Doctor Ex Machina: A Critical Assessment of the Use of Artificial Intelligence in Health Care.

This article examines the potential implications of the implementation of artificial intelligence (AI) in health care for both its delivery and the medical profession. To this end, the first section explores the basic features of AI and the yet theoretical concept of autonomous AI followed by an overview of current and developing AI applications. Against this background, the second section discusses the transforming roles of physicians and changes in the patient-physician relationship that could be a consequence of gradual expansion of AI in health care. Subsequently, an examination of the responsibilities physicians should assume in this process is explored. The third section describes conceivable practical and ethical challenges that implementation of a single all-encompassing AI healthcare system would pose. The fourth section presents arguments for regulation of AI in health care to ensure that these applications do not violate basic ethical principles and that human control of AI will be preserved in the future. In the final section, fundamental components of a moral framework from which such regulation may be derived are brought forward, and some possible strategies for building a moral framework are discussed.

Hemostasis testing and therapeutic plasma exchange: Results of a practice survey.

INTRODUCTION: Performing therapeutic plasma exchange (TPE) with albumin replacement decreases coagulation factor and platelet levels. No defined guidelines exist regarding laboratory testing to assess hemostasis in patients undergoing TPE. MATERIALS AND METHODS: A survey to evaluate hemostasis testing with TPE was distributed using online survey software. One response per institution was analyzed based on a hierarchical algorithm, excluding membrane filtration users, resulting in a maximum of 120 respondents per question. Descriptive analysis was performed with results reported as the number and/or frequency (%) of respondents to each question. RESULTS: The practices represented vary by institution type, number of apheresis procedures per year, and performance of TPE on children. Prior to TPE planned with albumin replacement, many respondents obtain laboratory studies for almost all patients (54.9% outpatients and 68.7% inpatients); however, some do not routinely obtain laboratory studies (9.7% outpatients and 4.4% inpatients). Hemoglobin/hematocrit, platelet count, fibrinogen, partial thromboplastin time (aPTT), and international normalized ratio (INR) are obtained prior to all TPE by 62.5%, 53.4%, 31.0%, 18.1%, and 17.7% of respondents, respectively; however, 1.0%, 8.7%, 29.0%, 38.3%, and 35.4%, respectively, do not routinely obtain these studies. Variation was observed in laboratory threshold values for action; the most common reported were hemoglobin/hematocrit <7 g/dL or 21% (31.0%), platelet count <50 × 109 /L (24.1%), fibrinogen <100 mg/dL (65.3%), aPTT >reference range and >1.5 times reference range (tied, 28.1%), and INR >1.5 (20.7%). CONCLUSIONS: Practice variation exists in hemostasis laboratory testing and threshold values for action with TPE. Further studies are needed to determine optimal hemostasis testing strategies with TPE.

Hemostasis management and therapeutic plasma exchange: Results of a practice survey.

BACKGROUND: Patients undergoing therapeutic plasma exchange (TPE) may present with risks for hemorrhage or thrombosis. Use of replacement fluids devoid of coagulation factors will decrease factor levels and platelet levels. There are no established guidelines for hemostasis management in these situations. MATERIALS AND METHODS: A survey to evaluate current hemostasis management practice during TPE was conducted using online survey software. One response per institution was analyzed based on a hierarchical algorithm, excluding membrane filtration users, resulting in a maximum of 107 respondents. Descriptive analysis was performed with results reported as the number and frequency (%) of respondents to each question. RESULTS: Apheresis Medicine physicians, alone (59.4%) or jointly with the requesting provider (29.2%), choose the replacement fluid. Based on a theoretical patient case receiving five TPEs approximately every other day, the percent of respondents who would use albumin with or without normal saline was 94.7% with no history of a bleeding or clotting disorder, 1.1% with active bleeding, and 8.8% with hypofibrinogenemia (<100 mg/dL) due to recent TPE. More respondents would use albumin with or without normal saline for replacement fluid when a minor invasive procedure (49.5%) vs a major surgery (8.9%) was performed 1 day before TPE. Replacement fluid selection varied among respondents for several other clinical conditions. The most frequent use for cryoprecipitate by respondents (14.3%) was hypofibrinogenemia. CONCLUSIONS: These survey results demonstrate wide interinstitutional variation in replacement fluid selection to manage hemostasis in patients undergoing TPE. Further studies are needed to guide optimal hemostasis management with TPE.

Considerations of red blood cell molecular testing in transfusion medicine.

The field of transfusion medicine is on the threshold of a paradigm shift, as the technology for genotyping of red blood cell antigens, including US FDA-approved arrays, is now moving into standard practice. Access to cost-efficient, high-resolution genotyping has the potential to increase the quality of care by decreasing the risk for alloimmunization and incompatible transfusions in individuals on long-term blood transfusion protocols, including patient groups with hemoglobinopathies and other chronic diseases. Current and future applications of molecular methods in transfusion medicine and blood banking are discussed, with emphasis on indications for genotyping in various clinical scenarios. Furthermore, limitations of the current gold standard methodology and serology, as well as of contemporary molecular methodology, are examined.

Pediatric T-cell prolymphocytic leukemia with an isolated 12(p13) deletion and aberrant CD117 expression.

T-cell Prolymphocytic leukemia (T-PLL) is a rare post-thymic T-cell malignancy that follows an aggressive clinical course. The classical presentation includes an elevated white blood cell (WBC) count with anemia and thrombocytopenia, hepatosplenomegaly, and lymphadenopathy. T-PLL is a disease of the elderly and to our knowledge it has never been described in the pediatric age group. We report a case of T-PLL in a 9 year old male who was initially diagnosed with T-cell acute lymphoblastic lymphoma (ALL), the diagnosis was later refined to T-PLL following additional analysis of bone marrow morphology and immunophenotype. Two unusual findings in our patient included CD117 expression and an isolated chromosomal 12(p13) deletion. The patient failed to respond to standard ALL induction chemotherapy, but achieved complete remission following treatment with a fludarabine and alemtuzumab-based regimen.

Comparison of analytical and clinical performance of three methods for detection of Clostridium difficile.

CONTEXT: Diagnostic laboratory testing for Clostridium difficile infection has undergone considerable and rapid evolution during the last decade. The ideal detection method(s), which should exhibit high analytical and clinical sensitivity and specificity, remains undefined. OBJECTIVE: We sought to evaluate the analytical and clinical performance characteristics of three methods for the laboratory detection of C difficile. DESIGN: This study used 114 consecutive stool samples to compare three methods of C difficile detection: an enzyme immunoassay (EIA) for toxins A/B, a lateral flow membrane immunoassay for glutamate dehydrogenase (GDH), and a qualitative real-time polymerase chain reaction (PCR) assay. Medical records of all patients having ≥1 positive test result were reviewed to estimate the clinical likelihood of C difficile infection. RESULTS: Based upon laboratory result consensus values, analytical sensitivity was significantly higher for GDH (94%) and PCR (94%) assays than for toxin EIA (25%). Analytical specificity was significantly higher for PCR (100%) and EIA (100%) than for GDH assay (93%). In contrast, assay performance based upon clinical probability of C difficile infection suggested lower discriminatory power (ie, clinical specificity) of the more analytically sensitive methods. CONCLUSIONS: Higher rates of C difficile detection will be realized upon implementation of GDH assay and/or real-time PCR-based testing algorithms than by testing with EIA alone. Further study is required to elucidate potential downstream costs for higher detection rates.

Pathology consultation on detection of Clostridium difficile.

Laboratory methods for detecting Clostridium difficile have undergone considerable evolution since the organism's etiologic association with antibiotic-associated diarrhea and colitis was established. Clearly, familiarity with the advantages and shortcomings of the various assays is essential for the laboratory director when choosing among these tests. For the consulting pathologist, furthermore, an understanding of the laboratory's role in securing a diagnosis of C difficile infection (CDI) is also required to identify requests for unnecessary testing that may be costly and potentially misleading. The purpose of this article is to highlight the major differences in laboratory test methods for CDI and to review a few commonly encountered provider ordering scenarios.

Implementation of a cost-effective unlabeled probe high-resolution melt assay for genotyping of Factor V Leiden.

The Factor V Leiden mutation (FVL; c.1601G>A, p.Arg534Gln), the most common aberration underlying activated Protein C resistance, results in disruption of a major anticoagulation pathway and is a leading cause of inherited thrombophilia. A high-throughput assay for FVL mutation detection was developed using a single unlabeled probe on a high-resolution platform, the 96-well Roche 480 LightCycler (LC480) instrument. This method replaced the U.S. Food and Drug Administration-approved Roche Factor V Leiden kit assay on the LightCycler PCR instrument, decreasing total cost by 48%. The analytical sensitivity and specificity of the LC480 high-resolution assay approached 100% for the FVL mutation. Factor V mutations in proximity to the FVL locus may influence probe binding efficiency and melt characteristics. One out of three very rare variants tested in a separate study, 1600delC, was not distinguishable from FVL using the described high-resolution assay. However, a c.1598G>A variant, which changes the amino acid sequence from arginine to lysine at position 533, was detected by this high-resolution assay and confirmed by bidirectional sequencing. In the labeled probe LightCycler assay, the c.1598G>A variant was indistinguishable from the heterozygous FVL control. The c.1598G>A variant has not been described previously and its clinical significance is uncertain. In conclusion, the LC480 FVL assay is cost effective in a high-throughput setting, with capability to detect both previously described and novel FV variants.

Detection of large rearrangements in the cystic fibrosis transmembrane conductance regulator gene by multiplex ligation-dependent probe amplification assay when sequencing fails to detect two disease-causing mutations.

AIMS: Most of the over 1600 mutations and sequence variants identified to date in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are point mutations or small deletions/insertions detectable by conventional sequencing. However, large rearrangements (deletions, duplications, or insertion/deletion mutations) have recently been reported to constitute 1-2% of CFTR mutations. The CFTR sequencing protocol at ARUP Laboratories interrogates the coding regions of all 27 exons and all intron/exon boundaries of the gene. This study was undertaken to determine whether testing for large gene rearrangements could improve the mutation detection rate. RESULTS: Nine cases with abnormal quantitative pilocarpine iontophoresis sweat chloride (SC) values (>60 mEq/L) and 20 cases with borderline SC levels (40-60 mEq/L) with only one or no mutations detected by the ARUP 32 mutation panel, including the 23 mutations recommended by American College of Medical Genetics (ACMG) for carrier screening, followed by sequencing, were tested using a multiplex ligation-dependent probe amplification (MLPA) assay. MLPA analysis identified one deletion among nine patients with SC >60 who had previously been tested with sequencing. None of the cases with borderline SC levels showed rearrangements. CONCLUSION: The MLPA assay for detection of large rearrangements may be valuable in individuals with positive SC levels where one or no mutations have been identified by sequencing.

Molecular diagnostics in hemostatic disorders.

The use of molecular diagnostic techniques in clinical and research hemostasis laboratories is increasing as genetic factors that affect the procoagulant and anticoagulant systems are identified. Many of these molecular alterations are associated with thrombotic tendencies, whereas others tip the hemostatic balance in favor of bleeding. In either scenario, molecular testing may serve as a primary diagnostic modality or may provide information that complements clot-based "functional" assays. The clinical application of DNA-based testing continues to expand since the discoveries of the factor V Leiden and prothrombin G20210A gene mutations. Indications for genetic testing continue to evolve as the underlying causes of hemostatic disorders are better understood. Further development of molecular assays depends on their proved utility in the clinical management and treatment of these complex multifactorial disorders.

Detection of a de novo interstitial 2q microdeletion by CGH microarray analysis in a patient with limb malformations, microcephaly and mental retardation.

We describe the cytogenetic diagnosis using BAC- and oligonucleotide microarrays of a 16-year-old Laotian-American female, who first presented at 2 1/2 years of age with microcephaly, developmental retardation, and skeletal abnormalities of the upper limb including mild syndactyly of the second and third and the third and fourth fingers, short middle phalanges and clinodactyly of the fifth digit at the distal interphalangel joint on both hands, and symphalangism of the metacarpal-phalangeal joints of the second and fifth digits bilaterally. Her lower limbs displayed symphalangism of the metatarsal-phalangeal joint of the second, third, and fourth digits on both feet, with fusion of the middle and distal phalanges of the second and fifth digits and hallux valgus bilaterally. G-banded chromosomal study at age 4 was normal. However, comparative genomic hybridization at age 15 with the Spectral Genomics 1 Mb Hu BAC array platform indicated a microdeletion involving two BAC clones, RP11-451F14 --> RP11-12N7 at 2q31.1. The maximal deletion on initial analysis comprised the HOXD cluster, which is implicated in limb development. Fluorescence in situ hybridization (FISH) using the RP11-451F14 probe confirmed the deletion. Both parents were negative for the deletion. Additional FISH using BAC RP11-387A1, covering the HOXD cluster, limited the maximal deletion to approximately 2.518 Mb, and excluded involvement of the HOXD cluster. The Agilent 44K and 244K platforms demonstrated a deletion of approximately 2,011,000 bp, which did not include the HOXD cluster. The malformations in our patient may be caused by deletion of a regulatory element far upstream of the HOXD cluster.

Effects of glucagon-like peptide-1-(7-36)-amide on pancreatic islet and intestinal blood perfusion in Wistar rats and diabetic GK rats.

The aim of the present study was to evaluate the effects of GLP-1 [glucagon-like peptide-1-(7-36)-amide] on total pancreatic, islet and intestinal blood perfusion in spontaneously hyperglycaemic GK rats and normal Wistar rats using a microsphere technique. GK rats had hyperglycaemia and increased pancreatic and islet blood flow. Blood glucose concentrations were not affected when measured shortly (8 min) after GLP-1 administration in either GK or Wistar rats. GLP-1 had no effects on baseline pancreatic or islet blood flow in Wistar rats, but did prevent the blood flow increase normally seen following glucose administration to these animals. In GK rats, administration of GLP-1 decreased both pancreatic and islet blood flow. Glucose administration to the GK rats decreased pancreatic and islet blood flow. This decrease was not affected by pre-treatment with GLP-1. We conclude that administration of GLP-1 leads to a decrease in the augmented blood flow seen in islets of diabetic GK rats. The GLP-1-induced action on islet blood perfusion may modulate output of islet hormones and contribute to the antidiabetogenic effects of the drug in Type 2 diabetes (non-insulin-dependent diabetes).

SELDI-TOF plasma profiles distinguish individuals in a protein C-deficient family with thrombotic episodes occurring before age 40.

We tested the hypothesis that differences in the low-molecular-weight (500-20,000 Da) proteomic profile of plasma may be detectable between members of a protein C-deficient family who have suffered thrombotic events before age 40 compared to family members without a history of venous thrombosis. Unfractionated plasma samples from members of a previously described large thrombophilic kindred with type I protein C deficiency were applied to ProteinChip weak cation exchange interaction arrays (WCX2; Ciphergen Biosystems, Fremont, CA, USA) and subjected to SELDI-TOF (surface-enhanced laser desorption/ionization time-of-flight) mass spectrometry using the Ciphergen PBSII ProteinChip System (Ciphergen Biosystems). Profiles were analyzed by a boosted decision-tree algorithm. When individuals who had presented with deep venous thrombosis (DVT) before the age of 40 (n = 21) were compared to age-matched, healthy family members (n = 50), the proteomic patterns defined by the decision-tree analysis could classify the entity of DVT before age 40 with 67% sensitivity, at a specificity of 86%. When a small group of cases with history of superficial venous thrombosis (n = 6) was added to the case group, the sensitivity was 87.5% at a specificity of 80%. These data support the hypothesis that members of the protein C deficient Vermont kindred II who suffer a thrombotic event before age 40 display significant differences in low-molecular-weight proteomics profile compared to those who remain disease-free. This is the first study to apply SELDI-TOF technology in conjunction with a bioinformatics tool to analyze low-molecular-weight proteomic patterns in patients with venous thrombosis.

Reversible Epstein-Barr virus-negative lymphadenopathy and bone marrow involved by Hodgkin's lymphoma in a rheumatoid arthritis patient undergoing long-term treatment with low-dose methotrexate: a case report and review of the literature.

We report a case of spontaneous regression of Epstein-Barr virus (EBV)-negative methotrexate-associated lymphadenopathy occurring with Hodgkin's lymphoma in the bone marrow of a 48-year-old woman with rheumatoid arthritis. Following 10 years of treatment with low-dose methotrexate, the patient developed pancytopenia, hypercalcemia, and elevated levels of liver enzymes over the course of 2 months. A computed tomography scan of the abdomen revealed splenomegaly and enlarged abdominal lymph nodes. A bone marrow biopsy demonstrated cellular marrow with 2 paratrabecular granuloma-like lesions composed of histiocytes, fibroblasts, small lymphocytes, a few plasma cells, and scattered CD30(+)CD15(+) Hodgkin's cells, including a classic Reed-Sternberg cell. The results of EBV studies of the bone marrow were negative. Within a month from withdrawal of methotrexate treatment, the patient's symptoms and the abnormalities in the laboratory results had regressed completely. A positron emission tomography scan failed to detect lymphadenopathy. Twelve months later, the patient remains free of symptoms.

Lack of compensatory increase in islet blood flow and islet mass in GK rats following 60% partial pancreatectomy.

The effects of a 60% partial pancreatectomy were studied in hyperglycemic GK (Goto-Kakizaki) rats. Partial pancreatectomy or a sham operation was performed on 12-week-old female Wistar rats, GK rats or hybrids between male GK rats and female Wistar rats. Measurements of pancreatic blood flow and islet blood flow were performed by a microsphere technique 2 weeks after surgery. Glucose tolerance was decreased in hybrid compared with Wistar rats, and in GK rats compared with both hybrid and Wistar rats before surgery. Partial pancreatectomy induced minor changes in glucose tolerance. Wistar rats had a decreased islet mass following partial pancreatectomy. Both hybrid and GK rats showed a significant decrease in relative islet volume, but only GK rats in total islet mass, compared with Wistar rats 2 weeks after surgery. Pancreatic blood flow and islet blood flow did not significantly differ between sham-operated Wistar, hybrid or GK rats. After partial pancreatectomy, islet blood flow in relation to islet mass increased 3-fold in Wistar rats and 2-fold in hybrid rats. In contrast, GK rats showed no increase in islet blood flow following partial pancreatectomy. It is concluded that compensatory mechanisms after partial pancreatectomy are operating less efficiently in hybrid and GK rats.

The protein C system in placental massive perivillous fibrin deposition.

Massive perivillous fibrin deposition (MPFD) is associated with intrauterine growth retardation and first-trimester and second-trimester spontaneous abortion. Histologically, villi near the maternal interface are completely surrounded by fibrinoid material. This work compared the expression of thrombomodulin (TM) and endothelial protein C receptor (EPCR) in early miscarriage specimens with and without MPFD. Ten specimens with a gestational age of 7-12 weeks (mean 10 weeks) and 10 age-matched miscarriage specimens lacking MPFD were sampled. Formalin-fixed paraffin-embedded sections were stained with monoclonal antibodies against TM and EPCR using an immunoperoxidase method. The slides were independently reviewed by two pathologists using a semiquantitative grading system. Among unaffected villi, there was no difference in staining for TM or EPCR in cases of massive perivillous fibrin deposition compared with the control group. In the MPFD cases, loss of membrane positivity was noted for both TM and EPCR at the junction between normal villous epithelium and villous epithelium with deposition of fibrin. This could imply an underlying defect of trophoblastic protein C activation. Alternatively, it may represent a degenerative change secondary to impedence of oxygen and nutrient supply to the trophoblastic epithelium.

Role of superoxide anion in pancreatic islet blood flow regulation in anesthetized rats.

The aim of the investigation was to study the influence of the superoxide anion on pancreatic islet blood flow in rats. For this purpose, blood flow measurements were conducted with a microsphere technique 10 min after intravenous administration of different doses of superoxide dismutase (5, 15, 50, 100 or 1000 kU/kg body weight). In separate experiments, diethyldithiodicarbamate, an inhibitor of endogenous superoxide dismutase, was given to nontreated control rats or to rats subjected to a bilateral abdominal vagotomy before the injection. Only the highest dose of superoxide dismutase increased both whole pancreatic and islet blood flow. A 50% augmentation of fractional islet blood flow was seen. Administration of diethyldithiocarbamate induced marked hyperglycemia, which was partly prevented by vagotomy. Diethyldithiocarbamate decreased the whole pancreatic blood flow, while islet blood flow was maintained in both control and vagotomized rats. Consequently, a pronounced increase in fractional islet blood flow was noted in both these groups. We conclude that administration of superoxide dismutase and its inhibitor diethyldithiocarbamate influences pancreatic blood perfusion. In particular, superoxide dismutase causes a general increase in the whole pancreatic and islet blood flow, and an augmented fractional islet blood flow, presumably by a decrease in the local concentration of O(2)(z.rad;-), leading to increased concentration of NO. Diethyldithiocarbamate, on the other hand, by increasing the levels of O(2)(z.rad;-), decreases the whole pancreatic blood flow, whereas islet blood flow remains unaffected.

An immunohistochemical approach to monitor the prolactin-induced activation of the JAK2/STAT5 pathway in pancreatic islets of Langerhans.

This study examined whether an immunohistochemical method examining the subcellular localization of STAT5 could be used to characterize the activation of the JAK2/STAT5 pathway by prolactin (PRL) in intact cells or tissues. In the Ins-1 beta-cell line, STAT5A and STAT5B were distributed almost equally in the cytoplasm and the nucleus in unstimulated cells. STAT5A was also detected along the border of cells and in the perinuclear region. After exposure to PRL, the redistribution from the cytoplasm to the nucleus was much higher for STAT5B compared to STAT5A. This translocation represented 12% of the STAT5A and 22% of the STAT5B originally located in the cytoplasm before stimulation. In isolated rat islets of Langerhans, PRL stimulated the nuclear translocation of both STAT5A and STAT5B only in beta-cells. The expression of the PRL receptor only by beta-cells was confirmed with a rabbit polyclonal antiserum raised against the rat PRL receptor. It was estimated that 4% of STAT5A and 9% of STAT5B originally located in the cytoplasm was translocated to the nucleus after stimulation. The presence of a functional JAK2/STAT5 signaling pathway in all islet cells was demonstrated by the nuclear translocation of STAT5B in all islet cells (i.e., alpha-, beta-, and delta-cells) after stimulation with fetal calf serum. The nuclear translocation and tyrosine phosphorylation of STAT5B was biphasic, with an initial peak within 30 min, a nadir between 1 and 3 hr, and prolonged activation after 4 hr. In contrast, the tyrosine phosphorylation of STAT5A was also biphasic but its nuclear translocation peaked within 30 min and was then reduced to a level slightly above that observed before PRL stimulation. This method is able to detect changes in STAT5 activation as small as 2% of the total cell content. These observations demonstrate the utility of this approach for studying the activation of STAT5 in a mixed population of cells within tissues or organs. In addition, the dose response for the nuclear translocation of STAT5B in normal beta-cells was similar to those for changes in proliferation and insulin secretion in isolated rat islets. Therefore, the subcellular localization can be used to monitor the activation of STAT5 and it may be a key event in the upregulation of the pancreatic islets of Langerhans during pregnancy.