Towards understanding the design of dual-modal MR/fluorescent probes to sense zinc ions

A series of gadolinium complexes were synthesised in order to test the design of dual-modal probes that display a change in fluorescence or relaxivity response upon binding of zinc. A dansyl-DO3ATA gadolinium complex [GdL1] displayed an increase and a slight blue-shift in fluorescence in the presence of zinc; however, a decrease in relaxation rate was observed. Consequently, the ability of the well-known zinc chelator, BPEN, was assessed for relaxivity response when conjugated to the gadolinium chelate. The success of this probe [GdL2], lead to the inclusion of the same zinc-probing moiety alongside a longer wavelength emitting fluorophore, rhodamine [GdL3], to arrive at the final iteration of these first generation dual-modal zinc-sensing probes. The compounds give insight into the design protocols required for the successful imaging of zinc ions

The "unknown territory" of goal-setting: Negotiating a novel interactional activity within primary care doctor-patient consultations for patients with multiple chronic conditions.

Goal-setting is widely recommended for supporting patients with multiple long-term conditions. It involves a proactive approach to a clinical consultation, requiring doctors and patients to work together to identify patient’s priorities, values and desired outcomes as a basis for setting goals for the patient to work towards. Importantly it comprises a set of activities that, for many doctors and patients, represents a distinct departure from a conventional consultation, including goal elicitation, goal-setting and action planning. This indicates that goal-setting is an uncertain interactional space subject to inequalities in understanding and expectations about what type of conversation is taking place, the roles of patient and doctor, and how patient priorities may be configured as goals. Analysing such spaces therefore has the potential for revealing how the principles of goal-setting are realised in practice. In this paper, we draw on Goffman’s concept of ‘frames’ to present an examination of how doctors’ and patients’ sense making of goal-setting was consequential for the interactions that followed. Informed by Interactional Sociolinguistics, we used conversation analysis methods to analyse 22 video-recorded goal-setting consultations with patients with multiple long-term conditions. Data were collected between 2016 and 2018 in three UK general practices as part of a feasibility study. We analysed verbal and non-verbal actions for evidence of GP and patient framings of consultation activities and how this was consequential for setting goals. We identified three interactional patterns: GPs checking and reframing patients’ understanding of the goal-setting consultation, GPs actively aligning with patients’ framing of their goal, and patients passively and actively resisting GP framing of the patient goals. These reframing practices provided “telling cases” of goal-setting interactions, where doctors and patients need to negotiate each other’s perspectives but also conflicting discourses of patient-centredness, population-based evidence for treating different chronic illnesses and conventional doctor-patient relations

An evaluation of the quality of statistical design and analysis of published medical research : results from a systematic survey of general orthopaedic journals

Background: The application of statistics in reported research in trauma and orthopaedic surgery has become ever more important and complex. Despite the extensive use of statistical analysis, it is still a subject which is often not conceptually well understood, resulting in clear methodological flaws and inadequate reporting in many papers. Methods: A detailed statistical survey sampled 100 representative orthopaedic papers using a validated questionnaire that assessed the quality of the trial design and statistical analysis methods. Results: The survey found evidence of failings in study design, statistical methodology and presentation of the results. Overall, in 17% (95% confidence interval; 10–26%) of the studies investigated the conclusions were not clearly justified by the results, in 39% (30–49%) of studies a different analysis should have been undertaken and in 17% (10–26%) a different analysis could have made a difference to the overall conclusions. Conclusion: It is only by an improved dialogue between statistician, clinician, reviewer and journal editor that the failings in design methodology and analysis highlighted by this survey can be addressed

Lanthanide(III) complexes of rhodamine-DO3A conjugates as agents for dual-modal imaging

Two novel dual-modal MRI/optical probes based on a rhodamine-DO3A conjugate have been prepared. The bis aqua-Gd(III) complex Gd.L1 and mono aqua-Gd(III) complex Gd.L2 behave as dual-modal imaging probes (r1 = 8.5 and 3.8 mM-1s-1 for Gd.L1 and Gd.L2 respectively; λex = 560 nm and λem = 580 nm for both complexes). The rhodamine fragment is pH sensitive and upon lowering of pH an increase in fluorescence intensity is observed as the spirolactam ring opens to give the highly fluorescent form of the molecule. The ligands are bimodal when coordinated to Tb(III) ions, inducing fluorescence from both the lanthanide center and the rhodamine fluorophore, on two independent time-frames. Confocal imaging experiments were carried out to establish the localization of Gd.L2 in HEK cells. Co-localisation with MitoTracker® Green confirmed that Gd.L2 compartmentalizes in the mitochondria. Gd.L2 was also evaluated as an MRI probe for imaging tumors in BALB/c nude mice bearing M21 xenografts. A 36.5% decrease in T1 within the tumor was observed 30 minutes post injection showing that Gd.L2 is preferentially up taken in the tumor. Gd.L2 is the first small molecule MR/fluorescent dual-modal imaging agent to display an off-on pH switch upon its preferential uptake within the more acidic micro-environment of tumor cells

The case for scaling up renewable energy investments in fragile and conflict-affected situations

The impressive drop in the cost of clean technologies and the local practical potential of solar PV are making renewable energy an increasingly viable option from an economic perspective in fragile settings. Clean energy investment also has direct implications for tackling climate change, improving the socioeconomic inclusion of marginalised groups, and state-building – through greater legitimacy, resilience, and commitment to peace. These elements highlight the great potential that investments in renewable, reliable, and affordable energy hold to help countries escape state fragility

Mean-state biases and interannual variability affect perceived sensitivities of the Madden-Julian oscillation to air-sea coupling

Atmosphere–ocean feedbacks often improve the Madden–Julian oscillation (MJO) in climate models, but these improvements are balanced by mean-state biases that can degrade the MJO through changing the basic state on which the MJO operates. The Super-Parameterized Community Atmospheric Model (SPCAM3) produces perhaps the best representation of the MJO among contemporary models, which improves further in a coupled configuration (SPCCSM3) despite considerable mean-state biases in tropical sea-surface temperatures and rainfall. We implement an atmosphere–ocean-mixed-layer configuration of SPCAM3 (SPCAM3-KPP) and use a flux-correction technique to isolate the effects of coupling and mean-state biases on the MJO. When constrained to the observed ocean mean state, air–sea coupling does not substantially alter the MJO in SPCAM3, in contrast to previous studies. When constrained to the SPCCSM ocean mean state, SPCAM3-KPP fails to produce an MJO, in stark contrast to the strong MJO in SPCCSM3. Further KPP simulations demonstrate that the MJO in SPCCSM3 arises from an overly strong sensitivity to El Niño–Southern Oscillation (ENSO) events. Our results show that simulated inter-annual variability and coupled-model mean-state biases affect the perceived response of the MJO to coupling. This is particularly concerning in the context of internal variability in coupled models, as many MJO sensitivity studies in coupled models use relatively short (20–50 year) simulations that undersample interannual–decadal variability. Diagnosing the effects of coupling on the MJO requires simulations that carefully control for mean-state biases and interannual variability

Diagnosing ocean feedbacks to the BSISO: SST-modulated surface fluxes and the moist static energy budget

The oceanic feedback to the atmospheric boreal summer intraseasonal oscillation (BSISO) is examined by diagnosing the sea surface temperature (SST) modification of surface fluxes and the moist static energy (MSE) on intraseasonal scales. SST variability affects intraseasonal surface latent heat (LH) and sensible heat (SH) fluxes, through its influence on air-sea moisture and temperature gradients (delta-q and delta-T). According to bulk formula decomposition, LH is mainly determined by wind-driven flux perturbations, while SH is more sensitive to thermodynamic flux perturbations. SST fluctuations tend to increase the thermodynamic flux perturbations over active BSISO regions, but this is largely offset by the wind-driven flux perturbations. Enhanced surface fluxes induced by intraseasonal SST anomalies are located ahead (north) of the convective center over both the Indian Ocean and western Pacific, favoring BSISO northward propagation. Analysis of budgets of column-integrated MSE () and its time rate of change (d/dt) show that SST-modulated surface fluxes can influence the development and propagation of the BSISO, respectively. LH and SH variability induced by intraseasonal SSTs maintain 1-2% of /day over the equatorial western Indian Ocean, Arabian Sea and Bay of Bengal, but damp about 1% of /day over the western North Pacific. The contribution of intraseasonal SST variability to d/dt can reach 12-20% over active BSISO regions. These results suggest that SST variability is conducive, but perhaps not essential, for the propagation of convection during the BSISO life cycle

Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice

In a mouse model of respiratory tract infection by Bordetella pertussis, bacteria multiply in the airways over the first week and are then cleared over the next 3–4 weeks by the host immune response. Pertussis toxin (PT), a virulence factor secreted exclusively by B. pertussis, promotes bacterial growth in the airways by suppression and modulation of host immune responses. By comparison of wild type and PT-deficient strains, we examined the role of PT in modulating airway cytokine and chemokine responses affecting neutrophil recruitment during B. pertussis infection in mice. We found that, despite early inhibition of neutrophil recruitment by PT, high numbers of neutrophils were recruited to the airways by 4 days post-infection with the wild type strain, but not with the PT-deficient strain, and that this correlated with upregulation of neutrophil-attracting chemokine gene expression. In addition, there was similar upregulation of genes expressing the cytokines IL-17A (IL-17), TNF-α and IFN-γ, indicating a mixed Th1/Th17 response. Expression of IL-6, a cytokine involved in Th17 induction, was upregulated earlier than the IL-17 response. We showed that PT, rather than bacterial numbers, was important for induction of these responses. Flow cytometric analysis revealed that the IL-17-producing cells were macrophages and neutrophils as well as T cells, and were present predominantly in the airways rather than the lung tissue. Antibody neutralization of IL-17 significantly reduced chemokine gene expression and neutrophil recruitment to the airways, but only modestly increased peak bacterial loads. These data indicate that PT stimulates inflammatory responses by induction of Th1- and Th17-associated cytokines, including IL-17, during B. pertussis infection in mice, but a role for IL-17 in protection against the infection remains to be established

Personalisation and the promise of independent living: Where now for cash, care and control for disability organisations across the UK?

Personalisation has dominated social care across OECD countries over the past 20 years. UK policy evolved from the efforts of disabled peoples’ organisations (DPOs) to secure the availability of cash payments as part of a wider drive to enable independent living. Implementation of personalisation across the UK has seen significant divergence in how governments have developed their own responses, but in each country the DPOs’ role and impact has shifted from campaigning and promoting the voices of disabled people to a more muted focus on service provision and limited policy engagement. This article draws on a series of interviews with DPOs and leading disabled activists. It highlights concerns raised related to themes around austerity, changing relationships with local government and the role of co-production in developing policy. We conclude the article by discussing the future directions for personalisation and developments in light of the COVID-19 pandemic