Framework for Classifying Explainable Artificial Intelligence (XAI) Algorithms in Clinical Medicine.

Artificial intelligence (AI) applied to medicine offers immense promise, in addition to safety and regulatory concerns. Traditional AI produces a core algorithm result, typically without a measure of statistical confidence or an explanation of its biological-theoretical basis. Efforts are underway to develop explainable AI (XAI) algorithms that not only produce a result but also an explanation to support that result. Here we present a framework for classifying XAI algorithms applied to clinical medicine: An algorithm's clinical scope is defined by whether the core algorithm output leads to observations (eg, tests, imaging, clinical evaluation), interventions (eg, procedures, medications), diagnoses, and prognostication. Explanations are classified by whether they provide empiric statistical information, association with a historical population or populations, or association with an established disease mechanism or mechanisms. XAI implementations can be classified based on whether algorithm training and validation took into account the actions of health care providers in response to the insights and explanations provided or whether training was performed using only the core algorithm output as the end point. Finally, communication modalities used to convey an XAI explanation can be used to classify algorithms and may affect clinical outcomes. This framework can be used when designing, evaluating, and comparing XAI algorithms applied to medicine.

Glioblastoma with novel EGFR mutations (T790M and exon 20 insertion) yet unresponsive to osimertinib: A case report.

Glioblastoma (GBM) is a high-grade adult-type IDH-wildtype diffuse glioma, commonly harboring epidermal growth factor receptor (EGFR) amplification. Here, we describe a case of a 49-year-old man with a GBM harboring a TERT promoter mutation. Despite surgical and chemoradiation therapy, the tumor recurred. At that time, comprehensive genomic profiling by next-generation sequencing identified two rare mutations in EGFR: T790M and an exon 20 insertion. Based on these findings, the patient elected to undergo off-label therapy with osimertinib, a third-generation EGFR tyrosine kinase inhibitor that has shown promising results in non-small cell lung carcinoma, including metastatic to brain, with exactly the same EGFR mutations. Moreover, the drug has excellent central nervous system penetration. Even so, no clinical response was observed, and the patient succumbed to the disease. The lack of response may be related to the specific nature of the EGFR mutations, and/or other unfavorable tumor biology overriding any benefit from osimertinib.

Biological data annotation via a human-augmenting AI-based labeling system.

Biology has become a prime area for the deployment of deep learning and artificial intelligence (AI), enabled largely by the massive data sets that the field can generate. Key to most AI tasks is the availability of a sufficiently large, labeled data set with which to train AI models. In the context of microscopy, it is easy to generate image data sets containing millions of cells and structures. However, it is challenging to obtain large-scale high-quality annotations for AI models. Here, we present HALS (Human-Augmenting Labeling System), a human-in-the-loop data labeling AI, which begins uninitialized and learns annotations from a human, in real-time. Using a multi-part AI composed of three deep learning models, HALS learns from just a few examples and immediately decreases the workload of the annotator, while increasing the quality of their annotations. Using a highly repetitive use-case-annotating cell types-and running experiments with seven pathologists-experts at the microscopic analysis of biological specimens-we demonstrate a manual work reduction of 90.60%, and an average data-quality boost of 4.34%, measured across four use-cases and two tissue stain types.

A novel activating JAK1 mutation in chronic eosinophilic leukemia.

Hypereosinophilia (HE) has been defined as persistent eosinophilia >1.5 × 109/L; it is broadly divided into primary HE (clonal or neoplastic; HEN), secondary/reactive HE (HER), or HE of undetermined significance (HEUS) when no cause is identified. The use of myeloid next-generation sequencing (NGS) panels has led to the detection of several mutations in patients previously diagnosed with HEUS, reassigning some patients to the category of HEN, specifically the World Health Organization category of chronic eosinophilic leukemia, not otherwise specified (CEL, NOS). Here, we describe a novel somatic JAK1 pseudokinase domain mutation (R629_S632delinsSA) in a patient with HE that had initially been characterized as a variant of uncertain significance. We performed functional studies that demonstrated that this mutation results in growth factor independence of Ba/F3 cells in vitro and activation of the JAK-STAT pathway. These effects were abrogated by the JAK1/JAK2 inhibitor ruxolitinib. R629_S632delinsSA is the first known somatic mutation in JAK1 linked to a clonal eosinophilic neoplasm, and highlights the importance of the JAK-STAT pathway in eosinophil survival.

A New Era in Pathology Consultation: The MyPathologist Electronic Consultation Tool.

Pathologists and laboratory scientists provide valuable guidance on laboratory utilization, test ordering, interpretation, and quality control provided that clinical staff can easily access the laboratory team. To encourage consultation between clinicians with laboratory scientists and pathologists, we developed an easily accessible electronic tool termed "MyPathologist," placed on the homepage of our electronic health record system. Over its 2-year pilot, utilization of this consultation tool climbed as we continued to publicize it and incorporated education into housestaff onboarding and electronic health record training. Physician satisfaction with the tool was high. Additionally, this became the primary source of consults to our residency call service. Evaluation of MyPathologist questions received during its pilot period showed that more than half the questions were of significant educational value to the residents, often focusing on results interpretation, appropriate test ordering, and quality control. MyPathologist is a novel electronic tool for pathology consultation within our electronic health record and also represents an avenue for educating residents, improving utilization of the laboratory, and improving patient care.

Total Laboratory Automation and Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry Improve Turnaround Times in the Clinical Microbiology Laboratory: a Retrospective Analysis.

Technological advances have changed the practice of clinical microbiology. We implemented Bruker matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and BD Kiestra total laboratory automation (TLA) 4 and 3 years ago, respectively. To assess the impact of these new technologies, we compared turnaround times (TATs) for positive and negative urine cultures before and after implementation. In comparison I, TATs for 61,157 urine cultures were extracted for two periods corresponding to pre-TLA and post-TLA, both using MALDI-TOF MS for organism identification. In comparison II, time to organism identification (ID) and antimicrobial susceptibility (AST) reports were calculated for 5,402 positive culture reports representing four different periods: (i) manual plating and conventional biochemical identification (CONV), (ii) manual plating and MALDI-TOF MS identification (MALDI), (iii) MALDI-TOF MS identification and early phase implementation of TLA (TLA1), and (iv) MALDI-TOF MS identification and late phase implementation of TLA (TLA2). By the comparison I results, median pre- and post-TLA TATs to organism IDs (18.5 to 16.9 h), AST results (41.8 to 40.8 h), and preliminary results for negative cultures (17.7 to 13.6 h), including interquartile ranges for all comparisons, were significantly decreased post-TLA (P < 0.001). By the comparison II results, MALDI significantly improved TAT to organism ID compared to CONV (21.3 to 18 h). TLA further improved overall TAT to ID (18 to 16.5 h) and AST (42.3 to 40.7 h) results compared to MALDI (P < 0.001). In summary, TLA significantly improved TAT to organism ID, AST report, and preliminary negative results. MALDI-TOF MS significantly improved TAT for organism ID. Use of MALDI-TOF MS and TLA individually and together results in significant decreases in microbiology report TATs.

Effect of omega-3 fatty acids on disease severity in patients with psoriasis: A systematic review.

AIM: Many randomized controlled trials have been performed on the efficacy and mechanism of action of omega-3 polyunsaturated fatty acids (n-3 PUFAs) on psoriasis. However, contradictory results have been obtained. This study wants to assess the effects of n-3 PUFAs on the severity of psoriasis. METHODS: The Cochrane Central Register of Controlled Trials, PubMed/MEDLINE and EMBASE were searched for all randomized controlled trials and prospective observational studies comparing the efficacy of n-3 PUFAs versus control in adult patients with psoriasis. The primary outcome was psoriasis severity as measured by the Psoriasis Area Severity Index (PASI) score. RESULTS: The initial search yielded 732 articles, 720 of which were excluded. The data of the 12 remaining studies were extracted. Some studies found that n-3 PUFAs were associated with improvements in the PASI score, erythema, scaling, itching, area involved and infiltration. However, some studies did not find reduction in scaling, erythema, area involved or thickness in the treatment group. CONCLUSION: It is still inconclusive whether use of n-3 PUFAs in patients with psoriasis is associated with improvements in severity of psoriasis and other outcomes.

Variable Potassium Concentrations: Which Is Right and Which Is Wrong?

Reverse pseudohyperkalemia is a term used to describe in vitro, falsely elevated potassium concentrations in plasma specimens that occur in association with extreme leukocytosis and are commonly associated with hematologic malignant neoplasms. Tumor lysis syndrome is an in vivo lysis of tumor cells that leads to elevated levels of potassium, uric acid, phosphate, and lactate dehydrogenase, as well as decreased calcium concentrations. Herein, we report a case of a 66-year-old Caucasian man with stage IV mantle-cell lymphoma who has elevated levels of potassium, uric acid, and phosphorus, as well as a white blood cell (WBC) count greater than 100,000 cells per mm3. The patient initially was diagnosed as having tumor lysis syndrome. His subsequent potassium concentrations in whole blood remained elevated even after hemodialysis; however, his serum potassium concentrations were decreased. The patient then was diagnosed accurately as having reverse pseudohyperkalemia, and accurate potassium measurements were obtained via serum specimens.

Screening of Potential Probiotic Lactic Acid Bacteria with Anticancer Properties.

Background: Probiotics have shown to reduce cancer recurrence and side effects in colorectal cancer patients. Objective: To isolate the lactic acid bacteria from Thai healthy newborn feces and screen good probiotics with anticancer properties. Material and Method: Lactic acid bacteria were isolated from newborn feces and selected for the cytotoxicity property against human cancer cell lines by MTT assay and probiotics property by acid and bile tolerance tests. Results: Among 200 lactic acid bacteria isolated, 3 and 1 isolates significantly demonstrated strong and moderate antiproliferative effect against Caco-2 cells, respectively. Likewise, 4 and 5 isolates showed significant strong and moderate inhibitory effect on U937 cells, respectively. Seven candidate strains did not displayed cytotoxic to normal cells (Vero), except MSMC 112-2. All candidates showed good probiotics properties in resistance to acidic condition (pH 2-4) and to 1-4% bile concentrations, except MSMC105-3 showed intolerance at 4% bile concentration. The nucleotide sequence homology showed that MSMC95-4, MSMC104-2, MSMC111-2, MSMC112-2 and MSMC215-1 strains belong to Enterococcus faecalis (99.4%, 98.8%, 99.5%, 98.7 and 98.9%, respectively), MSMC105-3 is Lactobacillus salivarius (99.1%) and MSMC171-1 is Enterococcus faecium (99.3%). Conclusion: The authors have isolated lactic acid bacteria which have anticancer and good probiotics properties.

In vitro modulation of tumor necrosis factor α production in THP-1 cells by lactic acid bacteria isolated from healthy human infants.

The human microbiota is a source of probiotics capable of modulating the host immune system. In this study, we collected fecal samples from 100 healthy infants and isolated lactic acid bacteria which were screened for immune modulating effects on tumor necrosis factor α (TNF-α) production. Cell-free culture supernatants from 26 isolates were able to decrease TNF-α production in vitro and three of the isolates were selected as candidate probiotics (MSMC39-1, MSMC39-3, MSMC57-1). These isolates were identified using 16S ribosomal DNA sequencing as Lactobacillus paracasei, Lactobacillus casei, and Weissella confusa respectively. All three isolates were acid tolerant and bile tolerant to pH 3.0 and 4% bile respectively. Preparations of cell-free culture supernatants were processed and tested, and revealed that cell-free culture supernatants of isolates L. paracasei MSMC39-1, L. casei MSMC39-3, and W. confusa MSMC57-1 decreased the production of TNF-α significantly and were heat resistant. Only L. paracasei MSMC39-1 supernatant was proteinase-K sensitive. The effects of viable bacteria, heat-killed bacteria, and sonicated bacteria were compared. The heat-killed preparations of isolate W. confusa MSMC57-1 decreased the production of TNF-α. Sonicated cell preparations did not significantly alter TNF-α production. For isolates L. paracasei MSMC39-1 and L. casei MSMC39-3, this suggests that a substance in the cell-free culture supernatant may be responsible for in vitro cytokine modulation.

Antimicrobial Properties of a Potential Probiotic Lactobacillus from Thai Newborn Feces.

BACKGROUND: Probiotics are increasingly used to treat infectious diarrhea and antibiotic-associated diarrhea. Many probiotic bacteria are classified in general such as Lactobacillus and are able to colonize the gastrointestinal tracts of infants. OBJECTIVE: This study was performed to detect antimicrobial substances and activity in 200 Lactobacillus isolates obtained from healthy Thai newborn feces. MATERIAL AND METHOD: Reuterin production was detected by the spot overlay technique and colorimetric assay. Antimicrobial activity was tested by using a well diffusion, agar method. RESULTS: Lactobacillus strain MSMC64-1 produced reuterin and demonstrated potent antimicrobial activity against seven pathogenic indicator strains with very strong inhibitory activities against Salmonella typhi DMST 5784 and methicillin resistant Staphylococcus aureus (MRSA) DMST 20651. There was strong inhibitory activity against methicillin resistant Staphylococcus aureus (MRSA) DMST20654, Vibrio parahaemolyticus DMST 5665 and Shigella dysenteriae DMST 15111. There was moderate to weak inhibitory activities against Vibrio cholerae DMST 2873 and Helicobacter pylori (H40). The Lactobacillus strain MSMC 64-1 showed resistance to acidic pH (pH 2, 3, 4) and tolerance to 1%, 2%, 3%, and 4% bile concentrations. Sequencing of the 16S ribosomal DNA identified the candidate's strain as Lactobacillus reuteri with 98% sequence homology. CONCLUSION: The active isolate could potentially be used as a probiotic to prevent and treat enteric infections.