Target identification of usnic acid in bacterial and human cells.

Usnic acid is a natural product with versatile biological activities against various organisms. Here, we utilise a chemical proteomic strategy to gain insights into its target scope in bacterial and human cells. First, we excluded DNA binding as a major reason for its antibacterial activity, and second, we commenced with target profiling, which unravelled several metal cofactor-dependent enzymes in both species indicating a polypharmacological mode of action. Interestingly, our synthetic studies revealed a selectivity switch at usnic acid, which maintains antibacterial activity but lacks strong cytotoxic effects.

A Review of the Validity and Reliability of Accelerometer-Based Metrics From Upper Back-Mounted GNSS Player Tracking Systems for Athlete Training Load Monitoring.

ABSTRACT: Dawson, L, Beato, M, Devereux, G, and McErlain-Naylor, SA. A review of the validity and reliability of accelerometer-based metrics from upper back-mounted GNSS player tracking systems for athlete training load monitoring. J Strength Cond Res 38(8): e460-e475, 2024-Athlete load monitoring using upper back-mounted global navigation satellite system (GNSS) player tracking is common within many team sports. However, accelerometer-based load monitoring may provide information that cannot be achieved with GNSS alone. This review focuses on the accelerometer-based metrics quantifying the accumulation of accelerations as an estimation of athlete training load, appraising the validity and reliability of accelerometer use in upper back-mounted GNSS player tracking systems, the accelerometer-based metrics, and their potential for application within athlete monitoring. Reliability of GNSS-housed accelerometers and accelerometer-based metrics are dependent on the equipment model, signal processing methods, and the activity being monitored. Furthermore, GNSS unit placement on the upper back may be suboptimal for accelerometer-based estimation of mechanical load. Because there are currently no feasible gold standard comparisons for field-based whole-body biomechanical load, the validity of accelerometer-based load metrics has largely been considered in relation to other measures of training load and exercise intensity. In terms of convergent validity, accelerometer-based metrics (e.g., PlayerLoad, Dynamic Stress Load, Body Load) have correlated, albeit with varying magnitudes and certainty, with measures of internal physiological load, exercise intensity, total distance, collisions and impacts, fatigue, and injury risk and incidence. Currently, comparisons of these metrics should not be made between athletes because of mass or technique differences or between manufacturers because of processing variations. Notable areas for further study include the associations between accelerometer-based metrics and other parts of biomechanical load-adaptation pathways of interest, such as internal biomechanical loads or methods of manipulating these metrics through effective training design.

Quantitative Magnetic Resonance Imaging (qMRI) of the Small Bowel in Crohn's Disease: State-of-the-Art and Future Directions.

Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract in which repeated episodes of acute inflammation may lead to long-term bowel damage. Cross-sectional imaging is used in conjunction with endoscopy to diagnose and monitor disease and detect complications. Magnetic resonance imaging (MRI) has demonstrable utility in evaluating inflammatory activity. However, subjective interpretation of conventional MR sequences is limited in its ability to fully phenotype the underlying histopathological processes in chronic disease. In particular, conventional MRI can be confounded by the presence of mural fibrosis and muscle hypertrophy, which can mask or sometimes mimic inflammation. Quantitative MRI (qMRI) methods provide a means to better differentiate mural inflammation from fibrosis and improve quantification of these processes. qMRI may also provide more objective measures of disease activity and enable better tailoring of treatment. Here, we review quantitative MRI methods for imaging the small bowel in CD and consider the path to their clinical translation. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Phase I and pharmacodynamic study of arsenic trioxide plus radiotherapy in patients with newly diagnosed glioblastoma.

Background: When arsenic trioxide (ATO) was combined with radiation for treatment of transplanted murine gliomas in the brain, tumor response improved with disrupted tumor blood flow and survival was significantly prolonged. Methods: Total of 31 patients with newly diagnosed glioblastoma were accrued to a multi-institutional, NCI-funded, phase I study to determine the maximum tolerated dose (MTD) of ATO administered with radiation. Secondary objectives were survival and pharmacodynamic changes in perfusion on magnetic resonance imaging (MRI). Patients (unknown MGMT and IDH status) received ATO either once or twice weekly during radiation without concurrent or adjuvant temozolomide. Results: Median age: 54.9 years, male: 68%, KPS ≥ 90: 77%, debulking surgery: 77%. Treatments were well-tolerated: 81% of patients received all the planned ATO doses. Dose-limiting toxicities included elevated liver function tests, hypokalemia, and edema. The MTD on the weekly schedule was 0.4 mg/kg and on the biweekly was 0.3 mg/kg. The median survival (mOS) for all patients was 17.7 months. Survival on the biweekly schedule (22.8 months) was longer than on the weekly schedule (12.1 months) (P = .039) as was progression-free survival (P = .004). Similarly, cerebral blood flow was significantly reduced in patients treated on the biweekly schedule (P = .007). Conclusions: ATO with standard radiation is well tolerated in patients with newly diagnosed glioblastoma. Even without temozolomide or adjuvant therapy, the overall survival of all patients (17.7 months) and especially patients who received biweekly ATO (22.8 months) is surprising and accompanied by pharmacodynamic changes on MRI. Further studies of this regimen are warranted.

Topical Cannabidiol Application May Not Attenuate Muscle Soreness or Improve Performance: A Randomized, Double-Blinded, Placebo-Controlled Pilot Study.

Purpose: The purpose of this pilot study was to investigate cannabidiol (CBD) cream's effects on muscle soreness and performance after exercise. Materials and Methods: This double-blinded, placebo-controlled experiment included 15 men and 13 women (n = 28; mean ± standard deviation age: 23.29 ± 2.54 years) untrained in lower-body resistance training. Participants were randomized into control (NG, n = 9), CBD (CG, n = 9), or placebo (PG, n = 10) groups. Participants completed a lower-body fatigue protocol (FP) consisting of unilateral maximal concentric and eccentric isokinetic muscle actions of the quadriceps and hamstrings (5 sets, 10 repetitions, both legs). CG and PG participants applied ∼100 mg CBD or placebo cream, respectively, matched for weight and appearance to the quadriceps on three separate days. NG participants engaged in a sitting rest period matched in duration to cream application processes. Questionnaires, pressure-pain threshold (PPT), peak torque test (PTT), and countermovement jump (CMJ) were assessed. Mixed-model analysis of variance was conducted to assess main effects and interactions (group × muscle × time; group × time). Results: There were no significant interactions or main effects for group for PPT, CMJ, or PTT. There were main effects for time (p < 0.05) for all soreness questions, PPT, CMJ, and PTT. There was one significant interaction (group × time; p = 0.045) for cream/rest effect questions, in which PG participants perceived the effect of cream to be greater than the effect of rest for NG participants. There were main effects for group (p ≤ 0.031) for all soreness questions, in which PG participants perceived enhanced recovery. Conclusions: The present pilot study did not discover any significant impacts of CBD cream use for muscle recovery. For individuals seeking to attenuate muscle soreness and improve performance, the current dose of this topical CBD product may not be an effective treatment.

A multicenter, phase 1, Adult Brain Tumor Consortium trial of oral terameprocol for patients with recurrent high-grade glioma (GATOR).

Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5 days/month), a transcriptional inhibitor of specificity protein 1 (Sp1)-regulated proteins, is 1,700 mg/day with median area under the plasma concentration-time curve (AUC) of 31.3 µg∗h/mL. Given potentially increased efficacy with sustained systemic exposure and challenging logistics of daily IV therapy, here we investigate oral terameprocol for rHGGs in a multicenter, phase 1 trial (GATOR). Using a 3 + 3 dose-escalation design, we enroll 20 patients, with median age 60 years (range 31-80), 70% male, and median one relapse (range 1-3). Fasting patients tolerate 1,200 mg/day (n = 3), 2,400 mg/day (n = 6), 3,600 mg/day (n = 3), and 6,000 mg/day (n = 2) oral doses without major toxicities. However, increased dosage does not lead to increased systemic exposure, including in fed state (6,000 mg/day, n = 4), with maximal AUC <5 µg∗h/mL. These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential. This study was registered at ClinicalTrials.gov (NCT02575794).

Strategies for DPYD testing prior to fluoropyrimidine chemotherapy in the US.

PURPOSE: Patients with dihydropyrimidine dehydrogenase (DPD) deficiency are at high risk for severe and fatal toxicity from fluoropyrimidine (FP) chemotherapy. Pre-treatment DPYD testing is standard of care in many countries, but not the United States (US). This survey assessed pre-treatment DPYD testing approaches in the US to identify best practices for broader adoption. METHODS: From August to October 2023, a 22-item QualtricsXM survey was sent to institutions and clinicians known to conduct pre-treatment DPYD testing and broadly distributed through relevant organizations and social networks. Responses were analyzed using descriptive analysis. RESULTS: Responses from 24 unique US sites that have implemented pre-treatment DPYD testing or have a detailed implementation plan in place were analyzed. Only 33% of sites ordered DPYD testing for all FP-treated patients; at the remaining sites, patients were tested depending on disease characteristics or clinician preference. Almost 50% of sites depend on individual clinicians to remember to order testing without the assistance of electronic alerts or workflow reminders. DPYD testing was most often conducted by commercial laboratories that tested for at least the four or five DPYD variants considered clinically actionable. Approximately 90% of sites reported receiving results within 10 days of ordering. CONCLUSION: Implementing DPYD testing into routine clinical practice is feasible and requires a coordinated effort among the healthcare team. These results will be used to develop best practices for the clinical adoption of DPYD testing to prevent severe and fatal toxicity in cancer patients receiving FP chemotherapy.

DNA N-glycosylases Ogg1 and EndoIII as components of base excision repair in Plasmodium falciparum organelles.

The integrity of genomes of the two crucial organelles of the malaria parasite - an apicoplast and mitochondrion in each cell - must be maintained by DNA repair mediated by proteins targeted to these compartments. We explored the localisation and function of Plasmodium falciparum base excision repair (BER) DNA N-glycosylase homologs PfEndoIII and PfOgg1. These N-glycosylases would putatively recognise DNA lesions prior to the action of apurinic/apyrimidinic (AP)-endonucleases. Both Ape1 and Apn1 endonucleases have earlier been shown to function solely in the parasite mitochondrion. Immunofluorescence localisation showed that PfEndoIII was exclusively mitochondrial. PfOgg1 was not seen clearly in mitochondria when expressed as a PfOgg1leader-GFP fusion, although chromatin immunoprecipitation assays showed that it could interact with both mitochondrial and apicoplast DNA. Recombinant PfEndoIII functioned as a DNA N-glycosylase as well as an AP-lyase on thymine glycol (Tg) lesions. We further studied the importance of Ogg1 in the malaria life cycle using reverse genetic approaches in Plasmodium berghei. Targeted disruption of PbOgg1 resulted in loss of 8-oxo-G specific DNA glycosylase/lyase activity. PbOgg1 knockout did not affect blood, mosquito or liver stage development but caused reduced blood stage infection after inoculation of sporozoites in mice. A significant reduction in erythrocyte infectivity by PbOgg1 knockout hepatic merozoites was also observed, thus showing that PbOgg1 ensures smooth transition from liver to blood stage infection. Our results strengthen the view that the Plasmodium mitochondrial genome is an important site for DNA repair by the BER pathway.

Intraoperative hemodialysis with supra- and infradiaphragmatic catheters for liver transplantation.

PURPOSE: The benefits of intraoperative dialysis during orthotopic liver transplantation remain controversial. In patients with anuric renal failure and portopulmonary hypertension, maintaining venous return during caval clamping and unclamping along with minimizing fluid overload is critical to avoiding right ventricular strain and failure. CLINICAL FEATURES: We present the case of a 54-yr-old female who underwent orthotopic liver transplantation for alcohol-related liver disease with acute decompensation including severe hepatorenal syndrome (anuric requiring dialysis), probable hepatopulmonary syndrome, moderate pulmonary hypertension (right ventricular systolic pressure, 44 mm Hg), hepatic encephalopathy (grade 2), and esophageal varices. Prior to incision, pulmonary arterial pressures were 48/28 (mean, 35) mm Hg with a central venous pressure of 30 mm Hg, cardiac output of 7.4 L·min-1, and pulmonary vascular resistance of 98 dynes·sec·cm-5. In the context of right ventricular strain and volume overload observed on transthoracic echocardiography, we inserted an additional dialysis catheter into the right femoral vein. We initiated dialysis using the two catheters as a circuit (femoral line to the dialysis machine; blood was reinjected via the subclavian line) acting as a limited venovenous bypass, allowing right ventricular offloading and hemodialysis throughout the case. We removed 4.5 L via hemodialysis during the surgery, while avoiding acidosis, hyperkalemia, and sodium shifts. The patient tolerated reperfusion adequately despite pre-existing right ventricular dilation and dysfunction. CONCLUSION: We report on the use two hemodialysis catheters in a patient undergoing orthotopic liver transplantation as a circuit for simultaneous anuric hepatorenal syndrome and moderate pulmonary hypertension with right ventricular dilation and dysfunction. We believe this technique was instrumental in the patient's successful transplant.

RéSUMé: OBJECTIF: Les avantages de la dialyse peropératoire pendant une transplantation hépatique orthotopique demeurent controversés. Chez la patientèle atteinte d'insuffisance rénale anurique et d'hypertension portopulmonaire, il est essentiel de maintenir le retour veineux pendant le clampage et le déclampage de la veine cave ainsi que de minimiser la surcharge hydrique, afin d'éviter la déformation et l'insuffisance ventriculaires droites. CARACTéRISTIQUES CLINIQUES : Nous présentons le cas d'une femme de 54 ans qui a bénéficié d'une transplantation hépatique orthotopique pour une maladie hépatique liée à l'alcool avec une décompensation aiguë comprenant un syndrome hépatorénal sévère (anurie nécessitant une dialyse), un syndrome hépatopulmonaire probable, une hypertension pulmonaire modérée (pression systolique ventriculaire droite, 44 mm Hg), une encéphalopathie hépatique (grade 2) et des varices œsophagiennes. Avant l'incision, les pressions artérielles pulmonaires étaient de 48/28 (moyenne, 35) mm Hg avec une pression veineuse centrale de 30 mm Hg, un débit cardiaque de 7,4 L·min−1 et une résistance vasculaire pulmonaire de 98 dynes·sec·cm−5. Dans le contexte de la déformation ventriculaire et de la surcharge volémique droites observées à l'échocardiographie transthoracique, nous avons inséré un cathéter de dialyse supplémentaire dans la veine fémorale droite. Nous avons amorcé la dialyse en créant un circuit avec les deux cathéters (ligne fémorale en direction de l'appareil de dialyse; sang réinjecté via la ligne sous-clavière) agissant comme un pontage veino-veineux limité, permettant la décharge du ventricule droit et l'hémodialyse tout au long du cas. Nous avons retiré 4,5 L par hémodialyse pendant la chirurgie, tout en évitant l'acidose, l'hyperkaliémie et les changements en sodium plasmatique. La patiente a toléré la reperfusion de manière adéquate malgré la dilatation et le dysfonctionnement préexistants du ventricule droit. CONCLUSION: Nous rapportons l'utilisation de deux cathéters d'hémodialyse pour créer un circuit chez une patiente bénéficiant d'une transplantation hépatique orthotopique pour le traitement d'un syndrome hépatorénal anurique simultané à une hypertension pulmonaire modérée avec dilatation et dysfonctionnement du ventricule droit. Nous pensons que cette technique a joué un rôle déterminant dans la réussite de la greffe chez la patiente.

Perioperative research into memory (PRiMe), part 2: Adult burns intensive care patients show altered structure and function of the default mode network.

BACKGROUND: Long-term cognitive impairment (LTCI) is experienced by up to two thirds of patients discharged from burns intensive care units (BICUs), however little is known about its neurobiological basis. This study investigated if patients previously admitted to BICU showed structural and functional MRI changes of the Default Mode Network (DMN). METHODS: Fifteen patients previously admitted to BICU with a significant burns injury, and 15 matched volunteers, underwent structural and functional MRI scans. Functional connectivity, fractional anisotropy and cortical thickness of the main DMN subdivisions (anterior DMN (aDMN), posterior DMN (pDMN) and right (rTPJ) and left (lTPJ) temporo-parietal junctions) were compared between patients and volunteers, with differences correlated against cognitive performance. RESULTS: Functional connectivity between rTPJ and pDMN (t = 2.91, p = 0.011) and between rTPJ and lTPJ (t = 3.18, p = 0.008) was lower in patients compared to volunteers. Functional connectivity between rTPJ and pDMN correlated with cognitive performance (r2 =0.33, p < 0.001). Mean fractional anisotropy of rTPJ (t = 2.70, p = 0.008) and lTPJ (T = 2.39, p = 0.015) was lower in patients but there was no difference in cortical thickness. CONCLUSIONS: Patients previously admitted to BICU show structural and functional disruption of the DMN. Since functional changes correlate with cognitive performance, this should direct further research into intensive-care-related cognitive impairment.

Detection of the benzodiazepine bromazolam by liquid chromatography with quadrupole time of flight mass spectrometry in postmortem toxicology casework and prevalence in Indiana (2023).

For the past 60 years, benzodiazepines such as chlordiazepoxide, diazepam, and alprazolam have been used as pharmaceutical medications for the treatment of myriad conditions including anxiety, seizures, and insomnia. In more recent years, novel benzodiazepine derivatives have emerged as illicit substances in powders and counterfeit tablets on the illicit drug market. In 2016, bromazolam, a brominated derivative of alprazolam, emerged on the illicit drug market in Europe, but the substance was not reported in the USA until 2019-2020. In this study, we report the emergence and subsequent prevalence of bromazolam in postmortem blood in the state of Indiana during 2023. Analysis was completed by a solvent protein precipitation extraction with acetonitrile and detection by liquid chromatography with quadrupole time of flight mass spectrometry. During 2023, bromazolam was detected in 94 cases across 25 counties in Indiana. It was never the sole substance detected and was commonly detected alongside fentanyl (83 cases), norfentanyl (77 cases), 4-anilino-N-phenethylpiperidine (76 cases), acetylfentanyl (49 cases), methamphetamine (32 cases), naloxone (25 cases), 11-nor-9-carboxy-tetrahydrocannabinol (24 cases), and benzoylecgonine (20 cases). After official query with the Indiana Department of Health, it was found that bromazolam was specifically included in the cause of death certification in 31 fatalities (32.9%). Due to the scarcity of information regarding this novel benzodiazepine derivative in postmortem toxicology and its involvement in fatalities, it is important that forensic toxicology laboratories consider adding bromazolam to their comprehensive scope of analysis.

Evaluating the Base Excision Repair Inhibitor TRC102 and Temozolomide for patients with Recurrent Glioblastoma in the Phase 2 Adult Brain Tumor Consortium Trial BERT.

PURPOSE: Patients with glioblastoma (GBM) have a dismal prognosis. While DNA alkylating agent temozolomide (TMZ) is mainstay of chemotherapy, therapeutic resistance develops rapidly in patients. Base excision repair inhibitor TRC102 (methoxyamine) reverses TMZ resistance in preclinical glioma models. We sought to investigate efficacy and safety of oral TRC102+TMZ for recurrent GBM (rGBM). PATIENTS AND METHODS: A pre-registered (NCT02395692), non-randomized, multicenter, phase 2 clinical trial (BERT) was planned and conducted through the Adult Brain Tumor Consortium (ABTC-1402). Arm 1 included bevacizumab-naïve GBM patients at first recurrence, with primary endpoint of response rates. If sufficient activity was identified, a second arm was planned in bevacizumab-refractory patients. Secondary endpoints were overall survival (OS), progression-free survival (PFS), PFS at six months (PFS-6), and toxicity. RESULTS: Arm 1 enrolled 19 patients with median of two treatment cycles. Objective responses were not observed, hence, arm 2 did not open. Median OS was 11.1 months (95%CI 8.2-17.9). Median PFS was 1.9 months (95%CI 1.8-3.7). PFS-6 was 10.5% (95%CI 1.3-33.1%). Most toxicities were Grade 1-2, with two Grade 3 lymphopenias and one Grade 4 thrombocytopenia. Two patients with PFS ≥17 months and OS >32 months were deemed 'extended survivors'. RNA sequencing of tumor tissue, obtained at diagnosis, demonstrated significantly enriched signatures of DNA damage response (DDR), chromosomal instability (CIN70, CIN25), and cellular proliferation (PCNA25) in 'extended survivors'. CONCLUSIONS: These findings confirm safety and feasibility of TRC102+TMZ for rGBM patients. They also warrant further evaluation of combination therapy in biomarker-enriched trials enrolling GBM patients with baseline hyperactivated DDR pathways.

Multivariable prognostic modelling to improve prediction of colorectal cancer recurrence: the PROSPeCT trial.

OBJECTIVE: Improving prognostication to direct personalised therapy remains an unmet need. This study prospectively investigated promising CT, genetic, and immunohistochemical markers to improve the prediction of colorectal cancer recurrence. MATERIAL AND METHODS: This multicentre trial (ISRCTN 95037515) recruited patients with primary colorectal cancer undergoing CT staging from 13 hospitals. Follow-up identified cancer recurrence and death. A baseline model for cancer recurrence at 3 years was developed from pre-specified clinicopathological variables (age, sex, tumour-node stage, tumour size, location, extramural venous invasion, and treatment). Then, CT perfusion (blood flow, blood volume, transit time and permeability), genetic (RAS, RAF, and DNA mismatch repair), and immunohistochemical markers of angiogenesis and hypoxia (CD105, vascular endothelial growth factor, glucose transporter protein, and hypoxia-inducible factor) were added to assess whether prediction improved over tumour-node staging alone as the main outcome measure. RESULTS: Three hundred twenty-six of 448 participants formed the final cohort (226 male; mean 66 ± 10 years. 227 (70%) had ≥ T3 stage cancers; 151 (46%) were node-positive; 81 (25%) developed subsequent recurrence. The sensitivity and specificity of staging alone for recurrence were 0.56 [95% CI: 0.44, 0.67] and 0.58 [0.51, 0.64], respectively. The baseline clinicopathologic model improved specificity (0.74 [0.68, 0.79], with equivalent sensitivity of 0.57 [0.45, 0.68] for high vs medium/low-risk participants. The addition of prespecified CT perfusion, genetic, and immunohistochemical markers did not improve prediction over and above the clinicopathologic model (sensitivity, 0.58-0.68; specificity, 0.75-0.76). CONCLUSION: A multivariable clinicopathological model outperformed staging in identifying patients at high risk of recurrence. Promising CT, genetic, and immunohistochemical markers investigated did not further improve prognostication in rigorous prospective evaluation. CLINICAL RELEVANCE STATEMENT: A prognostic model based on clinicopathological variables including age, sex, tumour-node stage, size, location, and extramural venous invasion better identifies colorectal cancer patients at high risk of recurrence for neoadjuvant/adjuvant therapy than stage alone. KEY POINTS: Identification of colorectal cancer patients at high risk of recurrence is an unmet need for treatment personalisation. This model for recurrence, incorporating many patient variables, had higher specificity than staging alone. Continued optimisation of risk stratification schema will help individualise treatment plans and follow-up schedules.

A global consensus on the definitions, diagnosis and management of fibrostenosing small bowel Crohn's disease in clinical practice.

Fibrostenosis of the small bowel is common in patients with Crohn's disease. No consensus recommendations on definition, diagnosis and management in clinical practice are currently available. In this Consensus Statement, we present a clinical practice RAND/UCLA appropriateness study on the definition, diagnosis and clinical management of fibrostenosing Crohn's disease. It was conducted by a panel of 28 global experts and one patient representative. Following a systematic literature review, 526 candidate items grouped into 136 questions were generated and subsequently evaluated for appropriateness. Strictures are best defined as wall thickening, luminal narrowing and prestenotic dilation. Cross-sectional imaging is required for accurate diagnosis of fibrostenosing Crohn's disease, and it is recommended before making treatment decisions. It should also assess the degree of inflammation in the bowel wall. Multiple options for medical anti-inflammatory, endoscopic and surgical therapies were suggested, including follow-up strategies following therapy. This Consensus Statement supports clinical practice through providing guidance on definitions, diagnosis and therapeutic management of patients with fibrostenosing small bowel Crohn's disease.

Identifying research priorities for improving information and support for patients undergoing breast cancer surgery: a UK patient-centred priority setting project.

PURPOSE: To use robust consensus methods with individuals with lived breast cancer experience to agree the top 10 research priorities to improve information and support for patients undergoing breast cancer surgery in the UK. METHODS: Research uncertainties related to information and support for breast cancer surgery submitted by patients and carers were analysed thematically to generate summary questions for inclusion in an online Delphi survey. Individuals with lived breast cancer experience completed two Delphi rounds including feedback in which they selected their top 10 research priorities from the list provided. The most highly ranked priorities from the survey were discussed at an in-person prioritisation workshop at which the final top 10 was agreed. RESULTS: The 543 uncertainties submitted by 156 patients/carers were categorised into 63 summary questions for inclusion in the Delphi survey. Of the 237 individuals completing Round 1, 190 (80.2%) participated in Round 2. The top 25 survey questions were carried forward for discussion at the in-person prioritisation workshop at which 17 participants from across the UK agreed the final top 10 research priorities. Key themes included ensuring patients were fully informed about all treatment options and given balanced, tailored information to support informed decision-making and empower their recovery. Equity of access to treatments including contralateral mastectomy for symmetry was also considered a research priority. CONCLUSION: This process has identified the top 10 research priorities to improve information and support for patients undergoing breast cancer surgery. Work is now needed to develop studies to address these important questions.

Stacking Fault-Enriched MoNi4/MoO2 Enables High-Performance Hydrogen Evolution.

Producing green hydrogen in a cost-competitive manner via water electrolysis will make the long-held dream of hydrogen economy a reality. Although platinum (Pt)-based catalysts show good performance toward hydrogen evolution reaction (HER), the high cost and scarce abundance challenge their economic viability and sustainability. Here, a non-Pt, high-performance electrocatalyst for HER achieved by engineering high fractions of stacking fault (SF) defects for MoNi4/MoO2 nanosheets (d-MoNi) through a combined chemical and thermal reduction strategy is shown. The d-MoNi catalyst offers ultralow overpotentials of 78 and 121 mV for HER at current densities of 500 and 1000 mA cm-2 in 1 M KOH, respectively. The defect-rich d-MoNi exhibits four times higher turnover frequency than the benchmark 20% Pt/C, together with its excellent durability (> 100 h), making it one of the best-performing non-Pt catalysts for HER. The experimental and theoretical results reveal that the abundant SFs in d-MoNi induce a compressive strain, decreasing the proton adsorption energy and promoting the associated combination of *H into hydrogen and molecular hydrogen desorption, enhancing the HER performance. This work provides a new synthetic route to engineer defective metal and metal alloy electrocatalysts for emerging electrochemical energy conversion and storage applications.