401 research outputs found

    Teaching Professional Formation in Response to the COVID-19 Pandemic.

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    In response to the COVID-19 pandemic, the Association of American Medical Colleges has called for a temporary suspension of clinical teaching activities for medical students. Planning for the continued involvement of learners in patient care during this pandemic should include teaching learners professional formation. The authors provide an ethical framework to guide such teaching, based on the ethical principle of beneficence and the professional virtues of courage and self-sacrifice from professional ethics in medicine. The authors show that these concepts support the conclusion that learners are ethically obligated to accept reasonable, but not unreasonable, risk. Based on this ethical framework, the authors provide an account of the process of teaching professional formation that medical educators and academic leaders should implement. Medical educators and academic leaders should embrace the opportunity that the COVID-19 pandemic presents for teaching professional formation. Learners should acquire the conceptual vocabulary of professional formation. Learners should recognize that risk of infection from patients is unavoidable. Learners should become aware of established ethical standards for professional responsibility during epidemics from the history of medicine. Learners should master understandable fear. Medical educators and academic leaders should ensure that didactic teaching of professional formation continues when it becomes justified to end learners\u27 participation in the processes of patient care; topics should include the professionally responsible management of scarce medical resources. The COVID-19 pandemic will not be the last major infectious disease that puts learners at risk. Professional ethics in medicine provides powerful conceptual tools that can be used as an ethical framework to guide medical educators to teach learners, who will bear leadership responsibilities in responses to future pandemics, professional formation

    Impact of age on cerebrovascular dilation versus reactivity to hypercapnia.

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    This study quantified the effect of age on cerebrovascular reactivity and cerebrovascular conductance while accounting for differences in grey matter volume in younger (YA: n = 12; 24 ± 4 years, six females) and older adults (OA: n = 10; 66 ± 7 years; five females). Cerebral blood flow velocity (CBFV; transcranial Doppler) in the middle cerebral artery (MCA), MCA cross-sectional area (CSA), intracranial volumes (magnetic resonance imaging), and mean arterial pressure (MAP; Finometer), were measured under normocapnic and hypercapnic (6% carbon dioxide) conditions. Cerebral blood flow (CBF) was quantified from CBFV and MCA CSA and normalized to grey matter volume. Grey matter volume was 719 ± 98 mL in YA and 622 ± 50 mL in OA (P = 0.009). Cerebrovascular reactivity (%ΔCBF/Δ

    'It feels like its sink or swim': newly qualified teachers' experiences of their induction year

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    This study examined the experiences of a small group of Newly Qualified Teachers (NQTs) during their NQT year. A focus group was used to explore the NQTs’ understandings of their role and the influence of the NQT year on the development of their professional teacher identity. Data were digitally recorded, transcribed and organised into themes. The data indicate that the participants had developed a strong sense of their own accountability for their own professionalism and for improving the academic performance of their pupils. They had been initiated into the discourse of performativity that is entrenched across the education system. Consequently, some, but not all, NQTs had rejected their personal educational philosophies and had embraced a socially assigned identity which embraced the principles of performativity

    Easy to synthesize, robust organo-osmium asymmetric transfer hydrogenation catalysts

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    Asymmetric transfer hydrogenation (ATH) is an important process in organic synthesis for which the Noyori-type RuII catalysts [(arene)Ru(Tsdiamine)] are now well established and widely used. We now demonstrate for the first time the catalytic activity of the osmium analogues. X-ray crystal structures of the 16-electron OsII catalysts are almost identical to those of RuII. Intriguingly the precursor complex was isolated as a dichlorido complex with a monodentate amine ligand. The OsII catalysts are readily synthesised (within 1 h) and exhibit excellent enantioselectivity in ATH reactions of ketones

    A metalloproteomic analysis of interactions between plasma proteins and zinc: elevated fatty acid levels affect zinc distribution

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    Serum albumin is a highly abundant plasma protein associated with the transport of metal ions, pharmaceuticals, fatty acids and a variety of small molecules in the blood. Once thought of as a molecular ‘sponge’, mounting evidence suggests that the albumin-facilitated transport of chemically diverse entities is not independent. One such example is the transport of Zn2+ ions and non-esterified ‘free’ fatty acids (FFAs) by albumin, both of which bind at high affinity sites located in close proximity. Our previous research suggests that their transport in blood plasma is linked via an allosteric mechanism on serum albumin. In direct competition, albumin-bound FFAs significantly decrease the binding capacity of albumin for Zn2+, with one of the predicted consequences being a change in plasma/serum zinc speciation. Using liquid chromatography (LC), ICP-MS and fluorescence assays, our work provides a quantitative assessment of this phenomenon, and finds that in the presence of high FFA concentrations encountered in various physiological conditions, a significant proportion of albumin-bound Zn2+ is re-distributed amongst plasma/serum proteins. Using peptide mass fingerprinting and immunodetection, we identify candidate acceptor proteins for Zn2+ liberated from albumin. These include histidine-rich glycoprotein (HRG), a multifunctional protein associated with the regulation of blood coagulation, and members of the complement system involved in the innate immune response. Our findings highlight how FFA-mediated changes in extracellular metal speciation might contribute to the progression of certain pathological conditions

    Acute changes in forearm vascular compliance during transient sympatho-excitation

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    The study of vascular regulation often omits important information about the elastic properties of arteries under conditions of pulsatile flow. The purpose of this study was to examine the relationship between muscle sympathetic nerve activity (MSNA), vascular bed compliance, and peripheral blood flow responses in humans. We hypothesized that increases in MSNA would correlate with reductions in vascular compliance, and that changes in compliance would correspond with changes in peripheral blood flow during sympatho-excitation. MSNA (microneurography), blood pressure (Finopres), and brachial artery blood flow (Doppler ultrasound), were monitored in six healthy males at baseline and during the last 15 s of voluntary end-inspiratory, expiratory apneas and 5 min of static handgrip exercise (SHG; 20% maximum voluntary contraction) and 3 min of post-exercise circulatory occlusion (SHG + PECO; measured in the non-exercising arm). A lumped Windkessel model was employed to examine vascular bed compliance. During apnea, indices of MSNA were inversely related with vascular compliance, and reductions in compliance correlated with decreased brachial blood flow rate. During SHG, despite increased MSNA, compliance also increased, but was unrelated to increases in blood flow. Neither during SHG nor PECO did indices of MSNA correlate with forearm vascular compliance nor did vascular compliance correlate with brachial flow. However, during PECO, a linear combination of blood pressure and total MSNA was correlated with vascular compliance. These data indicate the elastic components of the forearm vasculature are regulated by adrenergic and myogenic mechanisms during sympatho-excitation, but in a reflex-dependent manner

    In‐cell Catalysis by Tethered Organo−Osmium Complexes Generates Selectivity for Breast Cancer Cells

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    Anticancer agents that exhibit catalytic mechanisms of action offer a unique multi‐targeting strategy to overcome drug resistance. Nonetheless, many in‐cell catalysts in development are hindered by deactivation by endogenous nucleophiles. We have synthesised a highly potent, stable Os‐based 16‐electron half‐sandwich (‘piano stool’) catalyst by introducing a permanent covalent tether between the arene and chelated diamine ligand. This catalyst exhibits antiproliferative activity comparable to the clinical drug cisplatin towards triple‐negative breast cancer cells and can overcome tamoxifen resistance. Speciation experiments revealed Os to be almost exclusively albumin‐bound in the extracellular medium, while cellular accumulation studies identified an energy‐dependent, protein‐mediated Os accumulation pathway, consistent with albumin‐mediated uptake. Importantly, the tethered Os complex was active for in‐cell transfer hydrogenation catalysis, initiated by co‐administration of a non‐toxic dose of sodium formate as a source of hydride, indicating that the Os catalyst is delivered to the cytosol of cancer cells intact. The mechanism of action involves the generation of reactive oxygen species (ROS), thus exploiting the inherent redox vulnerability of cancer cells, accompanied by selectivity for cancerous cells over non‐tumorigenic cells

    Asymmetric transfer hydrogenation by synthetic catalysts in cancer cells

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    Catalytic anticancer metallodrugs active at low doses could minimise side-effects, introduce novel mechanisms of action which combat resistance, and widen the spectrum of anticancer drug activity. We have used new highly-stable chiral half-sandwich organometallic Os(II) arene sulfonyl diamine complexes, [Os(arene)(TsDPEN)] to achieve highly enantioselective reduction of pyruvate, a key intermediate in metabolic pathways, both in aqueous model systems and in human cancer cells, using non-toxic concentrations of sodium formate as a hydride source. Importantly the catalytic mechanism generates selectivity towards ovarian cancer cells versus non-cancerous fibroblasts (both ovarian and lung), which are commonly used as models of healthy proliferating cells. The formate precursor N-formylmethionine was explored as an alternative to formate in PC3 prostate cancer cells, which are known to over-express a deformylase enzyme. Transfer hydrogenation catalysts generating reductive stress in cancer cells offer a ground-breaking new approach to cancer therapy
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