Increased Virtual Visits to Physicians During the COVID-19 Pandemic and Estimated Impact on Physician Compensation: The Case of Lung and Colorectal Cancers, Chronic Obstructive Pulmonary Diseases, and Heart Failure in Alberta, Canada.

Introduction: The COVID-19 pandemic started in Alberta in March 2020 and significantly increased telehealth service use and provision reducing the risk of virus transmission. We examined the change in the number and proportion of virtual visits by physician specialty and condition (chronic obstructive pulmonary diseases [COPD], heart failure [HF], colorectal and lung cancers), as well as associated changes in physician compensation. Methods: A population-based design was used to analyze all processed physician claims comparing the number and proportion of virtual visits and associated physician billings relative to in-person between pre- (2019/2020) and intra-pandemic (2020/2021). Physician compensations were the claim amounts paid by the health insurance. Results: Pre-pandemic (intra-), there were 8,981 (8,897) lung cancer, 9,245 (9,029) colorectal, 37,558 (36,292) HF, and 68,270 (52,308) COPD patients. Each patient had totally 2.3-4.7 (of which 0.4-0.6% were virtual) general practitioner (GP) visits and 0.9-2.3 (0.2-0.7% were virtual) specialist visits per year pre-pandemic. The average number and proportion of per-patient virtual visits to GPs and specialists grew significantly pre- to intra-pandemic by 2,138-4,567%, and 2,201-7,104%, respectively. Given the lower fees of virtual compared with in-person visits, the reduction in physician compensation associated with the increased use of virtual care was estimated at $3.85 million, with $2.44 million attributed to specialist and $1.41 million to GP. Discussion: Utilization of telehealth increased significantly, while the physician billings per patient and physician compensation declined early in the pandemic in Alberta for the four chronic diseases considered. This study forms the basis for future study in understanding the impact of virtual care, now part of the fabric of health care delivery, on quality of care and patient safety, overall health service utilization (such as diagnostic imaging and other investigations), as well as economic impacts to patients, health care systems, and society.

Contrast Echocardiography in Heart Failure: Update 2023.

PURPOSE OF REVIEW: The application of ultrasound-enhancing agents (contrast agents) has improved the accuracy and reproducibility of echocardiography. The review focuses on the currently approved and evolving indications for contrast echocardiography in patients with heart failure, specifically examining clinical studies conducted after the publication of the guidelines in 2017 and 2018. RECENT FINDINGS: The current ASE/EACVI recommendations for contrast echocardiography are based on its accuracy and reproducibility in comparison to non-enhanced echocardiography or other imaging modalities like cardiac MRI. However, tissue characterization remains limited with contrast echocardiography. During the last few years, several studies have demonstrated the clinical impact of using contrast agents on the management of patients with heart failure. There is growing evidence on the benefit of using contrast echocardiography in critically ill patients where echocardiography without contrast agents is often suboptimal and other imaging methods are less feasible. There is no risk of worsening renal function after the administration of ultrasound-enhancing agents, and these agents can be administered even in patients with end-stage renal disease. Contrast echocardiography has become a valuable tool for first-line imaging of patients with heart failure across the spectrum of patients with chronic heart failure to critically ill patients.

Applicability of the Global Lung Function Initiative prediction equations in Hong Kong Chinese children.

BACKGROUND AND OBJECTIVE: This study aimed to assess the applicability of the Global Lung Function Initiative (GLI) prediction equations for spirometry in Hong Kong children and to develop prediction equations based on the Generalized Additive Models for Location, Scale, and Shape (GAMLSS) modeling. METHODS: Healthy Chinese children and adolescents aged 6-17 years old were recruited from randomly selected schools to undergo spirometry. The measurements were transformed to z-score according to the GLI-2012 equations for South East (SE) Asians and the GLI-2022 global race-neutral equations. Prediction equations for spirometric indices were developed with GAMLSS modeling to identify predictors. RESULTS: A total of 886 children (477 boys) with a mean age of 12.5 years (standard deviation [SD] 3.3 years) were included. By the GLI-2012 SE Asian equations, positive mean z-scores were observed in forced expiratory volume in 1 s (FEV1 ) (boys: 0.138 ± SD 0.828; girls: 0.206 ± 0.823) and forced vital capacity (FVC) (boys: 0.160 ± 0.930; girls: 0.310 ± 0.895) in both sexes. Negative mean z-scores were observed in FEV1 /FVC ratio (boys: -0.018 ± 0.998; girls: -0.223 ± 0.897). In contrast, negative mean z-scores in FEV1 and FVC, and positive mean z-scores in FEV1 /FVC were observed when adopting the GLI-2022 race-neutral equations. The mean z-scores were all within the range of ±0.5. By GAMLSS models, age and height were significant predictors for all four spirometric indices, while weight was an additional predictor for FVC and FEV1 . CONCLUSION: Our study provided data supporting the applicability of the GLI prediction equations in Hong Kong Chinese children. The GLI-2012 equations may underestimate FEV1 and FVC, while the GLI-2022 equations may overestimate the parameters, but the differences lie within the physiological limits. By GAMLSS modeling, weight was an additional predictor for FVC and FEV1 .

A Systems-Level Evaluation Framework for Virtual Care.

The virtual care landscape is significantly changing, largely due to an increased demand initiated by the COVID-19 pandemic and the evolution of technology. Complex questions about how to best leverage virtual care and its impact remain unanswered. Our team developed a systems-level evaluation framework to inform virtual care service design and evaluation to take a more comprehensive approach to planning and implementing virtual care. We designed the framework for application in Alberta Health Services (AHS) by engaging virtual care users (patients, families and healthcare providers), implementation staff and decision makers across the organization. Here we report our design process and key lessons learned. The framework received endorsement by AHS senior leadership for application across the system. Our next step is to test the framework. By sharing our design process and experiences, we aim to help inform other national and international jurisdictions plan virtual care evaluations within their context.

The complex web of FasL: cell type-specific roles in affecting and controlling acute graft-vs-host disease.

FasL has divergent roles in both causing graft-vs-host disease and preventing this condition, which depends on the immune cell type that expresses it.

Cytokine induction of HIF-1α during normoxia in A549 human lung carcinoma cells is regulated by STAT1 and JNK signalling pathways.

Hypoxia inducible factor-1ɑ (HIF-1ɑ) is the regulatory subunit of the HIF-1 transcription factor that is a regulator of cell physiological responses to hypoxia. However, the biological function and regulatory mechanisms controlling HIF-1α in normoxia are poorly understood. Here, we first examined the role of HIF-1α in the inflammatory activation of A549 human lung carcinoma cells in normoxia. Inactivation of the HIF-1α gene by CRISPR/Cas9 reduced the secretion of CXCL8 induced by stimulation with a cytokine mixture (CM) consisting of IL-1, TNFα and IFNγ. We next determined that cytokines act co-operatively to induce expression and nuclear accumulation of HIF-1α. To investigate the signalling mechanisms by which cytokines induce HIF-1α in normoxia, pharmacological inhibitors against the Jak/STAT, PI3K, NFκB, MEK/ERK, and JNK pathways were used. Inhibition of the Jak/STAT and JNK pathways inhibited the induction and nuclear accumulation of HIF-1ɑ by cytokines. Furthermore, siRNA knockdown of STAT1 and JNK also reduced the induction of HIF-1α by cytokines. Finally, pharmacological inhibition of these two pathways also blocked the trans-activation of HIF-1. These findings have implications for understanding the role and regulatory mechanisms of HIF-1ɑ in inflammation and cell biology.

Dysbiosis of the Female Murine Gut Microbiome Exacerbates Neutrophil-mediated Vascular Allograft Injury by Affecting Immunoregulation by Acetate.

BACKGROUND: The gut microbiota affects immune responses that cause organ transplant rejection, but the mechanisms by which this occurs remain poorly understood. METHODS: We have examined, in a murine model, how disruption of the gut microbiota with antibiotics early in life alters this microbial community later in life to affect immune responses that injure vascular allografts. RESULTS: Analysis of 16S rRNA and whole genome sequencing of the gut microbiota demonstrated that early life disruption of this microbial community with antibiotics caused a reduction in taxa and enzymatic genes involved in the synthesis of acetate, an immunoregulatory metabolite in mice and humans. When allograft vascular injury was examined, early life disruption of the gut microbiota increased neutrophil accumulation and related medial injury of transplanted arteries. Normalizing the gut microbiota by co-housing and oral administration of acetate prevented neutrophil-mediated vascular allograft injury. CONCLUSIONS: Dysbiosis of the gut microbiome that reduces its production of the immunoregulatory metabolite acetate exacerbates neutrophil-mediated allograft vascular injury.

Prevention of vascular-allograft rejection by protecting the endothelial glycocalyx with immunosuppressive polymers.

Systemic immunosuppression for the mitigation of immune rejection after organ transplantation causes adverse side effects and constrains the long-term benefits of the transplanted graft. Here we show that protecting the endothelial glycocalyx in vascular allografts via the enzymatic ligation of immunosuppressive glycopolymers under cold-storage conditions attenuates the acute and chronic rejection of the grafts after transplantation in the absence of systemic immunosuppression. In syngeneic and allogeneic mice that received kidney transplants, the steric and immunosuppressive properties of the ligated polymers largely protected the transplanted grafts from ischaemic reperfusion injury, and from immune-cell adhesion and thereby immunocytotoxicity. Polymer-mediated shielding of the endothelial glycocalyx following organ procurement should be compatible with clinical procedures for transplant preservation and perfusion, and may reduce the damage and rejection of transplanted organs after surgery.

High-Throughput Screening to Identify Small Molecules That Selectively Inhibit APOL1 Protein Level in Podocytes.

High-throughput phenotypic screening is a key driver for the identification of novel chemical matter in drug discovery for challenging targets, especially for those with an unclear mechanism of pathology. For toxic or gain-of-function proteins, small-molecule suppressors are a targeting/therapeutic strategy that has been successfully applied. As with other high-throughput screens, the screening strategy and proper assays are critical for successfully identifying selective suppressors of the target of interest. We executed a small-molecule suppressor screen to identify compounds that specifically reduce apolipoprotein L1 (APOL1) protein levels, a genetically validated target associated with increased risk of chronic kidney disease. To enable this study, we developed homogeneous time-resolved fluorescence (HTRF) assays to measure intracellular APOL1 and apolipoprotein L2 (APOL2) protein levels and miniaturized them to 1536-well format. The APOL1 HTRF assay served as the primary assay, and the APOL2 and a commercially available p53 HTRF assay were applied as counterscreens. Cell viability was also measured with CellTiter-Glo to assess the cytotoxicity of compounds. From a 310,000-compound screening library, we identified 1490 confirmed primary hits with 12 different profiles. One hundred fifty-three hits selectively reduced APOL1 in 786-O, a renal cell adenocarcinoma cell line. Thirty-one of these selective suppressors also reduced APOL1 levels in conditionally immortalized human podocytes. The activity and specificity of seven resynthesized compounds were validated in both 786-O and podocytes.

Lack of APOL1 in proximal tubules of normal human kidneys and proteinuric APOL1 transgenic mouse kidneys.

The mechanism of pathogenesis associated with APOL1 polymorphisms and risk for non-diabetic chronic kidney disease (CKD) is not fully understood. Prior studies have minimized a causal role for the circulating APOL1 protein, thus efforts to understand kidney pathogenesis have focused on APOL1 expressed in renal cells. Of the kidney cells reported to express APOL1, the proximal tubule expression patterns are inconsistent in published reports, and whether APOL1 is synthesized by the proximal tubule or possibly APOL1 protein in the blood is filtered and reabsorbed by the proximal tubule remains unclear. Using both protein and mRNA in situ methods, the kidney expression pattern of APOL1 was examined in normal human and APOL1 bacterial artificial chromosome transgenic mice with and without proteinuria. APOL1 protein and mRNA was detected in podocytes and endothelial cells, but not in tubular epithelia. In the setting of proteinuria, plasma APOL1 protein did not appear to be filtered or reabsorbed by the proximal tubule. A side-by-side examination of commercial antibodies used in prior studies suggest the original reports of APOL1 in proximal tubules likely reflects antibody non-specificity. As such, APOL1 expression in podocytes and endothelia should remain the focus for mechanistic studies in the APOL1-mediated kidney diseases.

Overlapping and distinct biological effects of IL-6 classic and trans-signaling in vascular endothelial cells.

IL-6 affects tissue protective/reparative and inflammatory properties of vascular endothelial cells (ECs). This cytokine can signal to cells through classic and trans-signaling mechanisms, which are differentiated based on the expression of IL-6 receptor (IL-6R) on the surface of target cells. The biological effects of these IL-6-signaling mechanisms are distinct and have implications for vascular pathologies. We have directly compared IL-6 classic and trans-signaling in ECs. Human ECs expressed IL-6R in culture and in situ in coronary arteries from heart transplants. Stimulation of human ECs with IL-6, to model classic signaling, triggered the activation of phosphatidylinositol 3-kinase (PI3K)-Akt and ERK1/2 signaling pathways, whereas stimulation with IL-6 + sIL-6R, to model trans-signaling, triggered activation of STAT3, PI3K-Akt, and ERK1/2 pathways. IL-6 classic signaling reduced persistent injury of ECs in an allograft model of vascular rejection and inhibited cell death induced by growth factor withdrawal. When inflammatory effects were examined, IL-6 classic signaling did not induce ICAM or CCL2 expression but was sufficient to induce secretion of CXCL8 and support transmigration of neutrophil-like cells. IL-6 trans-signaling induced all inflammatory effects studied. Our findings show that IL-6 classic and trans-signaling have overlapping but distinct properties in controlling EC survival and inflammatory activation. This has implications for understanding the effects of IL-6 receptor-blocking therapies as well as for vascular responses in inflammatory and immune conditions.

First Case of Regression of Carcinoid Heart Disease on Serial Transthoracic Echocardiograms following Octreotide Monotherapy in a Patient with Metastatic Pancreatic Neuroendocrine Tumor.

Well-differentiated neuroendocrine tumors (NETs) arising in the gastrointestinal (GI) tract and pancreas are relatively rare; however, the annual incidence has been increasing. Carcinoid syndrome (CS) is a constellation of symptoms that occur when a GI NET metastasizes to the liver and releases high levels of vasoactive substances into the systemic circulation. CS occurs in 19% of NETs patients at diagnosis and is associated with shorter survival. Carcinoid heart disease (CHD) occurs in over 50% of patients with CS and is associated with poor long-term prognosis. NET-induced valvular fibrosis is a significant cause of mortality and morbidity in these patients. Somatostatin analogs relieve CS symptoms, but they have never been shown to reverse CHD progression or improve overall survival. Surgical therapy for right-sided valve disease is associated with improved symptoms and quality of life and possibly improved survival, despite relatively high morbidity and mortality associated with cardiac intervention. A 65-year-old woman with a metastatic pancreatic NET had typical signs and symptoms of CS. She presented in congestive heart failure and was found to have severe tricuspid regurgitation with characteristic features of CHD on transthoracic echocardiogram (TTE). Following octreotide monotherapy, serial TTEs demonstrated regression of tricuspid valve involvement. The patient improved clinically and remained asymptomatic on subsequent visits. This is the first case of CHD regression with medical therapy supported by serial TTEs. Developing a deeper understanding of cases like this will help us unlock new intervention targets and strategies for treatments in the future.

Immunologic Effects of the Microbiota in Organ Transplantation.

The microbiota is a community of microbes that colonizes body surfaces. It has many effects that influence immune activation and regulation. The success of organ transplantation is limited by rejection of grafts by the immune system so it is important to understand how immunologic responses are controlled in this setting. This review discusses the immunologic effects of the microbiota and how this microbial community may affect organ transplant rejection.

Expression of human inducible nitric oxide synthase in response to cytokines is regulated by hypoxia-inducible factor-1.

The production of nitric oxide (NO) by inducible NO synthase (iNOS) and the regulation of gene expression by hypoxia-inducible factors (HIFs) are important for many aspects of human cell biology. However, little is known about whether iNOS expression is controlled by HIFs in human cells. Stimulation of A549 human lung epithelial cells with cytokines (TNF, IL-1 and IFNγ) increased the nuclear accumulation of HIF-1 in normoxic conditions. Activation of HIF-1 by hypoxia or CoCl2 was not sufficient to induce iNOS expression. However, pharmacological inhibition of HIF-1 reduced the induction of iNOS expression in A549 cells and primary human astrocytes. Moreover, elimination of HIF-1α expression and activity by CRISPR/Cas9 gene editing significantly reduced the induction of human iNOS gene promoter, mRNA and protein expression by cytokine stimulation. Three putative hypoxia response elements (HRE) are present within the human iNOS gene promoter and elimination of an HRE at -4981 bp reduced the induction of human iNOS promoter activity in response to cytokine stimulation. These findings establish an important role for HIF-1α in the induction of human iNOS gene expression in response to cytokine stimulation.

The Mechanism of Mitral Regurgitant Jets Identified by 3-Dimensional Transesophageal Echocardiography.

This study is a case report, which presents a case of severe mitral regurgitation in a 77-year-old man. Two-dimensional transesophageal echocardiography (TEE), regurgitant jets directed anteriorly in early systole and centrally to laterally in late systole were seen, while three-dimensional TEE showed a flail posterior middle scallop not only angulated centrally, but also laterally, which provided insight into the mechanism of mitral regurgitant jet direction. This case demonstrates the clinical usefulness of 3-dimensional TEE for identifying the mechanism of mitral regurgitant jets. The institution where the figures and the videos were recorded: Division of Cardiology, Mazankowski Alberta Heart Institute, University of Alberta Hospital, Edmonton, Alberta, Canada.

What is the minimum change in left ventricular ejection fraction, which can be measured with contrast echocardiography?

BACKGROUND: There are limited data on what is the minimum change that can be detected in cancer patients undergoing treatment with cardiotoxic drugs and are referred for monitoring left ventricular (LV) function. OBJECTIVE: To assess the variability in the measurement of LV volumes and ejection fraction (EF) in contrast echocardiography and to determine the minimum detectable difference (MDD) between two EF measurements that can be deemed significant. METHODS: A total of 150 patients were divided into three groups according to EF (EF <53, 53-60, and >60%). Each group consisted of 50 randomly selected cancer patients who underwent contrast echocardiography between July 2010 and May 2014. Repeated measurements of LV volumes and EF were performed offline by a sonographer and a cardiologist. Inter-observer variability was assessed by analysis of variance. Measurement error was estimated by standard error of measurement and MDD. RESULTS: The 95% confidence interval with a single measurement of EF was 2 percentage points in the groups of patients with EF <53% and EF >60%, and 2.5 percentage points for patients with EF 53-60%. The MDD for EF, end-diastolic volume and end-systolic volume that could be recognized with 95% confidence interval were 4 percentage points, 7 mL and 4 mL, respectively. CONCLUSION: Contrast echocardiography is a reliable tool for serial measurements of EF to monitor cardiotoxicity due to chemotherapy. In a high-volume echocardiography laboratory with experienced staff, the MDD for EF of 4 percentage points on a good-quality recording demonstrates the high reproducibility of the Simpson's method using contrast echocardiography.

Disruption of the Gut Microbiota With Antibiotics Exacerbates Acute Vascular Rejection.

BACKGROUND: The gut microbiota influences many immunological processes but how its disruption affects transplant rejection is poorly understood. METHODS: Interposition grafting of aortic segments was used to examine vascular rejection. The gut microbiota was disrupted in graft recipients using an antibiotic cocktail (ampicillin, vancomycin, metronidazole, neomycin sulfate) in their drinking water. RESULTS: Treatment of mice with antibiotics severely reduced total bacterial content in the intestine and disrupted the bacterial composition. Short-term treatment of mice for only the first 3 weeks of life resulted in the population of the intestine in mature mice with bacterial communities that were mildly different from untreated mice, containing slightly more Clostridia and less Bacteroides. Antibiotic disruption of the gut microbiota of graft recipients, either for their entire life or only during the first 3 weeks of life, resulted in increased medial injury of allograft arteries that is reflective of acute vascular rejection but did not affect intimal thickening reflective of transplant arteriosclerosis. Exacerbated vascular rejection resulting from disruption of the gut microbiota was related to increased infiltration of allograft arteries by neutrophils. CONCLUSIONS: Disruption of the gut microbiota early in life results in exacerbation of immune responses that cause acute vascular rejection.