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PurposeGene therapy employing AAV vector-mediated gene delivery has undergone substantial growth in recent years with promising results in both preclinical and clinical studies, as well as emerging regulatory approval. However, the lack of methods for quantifying the efficacy of gene therapy from cellular delivery of gene editing technology to specific functional outcomes remains an obstacle for the efficient development of gene therapy treatments. Building upon prior works that utilized a genetically encoded Lysine Rich Protein as a chemical exchange saturation transfer (CEST) reporter, we hypothesized that AAV viral capsids may generate endogenous CEST contrast from the large number of surface lysine residues.MethodsWater-suppressed NMR and NMR-CEST experiments were performed on isolated solutions of AAV serotypes 1-9 on a Bruker 800MHz vertical scanner. A series of in vitro experiments were performed for thorough testing of NMR-CEST contrast of AAV2 capsids under varying pH, density, biological transduction stage, and later across multiple serotypes and mixed biological media. Reverse transcriptase (RT)-polymerase chain reaction (PCR) was used to quantify virus concentration. Subsequent experiments determined the pH-dependent exchange rate and optimized CEST saturation schemes for AAV contrast detection at 7 T.ResultsNMR-CEST experiments revealed CEST contrast up to 52% for AAV2 viral capsids between 0.6-0.8 ppm. Evaluation of CEST contrast generated by AAV2 demonstrates high levels of CEST contrast across a variety of chemical environments, concentrations, and saturation schemes. AAV2 CEST contrast displayed significant positive correlations with capsid density (R2>0.99, P2=0.97, P=0.01), and viral titer per cell count (R2=0.92, PConclusionAAV2 viral capsids exhibit strong capacity as an endogenous CEST contrast agent and can potentially be used for monitoring and evaluation of AAV vector-mediated gene therapy protocols.

Workplace inclusion is a core component of corporate social responsibility (CSR) in Hong Kong. Workplace inclusion points to the need for employers to recognize diversity among employees, to acknowledge their contributions to the work environment and to raise professional standards for the work force. Diversity within a workplace indicates inclusion of persons with different backgrounds as in racial, ethnic, sex, health status, sexual orientation and gender identity. Women are already less represented at senior levels across various business sectors in Hong Kong. Lesbians and bisexual women face a double glass ceiling in the workplace as a result of both their gender and sexual orientation. Funded by Lingnan University’s Innovation and Impact Fund, and in partnership with Interbank Forum and Lesbians in Finance, Prof. Denise Tse-Shang Tang conducted an online survey and two focus groups targeting lesbians and bisexual women working in Hong Kong’s financial and banking industry. The aim of the study is to examine the specific challenges and barriers faced by lesbians and bisexual women in Hong Kong’s financial services industry. We found that only 37% of survey respondents were out at work, with 23% partially out to close colleagues. In other words, there are still key concerns with being out at work. On the issue of a glass ceiling for LGBT+ corporate employees, 18% of the survey respondents agreed and 47% somewhat agreed that such a ceiling exists. When asked whether it is harder for lesbians and bisexual women to come out in the workplace than it is for gay men, 32% agreed and 46% somewhat agreed. 27% agreed and 39% somewhat agreed with the statement that it is difficult for lesbians and bisexual women to climb up the corporate ladder. Other findings pointed to the low visibility of lesbians and bisexual women in corporate settings, lack of mentorship, increased levels of stress and anxiety, and the fear of being judged as both a woman and a lesbian. Masculine-presenting employees face significantly more scrutiny than cisgender female employees. Therefore, even though discussion on diversity and inclusion has been on the agenda for better corporate work environment in Hong Kong, there still remain gaps in raising awareness of lesbian and bisexual women’s issues.

Cardiac chemical exchange saturation transfer-magnetic resonance imaging (CEST-MRI) has been used to probe levels of various metabolites that provide insight into myocardial structure and function. However, imaging of the heart using CEST-MRI is prolonged by the need to repeatedly acquire multiple images for a full Z-spectrum and to perform saturation and acquisition around cardiac and respiratory cycles. Compressed sensing (CS) reconstruction of sparse data enables accelerated acquisition, but reconstruction artifacts may bias subsequently derived measures of CEST contrast. In this study, we examine the impact of CS reconstruction of increasingly under-sampled cardiac CEST-MRI data on subsequent CEST contrasts of amine-containing metabolites and amide-containing proteins. Cardiac CEST-MRI data sets were acquired in six mice using low and high RF saturation for single and dual contrast generation, respectively. CEST-weighted images were reconstructed using CS methods at 2-5× levels of under-sampling. CEST contrasts were derived from corresponding Z-spectra and the impact of accelerated imaging on accuracy was assessed via analysis of variance. CS reconstruction preserved myocardial signal to noise ratio as compared to conventional reconstruction. However, greater absolute error and distribution of derived contrasts was observed with increasing acceleration factors. The results from this study indicate that acquisition of radial cardiac CEST-MRI data can be modestly, but meaningfully, accelerated via CS reconstructions with little error in CEST contrast quantification.

Objective To compare the effects of treatments for coronavirus disease 2019 (covid-19). Design Living systematic review and network meta-analysis. Data sources WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, up to 1 March 2021 and six additional Chinese databases up to 20 February 2021. Studies identified as of 12 February 2021 were included in the analysis. Study selection Randomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles. Methods After duplicate data abstraction, a bayesian network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance. Results 196 trials enrolling 76 767 patients were included; 111 (56.6%) trials and 35 098 (45.72%) patients are new from the previous iteration; 113 (57.7%) trials evaluating treatments with at least 100 patients or 20 events met the threshold for inclusion in the analyses. Compared with standard care, corticosteroids probably reduce death (risk difference 20 fewer per 1000 patients, 95% credible interval 36 fewer to 3 fewer, moderate certainty), mechanical ventilation (25 fewer per 1000, 44 fewer to 1 fewer, moderate certainty), and increase the number of days free from mechanical ventilation (2.6 more, 0.3 more to 5.0 more, moderate certainty). Interleukin-6 inhibitors probably reduce mechanical ventilation (30 fewer per 1000, 46 fewer to 10 fewer, moderate certainty) and may reduce length of hospital stay (4.3 days fewer, 8.1 fewer to 0.5 fewer, low certainty), but whether or not they reduce mortality is uncertain (15 fewer per 1000, 30 fewer to 6 more, low certainty). Janus kinase inhibitors may reduce mortality (50 fewer per 1000, 84 fewer to no difference, low certainty), mechanical ventilation (46 fewer per 1000, 74 fewer to 5 fewer, low certainty), and duration of mechanical ventilation (3.8 days fewer, 7.5 fewer to 0.1 fewer, moderate certainty). The impact of remdesivir on mortality and most other outcomes is uncertain. The effects of ivermectin were rated as very low certainty for all critical outcomes, including mortality. In patients with non-severe disease, colchicine may reduce mortality (78 fewer per 1000, 110 fewer to 9 fewer, low certainty) and mechanical ventilation (57 fewer per 1000, 90 fewer to 3 more, low certainty). Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to reduce risk of death or have an effect on any other patient-important outcome. The certainty in effects for all other interventions was low or very low. Conclusion Corticosteroids and interleukin-6 inhibitors probably confer important benefits in patients with severe covid-19. Janus kinase inhibitors appear to have promising benefits, but certainty is low. Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to have any important benefits. Whether or not remdesivir, ivermectin, and other drugs confer any patient-important benefit remains uncertain. Systematic review registration This review was not registered. The protocol is publicly available in the supplementary material. Readers’ note This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This is the fourth version of the original article published on 30 July 2020 ( BMJ 2020;370:m2980), and previous versions can be found as data supplements. When citing this paper please consider adding the version number and date of access for clarity.

Resistance-based memory devices are considered as a strong candidate for next-generation nonvolatile memories as well as potential application in high density embedded cache. These devices can be programmed to different resistance states by applying electrical bias. Read operation then senses the programmed state by discharging a shared data line through the memory cell. However, as the dimensions of the device scale down, its resistance increases and the distribution widens, which leads to reduced sensing margins and degradation in read performance. In the proposed dual-data line (DDL) read scheme, we recycle current flowing through the memory cell during the read operation to create an additional voltage swing on a secondary data line, and combine it with the signal on the original data line to reduce sensing time and energy. Performance comparison with the conventional read scheme is derived theoretically by using circuit analysis and verified through simulation on an array critical path constructed in 65-nm technology. Results show that the DDL scheme can improve sensing margins by an average of 86%, which translates to a sensing time reduction of 47%, across various device conditions. For the same read performance, the sensing energy is decreased by 48%.

Purpose Cardiac native-T1 times have correlated to extracellular volume fraction in patients with confirmed fibrosis. However, whether other factors that can occur either alongside or independently of fibrosis including increased intracellular water volume, altered magnetization transfer (MT), or glycation of hemoglobin, lengthen T1 times in the absence of fibrosis remains unclear. The current study examined whether native-T1 times are elevated in hypertrophic diabetics with elevated hemoglobin A1C (HbA1c) without diffuse fibrosis. Methods Native-T1 times were quantified in 27 diabetic and 10 healthy adults using a modified Look-Locker imaging (MOLLI) sequence at 1.5 T. The MT ratio (MTR) was quantified using dual flip angle cine balanced steady-state free precession. Gadolinium (0.2 mmol/kg Gd-DTPA) was administered as a bolus and post-contrast T1-times were quantified after 15 min. Means were compared using a two-tailed student's t-test, while correlations were assessed using Pearson's correlations. Results While left ventricular volumes, ejection fraction, and cardiac output were similar between groups, left ventricular mass and mass-to-volume ratio (MVR) were significantly higher in diabetic adults. Mean ECV (0.25 ± 0.02 Healthy vs. 0.25 ± 0.03 Diabetic, P = 0.47) and MTR (125 ± 16% Healthy vs. 125 ± 9% Diabetic, P = 0.97) were similar, however native-T1 times were significantly higher in diabetics (1016 ± 21 ms Healthy vs. 1056 ± 31 ms Diabetic, P = 0.00051). Global native-T1 times correlated with MVR (ρ = 0.43, P = 0.008) and plasma HbA1c levels (ρ = 0.43, P = 0.0088) but not ECV (ρ = 0.06, P = 0.73). Septal native-T1 times correlated with septal wall thickness (ρ = 0.50, P = 0.001). Conclusion In diabetic adults with normal ECV values, elevated native-T1 times may reflect increased intracellular water volume and changes secondary to increased hemoglobin glycation.

Systolic cardiac function is typically preserved in obese adults, potentially masking underlying declines in cardiomyocyte metabolism that may contribute to heart failure. We used chemical exchange saturation transfer (CEST) MRI, a sensitive method for measurement of myocardial creatine, to examine whether myocardial creatine levels correlate with cardiac structure, contractile function, or visceral fat mass in obese adults. In this study, obese (body mass index, BMI > 30, n = 20) and healthy (BMI < 25, n = 11) adults were examined with dual-energy x-ray absorptiometry to quantify fat masses. Cine MRI and myocardial tagging were performed at 1.5 T to measure ventricular structure and global function. CEST imaging with offsets in the range of ±10 parts per million (ppm) were performed in one mid-ventricular slice, where creatine CEST contrast was calculated at 1.8 ppm following field homogeneity correction. Ventricular structure, global function (ejection fraction 69.4 ± 4.3% healthy versus 69.6 ± 9.3% obese, NS), and circumferential strain (-17.0 ± 2.3% healthy versus -16.5 ± 1.5% obese, NS) and strain rate were preserved in obese adults. However, creatine CEST contrast was significantly reduced in obese adults (6.8 ± 1.3% healthy versus 4.1 ± 2.7% obese, p = 0.001). Creatine CEST contrast was inversely correlated with total body fat% (ρ = -0.45, p = 0.011), visceral fat mass (ρ = -0.58, p = 0.001), and septal wall thickness (ρ = -0.44, p = 0.013), but uncorrelated to ventricular function or contractile function. In conclusion, creatine CEST-MRI reveals a strong correlation between heightened body and visceral fat masses and reduced myocardial metabolic function that is independent of ventricular structure and global function in obese adults.

In ultrasound imaging systems, a large number of waveforms are acquired in parallel from a transducer array. To facilitate the move to portable ultrasound systems with real-time displays, we implemented a low-power digital beamformer ASIC in 65 nm bulk CMOS technology. We describe three operating modes that provide a run-time tradeoff between image quality and system power consumption. A sliding window approach eliminates the need for an on-chip SRAM, which reduces area and power. The chip generates four output pixels per clock cycle from eight channel of input data, allowing 30 frames per second at 1.92 MHz. The prototype test chip is operational down to a core supply voltage of 0.49 V, with a measured power of 185 uW in real-time operation at 0.52 V.

The present study aims to describe early ED representation rates and identify the causes for this commonly seen problem.This was a retrospective chart review of all patients that represented within 72 h of discharge from a tertiary level ED in Sydney, Australia, over a 2 month period between 1 May 2010 and 30 June 2010. Presentations were categorised according to their diagnosis and cause for representation. Each representation was then classified as being avoidable or unavoidable.There were 10 141 presentations to the ED during the study period, with 497 patients (4.9%, 95% confidence interval [CI] 4.5-5.3) representing within 72 h of discharge. Disease-related causes of representation were seen in 55.1% (95% CI 50.7-59.5), with 39% (95% CI 34.8-43.4) of these caused by disease progression and 12.3% (95% CI 9.6-15.5) for scheduled review. Patient-related causes were seen in 32.2% (95% CI 28.2-36.4) of representations with 20.9% (95% CI 17.6-24.7) of these for patients who did not wait or left against medical advice. Physician-related causes were seen in 3.2% (95% CI 2.0-5.2) of representations. Furthermore, 23.7% (95% CI 20.2-27.7) of patients who represented to the ED required hospital admission. A total of 37.0% (95% CI 32.9-41.4) of representations were assessed as being preventable.Early ED representations are a common problem. The majority of preventable representations are patient related, and interventions to target these areas might be of benefit in reducing this problem.

As the lateral resolution and axial imaging depth of a ultrasound image increase, so do the number of transducer elements and the corresponding processing units. Conventional ultrasound systems are often large and expensive due to the intensive requirement of large beamforming arrays. But for applications such as point-of-care diagnostics in rural areas, the movement to a portable and low-power ultrasound imaging system is warranted. To address the low power requirement for portable applications, the proposed beamformer operates in one of three modes, namely quarter, half, and full resolution modes, selectable at runtime. In the first two modes, a subset of elements, with effective pitches of 4x and 2x of the transducer pitch, are processed for low quality images of the full region of interest. These modes provide run-time power reduction, because the Analog Front End (AFE) and Analog-to-Digital Converter (ADC) for the unused channels can be turned off by the feedback control signals from the beamformer. Based on the low quality image, the user can intuitively specify a smaller region where a higher quality image is desired, and the full resolution beamforming mode is used. A system energy model is set up to evaluate the image quality and frame rate performance, while providing realistic power consumption predictions. The model offers fast and accurate behavioral level understanding of the ultrasound system under optimization.

Introduced in this chapter is wireless middleware as a means of writing distributed applications for mobile environments. The concepts of middleware and the additional challenges that arise from wireless communications are introduced, in particular, low bandwidth and unreliability. Then described are the commercial wireless products currently available, with particular emphasis on the manner in which they solve challenges. The authors hope that greater appreciation of the capabilities of wireless middleware will enable future developers of applications for mobile environments to produce more efficient systems and researchers to produce better wireless middleware products.