Publications by authors named "Christopher Chan"

393 Publications

Quality of Life in Caregivers of Patients Randomized to Standard- Versus Extended-Hours Hemodialysis.

Kidney Int Rep 2021 Apr 1;6(4):1058-1065. Epub 2021 Feb 1.

Department of Nephrology, Sunshine Coast University Hospital, Birtinya, Australia.

Introduction: Caregivers are essential for the health, safety, and independence of many patients and incur financial and personal cost in this role, including increased burden and lower quality of life (QOL) compared to the general population. Extended-hours hemodialysis may be the preference of some patients, but little is known about its effects on caregivers.

Methods: Forty caregivers of participants of the ACTIVE Dialysis trial, who were randomized to 12 months extended (median 24 hours/wk) or standard (12 hours/wk) hemodialysis, were included. Utility-based QOL was measured by EuroQOL-5 Dimension-3 Level (EQ-5D-3L) and Short Form-6 Dimensions (SF-6D) and health-related QOL (HRQOL) was measured by the 36-Item Short Form Health Survey (SF-36) physical component summary (PCS) and mental component summary (MCS) and the Personal Wellbeing Index (PWI) at enrolment and then every 3 months until the end of the study.

Results: At baseline, utility-based QOL and HRQOL were similar in both groups. At follow-up, caregivers of people randomized to extended-hours dialysis experienced a greater decrease in utility-based QOL measured by EQ-5D-3L compared with caregivers of people randomized to standard hours (-0.18±0.30 vs. -0.02±0.16,  = 0.04). There were no differences between extended- and standard-hours groups in mean change in SF-6D (0.03±0.12 vs. -0.04±0.1,  = 0.8), PCS (-1.2±9.8 vs. -5.6±9.8,  = 0.2), MCS (-4.1±11.2 vs. -0.5±7.1,  = 0.4), and PWI (2.3±17.6 vs. 0.00±20.4,  = 0.9).

Conclusion: Poorer utility-based QOL, as measured by the EQ-5D-3L, was observed in caregivers of patients receiving extended-hours hemodialysis in this small study. Though the findings are exploratory, the possibility that mode of dialysis delivery negatively impacts on caregivers supports the prioritization of research on burden and impact of service delivery in this population.
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http://dx.doi.org/10.1016/j.ekir.2021.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071646PMC
April 2021

Suture osteosynthesis in the bony reconstruction of thumb duplication.

J Hand Surg Eur Vol 2021 Apr 22:17531934211010078. Epub 2021 Apr 22.

Department of Orthopaedic Surgery, KK Women's and Children's Hospital, Singapore, Republic of Singapore.

Metacarpal osteotomies are done to correct deviation deformity in thumb duplication. We describe a suture-only technique of metacarpal osteosynthesis, without using K-wires. Thirteen Flatt Type IV thumbs and five Wassel Type VII thumbs were reconstructed with this technique. The median follow-up was 23 months. After osteotomy, the metacarpal bone fragments were sutured together with 5-0 polyglactin or 4-0 polydioxanone sutures. Metacarpal fragment displacement was not observed on postoperative radiographs obtained at 1 and 2 weeks. Bony union was achieved at 6 weeks without loss of alignment. The metacarpophalangeal joint alignment was anatomical (≤5° deviation) in eight cases. The mean pre- and postoperative metacarpophalangeal joint alignments were 27° and 9°, respectively. The 11 patients who were available for grading with the Japanese Society for Surgery of the Hand Score were assessed as good. Complete internalization of the bony fixation eliminates infections associated with exposed K-wires without compromising the overall outcome. IV.
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http://dx.doi.org/10.1177/17531934211010078DOI Listing
April 2021

Cardiac afferent signaling partially underlies premature ventricular contraction-induced cardiomyopathy.

Heart Rhythm 2021 Apr 9. Epub 2021 Apr 9.

UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program of Excellence, University of California, Los Angeles, California. Electronic address:

Background: The mechanisms underlying premature ventricular contraction (PVC)-induced cardiomyopathy (PIC) remain unknown. Transient receptor potential vanilloid-1 (TRPV1) afferent fibers are implicated in the reflex processing of cardiac stress.

Objective: The purpose of this study was to determine whether cardiac TRPV1 afferent signaling promote PIC.

Methods: A PIC swine model (50% PVC burden) was created via an implanted pacemaker. We selectively depleted cardiac TRPV1 afferent fibers using percutaneous epicardial application of resiniferatoxin (RTX). Animals were randomized to PVC only (n = 11), PVC+RTX (n = 11), or control (n = 6). We examined early-stage (4 weeks after implantation; n = 5) and late-stage PIC (8 weeks after implantation; n = 6). At terminal experimentation, animals underwent echocardiography, serum sampling, and physiological and autonomic reflex testing.

Results: Depletion of cardiac TRPV1 afferents by RTX treatment was confirmed by absent sensory fibers and absent functional responses to TRPV1 activators. Left ventricular ejection fraction was worse in late-stage than early-stage PIC (P <.01). At 4 weeks (early stage), left ventricular ejection fraction was higher in PVC+RTX vs PVC animals (51.7% ± 1.6% vs 45.0% ± 2.1%; P = .030), whereas no significant difference between PVC and PVC+RTX was observed at 8 weeks (late stage). Histologic studies demonstrated reduced fibrosis in PVC+RTX vs PVC alone at 4 weeks (2.27% ± 0.14% vs 3.01% ± 0.21%; P = .020), suggesting that RTX mitigated profibrotic pathways induced by persistent PVCs.

Conclusion: TRPV1 afferent depletion alleviates left ventricular dysfunction in early- but not late-stage PIC. This temporal effect suggests that multiple pathways promote PIC, of which TRPV1 afferents are a part.
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http://dx.doi.org/10.1016/j.hrthm.2021.04.004DOI Listing
April 2021

The use of virtual physician mentoring to enhance home dialysis knowledge and uptake.

Nephrology (Carlton) 2021 Feb 25. Epub 2021 Feb 25.

Division of Nephrology, University Health Network, Toronto, Ontario, Canada.

Home dialysis therapies are flexible kidney replacement strategies with documented clinical benefits. While the incidence of end-stage kidney disease continues to increase globally, the use of home dialysis remains low in most developed countries. Multiple barriers to providing home dialysis have been noted in the published literature. Among known challenges, gaps in clinician knowledge are potentially addressable with a focused education strategy. Recent national surveys in the United States and Australia have highlighted the need for enhanced home dialysis knowledge especially among nephrologists who have recently completed training. Traditional in-person continuing professional educational programmes have had modest success in promoting home dialysis and are limited by scale and the present global COVID-19 pandemic. We hypothesize that the use of a 'Hub and Spoke' model of virtual home dialysis mentorship for nephrologists based on project ECHO would support home dialysis growth. We review the home dialysis literature, known educational gaps and plausible educational interventions to address current limitations in physician education.
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http://dx.doi.org/10.1111/nep.13867DOI Listing
February 2021

Proteomic profiling reveals biomarkers and pathways in type 2 diabetes risk.

JCI Insight 2021 Mar 8;6(5). Epub 2021 Mar 8.

Cardiovascular Institute.

Recent advances in proteomic technologies have made high-throughput profiling of low-abundance proteins in large epidemiological cohorts increasingly feasible. We investigated whether aptamer-based proteomic profiling could identify biomarkers associated with future development of type 2 diabetes (T2DM) beyond known risk factors. We identified dozens of markers with highly significant associations with future T2DM across 2 large longitudinal cohorts (n = 2839) followed for up to 16 years. We leveraged proteomic, metabolomic, genetic, and clinical data from humans to nominate 1 specific candidate to test for potential causal relationships in model systems. Our studies identified functional effects of aminoacylase 1 (ACY1), a top protein association with future T2DM risk, on amino acid metabolism and insulin homeostasis in vitro and in vivo. Furthermore, a loss-of-function variant associated with circulating levels of the biomarker WAP, Kazal, immunoglobulin, Kunitz, and NTR domain-containing protein 2 (WFIKKN2) was, in turn, associated with fasting glucose, hemoglobin A1c, and HOMA-IR measurements in humans. In addition to identifying potentially novel disease markers and pathways in T2DM, we provide publicly available data to be leveraged for insights about gene function and disease pathogenesis in the context of human metabolism.
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http://dx.doi.org/10.1172/jci.insight.144392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021115PMC
March 2021

Simultaneous LeFort III and LeFort I Osteotomies in Craniometaphyseal Dysplasia.

Cleft Palate Craniofac J 2021 Feb 10:1055665621990942. Epub 2021 Feb 10.

Division of Oral and Maxillofacial Surgery, University of Southern California, Los Angeles, CA, USA.

Craniometaphyseal dysplasia (CMD) is a rare genetic disease affecting bone metabolism with sclerosis of craniofacial bones. Orthognathic surgery has rarely been described in this patient population due to the bony thickness, making osteotomies challenging. We present a 19-year-old male with CMD with malocclusion, severe midface hypoplasia, and obstructive sleep apnea. With the aid virtual planning, we safely performed a combined LeFort III/I midface advancement to correct a negative overjet to improve occlusal balance, decrease scleral show, and diminish daytime sleepiness.
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http://dx.doi.org/10.1177/1055665621990942DOI Listing
February 2021

Stable bright perovskite nanoparticle thin porous films for color enhancement in modern liquid crystal displays.

Nanoscale 2021 Apr 4;13(13):6400-6409. Epub 2021 Feb 4.

State Key Laboratory of Advanced Displays and Optoelectronics Technologies, and Centre for Display Research, Department of Electronics and Computer Engineering, The Hong Kong University of Science and Technology, Hong Kong S.A.R, China.

Cesium-lead halide perovskite nanoparticles are a promising class of luminescent materials for color and efficient displays. However, material stability is the key issue to solve before we can use these materials in modern displays. Encapsulation is one of the most efficient methods that can markedly improve the stability of perovskite nanoparticles against moisture, heat, oxygen, and light. Thus, we urgently need a low-cost, reliable, and device-compatible encapsulation method for the integration of nanomaterials into display devices. Here, we propose a facile encapsulation method to stabilize perovskite nanoparticles in thin polymer porous films. Using porous polymer films, we achieved good photoluminescence stability in the harsh environment of high temperature, high humidity and strong UV illumination. The good UV stability benefitted from the unique optical properties of the porous film. Besides, we observed photoluminescence enhancement of CsPbBr nanoparticle films in a high humidity environment. The stable CsPbBr nanoparticle thin porous film provides high brightness (236 nits) and great color enhancement for LCDs and is characterized by simple fabrication with easy scalability, thus it is very suitable for modern LCDs.
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http://dx.doi.org/10.1039/d0nr07313jDOI Listing
April 2021

Risk factors for symptomatic anastomotic postoperative recurrence following ileo-colic resection in Crohn's disease.

Colorectal Dis 2021 Jan 15. Epub 2021 Jan 15.

Department of Colorectal Surgery, Barts Health NHS Trust, The Royal London Hospital, London, UK.

Aim: Crohn's disease is a chronic inflammatory bowel disease characterized by alternating periods of exacerbation and remission. Surgical resection is not curative and postoperative recurrence (POR) remains a challenge in these patients. The aim of this study was to identify clinical variables that influence the risk of symptomatic anastomotic POR in patients with ileo-colonic Crohn's disease.

Method: A retrospective study of Crohn's disease patients who had undergone ileo-colic resection between January 2014 and December 2018 was performed. For each patient, data including demographic information, Crohn's disease clinical setting, preoperative radiological data, operative and histological data, pre- and postoperative medication history and postoperative clinical course, including recurrence of disease, were extracted. Symptomatic anastomotic POR was defined as symptoms of Crohn's disease in the presence of confirmed anastomotic POR (endoscopic and/or radiological POR).

Results: For the study period, 104 patients were eligible and included for analysis. The cumulative probability of symptomatic anastomotic POR was 14%, 30%, 42%, 50% and 50% at 1, 2, 3, 4 and 5 years, respectively. Two clinical variables on multivariate analysis were associated with increased risk of symptomatic anastomotic POR, namely age <17 years at diagnosis [hazard ratio (HR) 2.17, p = 0.019] and gastrointestinal involvement (extent) >30 cm (HR 1.85, p = 0.048).

Conclusion: This study describes the natural history of POR after ileo-colic resection for Crohn's disease, as defined by endoscopic, radiological and clinical outcomes. Age <17 years at diagnosis and gastrointestinal involvement (extent) >30 cm were independent risk factors for symptomatic anastomotic POR.
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http://dx.doi.org/10.1111/codi.15530DOI Listing
January 2021

Inducible Stem-Cell-Derived Embryos Capture Mouse Morphogenetic Events In Vitro.

Dev Cell 2021 Feb 29;56(3):366-382.e9. Epub 2020 Dec 29.

Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK; Division of Biology and Biological Engineering, Caltech, Pasadena, CA 91125, USA. Electronic address:

The development of mouse embryos can be partially recapitulated by combining embryonic stem cells (ESCs), trophoblast stem cells (TS), and extra-embryonic endoderm (XEN) stem cells to generate embryo-like structures called ETX embryos. Although ETX embryos transcriptionally capture the mouse gastrula, their ability to recapitulate complex morphogenic events such as gastrulation is limited, possibly due to the limited potential of XEN cells. To address this, we generated ESCs transiently expressing transcription factor Gata4, which drives the extra-embryonic endoderm fate, and combined them with ESCs and TS cells to generate induced ETX embryos (iETX embryos). We show that iETX embryos establish a robust anterior signaling center that migrates unilaterally to break embryo symmetry. Furthermore, iETX embryos gastrulate generating embryonic and extra-embryonic mesoderm and definitive endoderm. Our findings reveal that replacement of XEN cells with ESCs transiently expressing Gata4 endows iETX embryos with greater developmental potential, thus enabling the study of the establishment of anterior-posterior patterning and gastrulation in an in vitro system.
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http://dx.doi.org/10.1016/j.devcel.2020.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883308PMC
February 2021

Retrospective single center cohort study: effect of intensive home hemodialysis on right ventricular systolic pressure and clinical outcomes.

BMC Nephrol 2020 11 25;21(1):508. Epub 2020 Nov 25.

Division of Nephrology, University Health Network, 200 Elizabeth Street, 8N room 846, Toronto, ON, M5G 2C4, Canada.

Background: Increased right ventricular systolic pressure (RVSP), a surrogate marker for pulmonary hypertension, is common in patients with end-stage kidney disease. Limited data suggest improvement of RVSP with intensive dialysis, but it is unknown whether these improvements translate to better clinical outcomes.

Methods: We conducted a retrospective single center cohort study at the Toronto General Hospital. All patients who performed intensive home hemodialysis (IHHD) for at least a year between 1999 and 2017, and who had a baseline as well as a follow-up echocardiogram more than a year after IHHD, were included. Patients were categorized into two groups based on the RVSP at follow-up: elevated (≥ 35 mmHg) and normal RVSP. Multivariate and cox regression analyses were done to identify risk factors for elevated RVSP at follow-up and reaching the composite endpoint (death, cardiovascular hospitalization, treatment failure), respectively.

Results: One hundred eight patients were included in the study. At baseline, 63% (68/108) of patients had normal RVSP and 37% (40/108) having elevated RVSP. After a follow-up of 4 years, 70% (76/108) patient had normal RVSP while 30% (32/108) had elevated RVSP. 8 (10%) out of the 76 patients with normal RVSP and 15 (47%) out of the 32 patients with elevated RVSP reached the composite endpoint of death, cardiovascular hospitalization or technique failure. In a multivariate analysis, age, diabetes and smoking were not associated with elevated RVSP at follow-up. Elevated RVSP at baseline was not associated with a higher likelihood in reaching the composite endpoint or mortality.

Conclusion: Mean RVSP did not increase in patients on IHHD over time, and maintenance of normal RVSP was associated with better clinical outcomes.
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http://dx.doi.org/10.1186/s12882-020-02159-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687753PMC
November 2020

High-Performance Blue Perovskite Light-Emitting Diodes Enabled by Efficient Energy Transfer between Coupled Quasi-2D Perovskite Layers.

Adv Mater 2021 Jan 20;33(1):e2005570. Epub 2020 Nov 20.

Department of Electrical and Electronic Engineering, The University of Hong Kong, Pokfulam Road, Hong Kong, China.

While there has been extensive investigation into modulating quasi-2D perovskite compositions in light-emitting diodes (LEDs) for promoting their electroluminescence, very few reports have studied approaches involving enhancement of the energy transfer between quasi-2D perovskite layers of the film, which plays very important role for achieving high-performance perovskite LEDs (PeLEDs). In this work, a bifunctional ligand of 4-(2-aminoethyl)benzoic acid (ABA) cation is strategically introduced into the perovskite to diminish the weak van der Waals gap between individual perovskite layers for promoting coupled quasi-2D perovskite layers. In particular, the strengthened interaction between coupled quasi-2D perovskite layers favors an efficient energy transfer in the perovskite films. The introduced ABA can also simultaneously passivate the perovskite defects by reducing metallic Pb for less nonradiative recombination loss. Benefiting from the advanced properties of ABA incorporated perovskites, highly efficient blue PeLEDs with external quantum efficiency of 10.11% and a very long operational stability of 81.3 min, among the best performing blue quasi-2D PeLEDs, are achieved. Consequently, this work contributes an effective approach for high-performance and stable blue PeLEDs toward practical applications.
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http://dx.doi.org/10.1002/adma.202005570DOI Listing
January 2021

Home Hemodialysis and Peritoneal Dialysis Patient and Technique Survival in Canada.

Kidney Int Rep 2020 Nov 26;5(11):1965-1973. Epub 2020 Aug 26.

University Health Network/Toronto General Hospital, Toronto, Ontario, Canada.

Introduction: As interest for home dialysis is growing, knowledge of comparative clinical outcomes between peritoneal dialysis (PD) and home hemodialysis (HHD) would help to better inform shared decision making with patients and caregivers during modality discussion. This study aimed to assess differences in risk of mortality and technique failure in an incident home dialysis cohort and, specifically, to assess change in this association through eras.

Methods: All adults patients initiating PD or HHD, in Canada (excluding Quebec), within 365 days after kidney replacement therapy (KRT) initiation between 2000 and 2013 were included (administrative censoring 31 December 2014). Mortality and treatment failure (transfer to another modality for >90 days or death) were assessed in a multivariable Cox proportional hazard model, with prespecified stratification based on the year of KRT initiation.

Results: The study included 959 HHD and 15,469 PD patients. Compared with incident PD, incident HHD was associated with a lower risk of mortality (adjusted hazard ratio [aHR] = 0.64, 95% confidence interval [CI] = 0.53-0.78), and treatment failure (aHR = 0.52, 95% CI = 0.45-0.60). These lower risks of mortality with HHD were more pronounced for older cohorts (2000-2005: aHR = 0.47, 95% CI = 0.31-0.70; 2006-2010: aHR = 0.70, 95% CI = 0.54-0.89) and not significantly different in the most recent era (2011-2013: aHR = 0.86, 95% CI = 0.51-1.47).

Conclusion: In Canadian incident KRT patients, HHD was associated with appreciably lower risks of mortality and treatment failure compared to PD, although this association appeared to be attenuated in the most contemporary era.
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http://dx.doi.org/10.1016/j.ekir.2020.08.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609902PMC
November 2020

Long-lived and disorder-free charge transfer states enable endothermic charge separation in efficient non-fullerene organic solar cells.

Nat Commun 2020 Nov 5;11(1):5617. Epub 2020 Nov 5.

Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay,, Hong Kong, China.

Organic solar cells based on non-fullerene acceptors can show high charge generation yields despite near-zero donor-acceptor energy offsets to drive charge separation and overcome the mutual Coulomb attraction between electron and hole. Here, we use time-resolved optical spectroscopy to show that free charges in these systems are generated by thermally activated dissociation of interfacial charge-transfer states that occurs over hundreds of picoseconds at room temperature, three orders of magnitude slower than comparable fullerene-based systems. Upon free electron-hole encounters at later times, both charge-transfer states and emissive excitons are regenerated, thus setting up an equilibrium between excitons, charge-transfer states and free charges. Our results suggest that the formation of long-lived and disorder-free charge-transfer states in these systems enables them to operate closely to quasi-thermodynamic conditions with no requirement for energy offsets to drive interfacial charge separation and achieve suppressed non-radiative recombination.
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http://dx.doi.org/10.1038/s41467-020-19332-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645751PMC
November 2020

A Higher Concentration of Dialysate Magnesium to Reduce the Frequency of Muscle Cramps: A Narrative Review.

Can J Kidney Health Dis 2020 22;7:2054358120964078. Epub 2020 Oct 22.

Division of Nephrology, Department of Medicine, Health Sciences Centre, University of Calgary, Calgary, AB, Canada.

Purpose Of Review: Strategies to mitigate muscle cramps are a top research priority for patients receiving hemodialysis. As hypomagnesemia is a possible risk factor for cramping, we reviewed the literature to better understand the physiology of cramping as well as the epidemiology of hypomagnesemia and muscle cramps. We also sought to review the evidence from interventional studies on the effect of oral and dialysate magnesium-based therapies on muscle cramps.

Sources Of Information: Peer-reviewed articles.

Methods: We searched for relevant articles in major bibliographic databases including MEDLINE and EMBASE. The methodological quality of interventional studies was assessed using a modified version of the Downs and Blacks criteria checklist.

Key Findings: The etiology of muscle cramps in patients receiving hemodialysis is poorly understood and there are no clear evidence-based prevention or treatment strategies. Several factors may play a role including a low concentration of serum magnesium. The prevalence of hypomagnesemia (concentration of <0.7 mmol/L) in patients receiving hemodialysis ranges from 10% to 20%. Causes of hypomagnesemia include a low dietary intake of magnesium, use of medications that inhibit magnesium absorption (eg, proton pump inhibitors), increased magnesium excretion (eg, high-dose loop diuretics), and a low concentration of dialysate magnesium. Dialysate magnesium concentrations of ≤0.5 mmol/L may be associated with a decrease in serum magnesium concentration over time. Preliminary evidence from observational and interventional studies suggests a higher dialysate magnesium concentration will raise serum magnesium concentrations and may reduce the frequency and severity of muscle cramps. However, the quality of evidence supporting this benefit is limited, and larger, multicenter clinical trials are needed to further determine if magnesium-based therapy can reduce muscle cramps in patients receiving hemodialysis. In studies conducted to date, increasing the concentration of dialysate magnesium appears to be well-tolerated and is associated with a low risk of symptomatic hypermagnesemia.

Limitations: Few interventional studies have examined the effect of magnesium-based therapy on muscle cramps in patients receiving hemodialysis and most were nonrandomized, pre-post study designs.
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http://dx.doi.org/10.1177/2054358120964078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585892PMC
October 2020

The concurrent use of two long-acting injectables in the maintenance treatment of bipolar disorder.

Bipolar Disord 2020 Oct 30. Epub 2020 Oct 30.

Institute of Mental Health, Singapore, Singapore.

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http://dx.doi.org/10.1111/bdi.13030DOI Listing
October 2020

Perspectives From an Onconephrology Interest Group: Conference Report.

Can J Kidney Health Dis 2020 15;7:2054358120962589. Epub 2020 Oct 15.

Department of Medicine, Division of Nephrology, The Scarborough Hospital, Toronto, ON, Canada.

Introduction And Objective: Onconephrology is a new and evolving field that deals with kidney complications in patients with cancer as well as the management of cancer in patients with preexisting kidney disease. With increasing numbers of patients with cancer with kidney-related complications, the field has garnered increased attention. Thus, an annual Greater Toronto Area Onconephrology Interest Group symposium was held in May 2019. The objective of the meeting was to demonstrate the junctures between oncology and nephrology by highlighting recent data regarding (1) kidney impairment in solid organ malignancies, (2) management and treatment of kidney cancer, (3) kidney impairment in hematologic malignancies, (4) malignancy and kidney transplantation, and (5) hyponatremia in patients with cancer.

Methods And Sources Of Information: Through a structured presentation, the group explored key topics discussed at a Kidney Disease Improving Global Outcomes (KDIGO) Controversies Conference on Onconephrology. Expert opinions, clinical trial findings, and publication summaries were used to illustrate patient and treatment-related considerations in onconephrology.

Key Findings: Kidney complications in patients with cancer are a central theme in onconephrology. An estimated 12% to 25% of patients with solid organ malignancies have chronic kidney disease (CKD), although in certain cancers, the prevalence of CKD is higher. Kidney impairment is also a common complication of some hematologic malignancies. The incidence of renal failure in patients with multiple myeloma is estimated at 18% to 56% and light chain cast nephropathy is seen in approximately 30% of these patients. In addition, there appears to be a bidirectional relationship between kidney cancer and CKD, with some data sets suggesting the risk increases as kidney function declines. Cancer is also of concern in patients with preexisting kidney disease. Kidney transplant recipients have a greater risk of cancer and a higher risk of cancer-related mortality. Kidney complications have also been associated with novel cancer therapies, such as immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapy. An estimated 2% to 4% of patients initiating an immune checkpoint inhibitor may develop nephrotoxicity, whereas up to 40% of patients on CAR T-cell therapy experience cytokine release syndrome (CRS). Tumor lysis syndrome and electrolyte abnormalities, such as hyponatremia, have also been reported with CAR T-cell therapy. While the incidence and prevalence of hyponatremia vary depending on the cancer type and serum sodium cutoff point, hyponatremia may be seen in up to 46% of patients hospitalized in cancer centers.

Conclusions: Onconephrology is a developing field and the themes arising from this meeting indicate a need for greater collaboration between oncologists and nephrologists. Educational symposia and onconephrology fellowship programs may allow for improved cancer care for patients with kidney disease.
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http://dx.doi.org/10.1177/2054358120962589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573731PMC
October 2020

Evaluating dialysis adequacy: Origins, evolution, and future directions.

Semin Dial 2020 Nov 16;33(6):468-474. Epub 2020 Oct 16.

Division of Nephrology, University Health Network, Toronto, Canada.

The expansion and transformation over time of dialysis therapies have been inexorably linked to the concept of adequacy. While initially the goal of dialysis was simple survival of patients until their next treatment, this changed with the publication of the National Cooperative Dialysis Study. It brought about a focus on defining adequate dialysis through measurements of the removal of small solutes, in particular urea. This spurred significant improvements in patient outcomes by standardizing therapy and providing benchmarks for each center to achieve. Over time, however, further research has found this narrow definition of adequacy to be insufficient to encompass the complexities of dialysis therapies. Factors such as residual kidney function (RKF), nutritional and volume status, and cardiovascular control all contribute to the outcomes for dialysis patients. We propose that an optimal definition of adequacy should not only focus on one factor but rather the interconnection and contribution to our patient's individual specific goals and their overall quality of life.
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http://dx.doi.org/10.1111/sdi.12926DOI Listing
November 2020

Response to: Loutradis et al. Longer Dialysis Sessions Improve Cardiac Systolic Function by Reducing Myocardial Stunning.

J Card Fail 2020 11 3;26(11):1028-1029. Epub 2020 Sep 3.

The George Institute for Global Health and University of New South Wales, Sydney, Australia; Renal Unit, Concord Repatriation General Hospital, Sydney, Australia.

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http://dx.doi.org/10.1016/j.cardfail.2020.09.001DOI Listing
November 2020

The need for outpatient back-up for home hemodialysis patients: Implications for resource utilization.

Hemodial Int 2020 10 7;24(4):454-459. Epub 2020 Aug 7.

Division of Nephrology, University Health Network, Toronto, Ontario, Canada.

Introduction: The provision of sufficient support contributes to home hemodialysis (HHD) technique survival. The need for back-up treatment in incident and prevalent patients on HHD has not been well described previously, and is important from both technique survival and resource allocation. We aimed to quantify the amount of back-up treatment given to patients in our HHD unit, and hypothesized that the provision of back-up HD facilitated technique survival.

Methods: This was a retrospective, single-center cohort study quantifying the provision of back-up HD between January and December 2018. Electronic and paper medical records were accessed for data collection.

Findings: One hundred and nineteen patients dialyzed independently at home during the study period (96 patient years of HHD). Seventy-eight (66%) patients required a total of 292 back-up HD sessions in the HHD unit, representing an average of three back-up HD runs per patient year of HHD. Fifty-three percent of back-up HD runs were required for vascular access related issues. The most common clinical issue requiring assessment and back-up HD was extracellular fluid volume management. An equal proportion (95%) of those that utilized back-up HD and those that did not utilize back-up HD maintained a positive disposition (transplant or ongoing HHD) in relation to technique survival in the short term.

Conclusions: From a resource viewpoint, this program of approximately 100 HHD patients required the availability of one to two staffed HD stations each weekday for back-up HD. The provision of back-up HD was not a harbinger of HHD discontinuation.
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http://dx.doi.org/10.1111/hdi.12856DOI Listing
October 2020

Delocalization of exciton and electron wavefunction in non-fullerene acceptor molecules enables efficient organic solar cells.

Nat Commun 2020 Aug 7;11(1):3943. Epub 2020 Aug 7.

State Key Laboratory of Luminescent Materials and Devices, Institute of Polymer Optoelectronic Materials and Devices, School of Materials Science and Engineering, South China University of Technology, 381 Wushan Road, 510640, Guangzhou, P. R. China.

A major challenge for organic solar cell (OSC) research is how to minimize the tradeoff between voltage loss and charge generation. In early 2019, we reported a non-fullerene acceptor (named Y6) that can simultaneously achieve high external quantum efficiency and low voltage loss for OSC. Here, we use a combination of experimental and theoretical modeling to reveal the structure-property-performance relationships of this state-of-the-art OSC system. We find that the distinctive π-π molecular packing of Y6 not only exists in molecular single crystals but also in thin films. Importantly, such molecular packing leads to (i) the formation of delocalized and emissive excitons that enable small non-radiative voltage loss, and (ii) delocalization of electron wavefunctions at donor/acceptor interfaces that significantly reduces the Coulomb attraction between interfacial electron-hole pairs. These properties are critical in enabling highly efficient charge generation in OSC systems with negligible donor-acceptor energy offset.
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http://dx.doi.org/10.1038/s41467-020-17867-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414148PMC
August 2020

Changes in pulmonary restrictive parameters by intensive home hemodialysis: a case report.

BMC Nephrol 2020 08 3;21(1):322. Epub 2020 Aug 3.

Division of Nephrology, University of Toronto, 200 Elizabeth Street, 8N room 846, Toronto, ON, M5G 2C4, Canada.

Background: Patients with End-Stage Renal Disease (ESRD) are at an increased risk for restrictive lung disease due to accumulation of uremic toxins and volume overload. Hemodialysis is the preferred treatment for improving lung function in dialysis patients. However, the effects of fluid removal and solute clearance by hemodialysis on lung function remain unclear.

Case Presentation: We report a case of restrictive lung disorder in a hemodialysis patient, who showed improvement in both clinical and spirometric lung function after initiation of intensive home hemodialysis (32 h per week).

Conclusion: Intensive hemodialysis augments fluid removal and solute clearance, which in turn may improve restrictive lung function.
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http://dx.doi.org/10.1186/s12882-020-01977-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397629PMC
August 2020

Liver X receptors are required for thymic resilience and T cell output.

J Exp Med 2020 10;217(10)

Center for Systems Biology and Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

The thymus is a primary lymphoid organ necessary for optimal T cell development. Here, we show that liver X receptors (LXRs)-a class of nuclear receptors and transcription factors with diverse functions in metabolism and immunity-critically contribute to thymic integrity and function. LXRαβ-deficient mice develop a fatty, rapidly involuting thymus and acquire a shrunken and prematurely immunoinhibitory peripheral T cell repertoire. LXRαβ's functions are cell specific, and the resulting phenotypes are mutually independent. Although thymic macrophages require LXRαβ for cholesterol efflux, thymic epithelial cells (TECs) use LXRαβ for self-renewal and thymocytes for negative selection. Consequently, TEC-derived LXRαβ protects against homeostatic premature involution and orchestrates thymic regeneration following stress, while thymocyte-derived LXRαβ limits cell disposal during negative selection and confers heightened sensitivity to experimental autoimmune encephalomyelitis. These results identify three distinct but complementary mechanisms by which LXRαβ governs T lymphocyte education and illuminate LXRαβ's indispensable roles in adaptive immunity.
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http://dx.doi.org/10.1084/jem.20200318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537384PMC
October 2020

Acute kidney injury associated with immune checkpoint inhibitor therapy: incidence, risk factors and outcomes.

J Immunother Cancer 2020 06;8(1)

Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada

Background: Immune checkpoint inhibitors (ICPi) are a novel and promising anti-cancer therapy. There are limited data on the incidence, risk factors and outcomes of acute kidney injury (AKI) in patients receiving ICPi.

Methods: We conducted a cohort study of patients receiving ICPi at our center between 2010 and 2017 via electronic health record. The primary outcome was AKI (increase of >50% from baseline serum creatinine (sCr)). Risk factors for AKI were assessed using logistic regression. Survival among those with and without AKI was compared using the Kaplan-Meier method.

Results: Among 309 patients on ICPi, 51 (16.5%) developed AKI (Kidney Disease Improving Global Outcomes (KDIGO) stages 1: 53%, 2: 22%, 3: 25%). AKI was associated with other immune-related adverse events (IRAE) (OR 3.2, 95% CI 1.6 to 6; p<0.001), hypertension (OR 4.3, 95% CI 1.8 to 6.1; p<0.001) and cerebrovascular disease (OR 9.2; 95% CI 2.1 to 40; p<0.001). Baseline sCr, cancer, and ICPi type was not associated with AKI. Use of angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (OR 2.9; 95% CI 1.5 to 5.7; p=0.002), diuretics (OR 4.3; 95% CI 1.9 to 9.8; p<0.001), and corticosteroid treatment (OR 1.9; 95% CI 1.1 to 3.6; p=0.03) were associated with AKI. In the multivariable analysis, AKI was associated only with other IRAE (OR 2.82; 95% CI 1.45 to 5.48; p=0.002) and hypertension (OR 2.96; 95% CI 1.33 to 6.59; p=0.008). AKI was not associated with increased risk of mortality (HR 1.1; 95% CI: 0.8 to 1.6; p=0.67). ICPi nephrotoxicity was attributed via biopsy or nephrologist assessment in 12 patients (six interstitial nephritis, two membranous nephropathy, two minimal change disease, and two thrombotic microangiopathy). Subsequent doses of ICPi were administered to 12 patients with prior AKI, with one (8.3%) having recurrent AKI.

Conclusion: AKI is a common complication in patients receiving ICPi treatment. The development of other IRAE and previous diagnosis of hypertension were associated with increased AKI risk. AKI was not associated with worse survival. Distinguishing kidney IRAE from other causes of AKI will present a frequent challenge to oncology and nephrology practitioners. Kidney biopsy should be considered to characterize kidney lesions and guide potential therapy.
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http://dx.doi.org/10.1136/jitc-2019-000467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326260PMC
June 2020

No evidence of a legacy effect on survival following randomization to extended hours dialysis in the ACTIVE Dialysis trial.

Nephrology (Carlton) 2020 Oct 2;25(10):792-800. Epub 2020 Jul 2.

Renal and Metabolic Division, The George Institute for Global Health and University of New South Wales, Sydney, New South Wales, Australia.

Aim: Extended hours haemodialysis is associated with superior survival to standard hours. However, residual confounding limits the interpretation of this observation. We aimed to determine the effect of a period of extended hours dialysis on long-term survival among participants in the ACTIVE Dialysis trial.

Methods: Two-hundred maintenance haemodialysis recipients were randomized to extended hours dialysis (median 24 h/wk) or standard hours dialysis (median 12 h/wk) for 12 months. Further pre-specified observational follow up occurred at 24, 36 and 60 months. Vital status and modality of renal replacement therapy were ascertained.

Results: Over the 5 years, 38 participants died, 30 received a renal transplant, and 6 were lost to follow up. Total weekly dialysis hours did not differ between standard and extended groups during the follow-up period (14.1 hours [95%CI 13.4-14.8] vs 14.8 hours [95%CI 14.1-15.6]; P = .16). There was no difference in all-cause mortality (hazard ratio for extended hours 0.91 [95%CI 0.48-1.72]; P = .77). Similar results were obtained after censoring participants at transplantation, and after adjusting for potential confounding variables. Subgroup analysis did not reveal differences in treatment effect by region, dialysis setting or vintage (P-interaction .51, .54, .12, respectively).

Conclusion: Twelve months of extended hours dialysis did not improve long-term survival nor affect dialysis hours after the intervention period. An urgent need remains to further define the optimal dialysis intensity across the broad range of dialysis recipients.
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http://dx.doi.org/10.1111/nep.13737DOI Listing
October 2020

Abdominal wall mesh infection presenting with ammonia encephalopathy.

IDCases 2020 18;21:e00822. Epub 2020 May 18.

Royal London Hospital, Whitechapel Road, London, E1 1FR, United Kingdom.

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http://dx.doi.org/10.1016/j.idcr.2020.e00822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251763PMC
May 2020

Ventricular ejection fraction over time in patients on intensive home hemodialysis: A retrospective cohort study.

Hemodial Int 2020 07 10;24(3):290-298. Epub 2020 May 10.

Division of Nephrology, University Health Network, Toronto, Ontario, Canada.

Introduction: Intensive hemodialysis has been demonstrated to have several beneficial cardiovascular effects. There is a paucity of studies examining the effect of intensive home hemodialysis (IHHD) on left ventricular ejection fraction (LVEF).

Methods: We conducted a retrospective cohort study at the Toronto General Hospital including all IHHD patients between 1999 and 2017 with baseline and follow-up echocardiograms for at least a year. Patients were categorized according to LVEF at follow-up: patients with normal and patients with abnormal LVEF and/or a decline in LVEF. Normal LVEF was defined as ≥55% and a decline as ≥5% at follow-up compared to baseline Cox regression analyses were performed to ascertain the association between reduced LVEF and reaching the composite endpoint of death, cardiovascular hospitalization, and technique failure, respectively. Multivariate logistic analysis was used to investigate possible risk factors for changes in LVEF.

Findings: A total of 154 patients were included in the study. At baseline, 18.8% (29/154) of patients had reduced LVEF. After a mean follow-up of 3.9 years, overall mean LVEF did not change (59.3% [at follow-up] vs. 59.9% [baseline], P = 0.45). Seventeen out of the 130 patients with normal LVEF (13.1%) and nine out of the 24 with abnormal LVEF (37.9%) reached the composite endpoint of death, cardiovascular hospitalization, or technique failure. Reduced LVEF at baseline odds ratio ((OR) 13.26 [95% confidence interval (CI) 4.62-38.05]) as well as coronary heart disease (OR 7.82 [95% CI 1.92-31.82]) were associated with reduced ejection fraction at follow-up. When adjusted for age and diabetes, patients with abnormal LVEF were more likely to reach the composite endpoint hazard ratio ((HR) 3.85, 95% CI 1.70-8.71). We did not identify a risk factor associated with progression or worsening of LVEF.

Discussion: Preserved LVEF occurs in most patients on IHHD and is associated with better clinical outcomes. Further studies are needed to identify the mechanism affecting left ventricular function in patients undergoing intensive hemodialysis.
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http://dx.doi.org/10.1111/hdi.12838DOI Listing
July 2020

Two Are Better Than One: A Design Principle for Ultralong-Persistent Luminescence of Pure Organics.

Adv Mater 2020 Jun 22;32(22):e2001026. Epub 2020 Apr 22.

Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, 999077, China.

Because of their innate ability to store and then release energy, long-persistent luminescence (LPL) materials have garnered strong research interest in a wide range of multidisciplinary fields, such as biomedical sciences, theranostics, and photonic devices. Although many inorganic LPL systems with afterglow durations of up to hours and days have been reported, organic systems have had difficulties reaching similar timescales. In this work, a design principle based on the successes of inorganic systems to produce an organic LPL (OLPL) system through the use of a strong organic electron trap is proposed. The resulting system generates detectable afterglow for up to 7 h, significantly longer than any other reported OLPL system. The design strategy demonstrates an easy methodology to develop organic long-persistent phosphors, opening the door to new OLPL materials.
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http://dx.doi.org/10.1002/adma.202001026DOI Listing
June 2020

Predictors of Change in Left-Ventricular Structure and Function in a Trial of Extended Hours Hemodialysis.

J Card Fail 2020 Jun 14;26(6):482-491. Epub 2020 Apr 14.

The George Institute for Global Health and University of New South Wales, Sydney, Australia; Renal Unit, Concord Repatriation General Hospital, Sydney, Australia.

Background: Myocardial pathology is common in patients undergoing hemodialysis. To explore the effects of differing aspects of dialysis treatment on its evolution, we examined the impact of change in markers of volume status, hemodynamics and solute clearance on left ventricular (LV) parameters in a randomized trial of extended hours dialysis.

Methods And Results: A Clinical Trial of IntensiVE (ACTIVE) Dialysis randomized 200 patients undergoing hemodialysis to extended dialysis hours (≥ 24 hours/week) or standard hours (12-18 hours/week) for 12 months. In a prespecified substudy, 95 participants underwent cardiac magnetic resonance imaging (CMR) at baseline and at the study's end. Generalized linear regression was used to model the relationship between changes in LV parameters and markers of volume status (normalized ultrafiltration rate and total weekly interdialytic weight gain), hemodynamic changes (systolic and diastolic blood pressure) and solute control (urea clearance, dialysis hours and phosphate). Randomization to extended hours dialysis was not associated with change in any CMR parameter. Reduction in ultrafiltration rate was associated with reduction in LV mass index (P = 0.049) and improved ejection fraction (P = 0.024); reduction in systolic blood pressure was also associated with improvement in ejection fraction (P = 0.045); reduction in interdialytic weight gain was associated with reduced stroke volume (P = 0.038). There were no associations between change in urea clearance, phosphate or total hours per week and CMR parameters.

Conclusions: Reduction in ultrafiltration rate and blood pressure are associated with improved myocardial parameters in hemodialysis recipients independently of solute clearance or dialysis time. These findings underscore the importance of fluid status and related parameters as potential treatment targets in this population.
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http://dx.doi.org/10.1016/j.cardfail.2020.03.010DOI Listing
June 2020

Cardiovascular Benefits of Extended-Time Nocturnal Hemodialysis.

Curr Vasc Pharmacol 2021 ;19(1):21-33

Humber River Hospital, University of Toronto, Toronto, Canada.

Hemodialysis (HD) remains the most utilized treatment for End-Stage Kidney Disease (ESKD) globally, mainly as conventional HD administered in 4 h sessions thrice weekly. Despite advances in HD delivery, patients with ESKD carry a heavy cardiovascular morbidity and mortality burden. This is associated with cardiac remodeling, left ventricular hypertrophy (LVH), myocardial stunning, hypertension, decreased heart rate variability, sleep apnea, coronary calcification and endothelial dysfunction. Therefore, intensive HD regimens closer to renal physiology were developed. They include longer, more frequent dialysis or both. Among them, Nocturnal Hemodialysis (NHD), carried out at night while asleep, provides efficient dialysis without excessive interference with daily activities. This regimen is closer to the physiology of the native kidneys. By providing increased clearance of small and middle molecular weight molecules, NHD can ameliorate uremic symptoms, control hyperphosphatemia and improve quality of life by allowing a liberal diet and free time during the day. Lastly, it improves reproductive biology leading to successful pregnancies. Conversion from conventional to NHD is followed by improved blood pressure control with fewer medications, regression of LVH, improved LV function, improved sleep apnea, and stabilization of coronary calcifications. These beneficial effects have been associated, among others, with better extracellular fluid volume control, improved endothelial- dependent vasodilation, decreased total peripheral resistance, decreased plasma norepinephrine levels and restoration of heart rate variability. Some of these effects represent improvements in outcomes used as surrogates of hard outcomes related to cardiovascular morbidity and mortality. In this review, we consider the cardiovascular effects of NHD.
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http://dx.doi.org/10.2174/1570161118666200401112106DOI Listing
January 2021

Hematogenous Donor Cell Routing Pathway After Transamniotic Stem Cell Therapy.

Stem Cells Dev 2020 06 29;29(12):755-760. Epub 2020 Apr 29.

Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Donor mesenchymal stem cells (MSCs) have been documented in fetal and maternal circulations after plain intra-amniotic injection, with diverse therapeutic effects. We sought to determine the pathway of this unique cell kinetic route. Rat fetuses ( = 226) were divided into two groups based on the content of intra-amniotic injections performed on gestational day 17 (E17): either a concentrated suspension of luciferase-labeled syngeneic amniotic fluid-derived MSCs (afMSCs;  = 111), or acellular luciferase ( = 115). Samples from placenta, chorion, amnion, amniotic fluid, stomach fluid, peripheral blood, and umbilical cord were procured at five daily time points thereafter until term (E18-22) for luminometry. In addition, 53 sets of fresh gestational membranes (chorion/amnion combined) from nonmanipulated term fetuses were secured to transwell inserts for in vitro analysis of MSC migration using luciferase-labeled afMSCs. Statistical analyses included the Mann-Whitney -test, Wald test, nonlinear regression modeling, and Fisher's exact test. In vivo, luciferase activity was observed in the amnion, chorion, and placenta of fetuses receiving cells, but not in those receiving acellular luciferase ( < 0.001). There was a consistent nonlinear age-dependent relationship of luciferase activity between the amnion, chorion, and placenta following a parabolic bimodal pattern characterized by significantly higher early preterm (E18) and late-term (E22) activities ( < 0.001), with no differences between E21 and E22 ( = 0.12). In vitro, the presence of cells was documented by luminometry in 21/53 (39.6%) of the assays, in suspension and/or attached to the plastic substrate, and within all screened gestational membrane sets, irrespective of stimuli with collagen coating or fetal bovine serum. We conclude that, after intra-amniotic injection, donor MSCs undergo controlled cell routing, as opposed to passive clearance. Transgestational membrane transport appears to constitute the path for donor cells to reach the placenta, a known gateway to the fetal circulation, significantly expanding the potential applications of transamniotic stem cell therapy.
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http://dx.doi.org/10.1089/scd.2020.0012DOI Listing
June 2020