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Gaurav P Patel, Susan A Smith, Michelle Romej, Billynda McAdoo, Elizabeth A Wilson Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USACorrespondence: Gaurav P Patel, Department of Anesthesiology, Emory University School of Medicine, 1364 Clifton Road, NE, Atlanta, GA, 30322, USA, Tel +1 404-778-3900, Email gppatel@emory.eduAbstract: Hypotension during kidney transplantation can be common. Vasopressor use during these procedures is often avoided, with a fear of decreasing renal perfusion in the transplanted kidney. However, adequate perfusion for the rest of the body is also necessary, and given that these patients often have underlying hypertension or other comorbid conditions, an appropriate mean arterial pressure (MAP) has to be maintained. Intramuscular injections of ephedrine have been studied in the anesthesiology literature in a variety of case types, and it is seen as a safe and effective method to boost MAP. We present a case series of three patients who underwent renal transplantation and who received an intramuscular injection of ephedrine for hypotension control. The medication worked well for increasing blood pressures without apparent side effects. All three patients were followed for more than one year, and all patients had good graft function at the end of that time period. This series shows that while further research is necessary in this arena, intramuscular ephedrine may have a place in the management of persistent hypotension in the operating room during kidney transplantation.Keywords: kidney transplant, hypotension, general anesthesia, intramuscular ephedrine, perfusion pressure

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. We present a silica nanoparticle (SNP) functionalized with polyphosphate (polyP) that accelerates the natural clotting process of the body. SNPs initiate the contact pathway of the blood-clotting system; short-chain polyP accelerates the common pathway by the rapid formation of thrombin, which enhances the overall blood-clotting system, both by accelerating fibrin generation and by facilitating the regulatory anticoagulation mechanisms essential for hemostasis. Analysis of the clotting properties of bare SNPs, bare polyP, and polyP-functionalized SNPs in plasma demonstrated that the attachment of polyP to SNPs to form polyP-SNPs creates a substantially enhanced synergistic effect that lowers clotting time and increases thrombin production at low concentrations. PolyP-SNP even retains its clotting function at ambient temperature. The polyP-SNP system has the potential to significantly improve trauma-treatment protocols and outcomes in hospital and prehospital settings.

The enormous composition possibilities and the potential of developing alloys with improved properties have resulted in a spike in research interest in the area of high entropy alloys (HEAs) since 2010. Being multicomponent alloys with five or more metallic elements mixed in equimolar or non-equimolar ratio, HEAs offer limitless possibilities in the development of new alloys with unique properties as compared to the conventional alloys development techniques that involve the addition of one or more alloying elements in minute quantity to the principal element. Despite the tremendous interest in the field of HEAs and the development of new HEAs with unique properties, a comprehensive review of the effects of fabrication techniques on the mechanical properties of the developed alloys is still limited in the open literature. Hence, an attempt was made in this review to show the different techniques used in the manufacturing and synthesizing of HEAs and the effects of the used techniques on the mechanical properties of the alloys. Finally, some of the major challenges associated with the manufacturing and synthesizing of HEAs are reported.

This review paper encompasses a comprehensive exploration of fatigue failure and fatigue life estimation techniques which spans from the classical methods to new and innovative approaches. The paper looks into the limitations and advancements of these techniques and highlights their respective strengths and areas for improvement. Some of the models such as artificial neural networks and genetic algorithms exhibit clear advantages in terms of processing speed, accuracy, and adaptability to diverse materials and loading scenarios. For instance, in estimating fatigue life under multiaxial loading, the stress scale factor model emerges as a viable alternative to the critical plane-based approach, as this technique offers superior efficiency under both constant and variable amplitude loadings. Additionally, optimization algorithms such as artificial neural networks and genetic algorithms show promising potential in efficiently estimating fatigue life due to their rapid computational capabilities. Despite the notable successes achieved by these techniques, none of them can be ascribed as a universal model capable of accurately estimating the fatigue life of all materials across diverse operating conditions as each of the techniques possesses its unique strengths and weaknesses, thus, necessitating the study for a better understanding of their applicability. Hence, this paper serves as a valuable compilation of various fatigue analysis techniques, targeted at paving the way towards the development of a universal model capable of handling different materials and loading conditions.

Investigating the structural behaviour and buckling susceptibility of cylindrical oil storage tanks is crucial for ensuring their safe and reliable operation. In this study, the structural behaviour and buckling susceptibility of closed roof-top cylindrical oil storage tanks under combined internal and external pressure scenarios were investigated using the finite element analysis (FEA) technique. By utilizing the FEA technique, the combined effect of wind-induced pressure of 250 Pa, applied on the outer surface of the tank and internal pressure of 0.5 MPa, applied on the outer surface of the storage was analysed. The result reveals significant stress concentrations and deformation patterns, particularly on the windward side of the tank, thus, emphasizing the susceptibility of the storage tank to buckling under the specified operating conditions for both the filled and half-filled tank; with internal pressure emerging as the primary contributor to mechanical strain and deformation experienced in the tank, while the wind load plays a secondary but significant role in the deformation of the tank. The fe-safe predicted useful life shows that under the specified operating conditions, the filled storage tank will survive 1 429 hours (2 months) while the half-filled tank will survive 3 551 hours (5 months) before failure due to buckling. Thus, the useful life estimation results show the importance of varying oil levels and operating conditions in the structural assessments of storage tanks.

Spark plasma sintering (SPS) technique was employed in the consolidation of Cr20Mn20Ni20Cu20Nb10Co10 high entropy alloy (HEA) reinforced aluminium matrix composites. Phase stability and prediction expressions were used in the determination of the powder combination for the HEA. The microstructural analysis showed that an interdiffusion layer was formed between the aluminium matrix and the HEA particles in the sintered composites. Further investigation of the composites by X-ray diffraction (XRD) showed that in addition to the Al matrix phase present, other new phases (BCC, FCC and other intermetallics) were formed as a result of the reaction between the Al matrix and the atoms precipitated from the added HEA during sintering. The density of the HEA-reinforced Al matrix composites decreases with an increase in the wt.% of HEA from 98.6 % for pure aluminium to 98.1 % for the reinforced alloy with 10 % HEA, while the microhardness increases with an increase in the wt.% of the HEA from 35 HV for pure aluminium to 96.0 HV for the alloy reinforced with 10 % HEA.

While IN738 Ni-based superalloy is a high strength alloy, it is feasible to improve its properties at the bulk level by reinforcing with graphene nanoplatelets (GNPs), taking advantage of the superior mechanical, tribological and thermal properties using the spark plasma sintering technique. In the present study, the influence of spark plasma sintering temperature range between 900 and 1100 °C on the microstructure, mechanical, tribological and thermophysical properties of GNPs/IN738 composite is assessed. The dispersion of GNPs reinforcement and alloying metals to form composite powder is conducted using a turbular mixer and low-frequency planetary ball milling, followed by spark plasma sintering. The relative density of the sintered samples assessed following Archimedes' method indicates increasing densification with the increasing sintering temperature from 94.7% (900 °C) to 98.5% (1100 °C). The microstructure assessed via SEM, XRD and Raman spectroscopy indicates the formation of precipitate gamma, intermetallic gamma prime, solid solution and GNPs strengthening phases. Thus, the mechanical (micro/nano hardness and Young's modulus), tribological (wear rate and coefficient of friction), and thermophysical (thermal diffusivity, thermal conductivity, and specific heat capacity) properties increased with the increasing sintering temperature. The microhardness increased from 354HV (900 °C) to 469HV (1100 °C), nanohardness from 8 GPa (900 °C) to 17 GPa (900 °C), and Young's modulus from 190 GPa (900 °C) to 291 GPa (1100 °C). The wear rate reduced with an increase in sintering temperature for the three loads of 5, 10 and 20N. The thermophysical properties assessed from 25 to 600 °C show the formation of few inflection points as the temperature increases, which is attributed to the dissolution and rearrangement of precipitate gamma prime and Cr in solid solution phases. Similarly, the small increment in the thermal diffusivity is equally associated with the smoother phonon transition at the GNPs/matrix interface.

Background Peripheral arterial disease is common and associated with increased cardiovascular morbidity and mortality. While patients with peripheral arterial disease are known to benefit from supervised exercise therapy, it is not always available. Neuromuscular electrical stimulation devices may offer a similar benefit. A randomised controlled trial was required to ascertain whether such devices can benefit patients who receive supervised exercise therapy and those who do not. Objective(s) The primary objective was to assess the mean difference in absolute walking distance at 3 months in intermittent claudication patients receiving either a neuromuscular electrical stimulation device and local standard care (intervention), or local standard care alone (control). Design A pragmatic, multicentre, randomised controlled trial stratified by centre. Setting Secondary-care National Health Service hospitals in the United Kingdom. Participants Patients aged ≥18 years, with a diagnosis of intermittent claudication according to the Edinburgh Claudication Questionnaire and ankle–brachial pressure index (or stress test), without contraindications to neuromuscular electrical stimulation were deemed eligible to partake. Interventions Participants were randomised 1 : 1 to either local standard care or local standard care and neuromuscular electrical stimulation. Due to the nature of the intervention, it was unfeasible to blind the research nurse or participant to the study allocation. Main outcome measures The primary outcome measure was absolute walking distance measured by treadmill testing at 3 months. Secondary outcomes included change in initial claudication distance, quality of life, compliance with interventions and haemodynamic assessments. Results Two hundred patients underwent randomisation, with 160 patients having analysable primary outcome data for the intention-to-treat analysis intervention (n = 80); control (n = 80). As the data were right-censored, a Tobit regression model was used to analyse the primary outcome, utilising the square root of the absolute walking distance to accommodate the skewed data. However, as this made the data difficult to interpret, a Tobit regression model using raw absolute walking distance data was used as well. Neuromuscular electrical stimulation improved the difference in absolute walking distance at 3 months but this was not statistically significant (square root of absolute walking distance: 0.835 units, 95% confidence interval −0.67 to 2.34 units; p = 0.28/absolute walking distance raw data: 27.18 m, 95% confidence interval −26.92 to 81.28 m; p = 0.323). Supervised exercise therapy participants showed a markedly improved absolute walking distance compared with patients receiving best medical therapy only at 3 months (square root of absolute walking distance: 3.295 units 95% confidence interval 1.77 to 4.82; p < 0.001/absolute walking distance raw data: 121.71 m, 95% confidence interval 67.32 to 176.10; p ≤ 0.001). Neuromuscular electrical stimulation significantly improved absolute walking distance at 3 months for mild claudicants (square root of absolute walking distance: 2.877 units, 95% confidence interval 0.51 to 5.25; p = 0.019/absolute walking distance raw data: 120.55 m, 95% confidence interval 16.03 to 225.06; p = 0.03) compared to the control arm. This was an unplanned (post hoc) analysis. There were no clear differences in mechanistic measurements between the two treatment groups over the follow-up period. Serious adverse events were evenly reported between the two groups; all being classified as either not related or unlikely to be related to the study device. Limitations Absolute walking distance was used as the primary outcome measure; there was a large range of baseline distances in both groups with right-skewed distribution. We did not stratify by baseline absolute walking distance for the primary outcome analysis. Additionally, only 160 patients had analysable primary outcome data due to missing treadmill data. Conclusions Supervised exercise therapy is an effective treatment for intermittent claudication. Neuromuscular electrical stimulation appears to be beneficial as an adjunct to supervised exercise therapy and on its own in mild claudicants. Future work Further studies are needed to confirm the effectiveness of neuromuscular electrical stimulation in combination with supervised exercise therapy, and in mild to moderate claudicants in a larger sample size. Study registration This trial is registered as ISRCTN18242823. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health and Care Research (NIHR) partnership (project number 15/180/68). This will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 2. See the NIHR Journals Library website for further project information. Infrastructure support for this research was provided by the NIHR Imperial Biomedical Research Centre (BRC) (with others, e.g. NIHR Imperial CRF, Imperial College ECMC, NIHR Imperial PSTRC, NIHR London MIC, etc.). Plain language summary Why did we conduct this research? Patients with intermittent claudication present with pain in the lower limbs on exercising, relieved by rest. This negatively impacts on exercise tolerance and quality of life. Initially, such patients should be offered best medical therapy, including exercise advice, and a supervised exercise therapy programme. Supervised exercise therapy involves leg and feet exercises supervised by health-care professionals and, despite evidence favouring supervised versus unsupervised exercise, are underutilised in the United Kingdom. Therefore, there remains a significant difference between recommended standard care (best medical therapy and supervised exercise therapy) and ‘real-world’ standard care (best medical therapy only). Neuromuscular electrical stimulation devices have emerged as safe, portable and readily accessible, with some evidence suggesting they can improve outcomes, including pain-free walking distance and quality of life. This study investigated whether a neuromuscular electrical stimulation device improved the walking distance of patients with intermittent claudication compared to local standard care available (which may include supervised exercise therapy). What did we do? Two hundred patients diagnosed with intermittent claudication at 11 hospitals in England took part. A computer program randomly assigned half the patients to local standard care only, while the other half were given a neuromuscular electrical stimulation device which delivers electrical stimulation to leg and feet muscles through foot-pads, plus local standard care. What did we find? There was no clear difference in maximal walking distances between those who received a device and those who didn’t. However, neuromuscular electrical stimulation improved walking distances in patients who attended a supervised exercise therapy programme (although not significant), and clearly improved walking distances in those patients with a good baseline upper walking limit. Supervised exercise therapy significantly improved walking distances. What could be done next? Future research studies should further evaluate the effectiveness of neuromuscular electrical stimulation in combination with supervised exercise therapy, and in patients who have a good baseline walking distance in a larger sample of patients with intermittent claudication. Scientific summary Background Peripheral arterial disease (PAD) is a common condition that is predominantly caused by atherosclerosis, resulting in a reduced blood flow to the affected limb. It presents a significant global health burden, affecting over 200 million people worldwide. These individuals are at higher risk of other cardiovascular events and PAD itself has its own associated sequelae – for example, ulcer development. Intermittent claudication (IC) is the commonest symptom of PAD, patients experiencing leg pain while walking which is relieved by rest. This has a significant impact on exercise tolerance and quality of life. According to National Institute for Health and Care Excellence guidelines, all patients suffering from IC should receive both first-line treatment of best medical therapy (BMT) (including exercise advice) and supervised exercise therapy (SET). SET is known to significantly improve absolute walking distance (AWD) in IC patients but despite these guidelines, recommended care for the first-line management of claudication is significantly below standard, largely due to lack of National Health Service capability. Without a demonstrable benefit of non-invasive strategies for the management of IC, there is an increased likelihood of invasive treatment options. Neuromuscular electrical stimulation (NMES) is an emerging technology and such devices are readily accessible and can be used in the patient’s own home. Although some evidence of the efficacy of NMES in the management of patients with IC exists, in improving both functional and quality-of-life measures, further high-quality research is required. The NESIC (A Multicenter Randomised Controlled Study: Does Neuromuscular Electrical Stimulation Improve the Absolute Walking Distance in Patients with Intermittent Claudication (NESIC) compared to best available treatment?) study provides an evidence base for the efficacy of the REVITIVE IXTM (Actegy Health Ltd, Bracknell, UK) device in the non-invasive management of claudicants and assesses the cost-effectiveness of the device compared to SET. Objectives (list of research questions) 1.Primary objective: To assess the clinical efficacy of a NMES device as an adjunct to the local standard care available at the study randomisation sites to improve AWD in patients with IC. 2.Secondary objectives: a.To understand the underlying mechanisms for change in clinical and subjective outcomes in the form of lower-limb gross (duplex ultrasound) and superficial haemodynamic assessment (laser doppler flowmetry) b.To determine compliance with NMES device and SET programme c.To compare quality of life between those receiving local standard care alone and those receiving both local standard care and NMES d.To assess the actual cost-effectiveness of the NMES device compared to SET. Methods Design A multicentre, pragmatic, randomised clinical trial to compare the mean difference in AWD in patients with IC who are given NMES in addition to local standard care and those receiving local standard care only. Setting Eleven secondary-care NHS hospitals across England; a combination of centres with and without established provision of SET. Participants Between March 2018 and 17 March 2020, 200 participants were randomised into the NESIC trial. Follow-up was completed on 31 March 2021. Written informed consent was obtained from all participants, who then underwent eligibility assessments. Participants, as defined by the inclusion and exclusion criteria, were randomised 1 : 1 to either local standard care alone (standard care), or NMES and local standard care (intervention). Inclusion criteria •positive Edinburgh Claudication Questionnaire •ankle–brachial pressure index 30 mmHg, 40 seconds post 1 minute treadmill at 10% gradient, 4 km/hour) •able to give informed consent to participate in the trial after reading the patient information documentation •age ≥18 years. Exclusion criteria •severe IC requiring invasive intervention as determined by the treating clinician •critical limb ischaemia as defined by the European Consensus Document •comorbid disease prohibiting walking on a treadmill or taking part in SET •able to walk for longer than 15 minutes on the study treadmill assessment •have attended SET classes in the previous 6 months •popliteal entrapment syndrome •commenced vascular-symptom-specific medication in previous 6 months – for example, naftidrofuryl oxalate, cilostazol •pregnancy •any implanted electronic, cardiac or defibrillator device •acute deep vein thrombosis •broken or bleeding skin, including leg ulceration •peripheral neuropathy •recent lower-limb injury or lower back pain •already using a NMES device. Randomisation Randomisation (1 : 1) was web-based and hosted by Oracle Health Sciences InForm™ (Oracle®; Health Sciences, Austin, TX, USA) electronic data capture on an Oracle platform. Randomisation used random block size and was stratified by centres. Interventions The NMES device (REVITIVE IX) can be used in the patient’s own home. It delivers a 30-minute pre-programmed session of electrical stimulation to the lower-limb muscles through foot pads while the patient is in a seated position. The user controls the intensity of the impulses, and therapeutic benefit is deemed to occur when impulses are sufficient to cause contraction of the calf muscles, increasing venous return to the heart. The IsoRocker feature allows the device to tilt back and forth as the muscles contract and relax. The device is to be used for at least one 30-minute session daily (up to a maximum of six sessions) for 3 months (treatment period). Diabetic patients are to use the device for a minimum of two 30-minute sessions daily for the duration of the treatment period to better reflect the evidence supporting the diabetic patient group and improvement of their symptoms. A SET programme is usually led by a physiotherapist or allied health-care provider supervising exercise, usually within the physiotherapy gymnasium with equipment including a treadmill, steps and walking cones. SET classes usually involve a circuit of lower-limb exercises, for a minimum of 30 minutes per week, and usually over a 3-month duration. Outcomes and follow-up The primary outcome was AWD at 3 months, measured by treadmill testing. Secondary outcomes included quality of life over 12 months as measured by generic health-related quality of life tools, European Quality of Life 5-Dimensions 5-Level (EQ-5D-5L®) (EuroQol Group, Rotterdam, The Netherlands), Short-Form Health Survey-36 (SF-36®) (RAND Health Care, Santa Monica, CA, USA) and the intermittent claudication questionnaire; compliance with NMES and SET as measured against self-report participant diaries and device data loggers; change in initial claudication distance measured by treadmill testing; and haemodynamic assessments measured by duplex ultrasound and laser doppler flowmetry. Participants in both groups were followed up for 12 months post randomisation. In-person visits were performed at screening/baseline (randomisation), 3 months, 6 months and 12 months. The treadmill assessment (Gardner-Skinner protocol) and laser doppler flowmetry of the foot were completed at each visit and the duplex ultrasound was performed by a vascular scientist at baseline and 3 months only. Self-report health resource-use participant diaries were completed throughout the 12-month duration of the study. Additionally, the self-report exercise diaries were completed by all participants for 3 months or for the duration of the SET programme, and the device compliance diaries were completed by participants randomised to NMES for the duration of the treatment period. A device experience questionnaire was completed at 3 months for participants in the NMES arm of the trial. The quality-of-life questionnaires were administered at baseline and each follow-up either in person, via the telephone or via post. Participant follow-up is summarised in Appendix 1. Due to the COVID-19 crisis, a substantial amendment was submitted to Ethics in April 2020 to allow all follow-up visits to take place remotely (i.e. over the telephone completely or in combination with postal questionnaires) in the event that the participant was unable to attend in clinic or the site was unable to accommodate the on-site visit. Missed (physical) assessments as a result of a remote visit were rescheduled at a later date as a separate on-site visit, where possible. If an on-site visit was rescheduled at a later date, all quality-of-life questionnaires that were completed remotely were repeated at the on-site visit. Results (research findings) Two hundred participants underwent randomisation and 160 were included in the intention-to-treat primary analysis [intervention (n = 80); control (n = 80)]. NMES improved AWD in patients with IC following the 3-month treatment period but this was not statistically significant [square root of AWD: 0.835 units, 95% confidence interval (CI) −0.67 to 2.34; p = 0.276/AWD raw data: 27.18 m, 95% CI −26.92 to 81.28; p = 0.323]. Participants who had access to a SET programme showed a clear improvement in AWD compared with patients who received BMT only at 3 months (square root of AWD: 3.295 units, 95% CI 1.77 to 4.82; p < 0.001/AWD raw data: 121.1 m, 95% CI 67.32 to 176.10; p < 0.001). Improvements in the AWD at 3 months were seen when NMES was used in combination with SET, but this was not significant (square root of AWD: 1.724 units, 95% CI −0.56 to 4.01; p = 0.137/AWD raw data: 64.26 units, 95% CI −20.03 to 148.54; p = 0.13). NMES significantly improved AWD at 3 months for patients who could walk for more than 340 m at baseline (square root of AWD: 2.877 units, 95% CI 0.51 to 5.25; p = 0.019/AWD raw data: 120.55 m, 95% CI 16.03 to 225.06; p = 0.03) compared to the control arm. Mechanistic findings of the laser doppler flowmetry found no clear differences in blood flux between the two treatment groups over the 12-month follow-up period, nor any significant differences in volume flow or time average mean velocity (duplex ultrasound) groups at 3 months. Serious adverse events (n = 29) were reported in 24 participants, with all events being classified as either not related or unlikely to be related to the study device. The number of SAEs in the treatment arm was 13 and 16 in the control arm. Most of the events required hospitalisation; there were four deaths. Conclusions The results of the NESIC trial indicate that SET is the most effective treatment option for patients with IC. Although not significant, NMES improves walking distances when used in combination with a SET programme, and significantly improves AWD in mild claudicants. Implications for health care Findings from this trial suggest that all IC patients should have access to a SET programme and changes to such programmes may need to be made to encourage and/or retain participants. NMES may be an effective adjunct to SET and in patients with a good baseline walking distance. Recommendations for research (numbered in priority order) 1.Randomised controlled trial of NMES as an adjunct to SET in IC patients stratified by baseline AWD, as the NESIC study showed promise of non-invasive effectiveness in mild and/or moderate claudicants at improving walking distances, but larger numbers are required to validate this finding. 2.Research to examine the poor patient motivation and adherence to SET, as SET is clearly an effective treatment option for claudicants as seen in this study and many other studies but uptake/compliance remains an issue. 3.Research to evaluate the long-term effectiveness of SET programmes on maximal walking distance (MWD) and secondary outcomes such as quality of life and long-term engagement in physical activity. The NESIC study showed the effectiveness of SET at 12 months at improving AWD but longer-term follow-up is required to evaluate whether this is sustained years later. Previous studies have shown mixed results on the impact of SET on other outcomes, such as quality of life, and therefore further research is required. Study registration This trial is registered as ISRCTN18242823. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health and Care Research (NIHR) partnership (project number 15/180/68). This will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 2. See the NIHR Journals Library website for further project information. Infrastructure support for this research was provided by the NIHR Imperial Biomedical Research Centre (BRC) (with others, e.g. NIHR Imperial CRF, Imperial College ECMC, NIHR Imperial PSTRC, NIHR London MIC, etc.).

The microstructure, mechanical and tribological properties of Ni–Cr–ZrO2 composites, manufactured by using the spark plasma sintering technique with different sintering temperatures, were investigated. The individual powder was measured and mixed thoroughly in a tubular mixer for 8 h before being transferred to the sintering machine. The sintering temperatures of: 800, 900, 950 and 1000 °C with a pressure of 50 MPa, a holding time of 5 min and heating rate of 100 °C/min were used as the process parameters in order to develop four compositional composite systems, used in this investigation. Wear tests were, performed on the sintered composites at 10 N, 15 N and 20 N loads. The microstructural analyses of the sintered sample revealed the associated compositional homogeneities, formation of phases and pores. The results showed that the sintering temperature influenced the mechanical and tribological properties of the sintered composites, such that the increasing sintering temperature led to an increase in the relative density. The microhardness and wear resistance increased with the increasing sintering temperature, which showed that the composites developed, possessed improved properties by using high sintering temperature. Thus, the sample sintered at 1000 °C maintained the least wear rate and consequently, the best hardness property.

The consolidation of polylactic acid/graphene nanocomposite via a novel SPS powder metallurgy route was elaborated in this study. The nanocomposite powders were prepared using the three-dimensional (3-D) tubular mixer and consolidated under different parameters of spark plasma sintering (SPS). The densification, porosity, hardness, and crystalline properties of the consolidated specimen were investigated as a measure of its mechanical strength. These properties were observed to have an obvious dependence on the sintering process parameters. The fracture morphology of the sample reveals the ductile fractured at elevated sintering temperature of 160 °C while a fragile intergranular fracture type was revealed at a lower sintering temperature of 135 °C. SEM images revealed a well-distributed and dispersed GNP in the PLA matrix across the varied process parameters of temperature and pressure. The crystallinity of the nanocomposite peak was enhanced via the process engineering of SPS. This was observed with increased crystalline peaks on the XRD and percentage crystallinity reported on the DSC. Changes in the range of transmittance with respect to sintering parameters were observed on the FTIR. The thermal stability improves with respect to the sintering temperature and pressure within the range of the parameters reported. This reveals a better mass barrier effect of the nanocomposite due to better intermolecular diffusion and reduced pore spaces in the sintered samples. The thermal stability was observed to appreciate due to the better polymer nanoparticle interaction. Hence, this study further attests that aside from the use of nucleation agents such as GNP and plasticisation, process engineering of SPS could help in modifying desired properties of nanocomposite.

Environmental conservation and waste control have informed and encouraged the use of biodegradable polymeric materials over synthetic non-biodegradable materials. It has been recognized that nano-sized biodegradable materials possess relatively good properties as compared to conventional micron-sized materials. However, the strength characteristics of these materials are inferior to fossil-based non-biodegradable materials. In this study, biodegradable polylactide (PLA), reinforced with treated coconut husk particulates (CCP) for improved mechanical properties, was fabricated using an electrospinning process and representative volume element (RVE) technique, and some of the obtained mechanical properties were compared. It was observed that the electrospun CCP-PLA nanofibre composites show improved mechanical properties, and some of these mechanical properties using both techniques compared favourably well. The electrospun fibres demonstrate superior properties, mostly at 4 wt.% reinforcement. Thus, achieving good mechanical properties utilising agro waste as reinforcement in PLA to manufacture nanocomposite materials by electrospinning method is feasible and provides insight into the development of biodegradable nanocomposite materials.

Background: While female survivors of Hodgkin lymphoma (HL) have an increased risk of breast cancer (BC), no BC risk prediction model is available. We developed such models incorporating mean radiation dose to the breast or breast quadrant-specific radiation doses., Methods: Relative risks and age-specific incidence for BC and competing events (mortality or other subsequent cancer) were estimated from 1194 Dutch five-year HL survivors, treated at ages 11-40 during 1965-2000. Predictors were doses to ten breast segments or mean breast radiation dose, BC family history, year of and age at HL diagnosis, ages at menopause and first live birth. Models were independently validated using U.S. Childhood Cancer Survivor Study cohort participants., Results: Predicted absolute BC risks 25 years after HL diagnosis ranged from 1.0% for survivors diagnosed at ages 20-24, with <10 Gy mean breast radiation dose and menopausal 5 years after HL diagnosis, to 22.0% for survivors 25-29 years at diagnosis, ≥25 Gy mean breast dose, and no menopause within 5 years. In external validation, the observed/expected BC case ratio was 1.19 (95% confidence interval 0.97 to 1.47) for the breast segment-specific doses model, and 1.29 (1.05 to 1.60) for the mean breast dose model. The areas under the receiver operating characteristic curve were 0.68 (0.63 to 0.74) and 0.68 (0.62 to 0.73), respectively., Conclusion: Breast segment-specific or mean breast radiation dose with personal and clinical characteristics predicted absolute BC risk in HL survivors with moderate discrimination but good calibration, rendering the models useful for clinical decision-making., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Accurate divergence times are essential for interpreting and understanding the context in which lineages have evolved. Over the past several decades, debates have surrounded the discrepancies between the inferred molecular ages of crown angiosperms, often estimated from the Late Jurassic into the Permian, and the fossil record, placing angiosperms in the Early Cretaceous. That crown angiosperms could have emerged as early as the Permian or even the Triassic would have major implications for the paleoecological context of the origin of one of the most consequential clades in the tree of life. Here, we argue, and demonstrate through simulations, that the older ages inferred from molecular data and relaxed-clock models are misled by lineage-specific rate heterogeneity resulting from life history changes that occurred several times throughout the evolution of vascular plants. To overcome persistent discrepancies in age estimates, more biologically informed and realistic models should be developed, and our results should be considered in the context of their biological implications before we accept inferences that are a major departure from our strongest evidence., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

While flowering plants have diversified in virtually every terrestrial clime, climate constrains the distribution of individual lineages. Overcoming climatic constraints may be associated with diverse evolutionary phenomena including whole genome duplication (WGD), gene-tree conflict, and life-history changes. Climatic shifts may also have facilitated increases in flowering plant diversification rates. We investigate climatic shifts in the flowering plant order Ericales, which consists of c. 14 000 species with diverse climatic tolerances. We estimate phylogenetic trees from transcriptomic data, 64 chloroplast loci, and Angiosperms353 nuclear loci that, respectively, incorporate 147, 4508, and 2870 Ericales species. We use these phylogenetic trees to analyse how climatic shifts are associated with WGD, gene-tree conflict, life-history, and diversification rates. Early branches in the phylogenetic trees are extremely short, and have high levels of gene-tree conflict and at least one WGD. On lineages descended from these early branches, there is a significant association between climatic shifts (primarily out of tropical climates), further WGDs, and life-history. Extremely short early branches, and their associated gene-tree conflict and WGDs, appear to underpin the explosive origin of numerous species rich Ericales clades. The evolution of diverse climatic tolerances in these species rich clades is tightly associated with WGD and life-history., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

The use of ultra-high-field 7-Tesla (7T) MRI in multiple sclerosis (MS) research has grown significantly over the past two decades. With recent regulatory approvals of 7T scanners for clinical use in 2017 and 2020, the use of this technology for routine care is poised to continue to increase in the coming years. In this context, the North American Imaging in MS Cooperative (NAIMS) convened a workshop in February 2023 to review the previous and current use of 7T technology for MS research and potential future research and clinical applications. In this workshop, experts were tasked with reviewing the current literature and proposing a series of consensus statements, which were reviewed and approved by the NAIMS. In this review and consensus paper, we provide background on the use of 7T MRI in MS research, highlighting this technology's promise for identification and quantification of aspects of MS pathology that are more difficult to visualize with lower-field MRI, such as grey matter lesions, paramagnetic rim lesions, leptomeningeal enhancement and the central vein sign. We also review the promise of 7T MRI to study metabolic and functional changes to the brain in MS. The NAIMS provides a series of consensus statements regarding what is currently known about the use of 7T MRI in MS, and additional statements intended to provide guidance as to what work is necessary going forward to accelerate 7T MRI research in MS and translate this technology for use in clinical practice and clinical trials. This includes guidance on technical development, proposals for a universal acquisition protocol and suggestions for research geared towards assessing the utility of 7T MRI to improve MS diagnostics, prognostics and therapeutic efficacy monitoring. The NAIMS expects that this article will provide a roadmap for future use of 7T MRI in MS., Competing Interests: D.M.H. has received research funding from EMD-Serono and Roche-Genentech, consulting fees from Horizon Therapeutics, TG Therapeutics and EMD-Serono and royalties from Up To Date, Inc. F.B. has received speaker honoraria from EMD-Serono, Sanofi and Novartis and serves/ed as site PI of multi-centre studies sponsored by EMD-Serono and Novartis and on advisory boards for Sanofi, EMD-Serono and Biogen. S.N. has received research funding from Roche-Genentech and Immunotec, consulting fees from Sana Biotechnology and personal compensation from NeuroRx Research. S.G. has received research funding from Roche-Genentech. E.S.B. has received consulting fees from EMD-Serono. .J.Z. has received research support from Novartis, I-Mab Biopharma and the Race to Erase MS Foundation. R.B. has received speaking honoraria from EMD-Serono and research support from Bristol-Myers Squibb, EMD-Serono and Novartis. A.C. was supported by the ECTRIMS post-doctoral training fellowship (2022). A.C. has received speaker honoraria from Novartis. S.Y.H. has received research funding and consulting fees from Siemens Healthineers. The University Hospital Basel (USB), as the employer of C.G., has received the following fees which were used exclusively for research support: (i) advisory board and consultancy fees from Actelion, Genzyme-Sanofi, Novartis, GeNeuro and Roche; (ii) speaker fees from Genzyme-Sanofi, Novartis, GeNeuro and Roche; and (iii) research support from Siemens, GeNeuro and Roche. E.C.K. has received research funding from Abbvie, Biogen and Genentech and consulting fees from EMD-Serono, Genentech, INmune Bio, Myrobalan Therapeutics, OM1, Inc. and TG Therapeutics. C.M. has received research funding from Genentech-Roche. C.L., J.D., M.D., D.A.R. and P.B. have no disclosures to report., (Published by Oxford University Press on behalf of the Guarantors of Brain 2024.)

Docosahexaenoic acid (DHA) supplementation has proven beneficial in reducing preterm births. However, the challenge lies in addressing nonadherence to prescribed supplementation regimens-a hurdle that significantly impacts clinical trial outcomes. Conventional methods of adherence estimation, such as pill counts and questionnaires, usually fall short when estimating adherence within a specific dosage group. Thus, we propose a Bayesian finite mixture model to estimate adherence among women with low baseline red blood cell phospholipid DHA levels (<6%) receiving higher DHA doses. In our model, adherence is defined as the proportion of participants classified into one of the two distinct components in a normal mixture distribution. Subsequently, based on the estimands from the adherence model, we introduce a novel Bayesian adaptive trial design. Unlike conventional adaptive trials that employ regularly spaced interim schedules, the novelty of our proposed trial design lies in its adaptability to adherence percentages across the treatment arm through irregular interims. The irregular interims in the proposed trial are based on the effect size estimation informed by the finite mixture model. In summary, this study presents innovative methods for leveraging the capabilities of Bayesian finite mixture models in adherence analysis and the design of adaptive clinical trials., Competing Interests: Data sharingFor data access, please see Carlson et al.5,15,16 Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Cross-talk between the microbiome and gut mucosa-resident immune cells plays a pivotal role in modulating immune responses to pathogens, including responses to HIV infection. However, how these interactions may differ between young MSM (YMSM) disproportionately impacted by HIV, as compared to older adult MSM (AMSM), is not well understood. A broad analysis of associations between the microbiome and rectal transcriptome revealed 10 microbial families/genera correlated with immunologic gene pathways. Specifically, the rectal transcriptome of YMSM is characterized by upregulation of T cell activation/differentiation pathways and signaling from multiple cytokine families, compared to AMSM. The microbiome of YMSM is enriched with pathogenic genera including Peptostreptococcus, shown to be positively correlated with type I interferon pathways important for antiviral immunity. These findings demonstrate that YMSM have a unique immune phenotype and rectal microenvironment and support further evaluation of biological factors that influence rectal HIV transmission.

The contact pathway of blood clotting has received intense interest in recent years as studies have linked it to thrombosis, inflammation, and innate immunity. Because the contact pathway plays little to no role in normal hemostasis, it has emerged as a potential target for safer thromboprotection, relative to currently approved antithrombotic drugs which all target the final common pathway of blood clotting. Research since the mid-2000s has identified polyphosphate, DNA, and RNA as important triggers of the contact pathway with roles in thrombosis, although these molecules also modulate blood clotting and inflammation via mechanisms other than the contact pathway of the clotting cascade. The most significant source of extracellular DNA in many disease settings is in the form of neutrophil extracellular traps (NETs), which have been shown to contribute to incidence and severity of thrombosis. This review summarizes known roles of extracellular polyphosphate and nucleic acids in thrombosis, with an emphasis on novel agents under current development that target the prothrombotic activities of polyphosphate and NETs., Competing Interests: S.V., S.A.S., J.H.M., and J.N.K. are inventors on issued patents and pending patent applications covering novel inhibitors of polyphosphate and NETs, some of which are optioned to TSRL, Inc., for licensing from the University of Michigan and the University of British Columbia. J.H.M. reports grants from the National Institutes of Health, and J.N.K. reports grants from the Canadian Institutes of Health Research and the Natural Sciences and Engineering Council of Canada. The laboratory of J.H.M. receives some research funding from Kerafast, Inc., through the sales of polyphosphates and polyphosphate derivatives., (Thieme. All rights reserved.)

Background: Heart failure is a leading cause of death in the USA, contributing to high expenditures near the end of life. Evidence remains lacking on whether billed advance care planning changes patterns of end-of-life healthcare utilization among patients with heart failure. Large-scale claims evaluation assessing billed advance care planning and end-of-life hospitalizations among patients with heart failure can fill evidence gaps to inform health policy and clinical practice., Objective: Assess the association between billed advance care planning delivered and Medicare beneficiaries with heart failure upon the type and quantity of healthcare utilization in the last 30 days of life., Design: This retrospective cross-sectional cohort study used Medicare fee-for-service claims from 2016 to 2020., Participants: A total of 48,466 deceased patients diagnosed with heart failure on Medicare., Main Measures: Billed advance care planning services between the last 12 months and last 30 days of life will serve as the exposure. The outcomes are end-of-life healthcare utilization and total expenditure in inpatient, outpatient, hospice, skilled nursing facility, and home healthcare services., Key Results: In the final cohort of 48,466 patients (median [IQR] age, 83 [76-89] years; 24,838 [51.2%] women; median [IQR] Charlson Comorbidity Index score, 4 [2-5]), 4406 patients had an advance care planning encounter. Total end-of-life expenditure among patients with billed advance care planning encounters was 19% lower (95% CI, 0.77-0.84) compared to patients without. Patients with billed advance care planning encounters had 2.65 times higher odds (95% CI, 2.47-2.83) of end-of-life outpatient utilization with a 33% higher expected total outpatient expenditure (95% CI, 1.24-1.42) compared with patients without a billed advance care planning encounter., Conclusions: Billed advance care planning delivery to individuals with heart failure occurs infrequently. Prioritizing billed advance care planning delivery to these individuals may reduce total end-of-life expenditures and end-of-life inpatient expenditures through promoting use of outpatient end-of-life services, including home healthcare and hospice., (© 2024. The Author(s).)

Vaccinieae is a morphologically diverse and species-rich (∼1430 species) tribe in Ericaceae. Although the majority of diversity is tropical, Vaccinieae are best known for temperate crops (i.e., blueberries, cranberries, and lingonberries) in Vaccinium. Vaccinium itself (∼500 species) has been previously suggested as highly polyphyletic and taxonomic boundaries among many of the other genera in the tribe remain uncertain. We assessed the evolutionary history of Vaccinieae with phylogenomic analyses based on a target-enrichment dataset containing 256 low-copy nuclear loci and 210 species representing 30 of the 35 genera in the tribe and 25 of the 29 sections of Vaccinium. We conducted time-calibrated biogeographic analyses and diversification analyses to explore the area of origin and global dispersal history of the tribe. The analysis recovered a temperate North American origin for Vaccinieae approximately 30 million years ago. Tropical diversity of Vaccinieae was inferred to result from multiple, independent movements into the tropics from north-temperate ancestors. Diversification rate increases corresponded to radiation into the Andes and SE Asia. The pseudo-10-locular ovary evolved once in the tribe from the five-locular state, coinciding with the diversification of a major clade that includes most Asian Vaccinium and the group from which commercial blueberries are derived (V. sect. Cyanococcus). A reconstruction from available chromosome counts suggests that a major polyploid event predated the evolution of nearly half the diversity of Vaccinieae. The extent of polyphyly in Vaccinium documented here supports the need for a generic reclassification of the tribe., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Ion channels and cytoskeletal proteins in the cardiac dyad play a critical role in maintaining excitation-contraction (E-C) coupling and provide cardiac homeostasis. Functional changes in these dyad proteins, whether induced by genetic, epigenetic, metabolic, therapeutic, or environmental factors, can disrupt normal cardiac electrophysiology, leading to abnormal E-C coupling and arrhythmias. Animal models and heterologous cell cultures provide platforms to elucidate the pathogenesis of arrhythmias for basic cardiac research; however, these traditional systems do not truly reflect human cardiac electro-pathophysiology. Notably, patients with the same genetic variants of inherited channelopathies (ICC) often exhibit incomplete penetrance and variable expressivity which underscores the need to establish patient-specific disease models to comprehend the mechanistic pathways of arrhythmias and determine personalized therapies. Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) inherit the genetic background of the patient and reflect the electrophysiological characteristics of the native cardiomyocytes. Thus, iPSC-CMs provide an innovative and translational pivotal platform in cardiac disease modeling and therapeutic screening. In this review, we will examine how patient-specific iPSC-CMs historically evolved to model arrhythmia syndromes in a dish, and their utility in understanding the role of specific ion channels and their functional characteristics in causing arrhythmias. We will also examine how CRISPR/Cas9 have enabled the establishment of patient-independent and variant-induced iPSC-CMs-based arrhythmia models. Next, we will examine the limitations of using human iPSC-CMs with respect to in vitro arrhythmia modeling that stems from variations in iPSCs or toxicity due to gene editing on iPSC or iPSC-CMs and explore how such hurdles are being addressed. Importantly, we will also discuss how novel 3D iPSC-CM models can better capture in vitro characteristics and how all-optical platforms provide non-invasive and high- throughput electrophysiological data that is useful for stratification of emerging arrhythmogenic variants and drug discovery. Finally, we will examine strategies to improve iPSC-CM maturity, including powerful gene editing and optogenetic tools that can introduce/modify specific ion channels in iPSC-CMs and tailor cellular and functional characteristics. We anticipate that an elegant synergy of iPSCs, novel gene editing, 3D- culture models, and all-optical platforms will offer a high-throughput template to faithfully recapitulate in vitro arrhythmogenic events necessary for personalized arrhythmia monitoring and drug screening process., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Joshi, Albers, Smole, Guo and Smith.)

Chronic active lesions (CAL) are an important manifestation of chronic inflammation in multiple sclerosis and have implications for non-relapsing biological progression. In recent years, the discovery of innovative MRI and PET-derived biomarkers has made it possible to detect CAL, and to some extent quantify them, in the brain of persons with multiple sclerosis, in vivo. Paramagnetic rim lesions on susceptibility-sensitive MRI sequences, MRI-defined slowly expanding lesions on T1-weighted and T2-weighted scans, and 18-kDa translocator protein-positive lesions on PET are promising candidate biomarkers of CAL. While partially overlapping, these biomarkers do not have equivalent sensitivity and specificity to histopathological CAL. Standardization in the use of available imaging measures for CAL identification, quantification and monitoring is lacking. To fast-forward clinical translation of CAL, the North American Imaging in Multiple Sclerosis Cooperative developed a consensus statement, which provides guidance for the radiological definition and measurement of CAL. The proposed manuscript presents this consensus statement, summarizes the multistep process leading to it, and identifies the remaining major gaps in knowledge., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. Elements of this work were written by employees of the US Government.)

Pain can be defined as an unpleasant sensory and emotional experience associated with or resembling that associated with actual or potential tissue damage. Though consistent with this definition, different types of pain result in different behavioural and psychophysiological responses. For example, the transient, non-threatening, acute muscle pain element of exercise-induced pain (EIP) is entirely different from other pain types like delayed onset muscle soreness, muscular injury or chronic pain. However, studies often conflate the definitions or assume parity between distinct pain types. Consequently, the mechanisms through which pain might impact exercise behaviour across different pain subcategories may be incorrectly assumed, which could lead to interventions or recommendations that are inappropriate. Therefore, this review aims to distinguish EIP from other subcategories of pain according to their aetiologies and characteristics, thereby providing an updated conceptual and operational definition of EIP. Secondly, the review will discuss the experimental pain models currently used across several research domains and their relevance to EIP with a focus on the neuro-psychophysiological mechanisms of EIP and its effect on exercise behaviour and performance. Finally, the review will examine potential interventions to cope with the impact of EIP and support wider exercise benefits. HIGHLIGHTS: What is the topic of this review? Considerations for future research focusing on exercise-induced pain within endurance exercise settings. What advances does it highlight? An updated appraisal and guide of research concerning exercise-induced pain and its impact on endurance task behaviour, particularly with reference to the aetiology, measurement, and manipulation of exercise-induced pain., (© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Atrial fibrillation (AF) is a common arrhythmic complication in cancer patients and can be exacerbated by traditional cytotoxic and targeted anticancer therapies. Increased incidence of AF in cancer patients is independent of confounding factors, including preexisting myocardial arrhythmogenic substrates, type of cancer, or cancer stage. Mechanistically, AF is characterized by fast unsynchronized atrial contractions with rapid ventricular response, which impairs ventricular filling and results in various symptoms such as fatigue, chest pain, and shortness of breath. Due to increased blood stasis, a consequence of both cancer and AF, concern for stroke increases in this patient population. To compound matters, cardiotoxic anticancer therapies themselves promote AF; thereby exacerbating AF morbidity and mortality in cancer patients. In this review, we examine the relationship between AF, cancer, and cardiotoxic anticancer therapies with a focus on the shared molecular and electrophysiological mechanisms linking these disease processes. We also explore the potential role of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in the management of anticancer-therapy-induced AF., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The exercise pressor reflex (EPR) is exaggerated in type 2 diabetes mellitus (T2DM), but the underlying central nervous system aberrations have not been fully delineated. Stimulation of muscle afferents within working skeletal muscle activates the EPR, by sending information to neurons in the brainstem, where it is integrated and results in reflexively increased mean arterial pressure (MAP) and sympathetic nerve activity. Brain insulin is known to regulate neural activity within the brainstem. We hypothesize that brain insulin injection in T2DM rats attenuates the augmented EPR, and that T2DM is associated with decreased brain insulin. Using male Sprague-Dawley rats, T2DM and control rats were generated via an induction protocol with two low doses of streptozotocin (35 and 25 mg/kg, i.p.) in combination with a 14-23-week high-fat diet or saline injections and a low-fat diet, respectively. After decerebration, MAP and renal sympathetic nerve activity (RSNA) were evaluated during EPR stimulation, evoked by electrically induced muscle contraction via ventral root stimulation, before and after (1 and 2 h post) intracerebroventricular (i.c.v.) insulin microinjections (500 mU, 50 nl). i.c.v. insulin decreased peak MAP (ΔMAP Pre (36 ± 14 mmHg) vs. 1 h (21 ± 14 mmHg) vs. 2 h (11 ± 6 mmHg), P < 0.05) and RSNA (ΔRSNA Pre (107.5 ± 40%), vs. 1 h (75.4 ± 46%) vs. 2 h (51 ± 35%), P < 0.05) responses in T2DM, but not controls. In T2DM rats, cerebrospinal fluid insulin was decreased (0.41 ± 0.19 vs. 0.11 ± 0.05 ng/ml, control (n = 14) vs. T2DM (n = 4), P < 0.01). The results demonstrated that insulin injections into the brain normalized the augmented EPR in brain hypoinsulinaemic T2DM rats, indicating that the EPR can be regulated by brain insulin. KEY POINTS: The reflexive increase in blood pressure and sympathetic nerve activity mediated by the autonomic nervous system during muscle contractions is also known as the exercise pressor reflex. The exercise pressor reflex is dangerously augmented in type 2 diabetes, in both rats and humans. In type 2 diabetic rats both cerebrospinal fluid insulin and phosphoinositide 3-kinase signalling within cardiovascular brainstem neurons decrease in parallel. Brain insulin injections decrease the magnitude of the reflexive pressor and sympathetic responses to hindlimb muscle contraction in type 2 diabetic rats. Partial correction of low insulin within the central nervous system in type 2 diabetes may treat aberrant exercise pressor reflex function., (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: Inorganic polyphosphates (polyPs) are linear chains of phosphates that accelerate blood clotting. Targeting polyP in vivo has been shown to reduce thrombosis., Objectives: To identify and characterize anti-polyP monoclonal antibodies that could be used as analytical tools and as antithrombotic agents., Methods: Hybridomas were prepared from spleen cells from autoimmune NZBWF1/J female mice and screened for anti-polyP antibodies. Antibodies that bound polyP using enzyme-linked immunosorbent assay and pull-down assays were further characterized with plate binding, surface plasmon resonance, and plasma-based clotting assays. Antithrombotic potential was evaluated in a murine ferric chloride-induced carotid artery thrombosis model., Results: Of 4 antibodies that bound polyP in our pull-down assay, 2 (PP2069 and PP2099) were available for further characterization. While analyzing these anti-polyP antibodies, we found secretory leukocyte peptidase inhibitor (SLPI) to be a common contaminant of these antibodies and that SLPI binds polyP. We removed SLPI quantitatively from our purified immunoglobulin G. Both PP2069 and PP2099 immunoglobulin G displayed high affinity for polyP but also bound to other polyanions such as DNA, heparin, and certain other glycosaminoglycans, indicating limited specificity. Both antibodies inhibited polyP-initiated plasma clotting in vitro . When tested in vivo in a mouse thrombosis model, however, neither PP2069 nor PP2099 exhibited a significant antithrombotic effect., Conclusion: Autoimmune mice spontaneously produce antibodies against polyP. The 2 examples of anti-polyP monoclonal antibodies studied here not only bound to polyP with high affinity but also cross-reacted with DNA and heparin. Neither antibody protected against thrombosis in a mouse model, but they might have some utility for in vitro studies of polyP., (© 2024 The Author(s).)

The combination of radiotherapy/chemoradiotherapy and immune checkpoint blockade can result in poor outcomes in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Here, we show that combining ATR inhibition (ATRi) with radiotherapy (RT) increases the frequency of activated NKG2A + PD-1 + T cells in animal models of HNSCC. Compared with the ATRi/RT treatment regimen alone, the addition of simultaneous NKG2A and PD-L1 blockade to ATRi/RT, in the adjuvant, post-radiotherapy setting induces a robust antitumour response driven by higher infiltration and activation of cytotoxic T cells in the tumour microenvironment. The efficacy of this combination relies on CD40/CD40L costimulation and infiltration of activated, proliferating memory CD8 + and CD4 + T cells with persistent or new T cell receptor (TCR) signalling, respectively. We also observe increased richness in the TCR repertoire and emergence of numerous and large TCR clonotypes that cluster based on antigen specificity in response to NKG2A/PD-L1/ATRi/RT. Collectively, our data point towards potential combination approaches for the treatment of HNSCC., (© 2024. The Author(s).)

Complex patterns of genome evolution associated with the end-Cretaceous [Cretaceous-Paleogene (K-Pg)] mass extinction limit our understanding of the early evolutionary history of modern birds. Here, we analyzed patterns of avian molecular evolution and identified distinct macroevolutionary regimes across exons, introns, untranslated regions, and mitochondrial genomes. Bird clades originating near the K-Pg boundary exhibited numerous shifts in the mode of molecular evolution, suggesting a burst of genomic heterogeneity at this point in Earth's history. These inferred shifts in substitution patterns were closely related to evolutionary shifts in developmental mode, adult body mass, and patterns of metabolic scaling. Our results suggest that the end-Cretaceous mass extinction triggered integrated patterns of evolution across avian genomes, physiology, and life history near the dawn of the modern bird radiation.

Thrombosis, the formation of blood clots within a blood vessel, can lead to severe complications including pulmonary embolism, cardiac arrest, and stroke. The most widely administered class of anticoagulants is heparin-based anticoagulants such as unfractionated heparin, low-molecular weight heparins (LMWHs), and fondaparinux. Protamine is the only FDA-approved heparin antidote. Protamine has limited efficacy neutralizing LMWHs and no reversal activity against fondaparinux. The use of protamine can lead to complications, including excessive bleeding, hypotension, and hypersensitivity, and has narrow therapeutic window. In this work, a new concept in the design of a universal heparin antidote: switchable protonation of cationic ligands, is presented. A library of macromolecular polyanion inhibitors (MPIs) is synthesized and screened to identify molecules that can neutralize all heparins with high selectivity and reduced toxicity. MPIs are developed by assembling cationic binding groups possessing switchable protonation states onto a polymer scaffold. By strategically selecting the identity and modulating the density of cationic binding groups on the polymer scaffold, a superior universal heparin reversal agent is developed with improved heparin-binding activity and increased hemocompatibility profiles leading to minimal effect on hemostasis. The activity of this heparin antidote is demonstrated using in vitro and in vivo studies., (© 2024 The Authors. Advanced Healthcare Materials published by Wiley‐VCH GmbH.)