X-ray-based machine vision system for distal locking of intramedullary nails

In surgical procedures for femoral shaft fracture treatment, current techniques for locking the distal end of intramedullary nails, using two screws, rely heavily on the use of two-dimensional X-ray images to guide three-dimensional bone drilling processes. Therefore, a large number of X-ray images are required, as the surgeon uses his/her skills and experience to locate the distal hole axes on the intramedullary nail. The long-term effects of X-ray radiation and their relation to different types of cancer still remain uncertain. Therefore, there is a need to develop a surgical technique that can limit the use of X-rays during the distal locking procedure. A robotic-assisted orthopaedic surgery system has been developed at Loughborough University to assist orthopaedic surgeons by reducing the irradiation involved in such operations. The system simplifies the current approach as it uses only two near-orthogonal X-ray images to determine the drilling trajectory of the distal locking holes, thereby considerably reducing irradiation to both the surgeon and patient. Furthermore, the system uses robust machine vision features to reduce the surgeon's interaction with the system, thus reducing the overall operating time. Laboratory test results have shown that the proposed system is very robust in the presence of variable noise and contrast in the X-ray images

Isothiourea-catalysed enantioselective pyrrolizine synthesis : synthetic and computational studies

We thank Syngenta and the EPSRC (grant code EP/K503162/1) (DGS), and the EPSRC Centre for Doctoral Training in Critical Resource Catalysis (CRITICAT, grant code EP/L016419/1) (ERG,SFM, RWFK) for funding. The European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) ERC Grant Agreement No. 279850 is also acknowledged (JET). ADS thanks the Royal Society for a Wolfson Research Merit Award.The catalytic enantioselective synthesis of a range of cis-pyrrolizine carboxylate derivatives with outstanding stereocontrol (14 examples,>95:5 dr, >98:2 er) through an isothiourea-catalyzed intramolecular Michael addition-lactonisation and ring opening approach from the corresponding enone acid is reported. An optimised and straightforward three-step synthetic route to the enone acid starting materials from readily available pyrrole-2-carboxaldehydes is delineated, with benzotetramisole (5 mol%) proving the optimal catalyst for the enantioselective process. Ring-opening of the pyrrolizine dihydropyranone products with either MeOH or a range of amines leads to the desired products in excellent yield and enantioselectivity. Computation has been used to probe the factors leading to high stereocontrol, with the formation of the observed cis-steroisomer predicted to be kinetically and thermodynamically favoured.Publisher PDFPeer reviewe

Beyond technical fixes: climate solutions and the great derangement

Climate change research is at an impasse. The transformation of economies and everyday practices is more urgent, and yet appears ever more daunting as attempts at behaviour change, regulations, and global agreements confront material and social-political infrastructures that support the status quo. Effective action requires new ways of conceptualizing society, climate and environment and yet current research struggles to break free of established categories. In response, this contribution revisits important insights from the social sciences and humanities on the co-production of political economies, cultures, societies and biophysical relations and shows the possibilities for ontological pluralism to open up for new imaginations. Its intention is to help generate a different framing of socionatural change that goes beyond the current science-policy-behavioural change pathway. It puts forward several moments of inadvertent concealment in contemporary debates that stem directly from the way issues are framed and imagined in contemporary discourses. By placing values, normative commitments, and experiential and plural ways of knowing from around the world at the centre of climate knowledge, we confront climate change with contested politics and the everyday foundations of action rather than just data

Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing:a population-based study

Background<p></p> Familial hypercholesterolaemia (FH) is a common Mendelian condition which, untreated, results in premature coronary heart disease. An estimated 88% of FH cases are undiagnosed in the UK. We previously validated a method for FH mutation detection in a lipid clinic population using next generation sequencing (NGS), but this did not address the challenge of identifying index cases in primary care where most undiagnosed patients receive healthcare. Here, we evaluate the targeted use of NGS as a potential route to diagnosis of FH in a primary care population subset selected for hypercholesterolaemia.<p></p> Methods<p></p> We used microfluidics-based PCR amplification coupled with NGS and multiplex ligation-dependent probe amplification (MLPA) to detect mutations in LDLR, APOB and PCSK9 in three phenotypic groups within the Generation Scotland: Scottish Family Health Study including 193 individuals with high total cholesterol, 232 with moderately high total cholesterol despite cholesterol-lowering therapy, and 192 normocholesterolaemic controls.<p></p> Results<p></p> Pathogenic mutations were found in 2.1% of hypercholesterolaemic individuals, in 2.2% of subjects on cholesterol-lowering therapy and in 42% of their available first-degree relatives. In addition, variants of uncertain clinical significance (VUCS) were detected in 1.4% of the hypercholesterolaemic and cholesterol-lowering therapy groups. No pathogenic variants or VUCS were detected in controls.<p></p> Conclusions<p></p> We demonstrated that population-based genetic testing using these protocols is able to deliver definitive molecular diagnoses of FH in individuals with high cholesterol or on cholesterol-lowering therapy. The lower cost and labour associated with NGS-based testing may increase the attractiveness of a population-based approach to FH detection compared to genetic testing with conventional sequencing. This could provide one route to increasing the present low percentage of FH cases with a genetic diagnosis

Determining Supersymmetric Parameters With Dark Matter Experiments

In this article, we explore the ability of direct and indirect dark matter experiments to not only detect neutralino dark matter, but to constrain and measure the parameters of supersymmetry. In particular, we explore the relationship between the phenomenological quantities relevant to dark matter experiments, such as the neutralino annihilation and elastic scattering cross sections, and the underlying characteristics of the supersymmetric model, such as the values of mu (and the composition of the lightest neutralino), m_A and tan beta. We explore a broad range of supersymmetric models and then focus on a smaller set of benchmark models. We find that by combining astrophysical observations with collider measurements, mu can often be constrained far more tightly than it can be from LHC data alone. In models in the A-funnel region of parameter space, we find that dark matter experiments can potentially determine m_A to roughly +/-100 GeV, even when heavy neutral MSSM Higgs bosons (A, H_1) cannot be observed at the LHC. The information provided by astrophysical experiments is often highly complementary to the information most easily ascertained at colliders.Comment: 46 pages, 76 figure

Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders

Antibody correlates of protection from SARS-CoV-2 reinfection prior to vaccination : a nested case-control within the SIREN study

Funding: This study was supported by the U.K. Health Security Agency, the U.K. Department of Health and Social Care (with contributions from the governments in Northern Ireland, Wales, and Scotland), the National Institute for Health Research, and grant from the UK Medical Research Council (grant number MR/W02067X/1). This work was supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (CC2087, CC1283), the UK Medical Research Council (CC2087, CC1283), and the Wellcome Trust (CC2087, CC1283).Objectives To investigate serological differences between SARS-CoV-2 reinfection cases and contemporary controls, to identify antibody correlates of protection against reinfection. Methods We performed a case-control study, comparing reinfection cases with singly infected individuals pre-vaccination, matched by gender, age, region and timing of first infection. Serum samples were tested for anti-SARS-CoV-2 spike (anti-S), anti-SARS-CoV-2 nucleocapsid (anti-N), live virus microneutralisation (LV-N) and pseudovirus microneutralisation (PV-N). Results were analysed using fixed effect linear regression and fitted into conditional logistic regression models. Results We identified 23 cases and 92 controls. First infections occurred before November 2020; reinfections occurred before February 2021, pre-vaccination. Anti-S levels, LV-N and PV-N titres were significantly lower among cases; no difference was found for anti-N levels. Increasing anti-S levels were associated with reduced risk of reinfection (OR 0·63, CI 0·47-0·85), but no association for anti-N levels (OR 0·88, CI 0·73-1·05). Titres >40 were correlated with protection against reinfection for LV-N Wuhan (OR 0·02, CI 0·001–0·31) and LV-N Alpha (OR 0·07, CI 0·009–0·62). For PV-N, titres >100 were associated with protection against Wuhan (OR 0·14, CI 0·03–0·64) and Alpha (0·06, CI 0·008–0·40). Conclusions Before vaccination, protection against SARS-CoV-2 reinfection was directly correlated with anti-S levels, PV-N and LV-N titres, but not with anti-N levels. Detectable LV-N titres were sufficient for protection, whilst PV-N titres >100 were required for a protective effect. Trial registration number ISRCTN11041050Publisher PDFPeer reviewe

Communicating with the dead:lipids, lipid mediators and extracellular vesicle

Apoptosis is a key event in the control of inflammation. However, for this to be successful, dying cells must efficiently and effectively communicate their presence to phagocytes to ensure timely removal of dying cells. Here we consider apoptotic cell-derived extracellular vesicles (ACdEV) and the role of contained lipids and lipid mediators in ensuring effective control of inflammation. We discuss key outstanding issues in the study of cell death and cell communication, and introduce the concept of the ‘active extracellular vesicle’ as a metabolically-active and potentially changing intercellular communicator