Ultrasonography Reliability in the Detection of Inflammatory and Structural Abnormalities: An Exercise in Multiple Joints.

BACKGROUND: Ultrasonography is an image technique that allows rheumatologists to visualize structural and inflammatory changes within a joint. The objective of this study was to assess the interobserver and intraobserver reliability of musculoskeletal ultrasound (US) in the detection of inflammatory and destructive joint changes in patients with polyarthritis. METHODS: A Delphi exercise was undertaken to standardize and adapt the EULAR-OMERACT elementary US definitions of inflammatory lesions (effusion, synovial hypertrophy, power Doppler, bone erosions, and synovitis) for each joint. Fifteen patients were analyzed, and video clips of 600 joints were collected. Each joint was scored for the presence of each elementary component, on 2 separate occasions, by 6 examiners. Interobserver and intraobserver agreement analysis was assessed through Fleiss κ coefficient (κ). RESULTS: Considering all patients and all joints, the interobserver values were highest for erosions and lowest for effusion (κ = 0.7314 and κ = 0.6044, respectively). When analyzing different regions, the highest interobserver agreement was for tibiotalar joint (κ = 0.8043) and the lowest for wrist (κ = 0.6767). Intraobserver reliability was excellent for each and all elementary components and anatomical region. CONCLUSIONS: The present study showed either a good or excellent US interobserver and intraobserver reliability in elementary elements and anatomical region. This kind of US reliability exercises are important for standardization of exploration in everyday practice by reducing the variability associated with this imaging technique, and ensuring a greater degree of homogeneity and future comparability in the assessment of disease activity in polyarthritis patients.

What is metacarpophalangeal joint swelling in psoriatic arthritis? Ultrasound findings and reliability assessment.

OBJECTIVES: To evaluate by ultrasound (US) the frequency and reliability of peritenon extensor tendon inflammation (PTI) and intra articular synovitis (IAS) in metacarpophalangeal joints (MCPj) of psoriatic arthritis (PsA) patients. METHODS: 27 PsA patients with clinical involvement of MCPj were consecutively included. Presence of PTI and IAS were evaluated by grey-scale (GS) and power Doppler (PD). Longitudinal and transverse 3-5 second videos of US examinations were recorded for reliability assessments by five readers. Consensus on positive US results was achieved when at least three readers agreed. RESULTS: Clinical swelling was present in 60 joints whereas US detected IAS and/or PTI in 75 MCPj. GS PTI in at least one MCPj was found in 19 patients and 41 joints, concurring with clinical swelling in 30/41. GS IAS in at least one MCPj was found in 23 patients and 63 joints, concurring with clinical swelling in 37/63. The inter-reader reliability was good for PD PTI and moderate for GS PTI. CONCLUSIONS: Our study identifies that both IAS and PTI cause MCPj swelling, where PTI is almost as frequent as IAS as a cause of swelling. The reliability of PTI is at least as good as for IAS.

Novel reduced graphene oxide-glycol chitosan nanohybrid for the assembly of an amperometric enzyme biosensor for phenols.

A novel water-soluble graphene derivative was prepared from graphene oxide via a two-step modification approach. Graphene oxide was first functionalised with reactive epoxy groups by covalent modification with (3-glycidyloxypropyl)trimethoxysilane and further cross-linked with glycol chitosan. This graphene derivative was characterized using different microscopy and physicochemical methods and employed as a coating material for a glassy carbon electrode. The nanostructured surface was used as a support for the covalent immobilization of the enzyme laccase through cross-linking with glutaraldehyde. The enzyme electrode was tested for the amperometric detection of different phenolic compounds, which displayed excellent analytical behaviour toward catechol with a linear range of response from 200 nM to 15 µM, sensitivity of 93 mA M(-1) cm(-2), and low detection limit of 76 nM. The enzyme biosensor showed high stability when stored at 4 °C under dry conditions and was successfully employed to quantify the total phenolic compounds in commercial herbal tea samples.

The impact of ligation of proximal side branches on blood flow and functional status of the internal thoracic artery in coronary anastomosis.

BACKGROUND: The effect of proximal side branches on the patency of the internal thoracic artery (ITA) is controversial. We used echocardiography and Doppler to verify the effect of ligation of branches on the flow and coronary flow reserve (CFR) of the grafted ITA in patients after coronary artery bypass grafting (CABG). METHODS: We prospectively investigated 53 patients with preserved left ventricular ejection fraction (LVEF >50%) who underwent CABG of the ITA. In Group I (25 patients), major branches were ligated during ITA anastomosis to the left anterior descending (LAD) coronary artery, whereas no ligation was performed in Group II (28 patients). Systolic flow (SF), diastolic flow (DF), and total flow (TF = SF + DF) were measured by Doppler echocardiography at the proximal level of the ITA preoperatively, at early postoperative stage, and 6 months after surgery. Dobutamine stress echocardiography (DSE) was performed at 6 months to determine CFR. RESULTS: The ITA flow was predominantly systolic before surgery and diastolic in the postoperative period. We found no differences between the groups in DF. On DSE, SF (19.5±9 mL/min vs 32.7±19 mL/min; P=.003) and TF (79±21 mL/min vs 101±47 mL/min; P=.037) were higher in Group II. There were no differences in CFR (1.9±0.46 vs 2.11±0.56; P=.143). CONCLUSION: In patients with preserved LVEF, ligation of major side branches during anastomosis to the LAD does not alter ITA flow or CFR.

Can we use enthesis ultrasound as an outcome measure of disease activity in spondyloarthritis? A study at the Achilles level.

OBJECTIVE: The aim of this study was to evaluate the construct validity of enthesis US in the assessment of disease activity in SpA. METHODS: A longitudinal Achilles enthesis US study in patients with early SpA was undertaken. Achilles US examinations were performed at baseline, 6 and 12 months and compared with clinical outcome measures collected at the baseline visit. RESULTS: Bilateral Achilles enthesis of 146 early SpA patients (68 women) were analysed. Basal mean BASFI, BASRI-spine, BASDAI and Ankylosing Spondylitis Disease Activity Score (ASDAS) were 2.44 (s.d. 2.05, range 0-8), 0.67 (s.d. 0.74, range 0-3), 4.60 (s.d. 2.07, range 0-9.5) and 2.51 (s.d. 1.16, range 0-5), respectively. The mean ESR was 15.0 mm/h (s.d. 16.99, range 0-109) and the mean CRP was 8.67 mg/l (s.d. 16.98, range 1-90). At baseline, the Achilles Doppler signal and US structure alteration were significantly associated with higher CRP and ESR levels. Patients who had very high disease activity at baseline, as assessed by the ASDAS (>3.5), had a significantly higher Achilles total US score at baseline (P = 0.04), and ASDAS <1.3 predicted no Doppler signal at 6 and 12 months. Overall, the Achilles total US score was significantly higher in patients with higher levels of CRP (baseline P = 0.04, 6 months P = 0.006, 12 months P = 0.03) and ESR (baseline P = 0.02, 6 months P = 0.04, 12 months P = 0.005) at baseline. The Doppler signal at the baseline visit predicted a higher total US score at 6 and 12 months. CONCLUSION: Doppler US has significant associations with other commonly accepted disease activity measures, such as ESR, CRP and ASDAS, and seems to be an objective outcome measure for enthesitis.

Dual-pore protocells with multitasking capacities for simultaneous delivery of therapeutic enzymes and drugs in macrophage depletion therapy.

Macrophages are usually present in solid tumors where they participate in tumor progression, angiogenesis, immunosuppression and metastasis. The design of nanocarriers capable of delivering therapeutic agents to specific cell populations has received considerable attention in the last decades. However, the capacity of many of these nanosystems to deliver multiple therapeutic agents with very different chemical properties is more limited. Herein, a novel multitasking nanoplatform capable of delivering large macromolecules and cytotoxic drugs to macrophages is presented. This novel nanosystem has exhibited excellent skills in performing simultaneous tasks, macrophage depletion and glucose starvation, maintaining the oxygen levels in the tissue. This nanodevice is composed of a dual-pore mesoporous silica core with the capacity to house small cytotoxic drugs, such as doxorubicin or zoledronic acid, and large macromolecules, such as glucose oxidase. The external surface of the silica core was coated with a lipid bilayer to avoid the premature release of the housed drugs. Finally, polymeric nanocapsules loaded with catalase were covalently anchored on the outer lipid bilayer, and carboxy-mannose was attached to the exposed side of the nanocapsules to provide selectivity to the macrophages. These nanoassemblies were able to transport enzymes (Gox and CAT), maintaining their catalytic activity. Therefore, they could induce glucose starvation, keeping the oxygen levels in the tissue, owing to the tandem enzymatic reaction. The capacity of these nanoassemblies to deliver therapeutic agents to macrophages was evaluated both in static and under flow conditions, showing a rapid capture of the nanoparticles by the macrophages. Once there, the nanoassemblies also exhibited excellent capacity to induce potent macrophage depletion. This strategy can be directly adapted for the treatment of different malignancies due to the modular nature of the nanoplatform, which can be loaded with different therapeutic agent combinations and pave the way for the development of personalized nanomedicines for diverse types of tumors.

Achilles enthesis ultrasound: the importance of the bursa in spondyloarthritis.

OBJECTIVES: This paper aims to assess the prevalence and relevance of the bursa-synovial lesion in spondyloarthritis (SpA). METHODS: A transversal blind and controlled two-dimensional (2D) and three-dimensional (3D) ultrasound (US) study of Achilles enthesis bursa in early SpA was undertaken. Clinical outcome measures were collected. RESULTS: Bilateral Achilles enthesis of 66 early SpA patients (34 women) and 46 control patients (23 asymptomatic healthy subjects and 23 rheumatoid arthritis [RA] patients) were analysed. Mean BASDAI, BASFI and BASRI-spine were 4.55±2.08, 2.16±1.95 and 0.65±0.77, respectively. Mean erythrocyte sedimentation rate (ESR) was 10.93±12.35 mm/h and C-reactive protein (CRP) was 6.46±10.09 mg/l. The κ-values for intra-reader agreement for 2D and 3D images and bursa measurement were 0.82 and 0.98, respectively. Bursas were visualised in 89/132 SpA enthesis (67.4%) vs. 27/46 enthesis (58.7%) of healthy controls (p<0.01), and 10/46 enthesis (21.7%) of RA controls (p<0.01). When the thicknesses of the bursas were analysed, the SpA group had a mean of 1.52±1.47 mm versus 0.76±0.76 mm in the healthy control group (p<0.0001), and 0.38±0.62 mm in the RA control group (p<0.0001). A positive likelihood ratio of 4.6 with a cut-off point of bursa >2 was found. No Doppler signal was detected in controls, but 6.6% of SpA Achilles enthesis had Doppler bursitis. Heel pain was more frequent when bursa was present (p<0.05). When Doppler was present, male predominance, HLA B27 positive, heel pain, and higher number of swollen joints, CRP levels, disease activity by the patient and BASDAI questions 2 and 3 achieved statistical significance (p<0.01). CONCLUSIONS: The presence of bursa and Doppler signal at retrocalcaneal bursa level could have a relevant contribution to differentiate SpA patients, and were correlated with clinical outcomes of SpA disease activity.

Incremental value of perfusion over wall-motion abnormalities with the use of dobutamine-atropine stress myocardial contrast echocardiography and magnetic resonance imaging for detecting coronary artery disease.

BACKGROUND: Recently, multimodality imaging has been demonstrated to improve the sensitivity of dobutamine stress for the diagnosis of coronary artery disease (CAD). OBJECTIVE: We sought to determine the additional value of myocardial perfusion (MP) over wall-motion (WM) analysis for detecting CAD, using real time myocardial contrast echocardiography (RTMCE) and cardiovascular magnetic resonance (CMR), in the same group of patients. METHODS: We studied 42 patients who underwent RTMCE and CMR during high-dose dobutamine stress with early injection of atropine. RESULTS: No difference was observed in the diagnostic accuracy of RTMCE and CMR for detecting angiographically significant CAD when considering WM analysis alone (73% [95% CI, 65-81] and 78% [95% CI, 70-84], respectively; P = NS) or combined analysis of WM and MP (80% [95% CI, 73-97] and 83% [95% CI, 77-90], respectively; P = NS). Combined analysis of WM and MP had higher sensitivity than the analysis of WM alone by RTMCE (88% [95% CI, 75-100] vs. 72% [95% CI, 54-90]) and by CMR (92% [95% CI, 81-100] vs. 80% [95% CI, 64-96]) with no differences in specificity. The association of abnormal WM and MP abnormalities during high-dose dobutamine-atropine stress had additional value for detecting CAD over the analysis of WM alone, both by RTMCE (χ(2) = 16.16-24.13; P = 0.005) and CMR (χ(2) = 12.73-27.41; P = 0.001). CONCLUSION: RTMCE and CMR using the same dobutamine-atropine stress protocol had comparable diagnostic accuracies for the detection of angiographically significant CAD. MP imaging had additional value over WM analysis for the diagnosis of CAD, both at RTMCE and CMR.

First-Row Transition 7-Oxo-5-phenyl-1,2,4-triazolo[1,5-a]pyrimidine Metal Complexes: Antiparasitic Activity and Release Studies.

Leishmaniasis and Chagas disease are still considered neglected illnesses due to the lack of investment in research, despite the fact that almost one million new cases are reported every year. Four 7-oxo-5-phenyl-1,2,4-triazolo[1,5-a]pyrimidine (HftpO) first-row transition complexes (Cu, Co, Ni, Zn) have been studied for the first time in vitro against five different species of Leishmania spp. (L. infantum, L. braziliensis, L. donovani, L. peruviana and L. mexicana) as well as Trypanosoma cruzi, showing higher efficacy than the reference commercial drugs. UV and luminescence properties were also evaluated. As a proof of concept, anchoring of a model high-effective-metal complex as an antiparasitic agent on silica nanoparticles was carried out for the first time, and drug-release behaviour was evaluated, assessing this new approach for drug vehiculation.

Position Statement on the Use of Myocardial Strain in Cardiology Routines by the Brazilian Society of Cardiology's Department Of Cardiovascular Imaging - 2023. / Posicionamento do Departamento de Imagem Cardiovascular da Sociedade Brasileira de Cardiologia sobre o Uso do Strain Miocárdico na Rotina do Cardiologista ­ 2023.

Central Illustration : Position Statement on the Use of Myocardial Strain in Cardiology Routines by the Brazilian Society of Cardiology's Department Of Cardiovascular Imaging - 2023 Proposal for including strain in the integrated diastolic function assessment algorithm, adapted from Nagueh et al.67 Am: mitral A-wave duration; Ap: reverse pulmonary A-wave duration; DD: diastolic dysfunction; LA: left atrium; LASr: LA strain reserve; LVGLS: left ventricular global longitudinal strain; TI: tricuspid insufficiency. Confirm concentric remodeling with LVGLS. In LVEF, mitral E wave deceleration time < 160 ms and pulmonary S-wave < D-wave are also parameters of increased filling pressure. This algorithm does not apply to patients with atrial fibrillation (AF), mitral annulus calcification, > mild mitral valve disease, left bundle branch block, paced rhythm, prosthetic valves, or severe primary pulmonary hypertension.

Figura Central : Posicionamento do Departamento de Imagem Cardiovascular da Sociedade Brasileira de Cardiologia sobre o Uso do Strain Miocárdico na Rotina do Cardiologista ­ 2023 Proposta de inclusão do strain no algoritmo integrado de avaliação da função diastólica, adaptado e traduzido de Nagueh et al. 67 AE: átrio esquerdo; Ap: duração da onda A reversa pulmonar; Am: duração da onda A mitral; DD: disfunção diastólica; FEVEr: fração de ejeção do ventrículo esquerdo reduzida; IT: insuficiência tricúspide; SAEr: strain do AE de reservatório; SLGVE: strain longitudinal global do ventrículo esquerdo. Se remodelamento concêntrico, confirmar com SLGVE. Na presença de FEVEr, tempo de desaceleração da onda E mitral (TDE) < 160 ms e onda S < D pulmonar também são parâmetros de pressão de enchimento aumentada. Esse algoritmo não se aplica a pacientes com fibrilação atrial (FA), calcificação do anel mitral ou valvopatia mitral maior que discreta, bloqueio de ramo esquerdo (BRE), ritmo de marca-passo, próteses valvares ou hipertensão pulmonar (HP) primária grave.

Myocarditis as the Initial Presentation of a Refractory Adult-Onset Still's Disease.

We present a case of adult-onset Still's disease, a rare disease that presented with a rare complication, myocarditis. After initial therapy with prednisolone 1 mg/kg/day, the patient experienced dyspnea due to severe pleural effusion and palpitations on account of new-onset supraventricular tachycardia. Therapy with three consecutive pulses of 1000 mg of methylprednisolone and anakinra 100 mg/day proved to be effective, with a progressive resolution of all symptoms. However, at three months follow-up, oligoarthritis recurred along with high serum ferritin. Secondary failure to anakinra was assumed, and a switch to tocilizumab 162 mg was made. Nevertheless, arthralgia of the wrists and knees as well as high serum ferritin still persisted after two months of therapy. Chronic disease was assumed, and the patient switched to canakinumab 4 mg/kg/dose q4week, and a complete resolution of symptoms occurred with normalization of inflammation markers. Follow-up cardiac magnetic resonance showed a complete resolution of heart involvement.

An enzyme-controlled mesoporous nanomachine for triple-responsive delivery.

The construction of a novel enzyme-controlled nanomachine with multiple release mechanisms for on-command delivery is described. This nanodevice was assembled by modifying mesoporous silica nanoparticles with 2-(benzo[d]thiazol-2-yl)phenyl 4-aminobenzoate moieties, and further capped with ß-cyclodextrin-modified glucose oxidase neoglycoenzyme. The device released the encapsulated payload in the presence of H2O2 and acidic media. The use of glucose as an input chemical signal also triggered cargo release through the enzymatic production of gluconic acid and hydrogen peroxide, and the subsequent disruption of the gating mechanism at the mesoporous surface. The nanodevice was successfully employed for the enzyme-controlled release of doxorubicin in HeLa cancer cells.

Enthesis erosion in spondyloarthritis is not a persistent structural lesion.

OBJECTIVE: To evaluate the ability of ultrasound (US) to detect the presence and change of Achilles erosions in spondyloarthritis (SpA). METHODS: A blind prospective two-dimensional (2D) and three-dimensional (3D) US study of Achilles enthesis erosions in early SpA was undertaken. US examinations were performed at baseline and at 6 and 12 months of follow-up. Clinical outcomes measures were collected. RESULTS: Bilateral Achilles entheses of 68 patients (35 women) were investigated. The mean Bath Ankylosing Spondylitis Disease Activity Index and C reactive protein (CRP) levels were 4.58 ± 2.05 and 5.97 ± 9.91 mg/l, respectively. The κ values for intrareader agreement for 2D and 3D images were 0.84 and 0.85 for two readers. 2D US visualised 10 erosions (7.4%) and 3D US visualised 13 erosions (9.6%) in 10 patients (14.7%). At 6 and 12 months of follow-up, 25% and 50% of basal erosions had disappeared, respectively and, of the new erosions that appeared at 6 months, 40% had disappeared 6 months later. A statistically significant association between erosion and CRP levels, entheseal Doppler signals and the number of tender and swollen joints was found. CONCLUSIONS: US examination of Achilles erosions is reliable and sensitive to change. An association was found between Achilles erosions and objective activity-based measurements of SpA outcomes.

Intravenous immunoglobulin as a therapeutic option for patients with worsening COVID-19 under rituximab.

Severe cases of the new COVID-19 are being reported in immunosuppressed patients. The risk seems to depend on the type of immunosuppressive agents used and it is particularly important in patients under the long-lasting effect of rituximab. Information regarding the best therapeutic approach to these patients is scarce and further studies are needed. We present a case of a young woman with rheumatoid arthritis treated with rituximab (last administration 4 months before her admission). She presented with a deteriorating and prolonged SARS-CoV-2 infection, with persistent fever, significant elevation of inflammatory markers and radiological progression. Glucocorticoids and antibiotic therapy were initiated, with no response. Intravenous immunoglobulin was then used with a rapid and exuberant response, anticipating a promising role of this therapy in immunosuppressed patients with COVID-19 under the effect of rituximab.

Sucrose-Responsive Intercommunicated Janus Nanoparticles Network.

Inspired by biological systems, the development of artificial nanoscale materials that communicate over a short distance is still at its early stages. This work shows a new example of a cooperating system with intercommunicated devices at the nanoscale. The system is based on the new sucrose-responsive Janus gold-mesoporous silica (Janus Au-MS) nanoparticles network with two enzyme-powered nanodevices. These nanodevices involve two enzymatic processes based on invertase and glucose oxidase, which are anchored on the Au surfaces of different Janus Au-MS nanoparticles, and N-acetyl-L-cysteine and [Ru(bpy)3]2+ loaded as chemical messengers, respectively. Sucrose acts as the INPUT, triggering the sequential delivery of two different cargoes through the enzymatic control. Nanoscale communication using abiotic nanodevices is a developing potential research field and may prompt several applications in different disciplines, such as nanomedicine.

Direct tissue-sensing reprograms TLR4+ Tfh-like cells inflammatory profile in the joints of rheumatoid arthritis patients.

CD4+ T cells mediate rheumatoid arthritis (RA) pathogenesis through both antibody-dependent and independent mechanisms. It remains unclear how synovial microenvironment impinges on CD4+ T cells pathogenic functions. Here, we identified a TLR4+ follicular helper T (Tfh) cell-like population present in the blood and expanded in synovial fluid. TLR4+ T cells possess a two-pronged pathogenic activity whereby direct TLR4+ engagement by endogenous ligands in the arthritic joint reprograms them from an IL-21 response, known to sponsor antibody production towards an IL-17 inflammatory program recognized to fuel tissue damage. Ex vivo, synovial fluid TLR4+ T cells produced IL-17, but not IL-21. Blocking TLR4 signaling with a specific inhibitor impaired IL-17 production in response to synovial fluid recognition. Mechanistically, we unveiled that T-cell HLA-DR regulates their TLR4 expression. TLR4+ T cells appear to uniquely reconcile an ability to promote systemic antibody production with a local synovial driven tissue damage program.

Musculoskeletal ultrasound among rheumatologists in Portugal: state of practice and training.

Over the last years, musculoskeletal ultrasound (MSUS) has been increasingly integrated by rheumatologists into clinical practice. Nowadays, it is considered an important imaging modality for the diagnosis, monitoring, and prognosis of various rheumatic diseases, along with its role in the guidance of interventional procedures. Formal training is needed to ensure a skilled and safe MSUS practice. Data regarding the use of MSUS by Portuguese rheumatologists is, however, lacking. Herein, we present a study on the current state of practice and training of MSUS in Portugal.

Peritenon Extensor Tendon Inflammation in Psoriatic Arthritis Is an Enthesitis-related Lesion.

OBJECTIVE: To analyze the association between enthesitis, synovitis, and peritenon extensor tendon inflammation (PTI) in psoriatic arthritis (PsA). METHODS: PsA patients with swelling of metacarpophalangeal joints were included. Greyscale and power Doppler (PD) were used for synovitis and PTI ultrasound identification. Madrid Sonographic Enthesis Index (MASEI) was used for enthesitis assessment. PD activity was evaluated using PD item of MASEI and PD Outcome Measures in Rheumatology (OMERACT) definition. RESULTS: Synovitis had no association with enthesitis. PTI was associated with PD MASEI and PD OMERACT. Only PD OMERACT showed a positive correlation with PTI. CONCLUSION: In PsA, PTI is associated to enthesitis, as opposed to synovitis.

Portuguese recommendations for the use of ultrasound in rheumatology.

INTRODUCTION: Ultrasound (US) is a relatively cheap, easily available and reliable method to improve the care of rheumatic patients. However, its use in rheumatology practice is very heterogeneous and needs to be standardized. OBJECTIVES: To develop recommendations for the use of US in rheumatic diseases endorsed by the Portuguese Society of Rheumatology. METHODS: A systematic literature review of the available recommendations on the use of ultrasound in rheumatic diseases was performed and presented in a Portuguese Society of Rheumatology meeting to a subgroup of rheumatologists and rheumatology trainees with special interest in the subject. The most important topics to be addressed were selected and assigned to subgroups for literature review and draft recommendations. Following an iterative process of consensus, the final recommendations were developed, and their level of agreement voted anonymously online. A recommendation was approved when the average level of agreement was ≥ 7.5 in a 10-point Likert scale. RESULTS: Fourteen recommendations were produced regarding nine rheumatology topics: rheumatoid arthritis, spondyloarthritis, connective tissue diseases, polymyalgia rheumatica, vasculitis, crystal-deposition diseases, soft tissue rheumatism, osteoarthritis and ultrasound-guided procedures. CONCLUSION: We developed an up-to-date guidance in the form of recommendations for the use of US in nine different areas of rheumatology. As ultrasound is an important imaging modality with increasing use in the rheumatology setting, and there are frequent technological advances in the ultrasound machines and probes, in parallel with continuous associated research, these recommendations should be regularly updated.

Glucose-Responsive Enzyme-Controlled Mesoporous Nanomachine with a Layer-by-Layer Supramolecular Architecture.

Here we describe the construction of an integrated and pH-sensitive nanomachine with layer-by-layer supramolecular design and enzymatic control for on-command delivery. The nanodevice comprises a first layer of ß-cyclodextrin-coated gold nanoparticles as capping element of benzimidazole functionalized mesoporous silica nanoparticles, and a second control layer based on an adatamantane-modified glucose oxidase derivative. The nanomachine was selectively fuelled by glucose and successfully employed for the autonomous release of doxorubicin in HeLa cancer cells.