Strengths-weaknesses-opportunities-threats analysis of artificial intelligence in anesthesiology and perioperative medicine.

The use of artificial intelligence (AI) and machine learning (ML) in anesthesiology and perioperative medicine is quickly becoming a mainstay of clinical practice. Anesthesiology is a data-rich medical specialty that integrates multitudes of patient-specific information. Perioperative medicine is ripe for applications of AI and ML to facilitate data synthesis for precision medicine and predictive assessments. Examples of emergent AI models include those that assist in assessing depth and modulating control of anesthetic delivery, event and risk prediction, ultrasound guidance, pain management, and operating room logistics. AI and ML support analyzing integrated perioperative data at scale and can assess patterns to deliver optimal patient-specific care. By exploring the benefits and limitations of this technology, we provide a basis of considerations for evaluating the adoption of AI models into various anesthesiology workflows. This analysis of AI and ML in anesthesiology and perioperative medicine explores the current landscape to understand better the strengths, weaknesses, opportunities, and threats (SWOT) these tools offer.

LOXL2 inhibition ameliorates pulmonary artery remodeling in pulmonary hypertension.

Background: Conduit pulmonary arterial stiffening and the resultant increase in pulmonary vascular impedance has emerged as an important underlying driver of pulmonary arterial hypertension (PAH). Given that matrix deposition is central to vascular remodeling, we evaluated the role of the collagen crosslinking enzyme lysyl oxidase like 2 (LOXL2) in this study. Methods and Results: Human pulmonary artery smooth muscle cells (PASMCs) subjected to hypoxia showed increased LOXL2 secretion. LOXL2 activity and expression were markedly higher in primary PASMCs isolated from pulmonary arteries of the rat Sugen 5416 + hypoxia (SuHx) model of severe PH. Similarly, LOXL2 protein and mRNA levels were increased in pulmonary arteries (PA) and lungs of rats with PH (SuHx and monocrotaline (MCT) models). Pulmonary arteries (PAs) isolated from rats with PH exhibited hypercontractility to phenylephrine and attenuated vasorelaxation elicited by acetylcholine, indicating severe endothelial dysfunction. Tensile testing revealed a a significant increase in PA stiffness in PH. Treatment with PAT-1251, a novel small-molecule LOXL2 inhibitor, improved active and passive properties of the PA ex vivo. There was an improvement in right heart function as measured by right ventricular pressure volume loops in-vivo with PAT-1251. Importantly PAT-1251 treatment ameliorated PH, resulting in improved pulmonary artery pressures, right ventricular remodeling, and survival. Conclusion: Hypoxia induced LOXL2 activation is a causal mechanism in pulmonary artery stiffening in PH, as well as pulmonary artery mechanical and functional decline. LOXL2 inhibition with PAT-1251 is a promising approach to improve pulmonary artery pressures, right ventricular elastance, cardiac relaxation, and survival in PAH. New & Noteworthy: Pulmonary arterial stiffening contributes to the progression of PAH and the deterioration of right heart function. This study shows that LOXL2 is upregulated in rat models of PH. LOXL2 inhibition halts pulmonary vascular remodeling and improves PA contractility, endothelial function and improves PA pressure, resulting in prolonged survival. Thus, LOXL2 is an important mediator of PA remodeling and stiffening in PH and a promising target to improve PA pressures and survival in PH.

Adenosine A2A Receptor Regulates microRNA-181b Expression in Aorta: Therapeutic Implications for Large-Artery Stiffness.

Background The identification of large-artery stiffness as a major, independent risk factor for cardiovascular disease-associated morbidity and death has focused attention on identifying therapeutic strategies to combat this disorder. Genetic manipulations that delete or inactivate the translin/trax microRNA-degrading enzyme confer protection against aortic stiffness induced by chronic ingestion of high-salt water (4%NaCl in drinking water for 3 weeks) or associated with aging. Therefore, there is heightened interest in identifying interventions capable of inhibiting translin/trax RNase activity, as these may have therapeutic efficacy in large-artery stiffness. Methods and Results Activation of neuronal adenosine A2A receptors (A2ARs) triggers dissociation of trax from its C-terminus. As A2ARs are expressed by vascular smooth muscle cells (VSMCs), we investigated whether stimulation of A2AR on vascular smooth muscle cells promotes the association of translin with trax and, thereby increases translin/trax complex activity. We found that treatment of A7r5 cells with the A2AR agonist CGS21680 leads to increased association of trax with translin. Furthermore, this treatment decreases levels of pre-microRNA-181b, a target of translin/trax, and those of its downstream product, mature microRNA-181b. To check whether A2AR activation might contribute to high-salt water-induced aortic stiffening, we assessed the impact of daily treatment with the selective A2AR antagonist SCH58261 in this paradigm. We found that this treatment blocked aortic stiffening induced by high-salt water. Further, we confirmed that the age-associated decline in aortic pre-microRNA-181b/microRNA-181b levels observed in mice also occurs in humans. Conclusions These findings suggest that further studies are warranted to evaluate whether blockade of A2ARs may have therapeutic potential in treating large-artery stiffness.

Pro-Con Debate: Should Code Sharing Be Mandatory for Publication?

In this Pro-Con commentary article, we discuss whether or not code sharing should be mandatory for scientific publications. Scientific programming is an increasingly prevalent tool in research. However, there are not unified guidelines for code availability requirements. Some journals require code sharing. Others require code descriptions. Yet others have no policies around code sharing. The Pro side presented here argues that code sharing should be mandatory for all scientific publications involving code. This Pro argument comes in 2 parts. First, any defensible reason for not sharing code is an equally valid a reason for the manuscript itself not being published. Second, lack of code sharing requirements creates 2 tiers of science: one where reproducibility is required and one where it is not. Additionally, the Pro authors suggest that a debate over code sharing is itself a decade out-of-date due to the emerging availability of containerization and virtual environment sharing software. The Pro argument concludes with an appeal that authors release code to make their work more understandable by other researchers. The Con side presented here argues that computer source codes of medical technology equipment should not be subject to mandatory public disclosure. The source code is a crucial part of what makes a particular device unique and allows that device to outperform its competition. The Con authors believe that public disclosure of this proprietary information would destroy all incentives for businesses to develop new and improved technologies. Competition in the free marketplace is what drives companies to constantly improve their products, to develop new and better medical devices. The open disclosure of these "trade secret" details would effectively end that competitive drive. Why invest time, money, and energy developing a "better mousetrap" if your competitors can copy it and produce it the next day?

Artificial Intelligence in Perioperative Medicine: A Proposed Common Language With Applications to FDA-Approved Devices.

As implementation of artificial intelligence grows more prevalent in perioperative medicine, a clinician's ability to distinguish differentiating aspects of these algorithms is critical. There are currently numerous marketing and technical terms to describe these algorithms with little standardization. Additionally, the need to communicate with algorithm developers is paramount to actualize effective and practical implementation. Of particular interest in these discussions is the extent to which the output or predictions of algorithms and tools are understandable by medical practitioners. This work proposes a simple nomenclature that is intelligible to both clinicians and developers for quickly describing the interpretability of model results. There are three high-level categories: transparent, translucent, and opaque. To demonstrate the applicability and utility of this terminology, these terms were applied to the artificial intelligence and machine-learning-based products that have gained Food and Drug Administration approval. During this review and categorization process, 22 algorithms were found with perioperative utility (in a database of 70 total algorithms), and 12 of these had publicly available citations. The primary aim of this work is to establish a common nomenclature that will expedite and simplify descriptions of algorithm requirements from clinicians to developers and explanations of appropriate model use and limitations from developers to clinicians.

Extracellular Vesicles From Women With Severe Preeclampsia Impair Vascular Endothelial Function.

BACKGROUND: Preeclampsia (PE) manifesting as hypertension and organ injury is mediated by vascular dysfunction. In biological fluids, extracellular vesicles (EVs) containing microRNA (miRNA), protein, and other cargo released from the placenta may serve as carriers to propagate injury, altering the functional phenotype of endothelial cells. PE has been consistently correlated with increased levels of placenta-derived EVs (pEVs) in maternal circulation. However, whether pEVs impaired endothelial cell function remains to be determined. In this study, we hypothesize that pEVs from pregnant women with severe PE (sPE) impair endothelial function through altered cell signaling. METHODS: We obtained plasma samples from women with sPE (n = 14) and normotensive pregnant women (n = 15) for the isolation of EVs. The total number of EV and pEV contribution was determined by quantifying immunoreactive EV-cluster of designation 63 (CD63) and placental alkaline phosphatase (PLAP) as placenta-specific markers, respectively. Vascular endothelial functional assays were determined by cell migration, electric cell-substrate impedance sensing in human aortic endothelial cells (HAECs), and wire myography in isolated blood vessels, preincubated with EVs from normotensive and sPE women. RESULTS: Plasma EV and pEV levels were increased in sPE when compared to normotensive without a significant size distribution difference in sPE (108.8 ± 30.2 nm) and normotensive-EVs (101.3 ± 20.3 nm). Impaired endothelial repair and proliferation, reduced endothelial barrier function, reduced endothelial-dependent vasorelaxation, and decreased nitrite level indicate that sPE-EVs induced vascular endothelial dysfunction. Moreover, sPE-EVs significantly downregulated endothelial nitric oxide synthase (eNOS and p-eNOS) when compared to normotensive-EV. CONCLUSIONS: EVs from sPE women impair endothelial-dependent vascular functions in vitro.

Deciphering the Role of microRNAs in Large-Artery Stiffness Associated With Aging: Focus on miR-181b.

Large artery stiffness (LAS) is a major, independent risk factor underlying cardiovascular disease that increases with aging. The emergence of microRNA signaling as a key regulator of vascular structure and function has stimulated interest in assessing its role in the pathophysiology of LAS. Identification of several microRNAs that display age-associated changes in expression in aorta has focused attention on defining their molecular targets and deciphering their role in age-associated arterial stiffening. Inactivation of the microRNA-degrading enzyme, translin/trax, which reverses the age-dependent decline in miR-181b, confers protection from aging-associated arterial stiffening, suggesting that inhibitors targeting this enzyme may have translational potential. As LAS poses a major public health challenge, we anticipate that future studies based on these advances will yield innovative strategies to combat aging-associated arterial stiffening.

Degradation of Premature-miR-181b by the Translin/Trax RNase Increases Vascular Smooth Muscle Cell Stiffness.

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Identification of novel bladder sensory GPCRs.

Sensory GPCRs such as olfactory receptors (ORs), taste receptors (TRs), and opsins (OPNs) are now known to play important physiological roles beyond their traditional sensory organs. Here, we systematically investigate the expression of sensory GPCRs in the urinary bladder for the first time. We find that the murine bladder expresses 16 ORs, 7 TRs, and 3 OPNs. We additionally explore the ectopic expression of these GPCRs in tissues beyond the bladder, as well as the localization within the bladder. In future work, understanding the functional roles of these bladder sensory GPCRs may shed light on novel mechanisms which modulate bladder function in health and disease.

Acetate, a Short-Chain Fatty Acid, Acutely Lowers Heart Rate and Cardiac Contractility Along with Blood Pressure.

Short-chain fatty acids (SCFAs) are metabolites produced almost exclusively by the gut microbiota and are an essential mechanism by which gut microbes influence host physiology. Given that SCFAs induce vasodilation, we hypothesized that they might have additional cardiovascular effects. In this study, novel mechanisms of SCFA action were uncovered by examining the acute effects of SCFAs on cardiovascular physiology in vivo and ex vivo. Acute delivery of SCFAs in conscious radiotelemetry-implanted mice results in a simultaneous decrease in both mean arterial pressure and heart rate (HR). Inhibition of sympathetic tone by the selective ß-1 adrenergic receptor antagonist atenolol blocks the acute drop in HR seen with acetate administration, yet the decrease in mean arterial pressure persists. Treatment with tyramine, an indirect sympathomimetic, also blocks the acetate-induced acute drop in HR. Langendorff preparations show that acetate lowers HR only after long-term exposure and at a smaller magnitude than seen in vivo. Pressure-volume loops after acetate injection show a decrease in load-independent measures of cardiac contractility. Isolated trabecular muscle preparations also show a reduction in force generation upon SCFA treatment, though only at supraphysiological concentrations. These experiments demonstrate a direct cardiac component of the SCFA cardiovascular response. These data show that acetate affects blood pressure and cardiac function through parallel mechanisms and establish a role for SCFAs in modulating sympathetic tone and cardiac contractility, further advancing our understanding of the role of SCFAs in blood pressure regulation. SIGNIFICANCE STATEMENT: Acetate, a short-chain fatty acid, acutely lowers heart rate (HR) as well as mean arterial pressure in vivo in radiotelemetry-implanted mice. Acetate is acting in a sympatholytic manner on HR and exerts negative inotropic effects in vivo. This work has implications for potential short-chain fatty acid therapeutics as well as gut dysbiosis-related disease states.

Opsin 3-Gαs Promotes Airway Smooth Muscle Relaxation Modulated by G Protein Receptor Kinase 2.

Recently, we characterized blue light-mediated relaxation (photorelaxation) of airway smooth muscle (ASM) and implicated the involvement of opsin 3 (OPN3), an atypical opsin. In the present study, we characterized the cellular signaling mechanisms of photorelaxation. We confirmed the functional role of OPN3 in blue light photorelaxation using trachea from OPN3 null mice (maximal relaxation 52 ± 13% compared with wild-type mice 90 ± 4.3%, P < 0.05). We then demonstrated colocalization of OPN3 and Gαs using co-IP and proximity ligation assays in primary human ASM cells, which was further supported by an increase in cAMP in mouse trachea treated with blue light compared with dark controls (23 ± 3.6 vs. 14 ± 2.6 pmol cAMP/ring, P < 0.05). Downstream PKA (protein kinase A) involvement was shown by inhibiting photorelaxation using Rp-cAMPS (P < 0.0001). Moreover, we observed converging mechanisms of desensitization by chronic ß2-agonist exposure in mouse trachea and correlated this finding with colocalization of OPN3 and GRK2 (G protein receptor kinase) in primary human ASM cells. Finally, an overexpression model of OPN1LW (a red light photoreceptor in the same opsin family) in human ASM cells showed an increase in intracellular cAMP levels following red light exposure compared with nontransfected cells (48 ± 13 vs. 13 ± 2.1 pmol cAMP/mg protein, P < 0.01), suggesting a conserved photorelaxation mechanism for wavelengths of light that are more tissue penetrant. Together, these results demonstrate that blue light photorelaxation in ASM is mediated by the OPN3 receptor interacting with Gαs, which increases cAMP levels, activating PKA and modulated by GRK2.

Light-Mediated Inhibition of Colonic Smooth Muscle Constriction and Colonic Motility via Opsin 3.

Opsin photoreceptors outside of the central nervous system have been shown to mediate smooth muscle photorelaxation in several organs. We hypothesized that opsin receptor activation in the colon would have a similar effect and influence colonic motility. We detected Opsin 3 (OPN3) protein expression in the colonic wall and demonstrated that OPN3 was present in enteric neurons in the muscularis propria of the murine colon. Precontracted murine colon segments demonstrated blue light (BL) -mediated relaxation ex vivo. This photorelaxation was wavelength specific and was increased with the administration of the chromophore 9-cis retinal and a G protein receptor kinase 2 (GRK2) inhibitor. Light-mediated relaxation of the colon was not inhibited by L-NAME or tetrodotoxin (TTX). Furthermore, BL exposure in the presence of 9-cis retinal decreased the frequency of colonic migrating motor complexes (CMMC) in spontaneously contracting mouse colons ex vivo. These results demonstrate for the first time a receptor-mediated photorelaxation of colonic smooth muscle and implicate opsins as possible new targets in the treatment of spasmodic gastrointestinal dysmotility.

Aging and chronic high-fat feeding negatively affect kidney size, function, and gene expression in CTRP1-deficient mice.

C1q/TNF-related protein 1 (CTRP1) is an endocrine factor with metabolic, cardiovascular, and renal functions. We previously showed that aged Ctrp1-knockout (KO) mice fed a control low-fat diet develop renal hypertrophy and dysfunction. Since aging and obesity adversely affect various organ systems, we hypothesized that aging, in combination with obesity induced by chronic high-fat feeding, would further exacerbate renal dysfunction in CTRP1-deficient animals. To test this, we fed wild-type and Ctrp1-KO mice a high-fat diet for 8 mo or longer. Contrary to our expectation, no differences were observed in blood pressure, heart function, or vascular stiffness between genotypes. Loss of CTRP1, however, resulted in an approximately twofold renal enlargement (relative to body weight), ∼60% increase in urinary total protein content, and elevated pH, and changes in renal gene expression affecting metabolism, signaling, transcription, cell adhesion, solute and metabolite transport, and inflammation. Assessment of glomerular integrity, the extent of podocyte foot process effacement, as well as renal response to water restriction and salt loading did not reveal significant differences between genotypes. Interestingly, blood platelet, white blood cell, neutrophil, lymphocyte, and eosinophil counts were significantly elevated, whereas mean corpuscular volume and hemoglobin were reduced in Ctrp1-KO mice. Cytokine profiling revealed increased circulating levels of CCL17 and TIMP-1 in KO mice. Compared with our previous study, current data suggest that chronic high-fat feeding affects renal phenotypes differently than similarly aged mice fed a control low-fat diet, highlighting a diet-dependent contribution of CTRP1 deficiency to age-related changes in renal structure and function.

Role of exosomal microRNA signatures: An emerging factor in preeclampsia-mediated cardiovascular disease.

Preeclampsia (PE) and vascular dysfunction are major causes of maternal and neonatal morbidity and mortality. Although extensively studied, the complete understanding of the pathophysiology behind PE remains unclear. Current reports indicate that exosomes are essential mediators in PE-related cardiovascular disease (CVDs). Exosomes are synthesized from multivesicular bodies (MVB) and contain functionally active microRNAs miRNAs). These miRNAs have been shown to mediate physiological and pathological functions through autocrine, paracrine, and endocrine signaling mechanisms. The role of miRNAs in pregnant women with PE has been studied extensively. However, little is known about the effect of exosomal miRNAs (exomiR) in PE. This paper will review and discuss the existing evidence for exomiR function in PE and highlight the need for future studies to explore the role that exomiR signatures have in cardiovascular dysfunction associated with PE.

The bio-sonographic index. A novel modality for early detection of acute kidney injury after complex vascular surgery. A protocol for an exploratory prospective study.

OBJECTIVE: Acute kidney injury (AKI) is a common complication of complex aortic surgery with high mortality, morbidity and health care expense. The current definition of AKI does not allow for structural characterization of the kidneys and utilizes functional indices with substantial limitations leading to delayed diagnosis and ineffective interventions. The aim of this study is to develop a method of early detection of structural renal abnormalities that can precede and predict the occurrence of AKI in this population. We propose a novel combined index of ultrasonography (shear wave elastography), biomarkers of renal stress (urinary insulin growth factor binding protein-7, IGFBP-7 and inhibitor of tissue metalloproteinase-2, TIMP-2) and renal injury markers (urinary neutrophil gelatinase-associated lipocalin -NGAL)- the bio-sonographic index (BSI). METHODS: A prospective observational study at a tertiary referral center will be performed enrolling 80 patients undergoing elective open and endovascular repair of the visceral aorta. The BSI will be evaluated at baseline, and at 6 and 24 hours after the procedure. The primary outcome is the occurrence of AKI according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria. Each patient will be his/her own control. A reference group of 15 healthy volunteers who are not undergoing interventions will be enrolled to test the feasibility of and to refine the novel SWE protocol. The BSI will be tested for its predictability of the occurrence of AKI. Comparisons will be made between individual and combined components of the BSI and traditional markers used in the KDIGO definition; serum creatinine and urine output in terms of baseline status of the kidney. Correlations will be made between the BSI and conventional indices of AKI and exploratory analyses will be conducted to identify individual disease patterns using the BSI. DISCUSSION: We hypothesize that the BSI will be a sensitive index of early structural abnormalities that precede and predict the occurrence of AKI as defined by KDIGO in complex vascular surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT04144894. Registered 1/6/2020.