Complement and cytokine response in acute Thrombotic Thrombocytopenic Purpura

Complement dysregulation is key in the pathogenesis of atypical Haemolytic Uraemic Syndrome (aHUS), but no clear role for complement has been identified in Thrombotic Thrombocytopenic Purpura (TTP). We aimed to assess complement activation and cytokine response in acute antibody-mediated TTP. Complement C3a and C5a and cytokines (interleukin (IL)-2, IL-4, IL-6, IL-10, tumour necrosis factor, interferon-γ and IL-17a) were measured in 20 acute TTP patients and 49 remission cases. Anti-ADAMTS13 immunoglobulin G (IgG) subtypes were measured in acute patients in order to study the association with complement activation. In acute TTP, median C3a and C5a were significantly elevated compared to remission, C3a 63·9 ng/ml vs. 38·2 ng/ml (P < 0·001) and C5a 16·4 ng/ml vs. 9·29 ng/ml (P < 0·001), respectively. Median IL-6 and IL-10 levels were significantly higher in the acute vs. remission groups, IL-6: 8 pg/ml vs. 2 pg/ml (P = 0·003), IL-10: 6 pg/ml vs. 2 pg/ml (P < 0·001). C3a levels correlated with both anti-ADAMTS13 IgG (rs  = 0·604, P = 0·017) and IL-10 (rs  = 0·692, P = 0·006). No anti-ADAMTS13 IgG subtype was associated with higher complement activation, but patients with the highest C3a levels had 3 or 4 IgG subtypes present. These results suggest complement anaphylatoxin levels are higher in acute TTP cases than in remission, and the complement response seen acutely may relate to anti-ADAMTS13 IgG antibody and IL-10 levels

Bypassing the proline/thiazoline requirement of the macrocyclase PatG

Peer reviewedPublisher PD

Delegation and supervision of health care assistants’ work in the daily management of uncertainty and the unexpected in clinical practice: invisible learning among newly qualified nurses

The invisibility of nursing work has been discussed in the international literature but not in relation to learning clinical skills. Evans and Guile’s (2012) theory of recontextualisation is used to explore the ways in which invisible or unplanned and unrecognised learning takes place as newly qualified nurses learn to delegate to and supervise the work of the health care assistant. In the British context, delegation and supervision are thought of as skills which are learnt ‘on the job’. We suggest that learning ‘on-the-job’ is the invisible construction of knowledge in clinical practice and that delegation is a particularly telling area of nursing practice which illustrates invisible learning. Using an ethnographic case study approach in three hospital sites in England from 2011-2014, we undertook participant observation, interviews with newly qualified nurses, ward managers and health care assistants. We discuss the invisible ways newly qualified nurses learn in the practice environment and present the invisible steps to learning which encompass the embodied, affective and social, as much as the cognitive components to learning. We argue that there is a need for greater understanding of the ‘invisible learning’ which occurs as newly qualified nurses learn to delegate and supervise

'Doing the writing' and 'working in parallel': how 'distal nursing' affects delegation and supervision in the emerging role of the newly qualified nurse

Background: The role of the acute hospital nurse has moved away from the direct delivery of patient care and more towards the management of the delivery of bedside care by healthcare assistants. How newly qualified nurses delegate to and supervise healthcare assistants is important as failures can lead to care being missed, duplicated and/or incorrectly performed. Objectives: The data described here form part of a wider study which explored how newly qualified nurses recontextualise knowledge into practice, and develop and apply effective delegation and supervision skills. This article analyses team working between newly qualified nurses and healthcare assistants, and nurses' balancing of administrative tasks with bedside care. Methods and Analysis: Ethnographic case studies were undertaken in three hospital sites in England, using a mixed methods approach involving: participant observations; interviews with 33 newly qualified nurses, 10 healthcare assistants and 12 ward managers. Data were analysed using thematic analysis, aided by the qualitative software NVivo. Findings:Multiple demands upon the newly qualified nurses' time, particularly the pressures tomaintain records, can influence how effectively they delegate to, and supervise, healthcare assistants. While some nurses and healthcare assistants work successfully together, others work ‘in parallel’ rather than as an efficient team. Conclusions: While some ward cultures and individual working styles promote effective team working, others lead to less efficient collaboration between newly qualified nurses and healthcare assistants. In particular the need for qualified nurses to maintain records can create a gap between them, and between nurses and patients. Newly qualified nurses require more assistance in managing their own time and developing successful working relationships with healthcare assistants

The diagnostic certainty levels of junior clinicians: A retrospective cohort study

BACKGROUND: Clinical decision-making is influenced by many factors, including clinicians' perceptions of the certainty around what is the best course of action to pursue. OBJECTIVE: To characterise the documentation of working diagnoses and the associated level of real-time certainty expressed by clinicians and to gauge patient opinion about the importance of research into clinician decision certainty. METHOD: This was a single-centre retrospective cohort study of non-consultant grade clinicians and their assessments of patients admitted from the emergency department between 01 March 2019 and 31 March 2019. De-identified electronic health record proformas were extracted that included the type of diagnosis documented and the certainty adjective used. Patient opinion was canvassed from a focus group. RESULTS: During the study period, 850 clerking proformas were analysed; 420 presented a single diagnosis, while 430 presented multiple diagnoses. Of the 420 single diagnoses, 67 (16%) were documented as either a symptom or physical sign and 16 (4%) were laboratory-result-defined diagnoses. No uncertainty was expressed in 309 (74%) of the diagnoses. Of 430 multiple diagnoses, uncertainty was expressed in 346 (80%) compared to 84 (20%) in which no uncertainty was expressed. The patient focus group were unanimous in their support of this research. CONCLUSION: The documentation of working diagnoses is highly variable among non-consultant grade clinicians. In nearly three quarters of assessments with single diagnoses, no element of uncertainty was implied or quantified. More uncertainty was expressed in multiple diagnoses than single diagnoses. IMPLICATIONS: Increased standardisation of documentation will help future studies to better analyse and quantify diagnostic certainty in both single and multiple working diagnoses. This could lead to subsequent examination of their association with important process or clinical outcome measures

Developing sexual competence? Exploring strategies for the provision of effective sexualities and relationships education

School-based sexualities and relationships education (SRE) offers one of the most promising means of improving young people's sexual health through developing 'sexual competence'. In the absence of evidence on whether the term holds the same meanings for young people and adults (e.g. teachers, researchers, policy-makers), the paper explores 'adult' notions of sexual competence as construed in research data and alluded to in UK Government guidance on SRE, then draws on empirical research with young people on factors that affect the contexts, motivations and outcomes of sexual encounters, and therefore have implications for sexual competence. These data from young people also challenge more traditional approaches to sexualities education in highlighting disjunctions between the content of school-based input and their reported sexual experience. The paper concludes by considering the implications of these insights for developing a shared notion of what SRE is trying to achieve and suggestions for recognition in the content and approaches to SRE.</p

Piperidinols that show anti-tubercular activity as inhibitors of arylamine N-acetyltransferase: an essential enzyme for mycobacterial survival inside macrophages

Latent M. tuberculosis infection presents one of the major obstacles in the global eradication of tuberculosis (TB). Cholesterol plays a critical role in the persistence of M. tuberculosis within the macrophage during latent infection. Catabolism of cholesterol contributes to the pool of propionyl-CoA, a precursor that is incorporated into cell-wall lipids. Arylamine N-acetyltransferase (NAT) is encoded within a gene cluster that is involved in the cholesterol sterol-ring degradation and is essential for intracellular survival. The ability of the NAT from M. tuberculosis (TBNAT) to utilise propionyl-CoA links it to the cholesterol-catabolism pathway. Deleting the nat gene or inhibiting the NAT enzyme prevents intracellular survival and results in depletion of cell-wall lipids. TBNAT has been investigated as a potential target for TB therapies. From a previous high-throughput screen, 3-benzoyl-4-phenyl-1-methylpiperidinol was identified as a selective inhibitor of prokaryotic NAT that exhibited antimycobacterial activity. The compound resulted in time-dependent irreversible inhibition of the NAT activity when tested against NAT from M. marinum (MMNAT). To further evaluate the antimycobacterial activity and the NAT inhibition of this compound, four piperidinol analogues were tested. All five compounds exert potent antimycobacterial activity against M. tuberculosis with MIC values of 2.3-16.9 µM. Treatment of the MMNAT enzyme with this set of inhibitors resulted in an irreversible time-dependent inhibition of NAT activity. Here we investigate the mechanism of NAT inhibition by studying protein-ligand interactions using mass spectrometry in combination with enzyme analysis and structure determination. We propose a covalent mechanism of NAT inhibition that involves the formation of a reactive intermediate and selective cysteine residue modification. These piperidinols present a unique class of antimycobacterial compounds that have a novel mode of action different from known anti-tubercular drugs

Temperature-Dependent Site Control of InAs/GaAs (001) Quantum Dots Using a Scanning Tunneling Microscopy Tip During Growth

Site-controlled InAs nano dots were successfully fabricated by a STMBE system (in situ scanning tunneling microscopy during molecular beam epitaxy growth) at substrate temperatures from 50 to 430°C. After 1.5 ML of the InAs wetting layer (WL) growth by ordinal Stranski–Krastanov dot fabrication procedures, we applied voltage at particular sites on the InAs WL, creating the site where In atoms, which were migrating on the WL, favored to congregate. At 240°C, InAs nano dots (width: 20–40 nm, height: 1.5–2.0 nm) were fabricated. At 430°C, InAs nano dots (width: 16–20 nm, height: 0.75–1.5 nm) were also fabricated. However, these dots were remained at least 40 s and collapsed less than 1000 s. Then, we fabricated InAs nano dots (width: 24–150 nm, height: 2.8–28 nm) at 300°C under In and As4 irradiations. These were not collapsed and considered to high crystalline dots