Site-Specific Metal Chelation Facilitates the Unveiling of Hidden Coordination Sites in an Fe II/Fe III -Seamed Pyrogallol[4]arene Nanocapsule

Under suitable conditions, C-alkylpyrogallol­[4]­arenes (PgCs) arrange into spherical metal–organic nanocapsules (MONCs) upon coordination to appropriate metal ions. Herein we present the synthesis and structural characterization of a novel FeII/FeIII-seamed MONC, as well as studies related to its electrochemical and magnetic behaviors. Unlike other MONCs that are assembled through 24 metal ions, this nanocapsule comprises 32 Fe ions, uncovering 8 additional coordination sites situated between the constituent PgC subunits. The FeII ions are likely formed by the reducing ability of DMF used in the synthesis, representing a novel synthetic route toward polynuclear mixed-valence MONCs

A genome-wide association study identifies risk alleles in plasminogen and P4HA2 associated with giant cell arteritis

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analysed in 2,134 cases and 9,125 unaffected controls from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, P = 1.94E-54, per-allele OR = 1.79; and rs9275592, P = 1.14E-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, P = 1.23E-10, OR = 1.28; and rs128738, P = 4.60E-09, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Thermofluorimetric Analysis (TFA) using Probes with Flexible Spacers: Application to Direct Antibody Sensing and to Antibody-Oligonucleotide (AbO) Conjugate Valency Monitoring

Antibodies have long been recognized as clinically relevant biomarkers of disease. The onset of a disease often stimulates antibody production at low quantities, making it crucial to develop sensitive, specific, and easy-to-use antibody assay platforms. Antibodies are also extensively used as probes in bioassays, and there is a need for simpler methods to evaluate specialized probes such as antibody-oligonucleotide (AbO) conjugates. Previously, we have demonstrated that thermofluorimetric analysis (TFA) of analyte-driven DNA assembly can be leveraged to detect protein biomarkers using AbO probes. A key advantage of this technique is its ability to circumvent autofluorescence arising from biological samples, which otherwise hampers homogenous assays. The analysis of differential DNA melt curves (dF/dT) successfully distinguishes the signal from background and interferences. Expanding the applicability of TFA further, here-in we demonstrate a unique proximity based TFA assay for antibody quantification which is functional in 90% human plasma. We show that conformational flexibility of the DNA-based proximity probes is critically important for optimal performance in these assays. To promote stable, proximity-induced hybridization of the short DNA strands, substitution of polyethylene glycol (PEG) spacers in place of ssDNA segments led to improved conformational flexibility and sensor performance. Finally, by applying these flexible spacers to study AbO conjugates directly, we validate this modified TFA approach as a novel tool to elucidate the probes valency, clearly distinguishing between monovalent and multivalent AbOs and reducing the reagent amounts by 12-fol

Building a nucleic acid nanostructure with DNA-epitope conjugates for a versatile electrochemical protein detection platform

The recent surge of effort in nucleic acid-based electrochemical (EC) sensors has been fruitful, and some have even shown real-time quantification of drugs in the blood of living animals. Yet there remains a need for more generalizable EC platforms for the detection of multiple classes of clinically relevant targets. Our group has recently reported a nucleic acid nanostructure that permits simple, economical, and generalizable EC readout of a wide range of analytes (small molecules, peptides, large proteins, or antibodies). The DNA nanostructure is built through on-electrode enzymatic ligation of three oligonucleotides for attachment, binding, and signaling. However, the signaling mechanism predominantly relies on tethered diffusion of methylene blue at the electrode surface, limiting the detection of larger proteins that have no readily available small molecule binding partners. In this study, we adapted the nanostructure sensor to quantify larger proteins in a more generic manner, through conjugating the proteins minimized antibody-binding epitope to the central DNA strand of the nanostructure (DNA-peptide conjugate). This concept was verified using creatine kinase (CK-MM), an important biomarker of muscle damage, myocardial infarction, overexertion/rhabdomyolysis, or neuromuscular disorders where clinical outcomes could be improved with rapid sensing. DNA-epitope conjugates permitted a competitive immunoassay protocol at the electrode surface for quantifying CK protein. Square-wave voltammetry (SWV) signal suppression was proportional to the amount of surface-bound antibody with a limit of detection (LOD) of 5 nM and a response time as low as 3 minutes, and displacement of antibody by native CK-MM protein analyte could also be assayed. CK was quantified from the LOD of 14 nM up to 100 nM, overlapping well with the normal (non-elevated) human clinical range of 3 37 nM, and the sensor response was validated in 98% human serum. While a need for improved DNA-epitope conjugate purification was identified, overall this approach not only allows the detection of a generic protein- or peptide-binding antibody, but it also should facilitate future quantitative EC readout of various clinically relevant protein analytes that were previously inaccessible to EC techniques

Single carrier frequency domain equalization based on on-off-keying for optical wireless communications

Single carrier systems with frequency domain equalization (SC-FDE) have been recently proposed for optical wireless systems as alternatives to optical orthogonal frequency division multiplexing (OFDM) to reduce the peak-to-average power ratio (PAPR) of the transmitted signal and improve the system performance. However, these SC-FDE systems have either higher complexity or lower spectrum efficiency. In this paper a low complexity SC-FDE system based on on-off-keying (OOK) modulation is proposed. Theoretical bit-error-rate (BER) analysis is provided based on minimum mean square error (MMSE) equalization for the proposed system and typical optical SC-FDE and OFDM systems. Both analytical and numerical results show that the proposed system significantly outperforms existing SC-FDE and OFDM systems in terms of PAPR, BER and implementation complexity.

In Situ X-ray Diffraction Study of the Formation of Fe(Se,Te) from Various Precursors

The formation of the FeSe0.5Te0.5 phase was studied by means of high energy synchrotron x-ray diffraction. The precursors consisted of Fe, Se and Te or Se0.5Te0.5 powder mixtures and were encased in a metal (Cu/Nb) composite sheath to prevent evaporation of Se and Te during high temperature processing. In all cases (Fe – Se – Te ternary mixture; Fe - Se0.5Te0.5 binary mixtures with two different Fe particle sizes) the ternary alloy forms via Fe(Se,Te)2 and Fe3(Se,Te)4 intermediate phases. When unreacted Se and Te powders are used in the precursor, partial Se1-xTex alloying takes place during heating prior and during the formation of the intermediate phases. As the alloying is incomplete, the resulting Fe(Se,Te) phase is not homogeneous. Using pre-alloyed Se0.5Te0.5 allows a better control of the reaction although homogeneisation also occurs in the Fe(Se,Te) phase as a consequence of the phase equilibria of the Se – Te system. The grain size of the starting Fe powder has no influence on the reaction path for the grain sizes used in the present study. However, the reaction rate for Fe(Se,Te) formation is clearly sensitive to this parameter