [ABSTRACT FROM AUTHOR]

This paper seeks to promote use of shear wave velocity (Vs) measurements in UK clays as a complement to more standard ground investigation techniques. Vs measurements seem to be repeatable and independent of the method of measurement used in isotropic soil conditions – for example, soft clays. However, in glacial tills, and especially in the overconsolidated clays of south-east UK, Vs measurements will differ depending on the direction of propagation and polarisation of the shear waves due to natural stress anisotropy and the fissured nature of the materials. Correlations between Vs and other in situ data and with a variety of soil properties can be very powerful and some have been proposed here for UK clays. However, these correlations should ideally be local and only applied to other soils and areas with great caution. Other uses of the techniques, beyond those of classical dynamic analyses, have been described together with some future challenges. Uncertainties in the methods have been well researched and several methods have been proposed to deal with these uncertainties. Nonetheless, advice from a geophysical colleague will enhance the geotechnical engineers' use of Vs data. [ABSTRACT FROM AUTHOR]

Background: While alopecia associated with hair cycle arrest (HCA, Alopecia X) is well‐recognised in Pomeranian dogs, the authors are unaware of reports of concurrent hair fragility. Hypothesis/Objectives: Following the observation of frequent hair shaft abnormalities in alopecic Pomeranians, we hypothesised that hair fragility events would be more frequent in dogs with a phenotype of HCA when compared to dogs with normal coats. Animals: Eight alopecic Pomeranian dogs or crosses with a phenotype of HCA and 36 unaffected Pomeranians with owner‐reported normal hair coats. Materials and Methods: All affected dogs underwent dermatological examination and clinicopathological evaluations. Hair samples, plucked from affected areas or obtained by brushing from unaffected dogs, were examined microscopically for structural abnormalities. Hair fragility events were characterised as trichorrhexis nodosa (TN) or longitudinal splits and were expressed per 10 mg of hair. A reference interval was calculated from the number of hair fragility events in the samples from unaffected dogs. Results: The upper reference limit (with 90% confidence) from samples of 35 unaffected Pomeranians (one outlier excluded) was 9.75 hair fragility events per 10 mg of hair. The median (range) of fragility events in eight dogs with a phenotype of HCA was 66.0 (30.2–166.7) per 10 mg of hair. Conclusions and Clinical Relevance: Clinicians should routinely perform trichography in Pomeranians with HCA because abundant hair abnormalities, particularly TN, may contribute to poor hair coat quality. Further studies are required to establish the pathophysiology of and treatments for these fragility events and to determine their predictive value for HCA. [ABSTRACT FROM AUTHOR]

Pathological analysis of 13 explanted CT Lucia 602 IOLs implanted in cases lacking capsular support (12 by the Yamane technique) showed free rotation of 4 haptics within their optic insertion. Purpose: To evaluate CT Lucia 602 intraocular lenses implanted in cases lacking capsular support and explanted because of decentration/dislocation with subsequent pathological analysis. The main objectives were to (1) document the status of haptics and (2) verify the presence of the rotisserie effect. Setting: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah. Design: Case series with clinicopathological correlation. Methods: 13 explanted CT Lucia 602 lenses were included: 12 implanted by the Yamane technique and 1 that was iris-fixated. 4 lenses were explanted between October 2020 and February 2022. 9 lenses, explanted between November 2022 and February 2024, also exhibited severe optic tilt, leading to explantation. A chart review was performed to obtain clinical information from each case. Explanted lenses underwent gross and microscopic examination for haptic status and rotation, in the dry state (room temperature) and after hydration (body temperature). Results: Time between implantation and explantation was longer for lenses explanted before November 2022 (without severe tilt). Among the 26 haptics evaluated, 15 were deformed, 6 were broken, 2 were detached, and 3 were unremarkable. 4 haptics of Yamane lenses explanted between November 2022 and February 2024 showed free rotation within the optic insertion, after hydration at body temperature. Conclusions: Anecdotal reports of the rotisserie effect of CT Lucia 602 lenses implanted by the Yamane technique appeared mostly during the second half of 2022 and suggested that affected lenses were from specific batches, which seems to be consistent with the findings of this study. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this retrospective study was to collect epidemiological, clinical, laboratory, imaging, management, and follow-up data on cases of alveolar echinococcosis (AE) diagnosed and/or followed up within the Namur Hospital Network (NHN) in order to gather information on the challenges, pitfalls, and overall experience in the diagnosis and treatment of AE. Methods: EchiNam was a multicenter retrospective study. Patients diagnosed and/or treated for probable or confirmed AE in the NHN between 2002 and 2023 were included in the study. Patient selection was based on diagnosis codes, laboratory results, and albendazole (ABZ) dispensing. Results: A total of 22 AE cases were retrieved, of which four were classified as probable and 18 as confirmed cases. Nine patients were either asymptomatic or had symptoms attributed to another disease. Clinical examination yielded pathologic findings in 10 patients. The median duration from the first AE-suggestive laboratory abnormalities to diagnosis was 176 days, and the median duration from the first AE-related imaging abnormalities to diagnosis was 133 days. Overall, 12 patients underwent surgical resection, with only four achieving complete lesion resection. Nine patients experienced ABZ-related adverse effects, with temporary ABZ discontinuation in five. Conclusion: Due to various factors such as a long incubation period and a lack of awareness among Belgian physicians, AE is often diagnosed at advanced disease stages. Treatment then becomes more complex or even suboptimal, resulting in prolonged therapy, higher risk of adverse effects, significantly impaired quality of life, poor prognosis, and higher mortality rates. Measures should be taken to achieve early diagnosis in endemic areas. [ABSTRACT FROM AUTHOR]

We sought to characterize the benefit of lymphadenectomy among patients undergoing curative-intent surgery for perihilar cholangiocarcinoma (pCCA) utilizing the therapeutic index. Data on patients who underwent curative-intent resection for pCCA were obtained from 8 high-volume international hepatobiliary centers. Multivariable Cox regression analysis was used to assess clinicopathological factors associated with overall survival (OS). The therapeutic index was determined to assess the therapeutic benefit of lymphadenectomy. Among 341 patients, median number of lymph nodes (LNs) evaluated was 7 (IQR: 4–11). A total of 127 (37.2 %) patients underwent lymphadenectomy of station 12 only, while 146 (42.8 %) patients had LNs from stations 12 plus 8 ± 13 harvested. On multivariable analysis, lymphadenectomy of stations 12 plus 8 ± 13 was associated with improved OS (referent, station 12 only: HR 0.51, 95%CI 0.32–0.80). The therapeutic index was highest among patients who underwent LN evaluation of stations 12 plus 8 ± 13 (33.1) and had ≥6 LNs harvested (26.3). At the time of surgery of pCCA, lymphadenectomy should include station 12, as well as stations 8 and 13, with the goal to evaluate ≥6 LNs to ensure optimal staging and maximize the therapeutic benefit for patients. [ABSTRACT FROM AUTHOR]

Context The significance of low mitotic activity in papillary thyroid cancer (PTC) is largely undefined. Objective We aimed to determine the behavioral landscape of PTC with low mitotic activity compared with that of no and high mitotic activity. Methods A single-institution consecutive series of patients with PTC from 2018 to 2022 was reviewed. Mitotic activity was defined as no mitoses, low (1-2 mitoses/2 mm2) or high (≥3 mitoses/2 mm2) per the World Health Organization. The 2015 American Thyroid Association risk stratification was applied to the cohort, and clinicopathologic features were compared between groups. For patients with ≥6 months of follow-up, Cox regression analyses for recurrence were performed. Results A total of 640 PTCs were included—515 (80.5%) no mitotic activity, 110 (17.2%) low mitotic activity, and 15 (2.3%) high mitotic activity. Overall, low mitotic activity exhibited rates of clinicopathologic features including vascular invasion, gross extrathyroidal extension, and lymph node metastases in between those of no and high mitotic activity. PTCs with low mitotic activity had higher rates of intermediate- and high-risk American Thyroid Association (ATA) risk stratification compared with those with no mitotic activity (P <.001). Low mitotic activity PTCs also had higher recurrence rates (15.5% vs 4.5%, P <.001). Low mitotic activity was associated with recurrence, independent of the ATA risk stratification (HR 2.96; 95% CI 1.28-6.87, P =.01). Conclusion Low mitotic activity is relatively common in PTC and its behavior lies within a spectrum between no and high mitotic activity. Given its association with aggressive clinicopathologic features and recurrence, low mitotic activity should be considered when risk stratifying patients with PTC for recurrence. [ABSTRACT FROM AUTHOR]

AbstractMonitoring individuals’ laboratory data is essential for assessing their health status, evaluating the effectiveness of treatments, predicting disease prognosis and detecting subclinical conditions. Currently, monitoring is performed intermittently, measuring serum, plasma, whole blood, urine and occasionally other body fluids at predefined time intervals. The ideal monitoring approach entails continuous measurement of concentration and activity of biomolecules in all body fluids, including solid tissues. This can be achieved through the use of biosensors strategically placed at various locations on the human body where measurements are required for monitoring. High-tech wearable biosensors provide an ideal, noninvasive, and esthetically pleasing solution for monitoring individuals’ laboratory data. However, despite significant advances in wearable biosensor technology, the measurement capacities and the number of different analytes that are continuously monitored in patients are not yet at the desired level. In this review, we conducted a literature search and examined: (i) an overview of the background of monitoring for personalized laboratory medicine, (ii) the body fluids and analytes used for monitoring individuals, (iii) the different types of biosensors and methods used for measuring the concentration and activity of biomolecules, and (iv) the statistical algorithms used for personalized data analysis and interpretation in monitoring and evaluation. [ABSTRACT FROM AUTHOR]

Estimating the trend of new infections was crucial for monitoring risk and for evaluating strategies and interventions during the COVID-19 pandemic. The pandemic revealed the utility of new data sources and highlighted challenges in interpreting surveillance indicators when changes in disease severity, testing practices or reporting occur. Our study aims to estimate the underlying trend in new COVID-19 infections by combining estimates of growth rates from all available surveillance indicators in Norway. We estimated growth rates by using a negative binomial regression method and aligned the growth rates in time to hospital admissions by maximising correlations. Using a meta-analysis framework, we calculated overall growth rates and reproduction numbers including assessments of the heterogeneity between indicators. We find that the estimated growth rates reached a maximum of 25% per day in March 2020, but afterwards they were between -10% and 10% per day. The correlations between the growth rates estimated from different indicators were between 0.5 and 1.0. Growth rates from indicators based on wastewater, panel and cohort data can give up to 14 days earlier signals of trends compared to hospital admissions, while indicators based on positive lab tests can give signals up to 7 days earlier. Combining estimates of growth rates from multiple surveillance indicators provides a useful description of the COVID-19 pandemic in Norway. This is a powerful technique for a holistic understanding of the trends of new COVID-19 infections and the technique can easily be adapted to new data sources and situations. [ABSTRACT FROM AUTHOR]

Objective: Reference intervals for hematologic and clinical chemistry values are useful when diagnosing a pathologic condition in animals. This study establishes relevant reference intervals for six species of wild birds that are frequently rescued at wildlife rescue centers in the Republic of Korea. Methods: Forty-two Eurasian eagle owls (Bubo bubo), 34 Oriental turtle doves (Streptopelia orientalis), 73 domestic pigeons (Columba livia domestica), 27 brown hawk-owls (Ninox scutulata), 76 common kestrels (Falco tinnunculus), and 25 Eurasian magpies (Pica pica) were included in this study. Only released birds were included because they were judged to be clinically healthy through physical examinations, blood examinations, radiographic examinations, and flight evaluations. The reference intervals were set according to the American Society for Veterinary Clinical Pathology guideline, and if there were fewer than 20 birds, the reference intervals were set between the 2.5th percentile and the 97.5th percentile. One-way ANOVA was performed to compare hematologic and clinical chemistry parameters among species. Results: The total protein levels in carnivorous birds (Eurasian eagle owl, brown hawk-owl, and common kestrel) were significantly higher than those in omnivorous birds (Oriental turtle dove and domestic pigeon). The common kestrel exhibited significantly lower white blood cell counts and heterophil counts than other species. The Eurasian magpie had significantly higher eosinophils than other species. Conclusion: This study provides reference intervals for wild birds often rescued at wildlife rescue centers in Korea. It is expected that these reference intervals will be used as important data in diagnosing diseases in rescued wild birds. [ABSTRACT FROM AUTHOR]

Tick-borne spotted fever rickettsioses (SFRs) continue to cause severe illness and death in otherwise-healthy individuals due to lack of a timely and reliable diagnostic laboratory test. We recently identified a diagnostic biomarker for SFRs, the putative N-acetylmuramoyl-l-alanine amidase RC0497. Here, we developed a prototype laboratory test that targets RC0497 for diagnosis of SFRs. The concentrations of RC0497 in sera of Rickettsia rickettsii-infected guinea pigs and R. conorii-infected mice were determined by stable isotope dilution–parallel reaction monitoring mass spectrometry (SID-PRM-MS), ranging from 0.1 to 1.1 ng/ml. Using europium chelate nanoparticle reporters, we developed a lateral flow assay (LFA) and evaluated the test with a panel of serum samples of mock and experimentally infected animals. Interestingly, 21 of 22 (95.5%) serum samples from R. rickettsii-infected guinea pigs and R. conorii-infected mice yielded positive results with a ratio of test line / control line greater than the cutoff value determined for non-infected animals. All uninfected samples were in agreement with the intended results, suggesting that the initially assessed specificity of the test is 100%, among these samples. Mice infected with a lethal dose of R. conorii and treated with doxycycline on day 3 post-infection (p.i.), upon RC0497 detection by LFA, displayed significantly decreased rickettsial loads, comparable to the sublethal infection group on day 5 p.i.. A panel of human serum samples spiked with various concentrations of recombinant RC0497 were analyzed by LFA, suggesting that the limit of detection of the LFA was 0.64 ng/mL. These findings suggest that the timely detection of RC0497 by a europium LFA offers guidance for treatment, leading to a significant improvement in infection outcomes. This work, for the first time, shows significant promise for a rapid and easy-to-use platform offering a timely diagnostic assay for severe SFRs. [ABSTRACT FROM AUTHOR]

Simple Summary: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Local treatment of tumors is typically straightforward. Yet, despite successful local treatment, a portion of patients will still develop subsequent distant metastases which are usually fatal. The current gold standard tool for prognostication is gene expression profiling (GEP), which is only available in the United States. The goal of this research is to develop an artificial intelligence (deep learning-based) tool which can predict patient survival directly from digital cytopathology images generated from fine-needle aspiration biopsies. Our deep learning model was able to predict Month 48 survival status directly from digital cytopathology images with reasonably robust performance. This approach, if validated prospectively, could serve as an alternative survival prediction tool for patients with UM to whom GEP is not available. Background: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. The median overall survival time for patients who develop metastasis is approximately one year. In this study, we aim to leverage deep learning (DL) techniques to analyze digital cytopathology images and directly predict the 48 month survival status on a patient level. Methods: Fine-needle aspiration biopsy (FNAB) of the tumor was performed in each patient diagnosed with UM. The cell aspirate was smeared on a glass slide and stained with H&E. Each slide then underwent whole-slide scanning. Within each whole-slide image, regions of interest (ROIs) with UM cells were automatically extracted. Each ROI was converted into super pixels, and the super pixels were automatically detected, segmented and annotated as "tumor cell" or "background" using DL. Cell-level features were extracted from the segmented tumor cells. The cell-level features were aggregated into slide-level features which were learned by a fully connected layer in an artificial neural network, and the patient survival status was predicted directly from the slide-level features. The data were partitioned at the patient level (78% training and 22% testing). Our DL model was trained to perform the binary prediction of yes-versus-no survival by Month 48. The ground truth for patient survival was established via a retrospective chart review. Results: A total of 74 patients were included in this study (43% female; mean age at the time of diagnosis: 61.8 ± 11.6 years), and 207,260 unique ROIs were generated for model training and testing. By Month 48 after diagnosis, 18 patients (24%) died from UM metastasis. Our hold-out test set contained 16 patients, where 6 patients had passed away and 10 patients were alive at Month 48. When using a sensitivity threshold of 80% in predicting UM-specific death by Month 48, our model achieved an overall accuracy of 75%. Within the subgroup of patients who died by Month 48, our model achieved a prediction accuracy of 83%. Of note, one patient in our test set was a clinical surprise, namely death by Month 48 despite having a GEP class 1A tumor, which typically portends a good prognosis. Our model correctly predicted this clinical surprise as well. Conclusions: Our DL model was able to predict the Month 48 survival status directly from digital cytopathology images obtained from FNABs of UM tumors with reasonably robust performance. This approach, if validated prospectively, could serve as an alternative survival prediction tool for patients with UM to whom GEP is not available. [ABSTRACT FROM AUTHOR]

M. ovipneumoniae is a respiratory pathogen that can cause mild to moderate pneumonia and reduced productivity in domestic lambs. However, studies on both natural and experimental M. ovipneumoniae infection have reported highly variable clinical signs and pathology. Here, we assessed the impact of administering M. ovipneumoniae to the upper respiratory tract (URT) or to the lower respiratory tract (LRT) of two-month-old specific pathogen-free lambs. Lambs were inoculated with PBS (control) or with ceftiofur-treated nasal wash fluid obtained from sheep with natural M. ovipneumoniae infection, monitored for eight weeks, and subsequently euthanized. All lambs in the URT and LRT groups developed a stable infection with M. ovipneumoniae. M. ovipneumoniae infection led to lower weight gains and mild respiratory disease, with significantly greater effects following LRT inoculation compared to URT inoculation. At necropsy, lambs inoculated via the LRT showed consolidation of the cranial lung lobes. In addition, histological signs of alveolar, bronchiolar, and interstitial inflammation were significantly more severe in the LRT compared to the URT group. M. ovipneumoniae loads in the trachea and bronchi also were significantly higher after LRT than URT inoculation. Interestingly, 9/10 inoculated lambs also tested positive for M. haemolytica in nasal swab but not in bronchial swab samples. In summary, our study suggests that bypassing protective mechanisms of the URT by delivering respiratory pathogens to the LRT leads to more severe respiratory disease and lung damage than delivery to the URT. [ABSTRACT FROM AUTHOR]

Skin diseases impact millions of people around the world and pose a severe risk to public health. These diseases have a wide range of effects on the skin's structure, functionality, and appearance. Identifying and predicting skin diseases are laborious processes that require a complete physical examination, a review of the patient's medical history, and proper laboratory diagnostic testing. Additionally, it necessitates a significant number of histological and clinical characteristics for examination and subsequent treatment. As a disease's complexity and quantity of features grow, identifying and predicting it becomes more challenging. This research proposes a deep learning (DL) model utilizing transfer learning (TL) to quickly identify skin diseases like chickenpox, measles, and monkeypox. A pre-trained VGG16 is used for transfer learning. The VGG16 can identify and predict diseases more quickly by learning symptom patterns. Images of the skin from the four classes of chickenpox, measles, monkeypox, and normal are included in the dataset. The dataset is separated into training and testing. The experimental results performed on the dataset demonstrate that the VGG16 model can identify and predict skin diseases with 93.29% testing accuracy. However, the VGG16 model does not explain why and how the system operates because deep learning models are black boxes. Deep learning models' opacity stands in the way of their widespread application in the healthcare sector. In order to make this a valuable system for the health sector, this article employs layer-wise relevance propagation (LRP) to determine the relevance scores of each input. The identified symptoms provide valuable insights that could support timely diagnosis and treatment decisions for skin diseases. [ABSTRACT FROM AUTHOR]

The EN ISO 15189:2022 standard, titled “Medical laboratories – Requirements for quality and competence,” is a significant update to the regulations for medical laboratories. The revised standard was published on December 6, 2022, replacing both EN ISO 15189:2012 and EN ISO 22870:2016. Key objectives of the revision include: 1. Alignment with ISO/IEC 17025:2017, 2. Removal of unintended prescription, 3. Focus on patient interest and safety, 4. Minimization of new requirements, and 5. Improved clarity of text. Dedicating to harmonizing accreditation processes across Europe the EFLM Committee on Accreditation and ISO/CEN standards (C: A/ISO) has produced this guidance document to assist the laboratory medicine community in understanding and implementing the criteria of the EN ISO 15189 revision. Two main objectives of the guidance in educating both laboratories and accreditation bodies with their assessors as well as other stakeholders in laboratory medicine were agreed on. Firstly, to clarify the relevant changes covering all paragraphs of the standard and secondly to make an impact analysis on previous C: A/ISO guidance documents. [ABSTRACT FROM AUTHOR]

Ischemia-reperfusion injury is a serious clinical pathology involving multiple organs such as the heart and brain. The injury results from oxidative stress, inflammatory response and cell death triggered by restoring tissue blood flow after ischemia, leading to severe cell and tissue damage. In recent years, the volume-regulated anion channel (VRAC) has gained attention as an important membrane protein complex. VRAC plays a dual role in ischemia-reperfusion injury: on the one hand, activated VRAC promotes the release of intracellular chloride and glutamate, exacerbating cellular swelling and excitotoxicity, and on the other hand, the regulatory effect of VRAC may also provide protection to cardiomyocytes. This article reviews the pathophysiological mechanisms of ischemia-reperfusion injury, existing therapeutic strategies and their limitations, focuses on the molecular structure of VRAC, its activation mechanism, and its role in ischemia-reperfusion injury, and concludes with a discussion of the potential of targeted inhibition of VRAC as an emerging therapeutic strategy and the challenges it faces. A deeper understanding of the role of VRAC in ischemia-reperfusion injury is expected to provide new therapeutic ideas to improve patient prognosis. [ABSTRACT FROM AUTHOR]

Simple Summary: This study utilized datasets from two ethnic groups to develop an AI diagnostic model. This model was trained using transfer learning, leveraging eight pre-trained models, including convolutional neural networks and vision transformers. The three-class AI model assists doctors in distinguishing between patients with melanoma who require urgent treatment, those with non-melanoma skin cancers who can be treated later, and benign cases that do not require intervention. The proposed two-stage classification strategy significantly improved diagnostic accuracy and reduced false negatives. This research demonstrates the success of the proposed method in both datasets. These findings highlight the potential of AI technology in skin cancer diagnosis, particularly in resource-limited medical settings, where it could become a valuable clinical tool to improve diagnostic accuracy, reduce skin cancer mortality, and decrease healthcare costs. Background: Skin cancer is the most common cancer worldwide, with melanoma being the deadliest type, though it accounts for less than 5% of cases. Traditional skin cancer detection methods are effective but are often costly and time-consuming. Recent advances in artificial intelligence have improved skin cancer diagnosis by helping dermatologists identify suspicious lesions. Methods: The study used datasets from two ethnic groups, sourced from the ISIC platform and CSMU Hospital, to develop an AI diagnostic model. Eight pre-trained models, including convolutional neural networks and vision transformers, were fine-tuned. The three best-performing models were combined into an ensemble model, which underwent multiple random experiments to ensure stability. To improve diagnostic accuracy and reduce false negatives, a two-stage classification strategy was employed: a three-class model for initial classification, followed by a binary model for secondary prediction of benign cases. Results: In the ISIC dataset, the false negative rate for malignant lesions was significantly reduced, and the number of malignant cases misclassified as benign dropped from 124 to 45. In the CSMUH dataset, false negatives for malignant cases were completely eliminated, reducing the number of misclassified malignant cases to zero, resulting in a notable improvement in diagnostic precision and a reduction in the false negative rate. Conclusions: Through the proposed method, the study demonstrated clear success in both datasets. First, a three-class AI model can assist doctors in distinguishing between melanoma patients who require urgent treatment, non-melanoma skin cancer patients who can be treated later, and benign cases that do not require intervention. Subsequently, a two-stage classification strategy effectively reduces false negatives in malignant lesions. These findings highlight the potential of AI technology in skin cancer diagnosis, particularly in resource-limited medical settings, where it could become a valuable clinical tool to improve diagnostic accuracy, reduce skin cancer mortality, and reduce healthcare costs. [ABSTRACT FROM AUTHOR]

Simple Summary: While many patients diagnosed with large B cell lymphomas (LBCL), specifically diffuse large B cell lymphoma (DLBCL) will be cured following treatment with first-line immunochemotherapy, those who are not are likely to die from complications of this disease. This discrepancy in outcome suggests biologic heterogeneity of this common lymphoid malignancy, and LBCL tumors can be both classified and risk-stratified by testing available in the clinical laboratory. Such testing may also identify opportunities to add targeted agents to first-line immunochemotherapy in homes of improving survival for patients whose tumors harbor high-risk pathologic features, examples of which are offered. Whether more complex comprehensive genomic analyses can be applied in clinical practice and enhance this effort remains to be determined. Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) and high-grade B cell lymphoma (HGBL) comprise the majority of large B-cell lymphomas (LBCL), and approximately two-thirds of patients diagnosed with these LBCLs are cured following treatment with first-line immunochemotherapy. While the International Prognostic Index (IPI) score is a validated prognostic tool used for patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), there is a growing body of evidence that suggests that LBCL tumor features, which can be detected by clinical laboratory testing, can predict patient survival following first-line immunochemotherapy. Conclusions: Clinical laboratory testing may also allow for rational identification of targeted agents that can be added to first-line immunochemotherapy for high-risk, pathologically defined subsets of LBCL patients, and this approach may result in better survival outcomes for the entire LBCL patient population as compared with adding pathologically "agnostic" agents for those defined as high risk by IPI score. [ABSTRACT FROM AUTHOR]

Pseudoachondroplasia (PSACH), a severe dwarfing condition characterized by impaired skeletal growth and early joint degeneration, results from mutations in cartilage oligomeric matrix protein (COMP). These mutations disrupt normal protein folding, leading to the accumulation of misfolded COMP in chondrocytes. The MT-COMP mouse is a murine model of PSACH that expresses D469del human COMP in response to doxycycline and replicates the PSACH chondrocyte and clinical pathology. The basis for the mutant-COMP pathology involves endoplasmic reticulum (ER) stress signaling through the PERK/eIF2α/CHOP pathway. C/EBP homologous protein (CHOP), in conjunction with a TNFα inflammatory process, upregulates mTORC1, hindering autophagy clearance of mutant COMP protein. Life-long joint pain/degeneration diminishes quality of life, and treatments other than joint replacements are urgently needed. To assess whether molecules that reduce CHOP activity should be considered as a potential treatment for PSACH, we evaluated MT-COMP mice with 50% CHOP (MT-COMP/CHOP+/−), antisense oligonucleotide (ASO)-mediated CHOP knockdown, and complete CHOP ablation (MT-COMP/CHOP−/−). While earlier studies demonstrated that loss of CHOP in MT-COMP mice reduced intracellular retention, inflammation, and growth plate chondrocyte death, we now show that it did not normalize limb growth. ASO treatment reduced CHOP mRNA by approximately 60%, as measured by RT-qPCR, but did not improve limb length similar to MT-COMP/CHOP+/−. Interestingly, both 50% genetic reduction and complete loss of CHOP alleviated pain, while total ablation of CHOP in MT-COMP mice was necessary to preserve joint health. These results indicate that (1) CHOP reduction therapy is not an effective strategy for improving limb length and (2) pain and chondrocyte pathology are more responsive to intervention than the prevention of joint damage. [ABSTRACT FROM AUTHOR]

Dysphagia is a common gastrointestinal complaint in the pediatric population and should raise concern for oropharyngeal as well as esophageal disorders. We describe a 7-year old patient who was admitted to the hospital for sudden onset dysphagia, abdominal pain, and decreased oral intake. Extensive evaluations including endoscopy eventually revealed herpes simplex esophagitis as well as eosinophilic esophagitis. Herpes simplex esophagitis is a rare condition in the immunocompetent population and is typically self-resolving. Eosinophilic esophagitis is a chronic, inflammatory condition characterized by esophageal eosinophilia and signs of esophageal dysfunction. The concurrent presentation of both conditions in the pediatric population has rarely been described. [ABSTRACT FROM AUTHOR]

Objective Mainstay therapy for fetuses affected by maternal red cell alloimmunization is serial intrauterine transfusion (IUT). Testing to determine when fetal red cells have been replaced with donor cells historically involves the use of the Kleihauer–Betke (KB) test. Hemoglobin (Hgb) electrophoresis testing may be more rapid with a reduced cost of analysis. We aimed to determine the correlation between fetal Hgb electrophoresis versus the traditional KB test. Study Design This is a retrospective analysis of all alloimmunized singleton pregnancies undergoing IUT between January 1, 2021, and July 1, 2023. Maternal and fetal characteristics were collected along with the indication for IUT. A final fetal blood sample was obtained at the conclusion of each transfusion and sent for KB testing and Hgb electrophoresis. The primary outcome was the assessment of these parameters in their ability to predict the replacement of the fetal circulating red cell population with donor cells. Linear regression analysis and repeated measures analysis of variance were performed, and p -values less than 0.05 were considered significant. Results A total of 56 IUTs were performed in 16 patients. There were 39 (69.6%) final KB test values collected and compared with 30 (53.6%) final Hgb electrophoresis values. Hgb electrophoresis when compared with the KB test demonstrated a significant correlation (R2 = 0.93; 95% confidence interval, 0.61–0.76; p < 0.001). This same finding held true when examining the correlation at each individual IUT as well. The final KB test and Hgb electrophoresis values significantly decreased with each transfusion (p = 0.003). A predominance of adult donor blood was noted by the third transfusion for both laboratory indices. Conclusion Fetal Hgb electrophoresis obtained at the time of IUT demonstrates a significant correlation with the traditional KB test. Key Points Fetal Hgb electrophoresis following IUT is underexplored Hgb electrophoresis is an automated evaluation The traditional KB test is a manual evaluation These two tests demonstrate significant correlation [ABSTRACT FROM AUTHOR]

Objective Pregnant women are at increased risk of coronavirus disease 2019 (COVID-19). This could be explained through the prism of physiologic and immunologic changes in pregnancy. In addition, certain immunological reactions originate in the placenta in response to viral infections. This study aimed to investigate whether severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) can infect the human placenta and discuss its implications in the pathogenesis of adverse pregnancy outcomes. Study Design We conducted a retrospective cohort study in which we collected placental specimens from pregnant women who had a laboratory-confirmed SARS-CoV-2 infection. We performed RNA in situ hybridization assay on formalin-fixed paraffin-embedded tissues to establish the in vivo evidence for placental infectivity by this corona virus. In addition, we infected trophoblast isolated from uninfected term human placenta with SARS-CoV-2 variants to further provide in vitro evidence for such an infectivity. Results There was a total of 21 cases enrolled, which included 5 cases of spontaneous preterm birth (SPTB) and 2 intrauterine fetal demises (IUFDs). Positive staining of positive-sense strand of SARS-CoV-2 virions was detected in 15 placentas including 4 SPTB and both IUFDs. In vitro infection assay demonstrated that SARS-CoV-2 virions were highly capable of infecting both cytotrophoblast and syncytiotrophoblast. Conclusion This study implies that placental SARS-CoV-2 infection may be associated with an increased risk of adverse obstetrical outcomes. Key Points SARS-CoV-2 can effectively infect human placenta. Such infectivity is confirmed by in vitro experiments. Placental SARS-CoV-2 corelates with adverse obstetrical outcomes. [ABSTRACT FROM AUTHOR]

Background: Available codes in the ICD-10 do not accurately reflect soft tissue sarcoma diagnoses, and this can result in an underrepresentation of soft tissue sarcoma in databases. The National VA Database provides a unique opportunity for soft tissue sarcoma investigation because of the availability of all clinical results and pathology reports. In the setting of soft tissue sarcoma, natural language processing (NLP) has the potential to be applied to clinical documents such as pathology reports to identify soft tissue sarcoma independent of ICD codes, allowing sarcoma researchers to build more comprehensive databases capable of answering a myriad of research questions. Questions/purposes: (1) What proportion of patients with myxofibrosarcoma within the National VA Database would be missed by searching only by soft tissue sarcoma ICD codes? (2) Is a de novo NLP algorithm capable of analyzing pathology reports to accurately identify patients with myxofibrosarcoma? Methods: All pathology reports (10.7 million) in the national VA corporate data warehouse were identified from 2003 to 2022. Using the word-search functionality, reports from 403 veterans were found to contain the term "myxofibrosarcoma." The resulting pathology reports were manually reviewed to develop a gold-standard cohort that contained only those veterans with pathologist-confirmed myxofibrosarcoma diagnoses. The cohort had a mean ± SD age of 70 ± 12 years, and 96% (287 of 300) were men. Diagnosis codes were abstracted, and differences in appropriate ICD coding were compared. An NLP algorithm was iteratively refined and tested using confounders, negation, and emphasis terms for myxofibrosarcoma. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated for the NLP-generated cohorts through comparison with the manually reviewed gold-standard cohorts. Results: The records of 27% (81 of 300) of myxofibrosarcoma patients within the VA database were missing a sarcoma ICD code. A de novo NLP algorithm more accurately (92% [276 of 300]) identified patients with myxofibrosarcoma compared with ICD codes (73% [219 of 300]) or basic word searches (74% [300 of 403]) (p < 0.001). Three final algorithm models were generated with accuracies ranging from 92% to 100%. Conclusion: An NLP algorithm can identify patients with myxofibrosarcoma from pathology reports with high accuracy, which is an improvement over ICD-based cohort creation and simple word search. This algorithm is freely available on GitHub (https://github.com/sarcoma-shark/myxofibrosarcoma-shark) and is available to facilitate external validation and improvement through testing in other cohorts. Level of Evidence: Level II, diagnostic study. [ABSTRACT FROM AUTHOR]

Following the COVID-19 pandemic, the concepts of value-based medicine (VBM) and value-based laboratory medicine (VBLM) are receiving increasing interest to improve the quality, sustainability and safety of healthcare. Laboratory medicine is well positioned to support the transition to value-based healthcare as it helps to improve clinical outcomes and healthcare sustainability by reducing the time to diagnosis, improving diagnostic accuracy, providing effective guidance for tailored therapies and monitoring, and supporting screening and wellness care. However, the perception of the value of laboratory medicine is still limited, to the extent that it has been defined a "profession without a face", often lacking visibility to patients and the public. In addition, in recent decades, clinical laboratories have sought to improve the ration between outcomes and costs by increasing efficiency and reducing the cost per test rather than improving clinical outcomes. The aim of this paper is to propose a 10-point manifesto for implementing value-based laboratory medicine in clinical practice. [ABSTRACT FROM AUTHOR]

The letter explores the use of sigma metrics in laboratory medicine, specifically examining the relationship between analytical imprecision and bias. Data from an external quality assurance program was used to analyze this correlation in participating laboratories. The study found that the correlation between 1/imprecision and sigma metric was stronger than that of bias and sigma metric, underscoring the significance of analytical imprecision in evaluating laboratory performance. The research emphasizes the importance of assessing both bias and imprecision separately to ensure accurate evaluation of laboratory methods for clinical use. [Extracted from the article]

Non-harmonization of laboratory results represents a concrete risk for patient safety. To avoid harms, it is agreed that measurements by in vitro diagnostic medical devices (IVD-MD) on clinical samples should be traceable to higher-order references and adjusted to give the same result. However, metrological traceability is not a formal claim and has to be correctly implemented, which in practice does not happen for a non-negligible number of measurands. Stakeholders, such as higher-order reference providers, IVD manufacturers, and External Quality Assessment organizers, have major responsibilities and should improve their contribution by unambiguously and rigorously applying what is described in the International Organization for Standardization 17511:2020 standard and other documents provided by the international scientific bodies, such as Joint Committee on Traceability in Laboratory Medicine and IFCC. For their part, laboratory professionals should take responsibility to abandon non-selective methods and move to IVD-MDs displaying proper selectivity, which is one of the indispensable prerequisites for the correct implementation of metrological traceability. The practicality of metrological traceability concepts is not impossible but relevant education and appropriate training of all involved stakeholders are essential to obtain the expected benefits in terms of standardization. [ABSTRACT FROM AUTHOR]

To develop two ethical checklists to evaluate (i) management of ethical concerns in research projects and (ii) awareness of ethical conduct of healthcare laboratory professionals. Comprehensive discussion among the members of IFCC Task Force on Ethics based on pertinent literature. This Checklist for Clinical Research Projects should be useful to evaluate research proposals from an ethical perspective before submitting it to an IRB or its equivalent, thereby diminishing rejection rates and resulting in more time-effective projects. The checklist designed to evaluate the ethical conduct in laboratory medicine could be useful for self evaluation (internal audits) and for certification/accreditation processes performed by third parties. These checklists are simple but powerful tools useful to guide professionals to adhere to ethical principles in their practice, especially in developing countries where accredited ethics committees may be difficult to find. [ABSTRACT FROM AUTHOR]

Point-of-care testing (POCT) is becoming an increasingly popular way to perform laboratory tests closer to the patient. This option has several recognized advantages, such as accessibility, portability, speed, convenience, ease of use, ever-growing test panels, lower cumulative healthcare costs when used within appropriate clinical pathways, better patient empowerment and engagement, and reduction of certain pre-analytical errors, especially those related to specimen transportation. On the other hand, POCT also poses some limitations and risks, namely the risk of lower accuracy and reliability compared to traditional laboratory tests, quality control and connectivity issues, high dependence on operators (with varying levels of expertise or training), challenges related to patient data management, higher costs per individual test, regulatory and compliance issues such as the need for appropriate validation prior to clinical use (especially for rapid diagnostic tests; RDTs), as well as additional preanalytical sources of error that may remain undetected in this type of testing, which is usually based on whole blood samples (i.e., presence of interfering substances, clotting, hemolysis, etc.). There is no doubt that POCT is a breakthrough innovation in laboratory medicine, but the discussion on its appropriate use requires further debate and initiatives. This collective opinion paper, composed of abstracts of the lectures presented at the two-day expert meeting "Point-Of-Care-Testing: State of the Art and Perspective" (Venice, April 4–5, 2024), aims to provide a thoughtful overview of the state-of-the-art in POCT, its current applications, advantages and potential limitations, as well as some interesting reflections on the future perspectives of this particular field of laboratory medicine. [ABSTRACT FROM AUTHOR]

The article presents a case study of an 8-year-old girl with pneumocephalus caused by sinusitis and a cerebrospinal fluid (CSF) leak. Topics discussed include the diagnostic evaluation and management of pneumocephalus, the pathophysiology of sinusitis-induced CSF rhinorrhea, and the significance of identifying bony cranial defects in persistent meningitis cases.

Context.--Laboratories performing predictive marker testing for breast carcinoma are encouraged to compare patient results to published benchmarks. Objective.--To collect expression rates for estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) in invasive breast carcinoma from multiple laboratories. Design.--Participants submitted data from up to 50 primary cases during the study period. Participants reported ER, PgR, and HER2 results in addition to demographic and histologic information. Participants also provided annual institution-level expression rates. Results.--A total of 21 institutions submitted data for 687 cases. Aggregate positivity rates for ER and PgR were 85.6% and 75.1%, respectively. Receptor positivity rates were higher in well-differentiated (grade 1) tumors (ER, 97.4%; PgR, 88.0%) compared with moderately differentiated (grade 2) tumors (ER, 92.4%; PgR, 84.0%) and poorly differentiated (grade 3) tumors (ER, 61.8%; PgR, 48.0%). Expression rates were higher in postmenopausal women (ER, 87.2%) than premenopausal women (ER, 79.6%) and higher in lobular carcinomas (ER, 98.7%; PgR, 85.3%) than ductal carcinomas (ER, 84.1%; PgR, 74.5%). The aggregate HER2 positivity (score 31) rate was 9.0%. The aggregate HER2 equivocal (score 21) rate was 14.5%. Of 81 equivocal (score 21) cases, 70 (86.4%) were nonamplified. Conclusions.--The data from this study provide multiinstitutional benchmark data to assist laboratories performing periodic comparisons as part of a quality management program. Overall expression rates were generally similar to those of other published reports, with the exception of the ER-negative and HER2-positive rates, both of which were somewhat lower. [ABSTRACT FROM AUTHOR]

We describe here a case of the sinus roundworm, Skrjabingylus chitwoodorum, found incidentally in a rabies-positive striped skunk (Mephitis mephitis) in Texas, USA. Skunks serve as a natural definitive host for this metastrongylid nematode in North America, in which infections result in observable damage to the host cranium, where adult parasites reside. Additionally, skunks are considered the primary reservoir of rabies in Texas. In November 2022, the animal was discovered in northern Texas displaying neurologic signs before euthanasia and submission to the Oklahoma Animal Disease Diagnostic Laboratory for rabies testing. Direct fluorescent antibody testing indicated that the animal was rabies-positive, and, upon tissue collection, numerous adult nematodes were recovered from the cranium and identified as S. chitwoodorum by morphology and amplification of the mitochondrial cytochrome c oxidase subunit I gene. Histologically, we found lymphohistiocytic meningitis in several loci and chronic sinusitis rostral to the cribriform plate. Due to behavioral abnormalities, we additionally tested for Toxoplasma gondii via PCR, but no parasite DNA was detected. Concurrent infection by S. chitwoodorum and rabies virus may contribute to neurologic signs in skunks. [ABSTRACT FROM AUTHOR]

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Machine learning (ML) is currently being widely studied and applied in data analysis and prediction in various fields, including laboratory medicine. To comprehensively evaluate the application of ML in laboratory medicine, we reviewed the literature on ML applications in laboratory medicine published between February 2014 and March 2024. A PubMed search using a search string yielded 779 articles on the topic, among which 144 articles were selected for this review. These articles were analyzed to extract and categorize related fields within laboratory medicine, research objectives, specimen types, data types, ML models, evaluation metrics, and sample sizes. Sankey diagrams and pie charts were used to illustrate the relationships between categories and the proportions within each category. We found that most studies involving the application of ML in laboratory medicine were designed to improve efficiency through automation or expand the roles of clinical laboratories. The most common ML models used are convolutional neural networks, multilayer perceptrons, and tree-based models, which are primarily selected based on the type of input data. Our findings suggest that, as the technology evolves, ML will rise in prominence in laboratory medicine as a tool for expanding research activities. Nonetheless, expertise in ML applications should be improved to effectively utilize this technology. [ABSTRACT FROM AUTHOR]

Artificial intelligence (AI) and machine learning (ML) are anticipated to transform the practice of medicine. As one of the largest sources of digital data in healthcare, laboratory results can strongly influence AI and ML algorithms that require large sets of healthcare data for training. Embedded bias introduced into AI and ML models not only has disastrous consequences for quality of care but also may perpetuate and exacerbate health disparities. The lack of test harmonization, which is defined as the ability to produce comparable results and the same interpretation irrespective of the method or instrument platform used to produce the result, may introduce aggregation bias into algorithms with potential adverse outcomes for patients. Limited interoperability of laboratory results at the technical, syntactic, semantic, and organizational levels is a source of embedded bias that limits the accuracy and generalizability of algorithmic models. Population-specific issues, such as inadequate representation in clinical trials and inaccurate race attribution, not only affect the interpretation of laboratory results but also may perpetuate erroneous conclusions based on AI and ML models in the healthcare literature. [ABSTRACT FROM AUTHOR]

Viral exanthems can present with diverse morphologies of rash, including macular, maculopapular, papular, urticarial and vesicular, or sometimes a combination of these. There has been an increasing trend towards emerging and re-emerging viral exanthems in recent years, the cause of which is multifactorial, including changing environmental conditions and altered host–vector–agent interaction. The significant temperature variations brought on by climate change and ever-increasing international travel has modified the host–agent interactions, and many re-emerging viral illnesses are now presenting with atypical presentations, including an increased frequency of affliction across broader age groups and heightened manifestations often posing as 'great imitators' mimicking a myriad of other dermatoses. Although final diagnosis often relies on serological and molecular tests, certain cutaneous clues can help arrive at a probable clinical diagnosis and help the clinicians order specific and relevant investigations, especially in resource-poor settings where access to laboratory diagnostic tests is likely to be limited. In this review we explore the changing disease dynamics of common viral infections, especially in resource-poor settings, including coronavirus disease 2019, chikungunya, hand-foot-and-mouth disease and some newly emerging ones like mpox (previously referred to as monkeypox), and highlight recent developments in our understanding of the clinical variations seen in their presentations. [ABSTRACT FROM AUTHOR]

This research presents an innovative design for a non-isolated DC-DC converter, which utilizes a single switch in a high step-up configuration. The key element of this design is a three-winding coupled inductor (TWCI), which plays a crucial role in achieving a substantial voltage increase. By utilizing a low duty cycle, the converter minimizes conduction losses in the power switch, resulting in enhanced efficiency. The converter offers several benefits, including reduced voltage stress on both power switches and diodes, a common ground, high efficiency, a simple structure and control mechanism, and fewer components. The study thoroughly examines the converter's operational modes and provides a comparison with other types of converters to highlight its distinctive characteristics. To validate the converter's performance, a 400 W prototype was developed and tested in the lab, operating with a 20 V input, a 260 V output, and a switching frequency of 50 kHz. [ABSTRACT FROM AUTHOR]

AbstractPoor analytical quality may be the bane of medical use of laboratory tests, and the fight against excessive analytical variability presents a daily struggle. Laboratories should prioritize the perspectives and needs of their customers (the patients and healthcare personnel). Among them, comparability of results from the same patient sample when measured by different laboratories using different in vitro diagnostic (IVD) medical devices is a logical priority to avoid result misinterpretation and potential patient harm. Harmonization (standardization) of laboratory measurements can be achieved by establishing metrological traceability of the results on clinical samples to stated higher-order references and providing an estimate of the uncertainty of measurement (MU). This estimate should be based on an MU budget including all known MU contributions generated by the employed calibration hierarchy, which in turn should be validated against fit-for-purpose maximum allowable MU derived according to internationally recommended models. In this report, we review the available strategies for establishing, evaluating, and monitoring analytical quality, drawing on three decades experience in the field. We discuss the most important aspects that may influence obtaining and maintaining analytical standardization in laboratory medicine, and offer practical solutions aimed at educating all stakeholders for the achievement of harmonized laboratory results. To fully implement the recommended approaches, all involved parties—i.e. reference providers, IVD manufacturers, medical laboratories, and External Quality Assessment organizers—must agree on their importance and enhance their specific knowledge. [ABSTRACT FROM AUTHOR]

As a highly reactive dialkenes similar to isoprene, 1,3‐butadiene (BD) is rapidly oxidized and fully involved in atmospheric oxidation processes. We have established a method for the online measurement of ambient BD using Differential Optical Absorption Spectroscopy (DOAS) technique. Lab testing demonstrated that DOAS technique can accurately measure BD concentrations in high temporal resolution of minute‐level, with accuracy and precision within ±5% and 1%, respectively. Following field measurement, the detection limit for BD reached 90 pptv, the r between DOAS and the online VOCs system results reached 0.885, and the nighttime hourly averaged concentration peaked at 0.75 ppbv. At this BD level, if the NO3 reaction pathway with BD was not considered, the maximum proportional variations in the NO3 concentration simulated by the box model exceeded 10%. In conclusion, DOAS is suitable for long‐term BD measurements, and continuous attention should be given to the potential alteration on atmospheric chemistry caused by this type of easily neglected compounds. Plain Language Summary: 1,3‐Butadiene (BD) is a highly reactive gas that plays an important role in atmospheric chemistry. We introduced a non‐contact optical method, Differential Optical Absorption Spectroscopy (DOAS), to measure BD concentration in the ambient air. Our lab tests showed that DOAS is accurate and precise in measuring BD with high time resolution. We thoroughly evaluated the performance of DOAS and then conducted real atmosphere measurements, comparing the results with other instruments. We also explored the impact of high ambient BD concentrations on atmospheric nighttime chemistry. Overall, DOAS proves to be a reliable method for long‐term BD measurements, and it is important to pay attention to how this kind of compound may alter atmospheric chemistry in the future. Key Points: The lab tests demonstrated that the DOAS technique is suitable for long‐term monitoring ambient BDThe evaluation and comparison with other methods testified the good performance of BD measured by DOAS techniqueHigh ambient BD have the potential to alter nighttime chemistry, with maximum proportional variations in NO3 concentration exceeding 10% [ABSTRACT FROM AUTHOR]

Background: Acute abdominal pain (AAP) constitutes 5–10% of all emergency department (ED) visits, with appendicitis being a prevalent AAP etiology often necessitating surgical intervention. The variability in AAP symptoms and causes, combined with the challenge of identifying appendicitis, complicate timely intervention. To estimate the risk of appendicitis, scoring systems such as the Alvarado score have been developed. However, diagnostic errors and delays remain common. Although various machine learning (ML) models have been proposed to enhance appendicitis detection, none have been seamlessly integrated into the ED workflows for AAP or are specifically designed to diagnose appendicitis as early as possible within the clinical decision-making process. To mimic daily clinical practice, this proof-of-concept study aims to develop ML models that support decision-making using comprehensive clinical data up to key decision points in the ED workflow to detect appendicitis in patients presenting with AAP. Methods: Data from the Dutch triage system at the ED, vital signs, complete medical history and physical examination findings and routine laboratory test results were retrospectively extracted from 350 AAP patients presenting to the ED of a Dutch teaching hospital from 2016 to 2023. Two eXtreme Gradient Boosting ML models were developed to differentiate cases with appendicitis from other AAP causes: one model used all data up to and including physical examination, and the other was extended with routine laboratory test results. The performance of both models was evaluated on a validation set (n = 68) and compared to the Alvarado scoring system as well as three ED physicians in a reader study. Results: The ML models achieved AUROCs of 0.919 without laboratory test results and 0.923 with the addition of laboratory test results. The Alvarado scoring system attained an AUROC of 0.824. ED physicians achieved AUROCs of 0.894, 0.826, and 0.791 without laboratory test results, increasing to AUROCs of 0.923, 0.892, and 0.859 with laboratory test results. Conclusions: Both ML models demonstrated comparable high accuracy in predicting appendicitis in patients with AAP, outperforming the Alvarado scoring system. The ML models matched or surpassed ED physician performance in detecting appendicitis, with the largest potential performance gain observed in absence of laboratory test results. Integration could assist ED physicians in early and accurate diagnosis of appendicitis. [ABSTRACT FROM AUTHOR]

Deep learning (DL) holds great promise to improve medical diagnostics, including pathology. Current DL research mainly focuses on performance. DL implementation potentially leads to environmental consequences but approaches for assessment of both performance and carbon footprint are missing. Here, we explored an approach for developing DL for pathology, which considers both diagnostic performance and carbon footprint, calculated as CO2 or equivalent emissions (CO2eq). We evaluated various DL architectures used in computational pathology, including a large foundation model, across two diagnostic tasks of low and high complexity. We proposed a metric termed 'environmentally sustainable performance' (ESPer), which quantitatively integrates performance and operational CO2eq during training and inference. While some DL models showed comparable diagnostic performance, ESPer enabled prioritizing those with less carbon footprint. We also investigated how data reduction approaches can improve the ESPer of individual models. This study provides an approach facilitating the development of environmentally friendly, sustainable medical AI. [ABSTRACT FROM AUTHOR]

Graves' disease (GD) is an autoimmune disorder characterized by activation of the TSH receptor by stimulatory autoantibodies (TSH Receptor Antibodies, or TRAbs), leading to unregulated thyroid hormone production. Diagnosis is largely based on the typical clinical picture and laboratory thyroid panel. Establishment of elevated serum levels of TRAbs by competitive binding assay or cell-binding assay has its unique role in diagnosis and management of GD, especially in the differential diagnosis, therapy selection, prognostication, evaluation of thyroid function during pregnancy, peri-conceptional and neonatal thyroid workup, and in certain special situation. Inclusion of TRAbs in GD diagnostic algorithm can improve cost-effectiveness of GD management. The current best practice guidelines were developed to provide evidence-based recommendations in the use of TRABs in GD management for healthcare providers in South Asia. A panel of endocrinologists with minimum 10 years of clinical experience in thyroid disorders reviewed existing literature and their quality, and after deliberation and discussion, developed 21 recommendations surrounding the best practices surrounding the role of TRAbs in GD management. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Methods Results Conclusion Investigation of bone marrow (BM) trephine biopsies and/or clot sections by CD34 immunohistochemistry (IHC) testing has been used by pathologists for several decades, and its clinical value has been well established with QBEND10 being the most frequently used primary antibody (Ab) clone. However, most other parameters related to the IHC protocol as well as the readout vary widely between clinical laboratories and in the published literature. The ICSH Working Group having reviewed the published evidence has established guidelines that will help to harmonize performance and reporting of CD34 IHC on BM biopsies.The methodology is based on the published “guidelines for guidelines” (GRADE, AGREE) with modifications to the specific laboratory medicine environment and to specific key questions. Review of the published literature resulted in 49 articles relevant to clinical applications of the BM CD34 IHC. Five key questions were addressed including testing indications, technical performance, readout methodology, terminology, and reporting.A total of 23 guidelines were grouped according to the key questions.BM CD34 IHC testing is complex with both the protocol and the pathologist's readout requiring validation to ensure reported results are reproducible and accurate. The readout/interpretation must be adapted to a specific purpose of the assay (clinicopathological question) and the type and overall sample quality. Standardized terminology and reporting are essential if CD34 IHC assay is being used for clinical diagnostics. [ABSTRACT FROM AUTHOR]

Background: The introduction of antiretroviral therapy (ART) has significantly improved the life expectancy of people living with HIV (PLHIV), leading to an increased prevalence of age-related comorbidities such as osteoporosis. This study investigates the incidence and characteristics of low bone mineral density (BMD) and the treatment effectiveness of low BMD participants among PLHIV in Kerman, Iran. Methods: A longitudinal study utilized dual-energy X-ray absorptiometry (DEXA) to screen 94 PLHIV in Kerman, Iran, for low BMD. Participants were aged 30 or older and had received antiretroviral therapy (ART) for at least 12 months. Those with low BMD were entered into a single-arm clinical trial and received the appropriate treatment. These people were checked to assess the treatment effectiveness 11 months after completion of the treatment. Those with normal BMD entered a cohort study and were checked to determine the cumulative incidence of low BMD. Data on demographics, medical history, and laboratory tests were collected. A chi-square test was used to assess the association between the categorical variables. A t-test (for normally distributed variables), or Mann-Whitney U (for non-normally distributed variables) was used to assess the differences of BMD between the two groups. Statistical significance was set at p ≤ 0.05, with analyses conducted in Stata 17. Results: Among 94 PLHIV at baseline, 48 participants (51%) had low BMD. During the follow-up, 11 participants (11.7%) missed the follow-up visits. In the follow-up, 83 PLHIV (40 with low BMD and 43 with normal BMD at baseline) were available. Among 40 participants who received treatment, 5 had normal BMD (treatment effectiveness: 12.5%). However, among 43 PLHIV with normal BMD at baseline, 7 PLHIV had low BMD at the follow-up visit (cumulative Incidence 16.3%). Those with lower body mass index (BMI) had a higher prevalence of low BMD than those with normal BMI during the follow-up (p-value: 0.003). Lumbar spine BMD increased modestly (0.005 g/cm2), while femoral neck and total hip BMD declined in total participants (0.011, 0.007 g/cm2, respectively). Osteocalcin and β-isomerized C-terminal telopeptides (β-CTx) levels were higher in the low BMD group in the follow-up, indicating increased bone turnover. Conclusions: The study highlights the high cumulative incidence of 16.3% and treatment effectiveness of 12.5% of low BMD among PLHIV in Kerman, Iran, with implications for fracture risk. Despite a steady state in spine BMD decline, the risk of fracture remains elevated due to continued femoral neck and total hip BMD reduction. Gender-specific factors and BMI may influence susceptibility to low BMD. [ABSTRACT FROM AUTHOR]