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No sign of quitting: incidental exposure to “no smoking” signs ironically boosts cigarette‐approach tendencies in smokers
AbstractThe unconscious mind tends to disregard negations in its processing of semantic meaning. Therefore, messages containing negated concepts can ironically prime mental representations and evaluations that are opposite to those intended. We hypothesized that the subtle presentation of a negated concept (e.g., “no smoking”) would activate ironic motivational orientations as well. We tested this hypothesis in a public health context. Smokers viewed photographs in which “no smoking” signs were either inconspicuously embedded (prime condition) or edited out (control condition). Primed smokers showed amplified automatic approach tendencies toward smoking‐related stimuli, but not toward smoking‐unrelated stimuli: an ironic motivational response to exposure to the signs. Since passive priming effects generally serve to facilitate forms of action, not inhibit them, antismoking and other public health campaigns may ironically increase the very behaviors they seek to reduce.
A preliminary study of medial temporal lobe function in youths with a history of caregiver deprivation and emotional neglect.
Previous research findings have linked caregiver deprivation and emotional neglect with sensitivity to threatening cues. The present preliminary study investigated whether dysfunctions of the medial temporal lobe could underlie these associations. Using fMRI, we measured medial temporal lobe responses to emotional faces (angry, fearful, happy, neutral) among 30 youths. Eleven of the youths had a history of caregiver deprivation and emotional neglect. Attention states (i.e., attention to anger, fear, or physical attributes, or passive viewing) were systematically manipulated. Relative to comparison youths, youths with a history of caregiver deprivation and emotional neglect showed significantly greater left amygdala and left anterior hippocampus activation during the processing of threatening information. To our knowledge, these findings are the first to demonstrate altered medial temporal lobe function during the processing of threat cues in youths with a history of caregiver deprivation and emotional neglect.
Feasibility assessment of radiolabeled FAPI-04 for diagnostic and therapeutic use in rheumatoid arthritis.
OBJECTIVE: Fibroblast activation protein alpha (FAPα) plays a key role in cartilage degradation, inflammation, and bone erosion, particularly in rheumatoid arthritis (RA) where fibroblast-like synoviocytes in synovial tissue show elevated FAPα expression. This study explored radiolabeled FAP inhibitors for arthritis diagnosis and therapy. DESIGN: We used the radiotracer 68Ga-FAPI-04 for PET/CT imaging to predict collagen-induced arthritis (CIA) onset. Weekly scans quantified tracer uptake via SUV values, correlating results with disease scores and incidence. For therapeutic evaluation, 177Lu-FAPI-04 targeted FAPα-expressing cells, and arthritis scores of treated CIA mice were compared with untreated controls using one-way ANOVA. RESULTS: CIA mice with elevated SUV one week post-booster immunization had a 94.6 % arthritis incidence. SUV correlated with arthritis severity, reflecting increased FAPα expression. Treatment with 177Lu-FAPI-04 reduced arthritis scores by 64 % compared to controls (p
Barrett's Oesophagus Surveillance versus endoscopy at need Study (BOSS): a randomized controlled trial.
BACKGROUND AND AIMS: Barrett's esophagus (BE) is a precursor lesion for esophageal adenocarcinoma (EA). Surveillance endoscopy aims to detect early malignant progression: though widely practised it has not previously been tested in a randomized trial. METHODS: BOSS was a randomized controlled trial at 109 centres in the UK. Patients with BE were randomized to two-yearly surveillance endoscopy or 'at need' endoscopy, offered only for symptoms. Follow up was a minimum of 10 years. The primary outcome was overall survival in the intention-to-treat population. Secondary outcomes included cancer-specific survival; time to diagnosis of EA; stage of EA at diagnosis; frequency of endoscopy and serious adverse events related to interventions. RESULTS: 3453 patients were recruited. 1733 patients were randomized to surveillance and 1719 to 'at need' endoscopy. Median follow up time was 12·8 years for the primary outcome. There was no evidence of a difference in overall survival between surveillance (333 deaths in 1733 patients) versus 'at need' arms (356 deaths in 1719 patients), hazard ratio 0·95 (95% CI 0·82-1·10), stratified log-rank p=0·503). There was no evidence of a difference for surveillance versus 'at need' endoscopy in cancer-specific survival (108 vs. 106 deaths from any cancer, HR 1·01 (95% CI 0·77-1·33), p=0·926), time to diagnosis of EA (40 vs. 31 patients had a diagnosis of EA, HR 1·32 (95% CI 0·82-2·11), p=0·254), or cancer stage at diagnosis. 8 (0·46%) surveillance patients and 7 (0·41%) 'at need' patients reported serious adverse events. CONCLUSION: Surveillance did not improve overall survival or cancer-specific survival. 'At need' endoscopy may be a safe alternative for low-risk patients.
Effect of intra-articular corticosteroid injections for knee osteoarthritis on the rates of subsequent knee replacement and post-operative outcomes: a national cohort study of England.
BACKGROUND: Intra-articular corticosteroid injection (IACI) is an established treatment option for uncontrolled pain in osteoarthritis. There is a lack of longer-term follow-up in most studies of the effects of IACI, meaning there is scarcity of data on the impact of IACI on the subsequent need for joint replacement. Our aim was to assess the effect of IACI for knee osteoarthritis on the subsequent incidence of knee replacement surgery and on associated post-operative outcomes. METHODS: We conducted a cohort study of knee osteoarthritis patients registered in the Clinical Practice Research Datalink (CPRD) GOLD database with an incident diagnosis between 2005 and 2019. Exposure was single or repeated IACI use, analysed separately. The primary outcome was knee replacement during 1-year and 5-year follow-ups. Secondary outcomes included post-operative patient-reported outcome measures and adverse events. Primary analyses used general practitioner practice preference for IACI as an instrumental variable given this methodology can account for strong and unmeasured confounding. Secondary analyses used propensity score matching, accounting for measured covariates only. RESULTS: During 1-year follow-up, 1628/33,357 (4.9%) knee osteoarthritis patients underwent knee replacement, for which single IACI was associated with lower risk, which persisted to 5-year follow-up (incidence rate ratio: 0.52 [0.36, 0.77]). Conversely, in secondary propensity score analyses no association was found between IACI use and knee replacement rate at 1-year follow-up, and an estimated increased rate of knee replacement at 5-year follow-up. Use of IACI pre-joint replacement was not associated with any adverse post-operative outcomes, for example, 1-year complication rates (per 100 person-years) following knee replacement were 4.6 (3.8, 5.8), 4.0 (2.7, 6.0) and 5.0 (3.1, 8.1) among patients with no, single and repeat pre-joint replacement IACI use, respectively. CONCLUSIONS: Findings from our main analysis suggest that short-term pain reduction following IACI for knee osteoarthritis may translate to lower rates of knee replacement over 5 years follow-up, although contradictory associations were observed in secondary analyses which likely reflected residual confounding by indication. Reassuringly, IACI use before knee replacement was not associated with post-operative adverse outcomes.
British Elbow and Shoulder Society patient care pathway: Frozen shoulder
Background Current guidelines from the British Elbow and Shoulder Society (BESS) were published in 2015 for managing frozen shoulders in the primary and secondary care setting. Updated guidelines have been developed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology. Methods A multi-disciplinary BESS Working Group defined key management questions based on agreed outcome measures and time points. A literature search, conducted up to March 2023 following PRISMA guidelines, identified randomised controlled trials, systematic reviews, and meta-analyses. Quality assessments were performed using the GRADE Decision Framework, considering bias, imprecision, indirectness, and inconsistency. Data were extracted for meta-analysis. In the absence of high-quality trials, narrative reviews were created. Results Consensus opinions produced statements based on the quality and volume of evidence and the magnitude of desirable and undesirable effects. These statements form a comprehensive framework for managing frozen shoulder. Discussion This updated guideline provides evidence-based guidance for managing frozen shoulder and identifies key areas for future research.
SPIRIT 2025 statement: Updated guideline for protocols of randomised trials.
IMPORTANCE: The protocol of a randomised trial is the foundation for study planning, conduct, reporting, and external review. However, trial protocols vary in their completeness and often do not address key elements of design and conduct. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement was first published in 2013 as guidance to improve the completeness of trial protocols. Periodic updates incorporating the latest evidence and best practices are needed to ensure that the guidance remains relevant to users. OBJECTIVE: To systematically update the SPIRIT recommendations for minimum items to address in the protocol of a randomised trial. DESIGN: We completed a scoping review and developed a project specific database of empirical and theoretical evidence to generate a list of potential changes to the SPIRIT 2013 checklist. The list was enriched with recommendations provided by lead authors of existing SPIRIT/CONSORT (Consolidated Standards of Reporting Trials) extensions (Harms, Outcomes, Non-pharmacological Treatment) and other reporting guidelines (TIDieR). The potential modifications were rated in a three-round Delphi survey followed by a consensus meeting. FINDINGS: Overall, 317 individuals participated in the Delphi consensus process and 30 experts attended the consensus meeting. The process led to the addition of two new protocol items, revision to five items, deletion/merger of five items, and integration of key items from other relevant reporting guidelines. Notable changes include a new open science section, additional emphasis on the assessment of harms and description of interventions and comparators, and a new item on how patients and the public will be involved in trial design, conduct, and reporting. The updated SPIRIT 2025 statement consists of an evidence-based checklist of 34 minimum items to address in a trial protocol, along with a diagram illustrating the schedule of enrolment, interventions, and assessments for trial participants. To facilitate implementation, we also developed an expanded version of the SPIRIT 2025 checklist and an accompanying explanation and elaboration document. CONCLUSIONS AND RELEVANCE: Widespread endorsement and adherence to the updated SPIRIT 2025 statement have the potential to enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, funders, research ethics committees, journals, trial registries, policymakers, regulators, and other reviewers.
SPIRIT 2025 statement: updated guideline for protocols of randomized trials.
The protocol of a randomized trial is the foundation for study planning, conduct, reporting and external review. However, trial protocols vary in their completeness and often do not address key elements of design and conduct. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement was first published in 2013 as guidance to improve the completeness of trial protocols. Periodic updates incorporating the latest evidence and best practices are needed to ensure that the guidance remains relevant to users. Here, we aimed to systematically update the SPIRIT recommendations for minimum items to address in the protocol of a randomized trial. We completed a scoping review and developed a project-specific database of empirical and theoretical evidence to generate a list of potential changes to the SPIRIT 2013 checklist. The list was enriched with recommendations provided by lead authors of existing SPIRIT/CONSORT (Consolidated Standards of Reporting Trials) extensions (Harms, Outcomes, Non-pharmacological Treatment) and other reporting guidelines (TIDieR). The potential modifications were rated in a three-round Delphi survey followed by a consensus meeting. Overall, 317 individuals participated in the Delphi consensus process and 30 experts attended the consensus meeting. The process led to the addition of two new protocol items, revision to five items, deletion/merger of five items, and integration of key items from other relevant reporting guidelines. Notable changes include a new open science section, additional emphasis on the assessment of harms and description of interventions and comparators, and a new item on how patients and the public will be involved in trial design, conduct and reporting. The updated SPIRIT 2025 statement consists of an evidence-based checklist of 34 minimum items to address in a trial protocol, along with a diagram illustrating the schedule of enrollment, interventions and assessments for trial participants. To facilitate implementation, we also developed an expanded version of the SPIRIT 2025 checklist and an accompanying explanation and elaboration document. Widespread endorsement and adherence to the updated SPIRIT 2025 statement have the potential to enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, funders, research ethics committees, journals, trial registries, policymakers, regulators and other reviewers.
SPIRIT 2025 statement: updated guideline for protocols of randomised trials.
IMPORTANCE: The protocol of a randomised trial is the foundation for study planning, conduct, reporting, and external review. However, trial protocols vary in their completeness and often do not address key elements of design and conduct. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement was first published in 2013 as guidance to improve the completeness of trial protocols. Periodic updates incorporating the latest evidence and best practices are needed to ensure that the guidance remains relevant to users. OBJECTIVE: To systematically update the SPIRIT recommendations for minimum items to address in the protocol of a randomised trial. DESIGN: We completed a scoping review and developed a project specific database of empirical and theoretical evidence to generate a list of potential changes to the SPIRIT 2013 checklist. The list was enriched with recommendations provided by lead authors of existing SPIRIT/CONSORT (Consolidated Standards of Reporting Trials) extensions (Harms, Outcomes, Non-pharmacological Treatment) and other reporting guidelines (TIDieR). The potential modifications were rated in a three-round Delphi survey followed by a consensus meeting. FINDINGS: Overall, 317 individuals participated in the Delphi consensus process and 30 experts attended the consensus meeting. The process led to the addition of two new protocol items, revision to five items, deletion/merger of five items, and integration of key items from other relevant reporting guidelines. Notable changes include a new open science section, additional emphasis on the assessment of harms and description of interventions and comparators, and a new item on how patients and the public will be involved in trial design, conduct, and reporting. The updated SPIRIT 2025 statement consists of an evidence based checklist of 34 minimum items to address in a trial protocol, along with a diagram illustrating the schedule of enrolment, interventions, and assessments for trial participants. To facilitate implementation, we also developed an expanded version of the SPIRIT 2025 checklist and an accompanying explanation and elaboration document. CONCLUSIONS AND RELEVANCE: Widespread endorsement and adherence to the updated SPIRIT 2025 statement have the potential to enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, funders, research ethics committees, journals, trial registries, policymakers, regulators, and other reviewers.
A Single-Domain VNAR Nanobody Binds with High-Affinity and Selectivity to the Heparin Pentasaccharide Fondaparinux
Glycosaminoglycans (GAGs) are key ligands for proteins involved in physiological and pathological processes. Specific GAG-binding patterns are rarely identified, with the heparin pentasaccharide as an Antithrombin-III ligand being the best characterized. Generating glycan-specific antibodies is difficult due to their size, pattern dispersion, and flexibility. Single-domain variable new antigen receptors (VNAR nanobodies) from nurse sharks are highly soluble, stable, and versatile. Their unique properties suggest advantages over conventional antibodies, particularly for challenging biotherapeutic targets. Here we have used VNAR semi-synthetic phage libraries to select high-affinity fondaparinux-binding VNARs that did not show cross-reactivity with other GAG species. Competition ELISA and surface plasmon resonance identified a single fondaparinux-selective VNAR clone. This VNAR exhibited an extraordinarily stable protein fold: the beta-strands are stabilized by a robust hydrophobic network, as revealed by heteronuclear NMR. Docking fondaparinux to the VNAR structure revealed a large contact surface area between the CDR3 loop of the antibody and the glycan. Fusing the VNAR with a human Fc domain resulted in a stable product with a high affinity for fondaparinux (Kd = 9.3 × 10−8 M) that could efficiently discriminate between fondaparinux and other glycosaminoglycans. This novel glycan-targeting screening technology represents a promising therapeutic strategy for addressing GAG-related diseases.