103 research outputs found

    Clinical, industrial, and research perspectives on powder bed fusion additively manufactured metal implants

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    For over ten years, metallic skeletal endoprostheses have been produced in select cases by additive manufacturing (AM) and increasing awareness is driving demand for wider access to the technology. This review brings together key stakeholder perspectives on the translation of AM research; clinical application, ongoing research in the field of powder bed fusion, and the current regulatory framework. The current clinical use of AM is assessed, both on a mass-manufactured scale and bespoke application for patient specific implants. To illuminate the benefits to clinicians, a case study on the provision of custom cranioplasty is provided based on prosthetist testimony. Current progress in research is discussed, with immediate gains to be made through increased design freedom described at both meso- and macro-scale, as well as long-term goals in alloy development including bioactive materials. In all cases, focus is given to specific clinical challenges such as stress shielding and osseointegration. Outstanding challenges in industrialisation of AM are openly raised, with possible solutions assessed. Finally, overarching context is given with a review of the regulatory framework involved in translating AM implants, with particular emphasis placed on customisation within an orthopaedic remit. A viable future for AM of metal implants is presented, and it is suggested that continuing collaboration between all stakeholders will enable acceleration of the translation process

    Pilot testing the feasibility of a game intervention aimed at improving help seeking and coping among sexual and gender minority youth: protocol for a randomized controlled trial

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    Background: Sexual and gender minority youth (SGMY; e.g., lesbian, gay, bisexual, and transgender youth) experience myriad substance use and mental health disparities compared with their cisgender (non-transgender) heterosexual peers. Despite much research showing these disparities are driven by experiences of bullying and cyberbullying victimization, few interventions have aimed to improve the health of bullied SGMY. One possible way to improve the health of bullied SGMY is via an online-accessible game intervention. Nevertheless, little research has examined the feasibility of using an online-accessible game intervention with SGMY. Objectives: To describe the protocol for a randomized controlled trial (RCT) pilot testing the feasibility and limited-efficacy of a game-based intervention for increasing help-seeking-related knowledge, intentions, self-efficacy, and behaviors, productive coping skills use, and coping flexibility, and reducing health risk factors and behaviors among SGMY. Methods: We enrolled 240 SGMY aged 14-18 years residing in the United States into a two-arm prospective RCT. The intervention is a theory-based, community-informed, computer-based, role playing game with three primary components: (1) encouraging help-seeking behaviors; (2) encouraging use of productive coping; and (3) raising awareness of online resources. SGMY randomized to both the intervention and control conditions will receive a list of SGMY-inclusive resources covering a variety of health-related topics. Control condition participants received only the list of resources. Notably, all study procedures are conducted online. We conveniently sampled SGMY using online website advertisements. Study assessments occur at enrollment, 1 month after enrollment, and 2 months after enrollment. The primary outcomes of this feasibility study include implementation procedures, game demand, and game acceptability. Secondary outcomes include help-seeking intentions, self-efficacy, and behaviors; productive coping strategies and coping flexibility; and knowledge and use of online resources. Tertiary outcomes include bullying and cyberbullying victimization; loneliness; mental health issues; substance use; and internalized sexual and gender minority stigma. Results: From April through July 2018, 240 participants were enrolled and randomized. Half of the enrolled participants (n=120) were randomized into the intervention condition, and half (n=120) into the control condition. At baseline, 52% of participants identified as gay or lesbian, 27% as bisexual, 24% as queer, and 12% as another non-heterosexual identity. Nearly half (47%) of participants were a gender minority, 37% were cisgender boys, and 16% were cisgender girls. There were no differences in demographic characteristics between intervention and control condition participants. Data collection is anticipated to end in November 2018. Conclusions: Online-accessible game interventions overcome common impediments of face-to-face interventions and present a unique opportunity to reach SGMY and improve their health. This trial will provide data on feasibility and limited-efficacy that can inform future online studies and a larger RCT aimed at improving health equity for SGMY. Trial Registration: ClinicalTrials.gov NCT03501264; https://clinicaltrials.gov/ct2/show/NCT03501264 (Archived by WebCite at http://www.webcitation.org/72HpafarW

    Amyloid binding and beyond: a new approach for Alzheimer's disease drug discovery targeting Aβo–PrPC binding and downstream pathways

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    Amyloid β oligomers (Aβo) are the main toxic species in Alzheimer's disease, which have been targeted for single drug treatment with very little success. In this work we report a new approach for identifying functional Aβo binding compounds. A tailored library of 971 fluorine containing compounds was selected by a computational method, developed to generate molecular diversity. These compounds were screened for Aβo binding by a combined 19F and STD NMR technique. Six hits were evaluated in three parallel biochemical and functional assays. Two compounds disrupted Aβo binding to its receptor PrPC in HEK293 cells. They reduced the pFyn levels triggered by Aβo treatment in neuroprogenitor cells derived from human induced pluripotent stem cells (hiPSC). Inhibitory effects on pTau production in cortical neurons derived from hiPSC were also observed. These drug-like compounds connect three of the pillars in Alzheimer's disease pathology, i.e. prion, Aβ and Tau, affecting three different pathways through specific binding to Aβo and are, indeed, promising candidates for further development

    HARMONI at ELT: overview of the capabilities and expected performance of the ELT's first light, adaptive optics assisted integral field spectrograph.

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    Blood transcriptional biomarkers of acute viral infection for detection of pre-symptomatic SARS-CoV-2 infection: a nested, case-control diagnostic accuracy study

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    Background We hypothesised that host-response biomarkers of viral infections might contribute to early identification of individuals infected with SARS-CoV-2, which is critical to breaking the chains of transmission. We aimed to evaluate the diagnostic accuracy of existing candidate whole-blood transcriptomic signatures for viral infection to predict positivity of nasopharyngeal SARS-CoV-2 PCR testing.Methods We did a nested case-control diagnostic accuracy study among a prospective cohort of health-care workers (aged ≥18 years) at St Bartholomew’s Hospital (London, UK) undergoing weekly blood and nasopharyngeal swab sampling for whole-blood RNA sequencing and SARS-CoV-2 PCR testing, when fit to attend work. We identified candidate blood transcriptomic signatures for viral infection through a systematic literature search. We searched MEDLINE for articles published between database inception and Oct 12, 2020, using comprehensive MeSH and keyword terms for “viral infection”, “transcriptome”, “biomarker”, and “blood”. We reconstructed signature scores in blood RNA sequencing data and evaluated their diagnostic accuracy for contemporaneous SARS-CoV-2 infection, compared with the gold standard of SARS-CoV-2 PCR testing, by quantifying the area under the receiver operating characteristic curve (AUROC), sensitivities, and specificities at a standardised Z score of at least 2 based on the distribution of signature scores in test-negative controls. We used pairwise DeLong tests compared with the most discriminating signature to identify the subset of best performing biomarkers. We evaluated associations between signature expression, viral load (using PCR cycle thresholds), and symptom status visually and using Spearman rank correlation. The primary outcome was the AUROC for discriminating between samples from participants who tested negative throughout the study (test-negative controls) and samples from participants with PCR-confirmed SARS-CoV-2 infection (test-positive participants) during their first week of PCR positivity.Findings We identified 20 candidate blood transcriptomic signatures of viral infection from 18 studies and evaluated their accuracy among 169 blood RNA samples from 96 participants over 24 weeks. Participants were recruited between March 23 and March 31, 2020. 114 samples were from 41 participants with SARS-CoV-2 infection, and 55 samples were from 55 test-negative controls. The median age of participants was 36 years (IQR 27–47) and 69 (72%) of 96 were women. Signatures had little overlap of component genes, but were mostly correlated as components of type I interferon responses. A single blood transcript for IFI27 provided the highest accuracy for discriminating between test-negative controls and test-positive individuals at the time of their first positive SARS-CoV-2 PCR result, with AUROC of 0·95 (95% CI 0·91–0·99), sensitivity 0·84 (0·70–0·93), and specificity 0·95 (0·85–0·98) at a predefined threshold (Z score >2). The transcript performed equally well in individuals with and without symptoms. Three other candidate signatures (including two to 48 transcripts) had statistically equivalent discrimination to IFI27 (AUROCs 0·91–0·95).Interpretation Our findings support further urgent evaluation and development of blood IFI27 transcripts as a biomarker for early phase SARS-CoV-2 infection for screening individuals at high risk of infection, such as contacts of index cases, to facilitate early case isolation and early use of antiviral treatments as they emerge

    Immune boosting by B.1.1.529 (Omicron) depends on previous SARS-CoV-2 exposure

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    The Omicron, or Pango lineage B.1.1.529, variant of SARS-CoV-2 carries multiple spike mutations with high transmissibility and partial neutralizing antibody (nAb) escape. Vaccinated individuals show protection from severe disease, often attributed to primed cellular immunity. We investigated T and B cell immunity against B.1.1.529 in triple mRNA vaccinated healthcare workers (HCW) with different SARS-CoV-2 infection histories. B and T cell immunity against previous variants of concern was enhanced in triple vaccinated individuals, but magnitude of T and B cell responses against B.1.1.529 spike protein was reduced. Immune imprinting by infection with the earlier B.1.1.7 (Alpha) variant resulted in less durable binding antibody against B.1.1.529. Previously infection-naïve HCW who became infected during the B.1.1.529 wave showed enhanced immunity against earlier variants, but reduced nAb potency and T cell responses against B.1.1.529 itself. Previous Wuhan Hu-1 infection abrogated T cell recognition and any enhanced cross-reactive neutralizing immunity on infection with B.1.1.529
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