From Ecological Epitome to Medical Model: An investigation into Applications for the use of Daphnia in Heart Science.

The primary aim of this research was to determine whether Daphnia might become a model for cardiovascular concentration-response trials. This would provide a high throughput means of testing cardiac therapeutics without resort to small mammal trials. We found Daphnia are inappropriate in this context due to high population variance and sensitivity to small, subtle, environmental changes. A new aim was developed to determine whether beat-to-beat variation could be correlated with an individual’s response to toxic insult. Further, to develop more accurate and efficient means of gathering heart rhythm data by recording heart movement from whole live Daphnia. This opens the way to individualising cardio therapeutics; by correlating the stability of individual hearts with response to cardiac insult, regression analysis provides a means of finding a prediction tool. Daphnia are a convenient example here, but successful scoring systems might also be applied to the human heart via analysis of ECG readouts. Collecting signals from whole live Daphnia did not fulfil the goal of gathering heart data as this instead recorded limb movement. However, this provides a means of improving toxicology testing in aquatic ecology. This thesis offers three contributions to knowledge: 1. Daphnia are an inappropriate model for cardiovascular therapeutic dose-response trials due to extreme environmental sensitivities. 2. Baseline heart rhythm can be correlated with paired response to cardiac insult, with significance at the 0.01 alpha level, using an adjusted version of the Lyapnov equation; Finite Time Growth (Wessel, 2010). However, this is only if population variation is adequate. It is better applied to a natural in situ population than a homegenic lab population. 3. A novel technique for measuring Daphnia electromechanical movement records feeding limbs rather than the heart. This offers a novel and more efficient technique for aquatic ecotoxicology, where visual observation or films of the same are currently used

National survey of attitudes towards and intentions to vaccinate against COVID-19: implications for communications

OBJECTIVES: To examine public views on COVID-19 vaccination and consider the implications for communications and targeted support. DESIGN: Cross-sectional study. SETTING: Online and telephone nationally representative survey in Great Britain, January to February 2021. PARTICIPANTS: 4978 adults. Survey response rate was 84%, among the 5931 panellists invited. MAIN OUTCOME MEASURES: Sociodemographic characteristics (age, gender, ethnicity, education, financial status), COVID-19 status, vaccine acceptance, trust in COVID-19 vaccination information sources, perceptions of vaccination priority groups and perceptions of importance of second dose. RESULTS: COVID-19 vaccine acceptance (83%) was associated with increasing age, higher level of education and having been invited for vaccination. Acceptance decreased with unconfirmed past COVID-19, greater financial hardship and non-white British ethnicity; black/black British participants had lowest acceptance. Overall, healthcare and scientific sources of information were most trusted. Compared with white British participants, other ethnicities had lower trust in healthcare and scientific sources. Those with lower educational attainment or financial hardship had lower trust in healthcare and scientific sources. Those with no qualifications had higher trust in media and family/friends. While trust was low overall in community or faith leaders, it was higher among those with Asian/Asian British and black/black British ethnicity compared with white British participants. Views of vaccine prioritisation were mostly consistent with UK official policy but there was support for prioritising additional groups. There was high support for having the second vaccine dose. CONCLUSIONS: Targeted engagement is needed to address COVID-19 vaccine hesitancy in non-white British ethnic groups, in younger adults, and among those with lower education, greater financial hardship and unconfirmed past infection. Healthcare professionals and scientific advisors should play a central role in communications and tailored messaging is needed for hesitant groups. Careful communication around vaccination prioritisation continues to be required

The Effect of Pulmonary Artery Catheter Use on Costs and Long-Term Outcomes of Acute Lung Injury

Background: The pulmonary artery catheter (PAC) remains widely used in acute lung injury (ALI) despite known complications and little evidence of improved short-term mortality. Concurrent with NHLBI ARDS Clinical Trials Network Fluid and Catheters Treatment Trial (FACTT), we conducted a prospectively-defined comparison of healthcare costs and long-term outcomes for care with a PAC vs. central venous catheter (CVC). We explored if use of the PAC in ALI is justified by a beneficial cost-effectiveness profile. Methods: We obtained detailed bills for the initial hospitalization. We interviewed survivors using the Health Utilities Index Mark 2 questionnaire at 2, 6, 9 and 12 m to determine quality of life (QOL) and post-discharge resource use. Outcomes beyond 12 m were estimated from federal databases. Incremental costs and outcomes were generated using MonteCarlo simulation. Results: Of 1001 subjects enrolled in FACTT, 774 (86%) were eligible for long-term follow-up and 655 (85%) consented. Hospital costs were similar for the PAC and CVC groups ($96.8k vs.$89.2k, p = 0.38). Post-discharge to 12 m costs were higher for PAC subjects ($61.1k vs. 45.4k, p = 0.03). One-year mortality and QOL among survivors were similar in PAC and CVC groups (mortality: 35.6$14.4k and mean loss of 0.3 quality-adjusted life years (QALYs)) and a 94.2% probability of being higher than the $100k/QALY willingness-to-pay threshold. Conclusion: PAC use increased costs with no patient benefit and thus appears unjustified for routine use in ALI. Trial Registration: www.clinicaltrials.gov NCT00234767. © 2011 Clermont et al

A lifetime’s adventure in extracellular K+ regulation: the Scottish connection

In a career that has spanned 45 years and shows no signs of slowing down, Dr Bruce Ransom has devoted considerable time and energy to studying regulation of interstitial K+. When Bruce commenced his studies in 1969 virtually nothing was known of the functions of glial cells, but Bruce’s research contributed to the physiological assignation of function to mammalian astrocytes, namely interstitial K+ buffering. The experiments that I describe in this review concern the response of the membrane potential (Em) of in vivo cat cortical astrocytes to changes in [K+]o, an experimental manoeuvre that was achieved in two different ways. The first involved recording the Em of an astrocyte while the initial aCSF was switched to one with different K+, whereas in the second series of experiments the cortex was stimulated and the response of the astrocyte Em to the K+ released from neighbouring neurons was recorded. The astrocytes responded in a qualitatively predictable manner, but quantitatively the changes were not as predicted by the Nernst equation. Elevations in interstitial K+ are not sustained and K+ returns to baseline rapidly due to the buffering capacity of astrocytes, a phenomenon studied by Bruce, and his son Chris, published 27 years after Bruce’s initial publications. Thus, a lifetime spent investigating K+ buffering has seen enormous advances in glial research, from the time cells were identified as ‘presumed’ glial cells or ‘silent cells’, to the present day, where glial cells are recognised as contributing to every important physiological brain function

Targeted knock-down of miR21 primary transcripts using snoMEN vectors induces apoptosis in human cancer cell lines

We have previously reported an antisense technology, 'snoMEN vectors', for targeted knock-down of protein coding mRNAs using human snoRNAs manipulated to contain short regions of sequence complementarity with the mRNA target. Here we characterise the use of snoMEN vectors to target the knock-down of micro RNA primary transcripts. We document the specific knock-down of miR21 in HeLa cells using plasmid vectors expressing miR21-targeted snoMEN RNAs and show this induces apoptosis. Knock-down is dependent on the presence of complementary sequences in the snoMEN vector and the induction of apoptosis can be suppressed by over-expression of miR21. Furthermore, we have also developed lentiviral vectors for delivery of snoMEN RNAs and show this increases the efficiency of vector transduction in many human cell lines that are difficult to transfect with plasmid vectors. Transduction of lentiviral vectors expressing snoMEN targeted to pri-miR21 induces apoptosis in human lung adenocarcinoma cells, which express high levels of miR21, but not in human primary cells. We show that snoMEN-mediated suppression of miRNA expression is prevented by siRNA knock-down of Ago2, but not by knock-down of Ago1 or Upf1. snoMEN RNAs colocalise with Ago2 in cell nuclei and nucleoli and can be co-immunoprecipitated from nuclear extracts by antibodies specific for Ago2

An addressable quantum dot qubit with fault-tolerant control fidelity

Exciting progress towards spin-based quantum computing has recently been made with qubits realized using nitrogen-vacancy (N-V) centers in diamond and phosphorus atoms in silicon, including the demonstration of long coherence times made possible by the presence of spin-free isotopes of carbon and silicon. However, despite promising single-atom nanotechnologies, there remain substantial challenges in coupling such qubits and addressing them individually. Conversely, lithographically defined quantum dots have an exchange coupling that can be precisely engineered, but strong coupling to noise has severely limited their dephasing times and control fidelities. Here we combine the best aspects of both spin qubit schemes and demonstrate a gate-addressable quantum dot qubit in isotopically engineered silicon with a control fidelity of 99.6%, obtained via Clifford based randomized benchmarking and consistent with that required for fault-tolerant quantum computing. This qubit has orders of magnitude improved coherence times compared with other quantum dot qubits, with T_2* = 120 mus and T_2 = 28 ms. By gate-voltage tuning of the electron g*-factor, we can Stark shift the electron spin resonance (ESR) frequency by more than 3000 times the 2.4 kHz ESR linewidth, providing a direct path to large-scale arrays of addressable high-fidelity qubits that are compatible with existing manufacturing technologies

Elevated hemostasis markers after pneumonia increases one-year risk of all-cause and cardiovascular deaths

Background: Acceleration of chronic diseases, particularly cardiovascular disease, may increase long-term mortality after community-acquired pneumonia (CAP), but underlying mechanisms are unknown. Persistence of the prothrombotic state that occurs during an acute infection may increase risk of subsequent atherothrombosis in patients with pre-existing cardiovascular disease and increase subsequent risk of death. We hypothesized that circulating hemostasis markers activated during CAP persist at hospital discharge, when patients appear to have recovered clinically, and are associated with higher mortality, particularly due to cardiovascular causes. Methods: In a cohort of survivors of CAP hospitalization from 28 US sites, we measured D-Dimer, thrombin-antithrombin complexes [TAT], Factor IX, antithrombin, and plasminogen activator inhibitor-1 at hospital discharge, and determined 1-year all-cause and cardiovascular mortality. Results: Of 893 subjects, most did not have severe pneumonia (70.6% never developed severe sepsis) and only 13.4% required intensive care unit admission. At discharge, 88.4% of subjects had normal vital signs and appeared to have clinically recovered. D-dimer and TAT levels were elevated at discharge in 78.8% and 30.1% of all subjects, and in 51.3% and 25.3% of those without severe sepsis. Higher D-dimer and TAT levels were associated with higher risk of all-cause mortality (range of hazard ratios were 1.66-1.17, p = 0.0001 and 1.46-1.04, p = 0.001 after adjusting for demographics and comorbid illnesses) and cardiovascular mortality (p = 0.009 and 0.003 in competing risk analyses). Conclusions: Elevations of TAT and D-dimer levels are common at hospital discharge in patients who appeared to have recovered clinically from pneumonia and are associated with higher risk of subsequent deaths, particularly due to cardiovascular disease. © 2011 Yende et al