Controlled side-by-side assembly of gold nanorods and dye molecules into polymer-wrapped SERRS-active clusters

The controlled side-by-side assembly of gold nanorods in solution together with Raman reporter dye molecules to create small SERRS-active clusters stabilised by a surrounding polymer layer is demonstrated. This promising new class of nanotags offers several advantages over spherical nanoparticles for bioimaging and is of potential importance for a wide range of plasmon-enhanced spectroscopies and can also serve as building blocks for more complex solution-phase nanostructures

Stabilized gold nanorod–dye conjugates with controlled resonance coupling create bright surface-enhanced resonance Raman nanotags

The preparation and characterization of stable and non-aggregated colloidal suspensions of gold nanorod–molecular dye complexes which exhibit very bright surface-enhanced resonance Raman scattering (SERRS) signals is described. A systematic study was performed where both the localized surface plasmon resonance (LSPR) of the nanorod and the molecular resonance of dyes adsorbed onto the rod surface were selectively tuned with respect to the laser excitation wavelengths. Resonance coupling was found to be a significant factor in the overall SERRS enhancement. The polymer stabilized nanorod–dye conjugates were prepared without the added complexity of nanoparticle aggregation as well as having good control over the surface coverage and orientation of the dye molecules. Furthermore, we demonstrate that this new class of Raman nanotags greatly outperforms an approach based on quasi-spherical gold nanoparticles

Universal surface-enhanced Raman tags : individual nanorods for measurements from the visible to the infrared (514 – 1064 nm)

Surface-enhanced Raman scattering (SERS) is a promising imaging modality for use in a variety of multiplexed tracking and sensing applications in biological environments. However, the uniform production of SERS nanoparticle tags with high yield and brightness still remains a significant challenge. Here, we describe an approach based on the controlled co-adsorption of multiple dye species onto gold nanorods to create tags that can be detected across a much wider range of excitation wavelengths (514 – 1064 nm) compared to conventional approaches that typically focus on a single wavelength. This was achieved without the added complexity of nanoparticle aggregation or growing surrounding metallic shells to further enhance the surface-enhanced resonance Raman scattering (SERRS) signal. Correlated Raman and scanning electron microscopy mapping measurements of individual tags were used to clearly demonstrate that strong and reproducible SERRS signals at high particle yields (>92 %) were readily achievable. The polyelectrolyte-wrapped nanorod-dye conjugates were also found to be highly stable as well as non-cytotoxic. To demonstrate the use of these universal tags for the multimodal optical imaging of biological specimens, confocal Raman and fluorescence maps of stained immune cells following nanoparticle uptake were acquired at several excitation wavelengths and compared with dark-field images. The ability to colocalize and track individual optically encoded nanoparticles across a wide range of wavelengths simultaneously will enable the use of SERS alongside other imaging techniques for the real-time monitoring of cell-nanoparticle interactions

Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial

BackgroundAnterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability.MethodsWe did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score—4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367.FindingsBetween Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5–13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications.InterpretationSurgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

Creating novel biofunctionalized nanorod-dye conjugates as bright tags for surface-enhanced resonance Raman scattering

Gold nanorods have attracted much attention in the literature due to the ability to tune the aspect ratio and hence localized surface plasmon resonance (LSPR) of these materials. When co-assembled with molecular dyes this provides new opportunities yet to be explored for the design of multimodal optical probes compatible with a range of spectroscopies, in particular surface-enhanced resonance Raman scattering (SERRS). This research describes the preparation and characterization of novel SERRS tags, capable of providing very bright Raman signals whilst remaining non-aggregated and thus hotspot-free. Additional advantages of this approach are the excellent control afforded over the dye surface coverage and surface orientation along with the very high level of stability displayed by these nanotags. An approach enabling a systematic study was developed where both the LSPR of the nanorod and the molecular resonance of the dye adsorbed onto the rod surface were varied with respect to the laser excitation wavelengths. Resonance coupling between dyes and nanorods was found to be a significant factor in the overall SERRS enhancement. Also when directly compared to quasi-spherical gold nanoparticles, significantly higher Raman intensities were obtained. The controlled side-by-side assembly of the nanorod-dye conjugates and subsequent stabilization of the suspended clusters for upwards of eight months was also demonstrated. A new class of tags, known as universal SERRS tags (USTs) were proposed. By co-assembling multiple dyes on the same nanorod, bright Raman signals were obtained at wavelengths ranging from 514 - 1064 nm, without requiring nanoparticle aggregation. In addition, correlated SEM and Raman mapping analysis showed it was possible to perform single particle SERRS, with close to 100% of the nanotags found to be SERRS active. The application of the USTs for cellular imaging was clearly demonstrated and the non-cytotoxicity of this system to dendritic cells was confirmed. Finally, a new methodology was introduced for the covalent functionalization of both polymer wrapped rod and spherical shaped nanoparticles.Gold nanorods have attracted much attention in the literature due to the ability to tune the aspect ratio and hence localized surface plasmon resonance (LSPR) of these materials. When co-assembled with molecular dyes this provides new opportunities yet to be explored for the design of multimodal optical probes compatible with a range of spectroscopies, in particular surface-enhanced resonance Raman scattering (SERRS). This research describes the preparation and characterization of novel SERRS tags, capable of providing very bright Raman signals whilst remaining non-aggregated and thus hotspot-free. Additional advantages of this approach are the excellent control afforded over the dye surface coverage and surface orientation along with the very high level of stability displayed by these nanotags. An approach enabling a systematic study was developed where both the LSPR of the nanorod and the molecular resonance of the dye adsorbed onto the rod surface were varied with respect to the laser excitation wavelengths. Resonance coupling between dyes and nanorods was found to be a significant factor in the overall SERRS enhancement. Also when directly compared to quasi-spherical gold nanoparticles, significantly higher Raman intensities were obtained. The controlled side-by-side assembly of the nanorod-dye conjugates and subsequent stabilization of the suspended clusters for upwards of eight months was also demonstrated. A new class of tags, known as universal SERRS tags (USTs) were proposed. By co-assembling multiple dyes on the same nanorod, bright Raman signals were obtained at wavelengths ranging from 514 - 1064 nm, without requiring nanoparticle aggregation. In addition, correlated SEM and Raman mapping analysis showed it was possible to perform single particle SERRS, with close to 100% of the nanotags found to be SERRS active. The application of the USTs for cellular imaging was clearly demonstrated and the non-cytotoxicity of this system to dendritic cells was confirmed. Finally, a new methodology was introduced for the covalent functionalization of both polymer wrapped rod and spherical shaped nanoparticles