Non-invasive assessment of proarrhythmic risks associated with isoprenaline and the dietary supplement ingredient synephrine using human induced pluripotent stem cell-derived cardiomyocytes.

Background: There have been conflicting reports about the proarrhythmic risk of p-synephrine (SYN). To address this, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with the microelectrode array (MEA) system have been utilized to assess arrhythmia risks, particularly in the context of adrenomimetic drugs. Aim: This study aims to determine whether MEA recordings from hiPSC-CMs could predict the proarrhythmic risk of adrenomimetic drugs and to investigate the cardiovascular effects and mechanisms of SYN. Materials and methods: We employed MEA recordings to assess the electrophysiological properties of hiPSC-CMs and conducted concentration-response analyses to evaluate the effects of SYN and Isoprenaline (ISO) on beating rate and contractility. A risk scoring system for proarrhythmic risks was established based on hiPSC-CMs in this study. ISO, a classic beta-adrenergic drug, was also evaluated. Furthermore, the study evaluated the risk of SYN and recorded the concentration-response of beating rate, contractility and the change in the presence or absence of selective ß1, ß2 and ß3 adrenergic blockers. Results: Our results suggested that ISO carries a high risk of inducing arrhythmias, aligning with existing literature. SYN caused a 30% prolongation of the field potential duration (FPD) at a concentration of 206.326 µM, a change significantly different from baseline measurements and control treatments. The half maximal effective concentration (EC50) of SYN (3.31 µM) to affect hiPSC-CM beating rate is much higher than that of ISO (18.00 nM). The effect of SYN at an EC50 of 3.31 µM is about ten times more potent in hiPSC-CMs compared to neonatal rat cardiomyocytes (34.12 µM). SYN increased the contractility of cardiomyocytes by 29.97 ± 11.65%, compared to ISO's increase of 50.56 ± 24.15%. ß1 receptor blockers almost eliminated the beating rate increase induced by both ISO and SYN, while neither ß2 nor ß3 blockers had a complete inhibitory effect. Conclusion: The MEA and hiPSC-CM system could effectively predict the risk of adrenomimetic drugs. The study concludes that the proarrhythmia risk of SYN at conventional doses is low. SYN is more sensitive in increasing beating rate and contractility in human cardiomyocytes compared to rats, primarily activating ß1 receptor.

Factors Influencing Adoption and Use of Telemedicine Services in Rural Areas of China: Mixed Methods Study.

BACKGROUND: The shortage of medical resources in rural China reflects the health inequity in resource-limited settings, whereas telemedicine could provide opportunities to fill this gap. However, evidence of patient acceptance of telemedicine services from low- and middle-income countries is still lacking. OBJECTIVE: We aimed to understand the profile of patient end-user telemedicine use and identify factors influencing telemedicine service use in rural China. METHODS: Our study followed a mixed methods approach, with a quantitative cross-sectional survey followed by in-depth semistructured interviews to describe telemedicine use and its associated factors among rural residents in Guangdong Province, China. In the quantitative analysis, explanatory variables included environmental and context factors, household-level factors, individual sociodemographic factors, access to digital health care, and health needs and demand factors. We conducted univariate and multivariate analyses using Firth logistic regression to examine the correlations of telemedicine uptake. A thematic approach was used, guided by the Social Cognitive Theory for the qualitative analysis. RESULTS: A total of 2101 households were recruited for the quantitative survey. With a mean age of 61.4 (SD 14.41) years, >70% (1364/2101, 72.94%) of the household respondents were male. Less than 1% (14/2101, 0.67%) of the respondents reported experience of using telemedicine. The quantitative results supported that villagers living with family members who had a fever in the past 2 weeks (adjusted odds ratio 6.96, 95% CI 2.20-21.98; P=.001) or having smartphones or computers (adjusted odds ratio 3.71, 95% CI 0.64-21.32; P=.14) had marginally higher telemedicine uptake, whereas the qualitative results endorse these findings. The results of qualitative interviews (n=27) also supplemented the potential barriers to telemedicine use from the lack of knowledge, trust, demand, low self-efficacy, and sufficient physical and social support. CONCLUSIONS: This study found extremely low use of telemedicine in rural China and identified potential factors affecting telemedicine uptake. The main barriers to telemedicine adoption among rural residents were found, including lack of knowledge, trust, demand as well as low self-efficacy, and insufficient physical and social support. Our study also suggests strategies to facilitate telemedicine engagement in low-resource settings: improving digital literacy and self-efficacy, building trust, and strengthening telemedicine infrastructure support.

Evaluation of a village-based digital health kiosks program: A protocol for a cluster randomized clinical trial.

Background: To address disparities in healthcare quality and access between rural and urban areas in China, reforms emphasize strengthening primary care and digital health utilization. Yet, evidence on digital health approaches in rural areas is lacking. Objective: This study will evaluate the effectiveness of Guangdong Second Provincial General Hospital's Digital Health Kiosk program, which uses the Dingbei telemedicine platform to connect rural clinicians to physicians in upper-level health facilities and provide access to artificial intelligence-enabled diagnostic support. We hypothesize that our interventions will increase healthcare utilization and patient satisfaction, decrease out-of-pocket costs, and improve health outcomes. Methods: This cluster randomized control trial will enroll clinics according to a partial factorial design. Clinics will be randomized to either a control arm with clinician medical training, a second arm additionally receiving Dingbei telemedicine training, or a third arm with monetary incentives for patient visits conducted through Dingbei plus all prior interventions. Clinics in the second and third arm will then be orthogonally randomized to a social marketing arm that targets villager awareness of the kiosk program. We will use surveys and Dingbei administrative data to evaluate clinic utilization, revenue, and clinician competency, as well as patient satisfaction and expenses. Results: We have received ethical approval from Guangdong Second Provincial General Hospital (IRB approval number: GD2H-KY IRB-AF-SC.07-01.1), Peking University (IRB00001052-21007), and the University of North Carolina at Chapel Hill (323385). Study enrollment began April 2022. Conclusions: This study has the potential to inform future telemedicine approaches and assess telemedicine as a method to address disparities in healthcare access.Trial registration number: ChiCTR2100053872.

Establishing an economical and widely accessible donation after circulatory death animal abattoir model for lung research using ex vivo lung perfusion.

BACKGROUND: Ex vivo lung perfusion (EVLP), is a platform that allows simultaneous testing and treatment of the lungs. However, use of EVLP is costly and requires access to lab animals and accompanying facilities. To increase the use of EVLP for research, we developed a method to perform EVLP using abattoir procured lungs. Furthermore, we were also able to significantly decrease costs. METHODS: Six pair of lungs were procured from abattoir sheep. The lungs were then flushed and stored in ice for 3 h. A low-flow (20% of cardiac output) approach, a tidal volume of 6 ml/kg bodyweight and total perfusion time of 3 h were chosen. Perfusion fluids and circuits were self-made. Lung biopsies, perfusate collection, respiratory values, circulatory pressures were recorded and hourly blood gas analyses were performed. RESULTS: Mean pO2 remained stable from 60 min (49.3 ± 7.1 kPa) to 180 min (51.5 kPa ± 8.0), p = 0.66. Pulmonary artery pressure remained ≤15 mm Hg and the left atrial pressure remained between 3 and 5 mm Hg and peak respiratory pressures ≤20 cmH2 O. Lactate dehydrogenase increased from start (96.3 ± 56.4 U/L) to the end of perfusion (315.8 ± 85.0 U/L), p < 0.05. No difference was observed in ATP between procurement and post-EVLP, 129.7 ± 37.4 µmol/g protein to 132.0 ± 23.4 µmol/g, p = 0.92. CONCLUSIONS: Sheep lungs, acquired from an abattoir, can be ex vivo perfused under similar conditions as lab animal lungs with similar results regarding e.g., oxygenation and ATP restoration. Furthermore, costs can be significantly reduced by making use of this abattoir model. By increasing accessibility and lowering costs for experiments using lung perfusion, more results may be achieved in the field of lung diseases.

External quality assessment (EQA) program for the immunohistochemical detection of ER, PR and Ki-67 in breast cancer: results of an interlaboratory reproducibility ring study in China.

BACKGROUND: An External Quality Assessment (EQA) program was developed to investigate the status of estrogen receptor (ER), progesterone receptor (PR), and Ki-67 immunohistochemical (IHC) detection in breast cancer and to evaluate the reproducibility of staining and interpretation in 44 pathology laboratories in China. METHODS: This program was implemented through three specific steps. In study I, three revising centres defined the reference value for 11 sections. In study II, 41 participating centres (PC) stained and interpreted 11 sections by their own daily practice IHC protocols. In study III, all cases received second interpretation opinions. RESULTS: The stained slides of 44 laboratories were up to the interpretation standard. The overall interpretation concordance rate of this study was over 90%. A perfect agreement was reached among the PCs for the cases with ER+ and PR+ > 50% and Ki-67 > 30%, whereas a moderate agreement was observed for intermediate categories. After second interpretations, the misclassification rates for ER were reduced by 12.20%, for PR were reduced by 17.07%, and for Ki-67 were reduced by 4.88%. Up to 31 PCs observed a benefit from the second opinion strategy. CONCLUSIONS: This project is the first EQA study performed on a national scale for assessment of ER, PR and Ki-67 status by IHC in China. In the whole IHC evaluation process, the intermediate categories were less reproducible than those with high expression rates. Second opinions can significantly improve the diagnostic agreement of pathologists' interpretations.

A decision tree-based prediction model for fluorescence in situ hybridization HER2 gene status in HER2 immunohistochemistry-2+ breast cancers: a 2538-case multicenter study on consecutive surgical specimens.

Objective: To investigate the proportion of HER2 gene amplifications and the association between the HER2-IHC-staining pattern and gene status in IHC-2+ breast cancers according to 2013 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines. Methods: We retrospectively analyzed and re-evaluated the IHC-staining pattern of 2538 IHC-2+ surgical specimens of breast cancer from November 2014 to October 2015 in 12 institutions. All cases used for building a prediction model of HER2 gene amplification according to the IHC-staining pattern and were randomly divided into a training set (n = 1914) or validation set (n = 624). Results: The overall HER2 fluorescence in situ hybridization (FISH) amplification, non-amplification and equivocation rates in HER2 IHC-2+ cases were 17.8%, 76.2% and 6.0%, respectively. In the training set, cases that had ≤ 10% of cells with intense, complete and circumferential membrane staining or had > 85% of cells with complete membrane staining of any staining intensity tended to be HER2 gene amplified (77.0% and 60.5%, respectively). And cases with weak and incomplete membrane staining had the lowest amplification rate of 6.1%. The prediction model was constructed based on IHC-staining pattern in the training set and validated using a validation set. The positive and negative prediction values were 51.6% and 79.2%, respectively, in the validation set. Moreover, the HER2 copy number per cell was much higher in cases with amplification-associated staining patterns (7.84 and 8.75) than in cases with non-amplification-associated staining patterns (2.97 to 4.41, P < 0.05). Conclusions: In HER2 IHC-2+ breast cancers, the staining pattern is associated with the HER2 gene status. This finding is compatible with recommendations of 2013 ASCO/CAP guidelines.

Assessment of an advanced virtual monoenergetic reconstruction technique in cerebral and cervical angiography with third-generation dual-source CT: Feasibility of using low-concentration contrast medium.

OBJECTIVES: To investigate the feasibility of low-concentration contrast media (LC-CM) in cerebral and cervical dual-energy CT angiography (DE-CTA) using an advanced monoenergetic (Mono+) reconstruction technique. METHODS: Sixty-five consecutive patients prospectively selected to undergo cerebral and cervical DE-CTA were randomised into two groups: 32 patients (63.7 ± 9.7 years) in the high-concentration contrast medium (HC-CM) group with iopromide 370 and 33 patients (60.7 ± 10.8 years) in the low-concentration contrast medium (LC-CM) group with iodixanol 270. Traditional monoenergetic (Mono) and Mono+ images from 40 to 100 keV levels (at 10-keV intervals) and the standard mixed (Mixed, 120 kVp equivalent) images were reconstructed. Subjective image quality parameters included the contrast-to-noise ratio (CNR) and objective image quality parameters were evaluated and compared between the two groups. RESULTS: The 40-keV Mono+ images in the LC-CM group showed comparable objective CNR (common carotid arteries: 83.7 ± 24.5 vs. 78.1 ± 23.2; internal carotid arteries: 82.2 ± 26.8 vs. 76.8 ± 24.1; middle cerebral arteries: 72.5 ± 24.6 vs. 70.6 ± 19.2; all p > 0.05) and subjective image scores (3.95 ± 0.19 vs. 3.83 ± 0.35; p > 0.05) compared with Mixed images in the HC-CM group. CONCLUSION: The Mono+ reconstruction technique could reduce the concentration of iodinated CM in the diagnosis of cerebral and cervical angiography. KEY POINTS: • Mono+ shows decreased noise and superior CNR compared with Mono. • The 40-keV Mono+ images show the highest CNR in the LC-CM group. • The Mono+ reconstruction technique could reduce the concentration of iodinated CM.

Dynamic Quantitative Assessment of Motor Axon Sprouting after Direct Facial-Hypoglossal End-To-Side Neurorrhaphy in Rats.

BACKGROUND: End-to-side (ETS) neurorrhaphy is a promising procedure for peripheral nerve repair, yet controversies regarding the efficacy of this repair in facial nerve anastomosis for facial paralysis still exist. MATERIALS AND METHODS: Thirty rats were divided into three groups: intact control group, direct facial-hypoglossal ETS neurorrhaphy, and end-to-end (ETE) neurorrhaphy. Nerve regeneration was assessed with vibrissae motor performance, electrophysiological tests, retrograde labeling, and histomorphological analysis at 4 and 8 months postoperatively. RESULTS: Both ETS and ETE neurorrhaphies resulted in axonal regeneration and functional recovery of the recipient nerve but did not reach the level of intact controls. Significantly higher numbers of myelinated axons and labeled neurons giving regenerating fibers were found in group ETE compared with group ETS at both time points, consistent with the functional and electrophysiological recovery. Group ETS showed significantly smaller fiber diameter and thinner myelin thickness than group ETE at 4 months, but the difference became nonsignificant at 8 months. ETS neurorrhaphy had a very slight effect on the donor nerve, as determined electrophysiologically and histomorphologically. Sparsely distributed double-labeled neurons and relatively large amounts of single-labeled neurons contributing to reinnervation were found through double retrograde neuronal labeling in group ETS. Further quantitative analysis of the percentage of double-labeled neurons showed a pronounced tendency to decline from 19.8% at 4 months to 6.0% at 8 months postoperatively. CONCLUSION: Successful reinnervation after ETS neurorrhaphy could be achieved through both collateral sprouting and terminal sprouting, with the latter seeming to be the principal origin of motor nerve sprouting.

[Measurements of Pulmonary Artery Size for Assessment of Pulmonary Hypertension by Cardiovascular Magnetic Resonance and Clinical Application].

BACKGROUND: Pulmonary hypertension (PH) often leads to dilatation of main pulmonary artery (MPA). MPA measurements can be used to predict PH. This aim of this study is to investigate power of MPA vessel indices, which are acquired from cardiovascular magnetic resonance, to evaluate PH. METHODS: Cardiovascular-magnetic-resonance-determined parameters of MPA were acquired and calculated in 83 PH patients, whose diagnosis were confirmed with right heart catheterization and 49 healthy volunteers; these parameters included MPA diameter (DPA), ratio of DPA and ascending aorta diameter (DPA/DAo), max mean diameter (MDmax), min mean diameter (MDmin), fraction transverse diameter (fTD), fraction longitudinal diameter (fLD), and distensibility. RESULTS: Compared with control group, DPA, DPA/DAo, MDmax, and MDmin were significantly higher in patients with PH (P<0.001); fTD, fLD, and distensibility significantly decreased (P<0.001). fTD was lesser than fLD in control group (P<0.001), whereas difference was not observed in PH (P=0.305). MPA indices were significantly correlated with mean pulmonary arterial pressure (mPAP) (P<0.05), and strongest correlation was observed for DPA/DAo (r=0.534, P<0.001). By receiver operating characteristic analysis, MDmin>28.4 mm, and MDmax>32.4 mm (area under the curve, AUC=0.979, 0.981) showed best performance in predicting PH, yielding highest specificity at 100%. CONCLUSIONS: Noninvasive cardiovascular-magnetic-resonance-derived MPA measurements provide excellent and practical reference in clinical settings for detecting PH.

Tumor radio-sensitivity assessment by means of volume data and magnetic resonance indices measured on prostate tumor bearing rats.

PURPOSE: Radiation therapy is one of the most common treatments in the fight against prostate cancer, since it is used to control the tumor (early stages), to slow its progression, and even to control pain (metastasis). Although many factors (e.g., tumor oxygenation) are known to influence treatment efficacy, radiotherapy doses and fractionation schedules are often prescribed according to the principle "one-fits-all," with little personalization. Therefore, the authors aim at predicting the outcome of radiation therapy a priori starting from morphologic and functional information to move a step forward in the treatment customization. METHODS: The authors propose a two-step protocol to predict the effects of radiation therapy on individual basis. First, one macroscopic mathematical model of tumor evolution was trained on tumor volume progression, measured by caliper, of eighteen Dunning R3327-AT1 bearing rats. Nine rats inhaled 100% O2 during irradiation (oxy), while the others were allowed to breathe air. Second, a supervised learning of the weight and biases of two feedforward neural networks was performed to predict the radio-sensitivity (target) from the initial volume and oxygenation-related information (inputs) for each rat group (air and oxygen breathing). To this purpose, four MRI-based indices related to blood and tissue oxygenation were computed, namely, the variation of signal intensity ΔSI in interleaved blood oxygen level dependent and tissue oxygen level dependent (IBT) sequences as well as changes in longitudinal ΔR1 and transverse ΔR2(*) relaxation rates. RESULTS: An inverse correlation of the radio-sensitivity parameter, assessed by the model, was found with respect the ΔR2(*) (-0.65) for the oxy group. A further subdivision according to positive and negative values of ΔR2(*) showed a larger average radio-sensitivity for the oxy rats with ΔR2(*)<0 and a significant difference in the two distributions (p < 0.05). Finally, a leave-one-out procedure yielded a radio-sensitivity error lower than 20% in both neural networks. CONCLUSIONS: While preliminary, these specific results suggest that subjects affected by the same pathology can benefit differently from the same irradiation modalities and support the usefulness of IBT in discriminating between different responses.

[The assessment of right ventricular function and pulmonary artery hemodynamics in patients with pulmonary hypertension by 1.5T MRI].

BACKGROUND AND OBJECTIVE: Pulmonary hypertension (PH) is characterized by rising pulmonary arterial pressure, decreasing right ventricular (RV) function, and ultimately, RV failure. Therefore, it is important to monitor RV function and pulmonary artery hemodynamics accurately and noninvasively. This study evaluates cardiac magnetic resonance imaging (CMRI) in assessing RV function and pulmonary artery hemodynamics in patients with PH. METHODS: Cine-MRI and phase-contrast MRI (PC-MRI) were performed in 25 PH patients and 30 healthy volunteers. Cine-MRI images were post-processed on Report Card software and the following parameters were obtained: RV end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF), and myocardial mass (MM). Except for EF, all of the above parameters were normalized to body surface area (BSA). PC-MRI images were post-processed on Report Card software, peak velocity and distensibility of main pulmonary artery (MPA) could also be obtained. Student t test was employed for statistical assessment. RESULTS: Compared with controls, RV EDV, ESV and MM index in PH patients were significantly increased (P<0.01), EF was significantly impaired (P<0.01), peak velocity and distensibility of MPA were significantly lower (P<0.01). SV index between the two groups had no significant difference (P>0.05). CONCLUSIONS: Cardiac MRI is of great value in the assessment of RV function and MPA hemodynamic parameters in patients with PH.

Assessment of coronary microcirculation in a swine animal model.

Coronary microvascular dysfunction has important prognostic implications. Several hemodynamic indexes, such as coronary flow reserve (CFR), microvascular resistance, and zero-flow pressure (P(zf)), were used to establish the most reliable index to assess coronary microcirculation. Fifteen swine were instrumented with a flow probe, and a pressure wire was advanced into the distal left anterior descending artery. Adenosine was used to produce maximum hyperemia. Microspheres were used to create microvascular dysfunction. An occluder was used to produce stenosis. Blood flow from the probe (Q(p)), aortic pressure, distal coronary pressure, and right atrium pressure were recorded. Angiographic flow (Q(a)) was calculated using a time-density curve. Flow probe-based CFR and angiographic CFR were calculated using Q(p) and Q(a), respectively. Flow probe-based (NMR(qh)) and angiographic normalized microvascular resistance (NMR(ah)) were determined using Q(p) and Q(a), respectively, during hyperemia. P(zf) was calculated using Q(p) and distal coronary pressure. Two series of receiver operating characteristic curves were generated: normal epicardial artery model (N model) and stenosis model (S model). The areas under the receiver operating characteristic curves for flow probe-based CFR, angiographic CFR, NMR(qh), NMR(ah), and P(zf) were 0.855, 0.836, 0.976, 0.956, and 0.855 in N model and 0.737, 0.700, 0.935, 0.889, and 0.698 in S model. Both NMR(qh) and NMR(ah) were significantly more reliable than CFR and P(zf) in detecting the microvascular deterioration. Compared with CFR and P(zf), NMR provided a more accurate assessment of microcirculation. This improved accuracy was more prevalent when stenosis existed. Moreover, NMR(ah) is potentially a less invasive method for assessing coronary microcirculation.