Accurate structure prediction of biomolecular interactions with AlphaFold 3.

The introduction of AlphaFold 21 has spurred a revolution in modelling the structure of proteins and their interactions, enabling a huge range of applications in protein modelling and design2-6. In this paper, we describe our AlphaFold 3 model with a substantially updated diffusion-based architecture, which is capable of joint structure prediction of complexes including proteins, nucleic acids, small molecules, ions, and modified residues. The new AlphaFold model demonstrates significantly improved accuracy over many previous specialised tools: far greater accuracy on protein-ligand interactions than state of the art docking tools, much higher accuracy on protein-nucleic acid interactions than nucleic-acid-specific predictors, and significantly higher antibody-antigen prediction accuracy than AlphaFold-Multimer v2.37,8. Together these results show that high accuracy modelling across biomolecular space is possible within a single unified deep learning framework.

Technical efficiency and its convergence among village clinics in rural China: evidence from Shanxi Province.

Introduction: Village clinics (VCs) are the foundation of the three-tiered health service system in China, delivering basic and routine outpatient services to citizens in rural China. VC technical efficiency and its convergence play a critical role in policy decisions regarding the distribution of health service resources in rural China. Methods: This study measured VC technical efficiency (using the slacks-based measure model), its convergence (using the convergence model), and the factors that influence the convergence in Shanxi Province, China. Data were obtained from the Shanxi Rural Health Institute 2014-2018 Health Statistics Report, which involved 3,543 VCs. Results: The results showed that VC technical efficiency was low and differed by region. There was no α convergence in VC technical efficiency, but evidence of ß convergence was found in Shanxi. The main factors that influence convergence were the building area of each VC (BA), proportion of government subsidies (PGS), and ratio of total expenditure to total income of each VC (RTETI). Conclusion: The government should increase investments in VCs and improve VC technical efficiency. Meanwhile, the government should be aware of and take measures to curb the inequity in VC technical efficiency among different regions and take suitable measures to curb this disparity.

Comparison between propofol and total inhalational anaesthesia on cardiovascular outcomes following on-pump cardiac surgery in higher-risk patients: a randomised controlled pilot and feasibility study.

OBJECTIVES: Myocardial revascularisation and cardiopulmonary bypass (CPB) can cause ischaemia-reperfusion injury, leading to myocardial and other end-organ damage. Volatile anaesthetics protect the myocardium in experimental studies. However, there is uncertainty about whether this translates into clinical benefits because of the coadministration of propofol and its detrimental effects, restricting myocardial protective processes. METHODS: In this single-blinded, parallel-group randomised controlled feasibility trial, higher-risk patients undergoing elective coronary artery bypass graft (CABG) surgery with an additive European System for Cardiac Operative Risk Evaluation ≥5 were randomised to receive either propofol or total inhalational anaesthesia as single agents for maintenance of anaesthesia. The primary outcome was the feasibility of recruiting and randomising 50 patients across two cardiac surgical centres, and secondary outcomes included the feasibility of collecting the planned perioperative data, clinically relevant outcomes and assessments of effective patient identification, screening and recruitment. RESULTS: All 50 patients were recruited within 11 months in two centres, allowing for a 13-month hiatus in recruitment due to the COVID-19 pandemic. Overall, 50/108 (46%) of eligible patients were recruited. One patient withdrew before surgery and one patient did not undergo surgery. All but one completed in-hospital and 30-day follow-up. CONCLUSIONS: It is feasible to recruit and randomise higher-risk patients undergoing CABG surgery to a study comparing total inhalational and propofol anaesthesia in a timely manner and with high acceptance and completion rates. TRIAL REGISTRATION NUMBER: NCT04039854.

Correction: Impact of maintaining serum potassium concentration ≥ 3.6mEq/L versus ≥ 4.5mEq/L for 120 hours after isolated coronary artery bypass graft surgery on incidence of new onset atrial fibrillation: Protocol for a randomized non-inferiority trial.

[This corrects the article DOI: 10.1371/journal.pone.0296525.].

Serial injections of 4% polyacrylamide hydrogel have no detrimental effects in equine joints following clinical, histologic, and synovial biomarker evaluation.

OBJECTIVE: Polyacrylamide hydrogel (4% PAHG) is an inert viscoelastic supplement used to manage osteoarthritis in horses. Even with a prolonged clinical effect, horses may be administered multiple doses during their performance career. The effect of the serial 4% PAHG treatments is not known. The objectives of this study were to evaluate the clinical, histologic, and synovial fluid biomarker effects following serial administration of 4% PAHG in normal equine fetlock joints. ANIMALS: 8 healthy horses. METHODS: In a blinded, controlled in vivo study, horses received serial intra-articular injections of 4% PAHG (Noltrex Vet; Nucleus ProVets LLC) and contralateral 0.9% saline control on days 0, 45, 90, and 135. Treatment and control joints were randomly assigned. Synovial fluid was collected before administration of 4% PAHG or 0.9% saline on day 0 and at study completion for cellular and biomarker evaluation. Serial physical and lameness examinations were performed throughout the study. On day 240, gross examination and harvest of cartilage and synovial membrane for histology were completed. RESULTS: There were no histologic changes in articular cartilage or synovial fluid biomarkers. The 4% PAHG was seen on the surface of the synovium in 5 of 8 treated joints 105 days after the last treatment. There are minimal effects following serial injections of 4% PAHG on normal joints in horses following administration at 0, 45, 90, and 135 days, with final evaluation on day 240. CLINICAL RELEVANCE: Serial administration of intra-articular 4% PAHG in horses may provide long-term joint lubrication with no detrimental effects.

Impact of maintaining serum potassium concentration ≥ 3.6mEq/L versus ≥ 4.5mEq/L for 120 hours after isolated coronary artery bypass graft surgery on incidence of new onset atrial fibrillation: Protocol for a randomized non-inferiority trial.

BACKGROUND: Atrial Fibrillation After Cardiac Surgery (AFACS) occurs in about one in three patients following Coronary Artery Bypass Grafting (CABG). It is associated with increased short- and long-term morbidity, mortality and costs. To reduce AFACS incidence, efforts are often made to maintain serum potassium in the high-normal range (≥ 4.5mEq/L). However, there is no evidence that this strategy is efficacious. Furthermore, the approach is costly, often unpleasant for patients, and risks causing harm. We describe the protocol of a planned randomized non-inferiority trial to investigate the impact of intervening to maintain serum potassium ≥ 3.6 mEq/L vs ≥ 4.5 mEq/L on incidence of new-onset AFACS after isolated elective CABG. METHODS: Patients undergoing isolated CABG at sites in the UK and Germany will be recruited, randomized 1:1 and stratified by site to protocols maintaining serum potassium at either ≥ 3.6 mEq/L or ≥ 4.5 mEq/L. Participants will not be blind to treatment allocation. The primary endpoint is AFACS, defined as an episode of atrial fibrillation, flutter or tachycardia lasting ≥ 30 seconds until hour 120 after surgery, which is both clinically detected and electrocardiographically confirmed. Assuming a 35% incidence of AFACS in the 'tight control group', and allowing for a 10% loss to follow-up, 1684 participants are required to provide 90% certainty that the upper limit of a one-sided 97.5% confidence interval (CI) will exclude a > 10% difference in favour of tight potassium control. Secondary endpoints include mortality, use of hospital resources and incidence of dysrhythmias not meeting the primary endpoint (detected using continuous heart rhythm monitoring). DISCUSSION: The Tight K Trial will assess whether a protocol to maintain serum potassium ≥ 3.6 mEq/L is non inferior to maintaining serum potassium ≥ 4.5 mEq/L in preventing new-onset AFACS after isolated CABG. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04053816. Registered on 13 August 2019. Last update 7 January 2021.

Percutaneous Left Ventricular Unloading During High-Risk Coronary Intervention: Rationale and Design of the CHIP-BCIS3 Randomized Controlled Trial.

INTRODUCTION: Percutaneous coronary intervention for complex coronary disease is associated with a high risk of cardiogenic shock. This can cause harm and limit the quality of revascularization achieved, especially when left ventricular function is impaired at the outset. Elective percutaneous left ventricular unloading is increasingly used to mitigate adverse events in patients undergoing high-risk percutaneous coronary intervention, but this strategy has fiscal and clinical costs and is not supported by robust evidence. METHODS: CHIP-BCIS3 (Controlled Trial of High-Risk Coronary Intervention With Percutaneous Left Ventricular Unloading) is a prospective, multicenter, open-label randomized controlled trial that aims to determine whether a strategy of elective percutaneous left ventricular unloading is superior to standard care (no planned mechanical circulatory support) in patients undergoing nonemergent high-risk percutaneous coronary intervention. Patients are eligible for recruitment if they have severe left ventricular systolic dysfunction, extensive coronary artery disease, and are due to undergo complex percutaneous coronary intervention (to the left main stem with calcium modification or to a chronic total occlusion with a retrograde approach). Cardiogenic shock and acute ST-segment-elevation myocardial infarction are exclusions. The primary outcome is a hierarchical composite of all-cause death, stroke, spontaneous myocardial infarction, cardiovascular hospitalization, and periprocedural myocardial infarction, analyzed using the win ratio. Secondary outcomes include completeness of revascularization, major bleeding, vascular complications, health economic analyses, and health-related quality of life. A sample size of 250 patients will have in excess of 80% power to detect a hazard ratio of 0.62 at a minimum of 12 months, assuming 150 patients experience an event across all follow-up. CONCLUSIONS: To date, 169 patients have been recruited from 21 National Health Service hospitals in the United Kingdom, with recruitment expected to complete in 2024. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05003817.

Simulation study of the Gilbert damping in Ni80Fe20/Nd bilayers: comparison with experiments.

We present an experimental and computational investigation the Neodymium thickness dependence of the effective damping constant (αeff) inNi80Fe20/Neodymium (Py/Nd) bilayers. The computational results show that the magnetic damping is strongly dependent on the thickness of Nd, which is in agreement with experimental data. Self consistent solutions of the spin accumulation model and the local magnetisation were used in the simulations. It was not possible to obtain agreement with experiment under the assumption of an enhanced damping in a single Py monolayer. Instead, it was found that the enhanced damping due to spin pumping needed to be spread across two monolayers of Py. This is suggested to arise from interface mixing. Subsequently, the temperature dependence of the effective damping was investigated. It is found that, with increasing temperature, the influence of thermally-induced spin fluctuations on magnetic damping becomes stronger with increasing Nd thickness.

Single-Shot Laser-Induced Switching of an Exchange Biased Antiferromagnet.

Ultrafast manipulation of magnetic order has challenged the understanding of the fundamental and dynamic properties of magnetic materials. So far single-shot magnetic switching has been limited to ferrimagnetic alloys, multilayers, and designed ferromagnetic (FM) heterostructures. In FM/antiferromagnetic (AFM) bilayers, exchange bias (He) arises from the interfacial exchange coupling between the two layers and reflects the microscopic orientation of the antiferromagnet. Here the possibility of single-shot switching of the antiferromagnet (change of the sign and amplitude of He) with a single femtosecond laser pulse in IrMn/CoGd bilayers is demonstrated. The manipulation is demonstrated in a wide range of fluences for different layer thicknesses and compositions. Atomistic simulations predict ultrafast switching and recovery of the AFM magnetization on a timescale of 2 ps. The results provide the fastest and the most energy-efficient method to set the exchange bias and pave the way to potential applications for ultrafast spintronic devices.

Quantification of putative ovarian cancer serum protein biomarkers using a multiplexed targeted mass spectrometry assay.

BACKGROUND: Ovarian cancer is the most lethal gynecologic malignancy in women, and high-grade serous ovarian cancer (HGSOC) is the most common subtype. Currently, no clinical test has been approved by the FDA to screen the general population for ovarian cancer. This underscores the critical need for the development of a robust methodology combined with novel technology to detect diagnostic biomarkers for HGSOC in the sera of women. Targeted mass spectrometry (MS) can be used to identify and quantify specific peptides/proteins in complex biological samples with high accuracy, sensitivity, and reproducibility. In this study, we sought to develop and conduct analytical validation of a multiplexed Tier 2 targeted MS parallel reaction monitoring (PRM) assay for the relative quantification of 23 putative ovarian cancer protein biomarkers in sera. METHODS: To develop a PRM method for our target peptides in sera, we followed nationally recognized consensus guidelines for validating fit-for-purpose Tier 2 targeted MS assays. The endogenous target peptide concentrations were calculated using the calibration curves in serum for each target peptide. Receiver operating characteristic (ROC) curves were analyzed to evaluate the diagnostic performance of the biomarker candidates. RESULTS: We describe an effort to develop and analytically validate a multiplexed Tier 2 targeted PRM MS assay to quantify candidate ovarian cancer protein biomarkers in sera. Among the 64 peptides corresponding to 23 proteins in our PRM assay, 24 peptides corresponding to 16 proteins passed the assay validation acceptability criteria. A total of 6 of these peptides from insulin-like growth factor-binding protein 2 (IBP2), sex hormone-binding globulin (SHBG), and TIMP metalloproteinase inhibitor 1 (TIMP1) were quantified in sera from a cohort of 69 patients with early-stage HGSOC, late-stage HGSOC, benign ovarian conditions, and healthy (non-cancer) controls. Confirming the results from previously published studies using orthogonal analytical approaches, IBP2 was identified as a diagnostic biomarker candidate based on its significantly increased abundance in the late-stage HGSOC patient sera compared to the healthy controls and patients with benign ovarian conditions. CONCLUSIONS: A multiplexed targeted PRM MS assay was applied to detect candidate diagnostic biomarkers in HGSOC sera. To evaluate the clinical utility of the IBP2 PRM assay for HGSOC detection, further studies need to be performed using a larger patient cohort.

Predictive Modeling for Hospital Readmissions for Patients with Heart Disease: An updated review from 2012-2023.

Hospital readmissions are a major concern for healthcare leaders, policy makers, and patients, resulting in adverse health outcomes and imposing an increased burden on hospital resources. This review aims to synthesize existing literature on predictive models focused on patients diagnosed with heart disease, which is known for its high readmission rates. Seven databases (i.e., Web of Science, Scopus, PubMed, ProQuest, Ovid, Cochrane Library and EBSCO) were consulted resulting in the inclusion of 56 eligible studies. Among these, 44 focused on model development, 7 on model validation, 4 on model improvement, and 1 on model implementation. Data were extracted on readmission types, data sources, modeling methods, and predictors, while assessments were conducted to analyze the quality of the studies. Findings showed that readmission types were significantly influenced by policy decisions, data predominantly originated from hospitals, and the prevalent modeling methods used were regression and single-layer machine learning techniques. The most important clinical predictors were related to comorbidities and complications, while the key demographic predictors were age and race. The study found that, despite advancements during the last decade, several limitations exist in current research, particularly in addressing attrition bias and handling missing data. Future research should, therefore, focus on optimizing readmission types, enhancing model generalization, using interpretable models, and emphasizing model implementation.

Why do Chinese Youth Seek Cancer Risk Information Online? Evidence from Four Cities.

This study, inspired by the Risk Information Seeking and Processing (RISP) model, examines the mechanisms by which perceived hazard characteristics and the informational subjective norms of Chinese youth, aged from 14 to 44 years old, become associated with their intentions to seek cancer risk information online. A sample of 684 Chinese youths was collected from four cities in Mainland China with results revealing that perceived hazard characteristics and informational subjective norms motivate their online cancer risk information seeking intentions. Specifically, perceived probability, perceived severity, and institutional trust are positively related to negative affect, however the relationship between personal control and negative affect is not significant. Institutional trust and personal control are positively related to positive affect while perceived probability and perceived severity have no significant effect on positive affect. Negative affect and informational subjective norms are positively related to perceived information insufficiency, while the relationship between positive affect and perceived information insufficiency is not significant. Negative affect, positive affect, informational subjective norms, and perceived information insufficiency are all positively related to the online cancer risk information seeking intentions of Chinese youth.

Assessing an innovative method to promote learning from patient narratives: Findings from a field experiment in ambulatory care.

OBJECTIVE: To assess whether an online interactive report designed to facilitate interpretation of patients' narrative feedback produces change in ambulatory staff learning, behavior at the individual staff and practice level, and patient experience survey scores. DATA SOURCES AND SETTING: We studied 22 ambulatory practice sites within an academic medical center using three primary data sources: 333 staff surveys; 20 in-depth interviews with practice leaders and staff; and 9551 modified CG-CAHPS patient experience surveys augmented by open-ended narrative elicitation questions. STUDY DESIGN: We conducted a cluster quasi-experimental study, comparing 12 intervention and 10 control sites. At control sites, narratives were delivered free-form to site administrators via email; at intervention sites, narratives were delivered online with interactive tools for interpretation, accompanied by user training. We assessed control-versus-intervention site differences in learning, behavior, and patient experience scores. DATA COLLECTION: Staff surveys and interviews were completed at intervention and control sites, 9 months after intervention launch. Patient surveys were collected beginning 4 months pre-launch through 9 months post-launch. We used control-versus-intervention and difference-in-difference analyses for survey data and thematic analysis for interview data. PRINCIPAL FINDINGS: Interviews suggested that the interface facilitated narrative interpretation and use for improvement. Staff survey analyses indicated enhanced learning from narratives at intervention sites (29% over control sites' mean of 3.19 out of 5 across eight domains, p < 0.001) and greater behavior change at staff and practice levels (31% and 21% over control sites' means of 3.35 and 3.39, p < 0.001, respectively). Patient experience scores for interactions with office staff and wait time information increased significantly at intervention sites, compared to control sites (3.7% and 8.2%, respectively); however, provider listening scores declined 3.3%. CONCLUSIONS: Patient narratives presented through structured feedback reporting methods can catalyze positive changes in staff learning, promote behavior change, and increase patient experience scores in domains of non-clinical interaction.

Qualitative Development of the Allergan Satisfaction with Treatment Experience Questionnaire (ASTEQ) Instrument, a Patient-Reported Outcome Measure in Glaucoma and Ocular Hypertension.

INTRODUCTION: Sustained-release intraocular implants provide a therapeutic option for open-angle glaucoma (OAG) and ocular hypertension (OHT) patients who are non-compliant with eyedrops. Currently, there are no published patient-reported outcome (PRO) measures that assess treatment satisfaction with intraocular implants. To address this gap, a new PRO instrument, the Allergan Satisfaction with Treatment Experience Questionnaire (ASTEQ), has been developed in accordance with Food and Drug Administration guidance. METHODS: Qualitative research interviews were conducted among patients with OAG/OHT who had received three intraocular injections of a sustained-release bimatoprost (10 or 15 µg) implant within the clinical trial setting. A preliminary conceptual framework capturing treatment satisfaction concepts in glaucoma, as identified from the literature, was used to develop a semi-structured interview guide. A concept elicitation (CE) interview to identify aspects of the glaucoma treatment experience pertinent to intraocular implants provided content for a draft instrument. A cognitive debriefing (CD) interview to test the instrument's interpretability, relevance, and validity informed its subsequent refinement. Interview analysis followed a grounded theory approach to identify data patterns and relationships. RESULTS: CE interviews (n = 19) indicated that participants' main considerations in rating satisfaction with implant treatment were physical comfort during preparation for the implant and implant administration, anxiety about the procedure, frequency of implant administration, possible side effects, convenience and accessibility of the implant, relationship with the clinician, and lifestyle fit. Draft ASTEQ revision based on CD interviews (n = 20) and readability tests yielded a nine-item ASTEQ instrument comprising satisfaction with overall implant experience and frequency of administration, occurrence/bother of immediate and long-term side effects, worry about implant administration and possible risks/side effects, and physical discomfort during preparation for the implant and implant administration. CONCLUSION: The ASTEQ instrument has demonstrated content validity in patients with OAG/OHT treated with a sustained-release bimatoprost implant. Further research is necessary to evaluate its psychometric properties.

Percutaneous Revascularization for Ischemic Left Ventricular Dysfunction: Cost-Effectiveness Analysis of the REVIVED-BCIS2 Trial.

BACKGROUND: Percutaneous coronary intervention (PCI) is frequently undertaken in patients with ischemic left ventricular systolic dysfunction. The REVIVED (Revascularization for Ischemic Ventricular Dysfunction)-BCIS2 (British Cardiovascular Society-2) trial concluded that PCI did not reduce the incidence of all-cause death or heart failure hospitalization; however, patients assigned to PCI reported better initial health-related quality of life than those assigned to optimal medical therapy (OMT) alone. The aim of this study was to assess the cost-effectiveness of PCI+OMT compared with OMT alone. METHODS: REVIVED-BCIS2 was a prospective, multicenter UK trial, which randomized patients with severe ischemic left ventricular systolic dysfunction to either PCI+OMT or OMT alone. Health care resource use (including planned and unplanned revascularizations, medication, device implantation, and heart failure hospitalizations) and health outcomes data (EuroQol 5-dimension 5-level questionnaire) on each patient were collected at baseline and up to 8 years post-randomization. Resource use was costed using publicly available national unit costs. Within the trial, mean total costs and quality-adjusted life-years (QALYs) were estimated from the perspective of the UK health system. Cost-effectiveness was evaluated using estimated mean costs and QALYs in both groups. Regression analysis was used to adjust for clinically relevant predictors. RESULTS: Between 2013 and 2020, 700 patients were recruited (mean age: PCI+OMT=70 years, OMT=68 years; male (%): PCI+OMT=87, OMT=88); median follow-up was 3.4 years. Over all follow-ups, patients undergoing PCI yielded similar health benefits at higher costs compared with OMT alone (PCI+OMT: 4.14 QALYs, £22 352; OMT alone: 4.16 QALYs, £15 569; difference: -0.015, £6782). For both groups, most health resource consumption occurred in the first 2 years post-randomization. Probabilistic results showed that the probability of PCI being cost-effective was 0. CONCLUSIONS: A minimal difference in total QALYs was identified between arms, and PCI+OMT was not cost-effective compared with OMT, given its additional cost. A strategy of routine PCI to treat ischemic left ventricular systolic dysfunction does not seem to be a justifiable use of health care resources in the United Kingdom. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920048.