Intravenous iron preparations transiently generate non-transferrin-bound iron from two proposed pathways

Intravenous iron-carbohydrate complex preparations (IVIPs) are non-interchangeable pro-drugs: their pharmacokinetics (PK) varies determined by semi-crystalline iron core and carbohydrate shell structures, influences pharmacodynamics (PD) and thus efficacy and safety. Examining PK/PD relationships of 3 IVIPs we identify a two-pathway model of transient NTBI generation following single dose administration. 28 hypoferremic non-anemic patients randomized to 200mg iron as ferric carboxymaltose (Fe-carboxymaltose), iron sucrose (Fe-sucrose), iron isomaltoside 1000 (Fe-isomaltoside-1000), n=8/arm, or placebo, n=4, on a 2-week PK/PD study, had samples analysed for total serum iron, IVIP-iron, transferrin-bound iron (TBI) by HPLC-ICP-MS, transferrin saturation (TSAT), serum ferritin (s-Ferritin) by standard methods, non-TBI (NTBI) and hepcidin as published before. IVIP-dependent increases in these parameters returned to baseline in 48-150h, except for s-Ferritin and TSAT. NTBI was low with Fe-isomaltoside-1000 (0.13µM at 8h), rapidly increased with Fe-sucrose (0.8µM at 2h, 1.25µM at 4h), and delayed for Fe-carboxymaltose (0.57µM at 24h). NTBI AUCs were 7-fold greater for Fe-carboxymaltose and Fe-sucrose than for Fe-isomaltoside-1000. Hepcidin peak time varied, but not AUC or mean levels. s-Ferritin levels and AUC were highest for Fe-carboxymaltose and greater than placebo for all IVIPs. We propose 2 mechanisms for the observed NTBI kinetics: rapid and delayed NTBI appearance consistent with direct (circulating IVIP-to-plasma) and indirect (IVIP-to-macrophage-to-plasma) iron release based on IVIP plasma half-life and s-Ferritin dynamics. IVIPs generate different, broadly stability- and PK-dependent, NTBI and s-Ferritin signatures, which may influence iron bioavailability, efficacy and safety. Longer-term studies should link NTBI exposure to subsequent safety and efficacy parameters and potential clinical consequences

Manipulation of the spin helix in FeGe thin films and FeGe/Fe multilayers

Magnetic materials without structural inversion symmetry can display the Dzyaloshinskii-Moriya interaction, which manifests itself as chiral magnetic ground states. These chiral states can interact in complex ways with applied fields and boundary conditions provided by finite sample sizes that are of the order of the lengthscale of the chiral states. Here we study epitaxial thin films of FeGe with a thickness close to the helix pitch of the helimagnetic ground state, which is about 70 nm, by conventional magnetometry and polarized neutron reflectometry. We show that the helix in an FeGe film reverses under the application of a field by deforming into a helicoidal form, with twists in the helicoid being forced out of the film surfaces on the way to saturation. An additional boundary condition was imposed by exchange coupling a ferromagnetic Fe layer to one of the interfaces of an FeGe layer. This forces the FeGe spins at the interface to point in the same direction as the Fe, preventing node expulsion and giving a handle by which the reversal of the helical magnet may be controlled

Evolutionary diversification of the RomR protein of the invasive deltaproteobacterium, Bdellovibrio bacteriovorus

This is the final version. Available on open access from Nature Research via the DOI in this recordBdellovibrio bacteriovorus is a predatory deltaproteobacterium that encounters individual Gram-negative prey bacteria with gliding or swimming motility, and then is able to invade such prey cells via type IVa pilus-dependent mechanisms. Movement control (pili or gliding) in other deltaproteobacteria, such as the pack hunting Myxococcus xanthus, uses a response regulator protein, RomRMx (which dynamically relocalises between the cell poles) and a GTPase, MglAMx, previously postulated as an interface between the FrzMx chemosensory system and gliding or pilus-motility apparatus, to produce regulated bidirectional motility. In contrast, B. bacteriovorus predation is a more singular encounter between a lone predator and prey; contact is always via the piliated, non-flagellar pole of the predator, involving MglABd, but no Frz system. In this new study, tracking fluorescent RomRBd microscopically during predatory growth shows that it does not dynamically relocalise, in contrast to the M. xanthus protein; instead having possible roles in growth events. Furthermore, transcriptional start analysis, site-directed mutagenesis and bacterial two-hybrid interaction studies, indicate an evolutionary loss of RomRBd activation (via receiver domain phosphorylation) in this lone hunting bacterium, demonstrating divergence from its bipolar role in motility in pack-hunting M. xanthus and further evolution that may differentiate lone from pack predators.Leverhulme TrustMedical Research Council (MRC)Biotechnology and Biological Sciences Research Council (BBSRC

Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation: challenges and opportunities

The COVID-19 pandemic is a global public health crisis, with considerable mortality and morbidity exerting pressure on health-care resources, including critical care. An excessive host inflammatory response in a subgroup of patients with severe COVID-19 might contribute to the development of acute respiratory distress syndrome (ARDS) and multiorgan failure. Timely therapeutic intervention with immunomodulation in patients with hyperinflammation could prevent disease progression to ARDS and obviate the need for invasive ventilation. Granulocyte macrophage colony-stimulating factor (GM-CSF) is an immunoregulatory cytokine with a pivotal role in initiation and perpetuation of inflammatory diseases. GM-CSF could link T-cell-driven acute pulmonary inflammation with an autocrine, self-amplifying cytokine loop leading to monocyte and macrophage activation. This axis has been targeted in cytokine storm syndromes and chronic inflammatory disorders. Here, we consider the scientific rationale for therapeutic targeting of GM-CSF in COVID-19-associated hyperinflammation. Since GM-CSF also has a key role in homoeostasis and host defence, we discuss potential risks associated with inhibition of GM-CSF in the context of viral infection and the challenges of doing clinical trials in this setting, highlighting in particular the need for a patient risk-stratification algorithm

Interesting case of ovarian sarcoidosis: The value of multi disciplinary team working

BACKGROUND: Sarcoidosis of the genital tract is a rare condition. Ovarian manifestation of this disease is rarer still. CASE PRESENTATION: The case presented here represents ovarian manifestation of sarcoidosis. At the point of referral to our hospital, based on computerised tomography (CT) ovarian carcinoma was a differential diagnosis. Further magnetic resonance imaging along with CT guided biopsy aided by laboratory study supported a diagnosis of sarcoidosis. Patient responded to medical management by a multidisciplinary team. CONCLUSION: The case shows the importance of FNAC and biopsy in case or ovarian masses and multi disciplinary team approach to management

Plasma cholesterol levels and brain development in preterm newborns.

BackgroundTo assess whether postnatal plasma cholesterol levels are associated with microstructural and macrostructural regional brain development in preterm newborns.MethodsSixty preterm newborns (born 24-32 weeks gestational age) were assessed using MRI studies soon after birth and again at term-equivalent age. Blood samples were obtained within 7 days of each MRI scan to analyze for plasma cholesterol and lathosterol (a marker of endogenous cholesterol synthesis) levels. Outcomes were assessed at 3 years using the Bayley Scales of Infant Development, Third Edition.ResultsEarly plasma lathosterol levels were associated with increased axial and radial diffusivities and increased volume of the subcortical white matter. Early plasma cholesterol levels were associated with increased volume of the cerebellum. Early plasma lathosterol levels were associated with a 2-point decrease in motor scores at 3 years.ConclusionsHigher early endogenous cholesterol synthesis is associated with worse microstructural measures and larger volumes in the subcortical white matter that may signify regional edema and worse motor outcomes. Higher early cholesterol is associated with improved cerebellar volumes. Further work is needed to better understand how the balance of cholesterol supply and endogenous synthesis impacts preterm brain development, especially if these may be modifiable factors to improve outcomes

Support and Assessment for Fall Emergency Referrals (SAFER 1) trial protocol. Computerised on-scene decision support for emergency ambulance staff to assess and plan care for older people who have fallen: evaluation of costs and benefits using a pragmatic cluster randomised trial

Background: Many emergency ambulance calls are for older people who have fallen. As half of them are left at home, a community-based response may often be more appropriate than hospital attendance. The SAFER 1 trial will assess the costs and benefits of a new healthcare technology - hand-held computers with computerised clinical decision support (CCDS) software - to help paramedics decide who needs hospital attendance, and who can be safely left at home with referral to community falls services. Methods/Design: Pragmatic cluster randomised trial with a qualitative component. We shall allocate 72 paramedics ('clusters') at random between receiving the intervention and a control group delivering care as usual, of whom we expect 60 to complete the trial. Patients are eligible if they are aged 65 or older, live in the study area but not in residential care, and are attended by a study paramedic following an emergency call for a fall. Seven to 10 days after the index fall we shall offer patients the opportunity to opt out of further follow up. Continuing participants will receive questionnaires after one and 6 months, and we shall monitor their routine clinical data for 6 months. We shall interview 20 of these patients in depth. We shall conduct focus groups or semi-structured interviews with paramedics and other stakeholders. The primary outcome is the interval to the first subsequent reported fall (or death). We shall analyse this and other measures of outcome, process and cost by 'intention to treat'. We shall analyse qualitative data thematically. Discussion: Since the SAFER 1 trial received funding in August 2006, implementation has come to terms with ambulance service reorganisation and a new national electronic patient record in England. In response to these hurdles the research team has adapted the research design, including aspects of the intervention, to meet the needs of the ambulance services. In conclusion this complex emergency care trial will provide rigorous evidence on the clinical and cost effectiveness of CCDS for paramedics in the care of older people who have fallen

Developing an award program for children's settings to support healthy eating and physical activity and reduce the risk of overweight and obesity

<p>Abstract</p> <p>Background</p> <p>This paper aimed to identify the best way to engage, motivate and support early childhood services (ECS) and primary schools (PS) to create policy and practise changes to promote healthy eating and physical activity. This information would be used to develop a suitable program to implement within these children's settings to reduce the risk of childhood overweight and obesity.</p> <p>Methods</p> <p>The Medical Research Council's (UK) framework for the design and evaluation of complex interventions was used to guide the development of the healthy eating and physical activity program suitable for ECS and PS. Within this framework a range of evaluation methods, including stakeholder planning, in-depth interviews with ECS and PS staff and acceptability and feasibility trials in one local government area, were used to ascertain the best way to engage and support positive changes in these children's settings.</p> <p>Results</p> <p>Both ECS and PS identified that they had a role to play to improve children's healthy eating and physical activity. ECS identified their role in promoting healthy eating and physical activity as important for children's health, and instilling healthy habits for life. PS felt that these were health issues, rather than educational issues; however, schools saw the link between healthy eating and physical activity and student learning outcomes. These settings identified that a program that provides a simple guide that recognises good practise in these settings, such as an award scheme using a health promoting schools approach, as a feasible and acceptable way for them to support children's healthy eating and physical activity.</p> <p>Conclusion</p> <p>Through the process of design and evaluation a program - <it>Kids - 'Go for your life'</it>, was developed to promote and support children's healthy eating and physical activity and reduce the risk of childhood overweight and obesity. <it>Kids - 'Go for your life' </it>used an award program, based on a health promoting schools approach, which was demonstrated to be a suitable model to engage ECS and PS and was acceptable and feasible to create policy and practise changes to support healthy eating and physical activity for children.</p