Understanding the impact of professional motivation on the workforce crisis in medicine: a rapid review

Background: The NHS is facing a workforce crisis. Responses to date have focused on improving recruitment of staff, but less attention has been paid to retention. Aim: To conduct a rapid review using Rosabeth Moss Kanter's three Ms model of workforce motivation as a sensitising framework to examine the current medical workforce crisis. The work considers how insights from research in other professions offers new thinking for understanding what motivates doctors to continue working. Design & setting: Rapid literature review with secondary analysis of existing research examining reasons for leaving medicine. Method: A systematic search strategy was developed with the aid of an information specialist. The search terms used were: medical professionals, retention, and NHS. The exclusions were: commentaries, non-medical professionals, non-English language, and it was limited to post-1990. The search was applied to three electronic databases, MEDLINE, Embase, and Healthcare Management Information Consortium (HMIC). This produced a dataset describing study design, and factors related to motivation for leaving the medical profession. Comparative thematic analysis distilled core themes explaining the reasons for leaving and their relation to the three Ms model. Results: Of 3389 abstracts identified, screening and assessment produced 82 articles included in the final analysis. Thematic analysis identified four key themes: low morale, disconnect, unmanageable change, and lack of personal and professional support. The themes of mastery, membership, and meaning were substantially present within the dataset. Conclusion: Kanter's three Ms model of motivation can be applied to the medical workforce to understand retention issues. This work supports the development of targeted solutions to tackle the worsening workforce crisis

Autoreactivity and Exceptional CDR Plasticity (but Not Unusual Polyspecificity) Hinder Elicitation of the Anti-HIV Antibody 4E10

The broadly-neutralizing anti-HIV antibody 4E10 recognizes an epitope in the membrane-proximal external region of the HIV envelope protein gp41. Previous attempts to elicit 4E10 by vaccination with envelope-derived or reverse-engineered immunogens have failed. It was presumed that the ontogeny of 4E10-equivalent responses was blocked by inherent autoreactivity and exceptional polyreactivity. We generated 4E10 heavy-chain knock-in mice, which displayed significant B cell dysregulation, consistent with recognition of autoantigen/s by 4E10 and the presumption that tolerance mechanisms may hinder the elicitation of 4E10 or 4E10-equivalent responses. Previously proposed candidate 4E10 autoantigens include the mitochondrial lipid cardiolipin and a nuclear splicing factor, 3B3. However, using carefully-controlled assays, 4E10 bound only weakly to cardiolipin-containing liposomes, but also bound negatively-charged, non-cardiolipin-containing liposomes comparably poorly. 4E10/liposome binding was predominantly mediated by electrostatic interactions rather than presumed hydrophobic interactions. The crystal structure of 4E10 free of bound ligands showed a dramatic restructuring of the combining site, occluding the HIV epitope binding site and revealing profound flexibility, but creating an electropositive pocket consistent with non-specific binding of phospholipid headgroups. These results strongly suggested that antigens other than cardiolipin mediate 4E10 autoreactivity. Using a synthetic peptide library spanning the human proteome, we determined that 4E10 displays limited and focused, but unexceptional, polyspecificity. We also identified a novel autoepitope shared by three ER-resident inositol trisphosphate receptors, validated through binding studies and immunohistochemistry. Tissue staining with 4E10 demonstrated reactivity consistent with the type 1 inositol trisphosphate receptor as the most likely candidate autoantigen, but is inconsistent with splicing factor 3B3. These results demonstrate that 4E10 recognition of liposomes competes with MPER recognition and that HIV antigen and autoepitope recognition may be distinct enough to permit eliciting 4E10-like antibodies, evading autoimmunity through directed engineering. However, 4E10 combining site flexibility, exceptional for a highly-matured antibody, may preclude eliciting 4E10 by conventional immunization strategies

Ontogeny of Recognition Specificity and Functionality for the Broadly Neutralizing Anti-HIV Antibody 4E10

The process of antibody ontogeny typically improves affinity, on-rate, and thermostability, narrows polyspecificity, and rigidifies the combining site to the conformer optimal for binding from the broader ensemble accessible to the precursor. However, many broadly-neutralizing anti-HIV antibodies incorporate unusual structural elements and recognition specificities or properties that often lead to autoreactivity. The ontogeny of 4E10, an autoreactive antibody with unexpected combining site flexibility, was delineated through structural and biophysical comparisons of the mature antibody with multiple potential precursors. 4E10 gained affinity primarily by off-rate enhancement through a small number of mutations to a highly conserved recognition surface. Controverting the conventional paradigm, the combining site gained flexibility and autoreactivity during ontogeny, while losing thermostability, though polyspecificity was unaffected. Details of the recognition mechanism, including inferred global effects due to 4E10 binding, suggest that neutralization by 4E10 may involve mechanisms beyond simply binding, also requiring the ability of the antibody to induce conformational changes distant from its binding site. 4E10 is, therefore, unlikely to be re-elicited by conventional vaccination strategies

First evidence of Renlandian (c. 950–940 Ma) orogeny in mainland Scotland:Implications for the status of the Moine Supergroup and circum-North Atlantic correlations

Central problems in the interpretation of the Neoproterozoic geology of the North Atlantic region arise from uncertainties in the ages of, and tectonic drivers for, Tonian orogenic events recorded in eastern Laurentia and northern Baltica. The identification and interpretation of these events is often problematic because most rock units that record Tonian orogenesis were strongly reworked at amphibolite facies during the Ordovician-Silurian Caledonian orogeny. Lu-Hf and Sm-Nd geochronology and metamorphic modelling carried out on large (>1 cm) garnets from the Meadie Pelite in the Moine Nappe of the northern Scottish Caledonides indicate prograde metamorphism between 950 and 940 Ma at pressures of 6–7 kbar and temperatures of 600 °C. This represents the first evidence for c. 950 Ma Tonian (Renlandian) metamorphism in mainland Scotland and significantly extends its geographic extent along the palaeo-Laurentian margin. The Meadie Pelite is believed to be part of the Morar Group within the Moine Supergroup. If this is correct: 1) the Morar Group was deposited between 980 ± 4 Ma (age of the youngest detrital zircon; Peters, 2001, youngest published zircon date is 947 ± 189 (Friend et al., 2003)) and c. 950 Ma (age of regional metamorphism reported here), 2) an orogenic unconformity must separate the Morar Group from the 883 ± 35 Ma (Cawood et al., 2004) Glenfinnan and Loch Eil groups, and 3) the term ‘Moine Supergroup’ may no longer be appropriate. The Morar Group is broadly correlative with similar aged metasedimentary successions in Shetland, East Greenland, Svalbard, Ellesmere Island and northern Baltica. All these successions were deposited after c. 1030 Ma, contain detritus from the Grenville orogen, and were later deformed and metamorphosed at 950–910 Ma during accretionary Renlandian orogenesis along an active plate margin developed around this part of Rodinia

Report from IPITA-TTS opinion leaders meeting on the future of β-cell replacement

Peer reviewe

Effects of HLA single chain trimer design on peptide presentation and stability

MHC class I “single-chain trimer” molecules, coupling MHC heavy chain, β2-microglobulin, and a specific peptide into a single polypeptide chain, are widely used in research. To more fully understand caveats associated with this design that may affect its use for basic and translational studies, we evaluated a set of engineered single-chain trimers with combinations of stabilizing mutations across eight different classical and non-classical human class I alleles with 44 different peptides, including a novel human/murine chimeric design. While, overall, single-chain trimers accurately recapitulate native molecules, care was needed in selecting designs for studying peptides longer or shorter than 9-mers, as single-chain trimer design could affect peptide conformation. In the process, we observed that predictions of peptide binding were often discordant with experiment and that yields and stabilities varied widely with construct design. We also developed novel reagents to improve the crystallizability of these proteins and confirmed novel modes of peptide presentation

Subduction or sagduction? Ambiguity in constraining the origin of ultramafic–mafic bodies in the Archean crust of NW Scotland

The Lewisian Complex of NW Scotland is a fragment of the North Atlantic Craton. It comprises mostly Archean tonalite–trondhjemite–granodiorite (TTG) orthogneisses that were variably metamorphosed and reworked in the late Neoarchean to Paleoproterozoic. Within the granulite facies central region of the mainland Lewisian Complex, discontinuous belts composed of ultramafic–mafic rocks and structurally overlying garnet–biotite gneiss (brown gneiss) are spatially associated with steeply-inclined amphibolite facies shear zones that have been interpreted as terrane boundaries. Interpretation of the primary chemical composition of these rocks is complicated by partial melting and melt loss during granulite facies metamorphism, and contamination with melts derived from the adjacent migmatitic TTG host rocks. Notwithstanding, the composition of the layered ultramafic–mafic rocks is suggestive of a protolith formed by differentiation of tholeiitic magma, where the ultramafic portions of these bodies represent the metamorphosed cumulates and the mafic portions the metamorphosed fractionated liquids. Although the composition of the brown gneiss does not clearly discriminate the protolith, it most likely represents a metamorphosed sedimentary or volcano-sedimentary sequence. For Archean rocks, particularly those metamorphosed to granulite facies, the geochemical characteristics typically used for discrimination of paleotectonic environments are neither strictly appropriate nor clearly diagnostic. Many of the rocks in the Lewisian Complex have ‘arc-like’ trace element signatures. These signatures are interpreted to reflect derivation from hydrated enriched mantle and, in the case of the TTG gneisses, partial melting of amphibolite source rocks containing garnet and a Ti-rich phase, probably rutile. However, it is becoming increasingly recognised that in Archean rocks such signatures may not be unique to a subduction environment but may relate to processes such as delamination and dripping. Consequently, it is unclear whether the Lewisian ultramafic–mafic rocks and brown gneisses represent products of plate margin or intraplate magmatism. Although a subduction-related origin is possible, we propose that an intraplate origin is equally plausible. If the second alternative is correct, the ultramafic–mafic rocks and brown gneisses may represent the remnants of intracratonic greenstone belts that sank into the deep crust due to their density contrast with the underlying partially molten low viscosity TTG orthogneisses

Epilepsy and mental retardation limited to females: an under-recognized disorder

Epilepsy and Mental Retardation limited to Females (EFMR) which links to Xq22 has been reported in only one family. We aimed to determine if there was a distinctive phenotype that would enhance recognition of this disorder.We ascertained four unrelated families (two Australian, two Israeli) where seizures in females were transmitted through carrier males. Detailed clinical assessment was performed on 58 individuals, using a validated seizure questionnaire, neurological examination and review of EEG and imaging studies. Gene localization was examined using Xq22 microsatellite markers. Twenty-seven affected females had a mean seizure onset of 14 months (range 6^36) typically presenting with convulsions. All had convulsive attacks at some stage, associated with fever in 17 out of 27 (63%). Multiple seizure types occurred including tonic-clonic (26), tonic (4), partial (11), absence (5), atonic (3) and myoclonic (4). Seizures ceased at mean 12 years. Developmental progress varied from normal (7), to always delayed (4) to normal followed by regression (12). Intellect ranged from normal to severe intellectual disability (ID), with 67% of females having ID or being of borderline intellect. Autistic (6), obsessive (9) and aggressive (7) features were prominent. EEGs showed generalized and focal epileptiform abnormalities. Five obligate male carriers had obsessional tendencies. Linkage to Xq22 was confirmed (maximum lod 3.5 at h = 0).We conclude that EFMR is a distinctive, under-recognized familial syndrome where girls present with convulsions in infancy, often associated with intellectual impairment and autistic features. The unique inheritance pattern with transmission by males is perplexing. Clinical recognition is straightforward in multiplex families due to the unique inheritance pattern; however, this disorder should be considered in smaller families where females alone have seizures beginning in infancy, particularly in the setting of developmental delay. In single cases, diagnosis will depend on identification of the molecular basis. Keywords: epilepsy; intellectual disability; females; X-linked inheritance; autistic features Abbreviations: BAC = bacterial artificial chromosome; CFNS = craniofrontonasal syndrome; EFMR = epilepsy and mental retardation limited to females; ID = intellectual disability