Artificial intelligence (AI) in health care has the promise of providing accurate and efficient results. However, AI can also be a black box, where the logic behind its results is nonrational. There ...are concerns if these questionable results are used in patient care. As physicians have the duty to provide care based on their clinical judgment in addition to their patients' values and preferences, it is crucial that physicians validate the results from AI. Yet, there are some physicians who exhibit a phenomenon known as automation bias, where there is an assumption from the user that AI is always right. This is a dangerous mindset, as users exhibiting automation bias will not validate the results, given their trust in AI systems. Several factors impact a user's susceptibility to automation bias, such as inexperience or being born in the digital age. In this editorial, I argue that these factors and a lack of AI education in the medical school curriculum cause automation bias. I also explore the harms of automation bias and why prospective physicians need to be vigilant when using AI. Furthermore, it is important to consider what attitudes are being taught to students when introducing ChatGPT, which could be some students' first time using AI, prior to their use of AI in the clinical setting. Therefore, in attempts to avoid the problem of automation bias in the long-term, in addition to incorporating AI education into the curriculum, as is necessary, the use of ChatGPT in medical education should be limited to certain tasks. Otherwise, having no constraints on what ChatGPT should be used for could lead to automation bias.
This book explores the ethical governance of Artificial Intelligence (AI) & Machine Learning (ML) in healthcare. AI/ML usage in healthcare as well as our daily lives is not new. However, the direct, ...and oftentimes long-term effects of current technologies, in addition to the onset of future innovations, have caused much debate about the safety of AI/ML. On the one hand, AI/ML has the potential to provide effective and efficient care to patients, and this sways the argument in favor of continuing to use AI/ML; but on the other hand, the dangers (including unforeseen future consequences of the further development of the technology) leads to vehement disagreement with further AI/ML usage. Due to its potential for beneficial outcomes, the book opts to push for ethical AI/ML to be developed and examines various areas in healthcare, such as big data analytics and clinical decision-making, to uncover and discuss the importance of developing ethical governance for AI/ML in this setting.
The risk factors for preeclampsia, extremes of maternal age, changing paternity, concomitant maternal autoimmunity, and/or birth intervals greater than 5 years, suggest an underlying immunopathology. ...We used peripheral blood and lymphocytes from the UteroPlacental Interface (UPI) of 3rd trimester healthy pregnant women in multicolor flow cytometry-and in vitro suppression assays. The major end-point was the characterization of activation markers, and potential effector functions of different CD4-and CD8 subsets as well as T regulatory cells (Treg). We observed a significant shift of peripheral CD4 -and CD8- T cells from naïve to memory phenotype in preeclamptic women compared to healthy pregnant women consistent with long-standing immune activation. While the proportions of the highly suppressive Cytokine and Activated Treg were increased in preeclampsia, Treg tolerance toward fetal antigens was dysfunctional. Thus, our observations indicate a long-standing inflammatory derangement driving immune activation in preeclampsia; in how far the Treg dysfunction is caused by/causes this immune activation in preeclampsia will be the object of future studies.
In the development of the skeleton, the long bones are arising from the process of endochondral ossification (EO) in which cartilage is replaced by bone. This complex process is regulated by various ...factors including genetic, epigenetic, and environmental elements. It is recognized that DNA methylation, higher-order chromatin structure, and post-translational modifications of histones regulate the EO. With emerging understanding, non-coding RNAs (ncRNAs) have been identified as another mode of EO regulation, which is consist of microRNAs (miRNAs or miRs) and long non-coding RNAs (lncRNAs). There is expanding experimental evidence to unlock the role of ncRNAs in the differentiation of cartilage cells, as well as the pathogenesis of several skeletal disorders including osteoarthritis. Cutting-edge technologies such as epigenome-wide association studies have been employed to reveal disease-specific patterns regarding ncRNAs. This opens a new avenue of our understanding of skeletal cell biology, and may also identify potential epigenetic-based biomarkers. In this review, we provide an updated overview of recent advances in the role of ncRNAs especially focus on miRNA and lncRNA in the development of bone from cartilage, as well as their roles in skeletal pathophysiology.
To evaluate the effect of a postpartum hypertension standardized clinical assessment and management plan on postpartum readmissions and emergency department (ED) visits.
We conducted a prospective ...cohort study of patients with postpartum hypertension (either chronic hypertension or hypertensive disorders of pregnancy) who delivered at a single tertiary care center for 6 months after enacting an institution-wide standardized clinical assessment and management plan (postintervention group). Patients in the postintervention group were compared with patients in a historical control group. The standardized clinical assessment and management plan included 1) initiation or uptitration of medication for any blood pressure (BP) higher than 150/100 mm Hg or any two BPs higher than 140/90 mm Hg within a 24-hour period, with the goal of achieving normotension (BP lower than 140/90 mm Hg) in the 12 hours before discharge; and 2) enrollment in a remote BP monitoring system on discharge. The primary outcome was postpartum readmission or ED visit for hypertension. Multivariable logistic regression was used to evaluate the association between standardized clinical assessment and management plan and the selected outcomes. A sensitivity analysis was performed with propensity score weighting. A planned subanalysis in the postintervention cohort identified risk factors associated with requiring antihypertensive uptitration after discharge. For all analyses, the level of statistical significance was set at P <.05.
Overall, 390 patients in the postintervention cohort were compared with 390 patients in a historical control group. Baseline demographics were similar between groups with the exception of lower prevalence of chronic hypertension in the postintervention cohort (23.1% vs 32.1%, P =.005). The primary outcome occurred in 2.8% of patients in the postintervention group and in 11.0% of patients in the historical control group (adjusted odds ratio aOR 0.24, 95% CI 0.12-0.49, P <.001). A matched propensity score analysis controlling for chronic hypertension similarly demonstrated a significant reduction in the incidence of the primary outcome. Of the 255 patients (65.4%) who were compliant with outpatient remote BP monitoring, 53 (20.8%) had medication adjustments made per protocol at a median of 6 days (interquartile range 5-8 days) from delivery. Non-Hispanic Black race (aOR 3.42, 95% CI 1.68-6.97), chronic hypertension (aOR 2.09, 95% CI 1.13-3.89), having private insurance (aOR 3.04, 95% CI 1.06-8.72), and discharge on antihypertensive medications (aOR 2.39, 95% CI 1.33-4.30) were associated with requiring outpatient adjustments.
A standardized clinical assessment and management plan significantly reduced postpartum readmissions and ED visits for patients with hypertension. Close outpatient follow-up to ensure appropriate medication titration after discharge may be especially important in groups at high risk for readmission.
Epithelial-mesenchymal transition (EMT) contributes significantly to interstitial matrix deposition in diabetic kidney disease (DKD). However, detection of EMT in kidney tissue is impracticable, and ...anti-EMT therapies have long been hindered. We reported that phosphatase and tensin homolog (PTEN) promoted transforming growth factor beta 1 (TGF-β), sonic hedgehog (SHH), connective tissue growth factor (CTGF), interleukin 6 (IL-6), and hyperglycemia-induced EMT when PTEN was modified by a MEX3C-catalyzed K27-linked polyubiquitination at lysine 80 (referred to as PTENK27-polyUb). Genetic inhibition of PTENK27-polyUb alleviated Col4a3 knockout-, folic acid-, and streptozotocin-induced (STZ-induced) kidney injury. Serum and urine PTENK27-polyUb concentrations were negatively correlated with glomerular filtration rate (GFR) for diabetic patients. Mechanistically, PTENK27-polyUb facilitated dephosphorylation and protein stabilization of TWIST, SNAI1, and YAP in renal epithelial cells, leading to enhanced EMT. We identified that a small molecule, triptolide, inhibited MEX3C-catalyzed PTENK27-polyUb and EMT of renal epithelial cells. Treatment with triptolide reduced TWIST, SNAI1, and YAP concurrently and improved kidney health in Col4a3 knockout-, folic acid-injured disease models and STZ-induced, BTBR ob/ob diabetic nephropathy models. Hence, we demonstrated the important role of PTENK27-polyUb in DKD and a promising therapeutic strategy that inhibited the progression of DKD.
Pregnancy poses a unique challenge to the human immune system: the semi-allogeneic fetus must be protected from maternal immune attack while immunity towards pathogens is maintained. Breakdown in ...maternal-fetal tolerance can lead to pregnancy-specific diseases with potentially high degrees of morbidity and mortality for both the mother and her fetus. Various immune cell-types could mediate these functions, but a comprehensive evaluation of the peripheral and local maternal T cell and regulatory T cell compartments in normal human pregnancy is lacking. In this case-control study, we apply the Human Immunology Project Consortium proposed gating strategies to samples from healthy 3rd trimester human subjects compared with healthy non-pregnant controls. The proportions of HLA-DR+ and CD38+ effector- and effector memory CD8 T cells are significantly increased in the peripheral blood of pregnant women. Utilizing a novel technique that takes advantage of the standard protocol for intrauterine cleanup after cesarean section, we isolate lymphocytes resident at the uteroplacental interface (UPI). At the UPI, the CD4 and CD8 T cell compartments largely mirror the peripheral blood, except that the proportion of HLA-DR+ activated T regulatory cells is significantly increased in direct proportion to an observed increase in the number of activated CD8 T cells. We find that cryopreservation and delayed sample processing (>12 hours) decreases our ability to identify regulatory T cell subsets. Further, the Consortium proposed method for Treg identification underrepresents Resting and Cytokine Tregs compared with Activated Tregs, thus skewing the entire population. Better understanding of the changes in the immune system during pregnancy in the peripheral blood and at the uteroplacental interface are essential for progress in treatment of pregnancy diseases such as pre-eclampsia and recurrent miscarriage.
How tumor cells genetically lose antigenicity and evade immune checkpoints remains largely elusive. We report that tissue-specific expression of the human long noncoding RNA LINK-A in mouse mammary ...glands initiates metastatic mammary gland tumors, which phenotypically resemble human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate and inhibitory G-protein-coupled receptor (GPCR) pathways, attenuating protein kinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48-polyubiquitination-mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb and p53, and sensitized mammary gland tumors to immune checkpoint blockers. Patients with programmed ccll death protein-1(PD-1) blockade-resistant TNBC exhibited elevated LINK-A levels and downregulated PLC components. Hence we demonstrate lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which provides the basis for developing combinational immunotherapy treatment regimens and early TNBC prevention.
The placenta promotes fetal growth through nutrient transfer and selective barrier systems. An optimally developed placenta can adapt to changes in the pregnancy environment, buffering the fetus from ...adverse exposures. We hypothesized that the placenta adapts differently to suboptimal maternal diets, evidenced by changes in placental morphology, developmental markers and key transport systems. Mice were fed a control diet (CON) during pregnancy, undernourished (UN) by 30% of control intake from gestational day (GD) 5.5–18.5 or fed 60% high-fat diet (HF) 8 weeks before and during pregnancy. At GD18.5, placental morphometry, development and transport were assessed. Junctional and labyrinthine areas of UN and HF placentae were smaller than CON by >10%. Fetal blood space area and fetal blood space:fetal weight ratios were reduced in HF vs. CON and UN. Trophoblast giant cell marker Ctsq mRNA expression was lower in UN vs. HF, and expression of glycogen cell markers Cx31.1 and Pcdh12 was lower in HF vs. UN. Efflux transporter Abcb1a mRNA expression was lower in HF vs. UN, and Abcg2 expression was lower in UN vs. HF. mRNA expression of fatty acid binding protein Fabppm was higher in UN vs. CON and HF. mRNA and protein levels of the lipid transporter FAT/CD36 were lower in UN, and FATP4 protein levels were lower in HF vs. UN. UN placentae appear less mature with aberrant transport, whereas HF placentae adapt to excessive nutrient supply. Understanding placental adaptations to common nutritional adversities may reveal mechanisms underlying the developmental origins of later disease.
Immune checkpoint inhibitors (ICIs) have been increasingly used in combination for cancer treatment but are associated with myocarditis. Here, we report that tumor-bearing mice exhibited response to ...treatment with combinatorial anti-programmed cell death 1 and anti-cytotoxic T lymphocyte antigen-4 antibodies but also presented with cardiovascular toxicities observed clinically with ICI therapy, including myocarditis and arrhythmia. Female mice were preferentially affected with myocarditis compared to male mice, consistent with a previously described genetic model of ICI myocarditis and emerging clinical data. Mechanistically, myocardial tissue from ICI-treated mice, the genetic mouse model, and human heart tissue from affected patients with ICI myocarditis all exhibited down-regulation of
(mesencephalic astrocyte-derived neurotrophic factor) and
(heat shock 70-kDa protein 5) in the heart; this down-regulation was particularly notable in female mice. ICI myocarditis was amplified by heart-specific genetic deletion of mouse
and was attenuated by administration of recombinant MANF protein, suggesting a causal role. Ironically, both
and
were transcriptionally induced by liganded estrogen receptor β and inhibited by androgen receptor. However, ICI treatment reduced serum estradiol concentration to a greater extent in female compared to male mice. Treatment with an estrogen receptor β-specific agonist and androgen depletion therapy attenuated ICI-associated cardiac effects. Together, our data suggest that ICI treatment inhibits estradiol-dependent expression of
in the heart, curtailing the cardiomyocyte response to immune injury. This endocrine-cardiac-immune pathway offers new insights into the mechanisms of sex differences in cardiac disease and may offer treatment strategies for ICI myocarditis.
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