Single-cell transcriptomic analysis of renal allograft rejection reveals insights into intragraft TCR clonality.

Bulk analysis of renal allograft biopsies (rBx) identified RNA transcripts associated with acute cellular rejection (ACR); however, these lacked cellular context critical to mechanistic understanding of how rejection occurs despite immunosuppression (IS). We performed combined single-cell RNA transcriptomic and TCR-α/ß sequencing on rBx from patients with ACR under differing IS drugs: tacrolimus, iscalimab, and belatacept. We found distinct CD8+ T cell phenotypes (e.g., effector, memory, exhausted) depending upon IS type, particularly within expanded CD8+ T cell clonotypes (CD8EXP). Gene expression of CD8EXP identified therapeutic targets that were influenced by IS type. TCR analysis revealed a highly restricted number of CD8EXP, independent of HLA mismatch or IS type. Subcloning of TCR-α/ß cDNAs from CD8EXP into Jurkat 76 cells (TCR-/-) conferred alloreactivity by mixed lymphocyte reaction. Analysis of sequential rBx samples revealed persistence of CD8EXP that decreased, but were not eliminated, after successful antirejection therapy. In contrast, CD8EXP were maintained in treatment-refractory rejection. Finally, most rBx-derived CD8EXP were also observed in matching urine samples, providing precedent for using urine-derived CD8EXP as a surrogate for those found in the rejecting allograft. Overall, our data define the clonal CD8+ T cell response to ACR, paving the next steps for improving detection, assessment, and treatment of rejection.

Single cell transcriptomic analysis of renal allograft rejection reveals novel insights into intragraft TCR clonality.

Bulk analysis of renal allograft biopsies (rBx) identified RNA transcripts associated with acute cellular rejection (ACR); however, these lacked cellular context critical to mechanistic understanding. We performed combined single cell RNA transcriptomic and TCRα/ß sequencing on rBx from patients with ACR under differing immunosuppression (IS): tacrolimus, iscalimab, and belatacept. TCR analysis revealed a highly restricted CD8 + T cell clonal expansion (CD8 EXP ), independent of HLA mismatch or IS type. Subcloning of TCRα/ß cDNAs from CD8 EXP into Jurkat76 cells (TCR -/- ) conferred alloreactivity by mixed lymphocyte reaction. scRNAseq analysis of CD8 EXP revealed effector, memory, and exhausted phenotypes that were influenced by IS type. Successful anti-rejection treatment decreased, but did not eliminate, CD8 EXP , while CD8 EXP were maintained during treatment-refractory rejection. Finally, most rBx-derived CD8 EXP were also observed in matching urine samples. Overall, our data define the clonal CD8 + T cell response to ACR, providing novel insights to improve detection, assessment, and treatment of rejection.

Relationship between piperacillin concentrations, clinical factors and piperacillin/tazobactam-associated acute kidney injury.

BACKGROUND: Piperacillin/tazobactam, a commonly used antibiotic, is associated with acute kidney injury (AKI). The relationship between piperacillin concentrations and AKI remains unknown. OBJECTIVE: Estimate piperacillin exposures in critically ill children and young adults administered piperacillin/tazobactam to identify concentrations and clinical factors associated with piperacillin-associated AKI. PATIENTS AND METHODS: We assessed piperacillin pharmacokinetics in 107 patients admitted to the paediatric ICU who received at least one dose of piperacillin/tazobactam. Piperacillin AUC, highest peak (Cmax) and highest trough (Cmin) in the first 24 hours of therapy were estimated. Piperacillin-associated AKI was defined as Kidney Disease: Improving Global Outcomes (KDIGO) Stage 2/3 AKI present >24 hours after initial piperacillin/tazobactam dose. Likelihood of piperacillin-associated AKI was rated using the Naranjo Adverse Drug Reaction Probability Scale. Multivariable logistic regression was performed to identify patient and clinical predictors of piperacillin-associated AKI. RESULTS: Out of 107 patients, 16 (15%) were rated as possibly or probably having piperacillin-associated AKI. Estimated AUC and highest Cmin in the first 24 hours were higher in patients with piperacillin-associated AKI (2042 versus 1445 mg*h/L, P = 0.03; 50.1 versus 10.7 mg/L, P < 0.001). Logistic regression showed predictors of piperacillin-associated AKI included higher Cmin (OR: 5.4, 95% CI: 1.7-23) and age (OR: 1.13, 95% CI: 1.05-1.25). CONCLUSIONS: We show a relationship between estimated piperacillin AUC and highest Cmin in the first 24 hours of piperacillin/tazobactam therapy and piperacillin-associated AKI, suggesting total piperacillin exposure early in the course is associated with AKI development. These data could serve as the foundation for implementation of model-informed precision dosing to reduce AKI incidence in patients given piperacillin/tazobactam.

Dual Task Performance Is Associated with Amyloidosis in Cognitively Healthy Adults.

BACKGROUND: Preclinical Alzheimer's disease (AD) provides an opportunity for the study and implementation of interventions and strategies aimed at delaying, mitigating, and preventing AD. While this preclinical state is an ideal target, it is difficult to identify efficiently and cost-effectively. Recent findings have suggested that cognitive-motor dual task paradigms may provide additional inference. OBJECTIVES: Investigate the relationship between dual task performance and amyloidosis, suggestive of preclinical Alzheimer's disease and whether dual task performance provides additional information beyond a cognitive composite, to help in the identification of amyloidosis. DESIGN: Cross-sectional. SETTING: Outpatient specialty brain health clinical research institution in the United States. PARTICIPANTS: 52 cognitively healthy adults. MEASUREMENTS: The data included demographics, amyloid standardized uptake value ratio obtained via florbetapir-PET, neuropsychological testing, apolipoprotien E genotype, and dual task performance measures. Data were analyzed via hierarchal multiple linear regression or logistic regression, controlling for age, education, and apolipoprotien E genotype. Receiver operating characteristic curves were plotted, and sensitivity and specificity calculated via 2x2 contingency tables. RESULTS: There was a moderate relationship (rs>.30) between motor and cognitive dual task effects and amyloid standardized uptake value ratio (ps<.042). A strong relationship (r=.58) was found between combined dual task effect, a measure of automaticity derived from dual task performance, and amyloid standardized uptake value ratio (p<.001). Additionally, combined dual task effect showed promise in its unique contributions to amyloid standardized uptake value ratio, accounting for 7.8% of amyloid standardized uptake value ratio variance beyond cognitive composite scores (p=.018). Additionally, when incorporated into the cognitive composite, combined dual task effect resulted in improved diagnostic accuracy for determining elevated amyloid standardized uptake value ratio, and increased the sensitivity and specificity of the cognitive composite. CONCLUSSION: Dual task performance using the combined dual task effect, a measure of automaticity, was a moderate predictor of cerebral amyloidosis, which suggests that it has utility in the screening and diagnosis of individuals for preclinical AD. Additionally, when combined with the cognitive composite, the combined dual task effect improves diagnostic accuracy. Further research is warranted.

Quality initiative to improve emergency department sepsis bundle compliance through utilisation of an electronic health record tool.

INTRODUCTION: Sepsis is a common cause of emergency department (ED) presentation and hospital admission, accounting for a disproportionate number of deaths each year relative to its incidence. Sepsis outcomes have improved with increased recognition and treatment standards promoted by the Surviving Sepsis Campaign. Due to delay in recognition and other barriers, sepsis bundle compliance remains low nationally. We hypothesised that a targeted education intervention regarding use of an electronic health record (EHR) tool for identification and management of sepsis would lead to increased EHR tool utilisation and increased sepsis bundle compliance. METHODS: We created a multidisciplinary quality improvement team to provide training and feedback on EHR tool utilisation within our ED. A prospective evaluation of the rate of EHR tool utilisation was monitored from June through December 2020. Simultaneously, we conducted two retrospective cohort studies comparing overall sepsis bundle compliance for patients when EHR tool was used versus not used. The first cohort was all patients with intention-to-treat for any sepsis severity. The second cohort of patients included adult patients with time of recognition of sepsis in the ED admitted with a diagnosis of severe sepsis or septic shock. RESULTS: EHR tool utilisation increased from 23.3% baseline prior to intervention to 87.2% during the study. In the intention-to-treat cohort, there was a statistically significant difference in compliance between EHR tool utilisation versus no utilisation in overall bundle compliance (p<0.001) and for several individual components: initial lactate (p=0.009), repeat lactate (p=0.001), timely antibiotics (p=0.031), blood cultures before antibiotics (p=0.001), initial fluid bolus (p<0.001) and fluid reassessment (p<0.001). In the severe sepsis and septic shock cohort, EHR tool use increased from 71.2% pre-intervention to 85.0% post-intervention (p=0.008). CONCLUSION: With training, feedback and EHR optimisation, an EHR tool can be successfully integrated into current workflows and appears to increase sepsis bundle compliance.

Differential effects of modafinil on performance of low-performing and high-performing individuals during total sleep deprivation.

BACKGROUND: Individual responses to the effects of inadequate sleep have been well documented; some people are more vulnerable to the effects of sleep loss than others. Fatigue-vulnerable individuals generally require access to effective fatigue countermeasures; however, the question arises as to whether these fatigue-vulnerable individuals receive the same benefits shown in group efficacy data. The present study administered modafinil to individuals to determine its differential effects on performance of best and worst performers during sleep deprivation. METHODS: A sample of 22 men, age 21-40 yrs., was tested on 2 separate occasions during which they were kept awake for 36 h. During one period they received 200 mg modafinil; during the other they received placebo. Participants were tested on a variety of tasks while rested and at 5-hr intervals across the continuous wakefulness period. Performance for each cognitive task and subjective measure of fatigue from the placebo period was used to group individuals into high (HP) or low performance (LP) groups to indicate fatigue vulnerability for each task. RESULTS: Results indicated that on the MTS task, the HP group performed the same throughout the testing period, regardless of whether they received modafinil or not. However, the LP group significantly improved after receiving modafinil compared to placebo. Performance on the PVT showed the HP group had a small decrease in the number of lapses after receiving modafinil compared to placebo, whereas the LP group had a large decrease in lapses after receiving modafinil compared to placebo. Performance on the RDM showed no difference between groups, regardless of drug condition. Groups did not differ after receiving modafinil on subjective fatigue measured by the POMS. CONCLUSIONS: Depending on the task, HP individuals did not benefit substantially when administered modafinil compared to placebo. However, the LP individuals improved after receiving modafinil compared to placebo.

Evaluating networked drug checking services in Toronto, Ontario: study protocol and rationale.

BACKGROUND: The increasing incidence of fatal opioid overdose is a public health crisis in Canada. Given growing consensus that this crisis is related to the presence of highly potent opioid adulterants (e.g., fentanyl) in the unregulated drug supply, drug checking services (DCS) have emerged as part of a comprehensive approach to overdose prevention. In Canada's largest city, Toronto, a network of DCS launched in 2019 to prevent overdose and overdose-related risk behaviors. This network employs mass spectrometry technologies, with intake sites co-located with supervised consumption services (SCS) at three frontline harm reduction agencies. The protocol and rationale for assessing the impact of this multi-site DCS network in Toronto is described herein. The aims of this study are to (1) evaluate the impact of DCS access on changes in and factors influencing overdose and related risk behaviors, (2) investigate the perceived capacity of DCS to prevent overdose, and (3) identify composition (qualitative and quantitative) trends in Toronto's unregulated drug supply. METHODS: We will use a parallel-mixed-methods design with complementary data sources (including data from chemical analysis of drug samples, quantitative intake and post-test surveys, SCS, coroners, paramedic services, and qualitative interviews), followed by a meta-inference process wherein results from analyses are synthesized. RESULTS: Whereas most DCS globally target "recreational drug users," in Toronto, this networked DCS will primarily target marginalized people who use drugs accessing frontline services, many of whom use drugs regularly and by injection. This evolution in the application of DCS poses important questions that have not yet been explored, including optimal service delivery models and technologies, as well as unique barriers for this population. Increasing information on the unregulated drug supply may modify the risk environment for this population of people who use drugs. CONCLUSIONS: This study addresses evidence gaps on the emerging continuum of overdose prevention responses and will generate critical evidence on a novel approach to reducing the ongoing high incidence of drug-related morbidity and mortality in Canada and elsewhere.

European multicentre experience of staged hybrid atrial fibrillation ablation for the treatment of persistent and longstanding persistent atrial fibrillation.

The management of non-paroxysmal atrial fibrillation (AF) remains controversial. We examined the efficacy and safety of the 2 stage Hybrid AF ablation approach by analysing the largest series of this technique reported so far. METHODS: The approach aims to electrically isolate the left atrial posterior wall incorporating the pulmonary veins ('box-set'pattern). An initial video-assisted thoracoscopic (VATS) epicardial ablation is followed after a minimum of 8 weeks by endocardial radiofrequency catheter ablation. RESULTS: Of 175 patients from 4 European cardiothoracic centers, who underwent the surgical (COBRA Fusion, AtriCure Inc) 1st stage ablation, 166 went on to complete 2nd stage catheter ablation. At median follow up of 18 months post 2nd stage procedure 93/166 (56%) had remained free of AF or atrial tachycardia (AT) recurrence off antiarrhythmic drugs. 110/175 62.9% were in sinus rhythm off all antiarrhythmic drugs at last clinic follow-up (132/175 75.4% including those on antiarrhythmic drugs). 18 patients (10.8%) underwent a further re-do ablation (mean of 1.1 ablations per patient) 105/166 (63%) remained free of AF/AT recurrence off antiarrhythmic drugs following last ablation procedure.Latterly, ILRs have been implanted in patients (n = 56); 60% have remained fully arrhythmia free and 80% have shown AF burden < 5% at a median 14 months follow-up [IQR: 13.5 (8-21.5)]. Only 10.9% have reverted to persistent AF. 5 patients (2.9%) had a perioperative stroke and 4 patients (2.3%) exhibited persistent weakness of the right hemidiaphragm following stage 1 VATS epicardial ablation. One patient died following stroke (overall mortality 0.6%). CONCLUSIONS: In patients with non-paroxysmal AF with unfavourable characteristics for catheter ablation, the staged hybrid approach results in acceptable levels of freedom from recurrent atrial arrhythmia, however, complication rates are higher than with catheter ablation alone.

A pilot randomised controlled trial of the management of systolic blood pressure during endovascular thrombectomy for acute ischaemic stroke.

It is unknown whether systolic blood pressure augmentation during endovascular thrombectomy improves clinical outcomes. This pilot randomised controlled trial aimed to assess the feasibility of differential systolic blood pressure targeting during endovascular thrombectomy procedures for anterior circulation ischaemic stroke. Fifty-one eligible patients fulfilling the national criteria for endovascular thrombectomy were randomly assigned to receive either standard or augmented systolic blood pressure management from the start of anaesthesia to recanalisation of the target vessel. Systolic blood pressure targets for the standard and augmented groups were 130-150 mmHg and 160-180 mmHg, respectively. The study achieved all feasibility targets, including a recruitment rate of 3.5 participants per week and median (IQR [range]) of mean systolic blood pressure separation between groups of 139 (135-143 [115-154]) vs. 167 (150-175 [113-188]) mmHg, p < 0.001. Data completeness was 99%. Independent functional recovery at 90 days (modified Rankin Scale 0, 1 or 2) was achieved in 30 (59%) patients, which is consistent with previously published data. There were no safety concerns with trial procedures. In conclusion, a large randomised controlled efficacy trial of standard vs. augmented systolic blood pressure management during endovascular thrombectomy is feasible.

Prospective clinical testing and experimental validation of the Pediatric Sepsis Biomarker Risk Model.

Sepsis remains a major public health problem with no major therapeutic advances over the last several decades. The clinical and biological heterogeneity of sepsis have limited success of potential new therapies. Accordingly, there is considerable interest in developing a precision medicine approach to inform more rational development, testing, and targeting of new therapies. We previously developed the Pediatric Sepsis Biomarker Risk Model (PERSEVERE) to estimate mortality risk and proposed its use as a prognostic enrichment tool in sepsis clinical trials; prognostic enrichment selects patients based on mortality risk independent of treatment. Here, we show that PERSEVERE has excellent performance in a diverse cohort of children with septic shock with potential for use as a predictive enrichment strategy; predictive enrichment selects patients based on likely response to treatment. We demonstrate that the PERSEVERE biomarkers are reliably associated with mortality in mice challenged with experimental sepsis, thus providing an opportunity to test precision medicine strategies in the preclinical setting. Using this model, we tested two clinically feasible therapeutic strategies, guided by the PERSEVERE-based enrichment, and found that mice identified as high risk for mortality had a greater bacterial burden and could be rescued by higher doses of antibiotics. The association between higher pathogen burden and higher mortality risk was corroborated among critically ill children with septic shock. This bedside to bench to bedside approach provides proof of principle for PERSEVERE-guided application of precision medicine in sepsis.

Electron microscopy and tomography reveal that sodium 2-naphthalene sulfonate incorporated into perming solutions swells and tilts trichocyte intermediate filaments causing straightening of curly Japanese human hair.

OBJECTIVE: A new hair-care process has been specifically developed for the straightening of curved Japanese woman's hair . The process included sodium 2-naphthalene sulfonate (SNS) in the reduction and oxidation steps of a conventional perming process. Our objective was to develop an understanding of how this process caused hair straightening by measuring the changes to morphology and ultrastructure between untreated, conventionally permed and SNS permed hair. Untreated and SNS permed Merino wool fibres were used to confirm structural changes. METHODS: Japanese hair samples were measured for single-fibre curvature before and after perming treatments. A silver staining method was developed to stain hair fibres without changing fibre curvature so that transmission electron microscopy could be used to measure changes in the lateral dimensions of all structural components from the cellular to protein filament level. Electron tomography determined intermediate filament slopes and slope changes after SNS perming relative to the central longitudinal axis of the fibre. RESULTS: SNS perming was found to cause greater lateral swelling than conventional perming of: the paracortical cells of wool; the cuticle, the cuticular cell membrane complex and the macrofibrillar centre-to-centre distance of hair; and of the intermediate filaments in wool and hair. In curved hair, SNS perming caused the intermediate filaments of the helical macrofibrils to simultaneously swell and to tilt further, resulting in the slight longitudinal contraction of the macrofibrils. The overall swelling and tilting was greatest in the helical macrofibrils of Type B cortical cells predominately located in the convex fibre half. The presence of a higher percentage of helical macrofibrils in the convex fibre half than in the concave fibre half caused a contraction differential between the two halves leading to straighten of the curved fibre. A mechanical model was proposed to explain how SNS perming straightened curly hair. CONCLUSION: The effects of conventional and SNS perming on the morphological and ultrastructural components of curved Japanese hair and high-curl Merino wool fibres have given clear insights into understanding the mechanism of fibre curvature change.

OBJECTIF: Un nouveau procédé de soin des cheveux a été spécialement conçu pour lisser les cheveux ondulés des Japonaises[1]. Le procédé utilise le sulfonate de naphthalène-2 sodium (SNS) dans les étapes de réduction et d'oxydation du procédé conventionnel de permanente. Notre objectif était de comprendre la façon dont ce procédé induisait le lissage des cheveux en mesurant les différences de changement morphologique et ultrastructural entre les cheveux non traités et ceux soumis à une permanente conventionnelle et une permanente à base de SNS. Des fibres de laine de mérinos non traitées et soumises à une permanente à base de SNS ont été utilisées pour confirmer les changements structurels. MÉTHODES: Des échantillons de cheveux japonais ont été utilisés pour mesurer la courbure d'une fibre isolée avant et après le traitement de permanente. Une méthode de coloration argent a été mise au point pour colorer les fibres de cheveux sans changer la courbure des fibres afin de pouvoir utiliser la microscopie électronique en transmission pour mesurer les modifications des dimensions en largeur de tous les composants structurels du filament, de la cellule aux protéines. Une tomographie électronique a déterminé les pentes intermédiaires et les changements de pente des filaments après permanente à base de SNS par rapport à l'axe longitudinal central de la fibre. RÉSULTATS: On a constaté que la permanente à base de SNS induisait un gonflement en largeur plus important que la permanente classique des cellules paracorticales de la laine; de la cuticule, du complexe de la membrane cellulaire cuticulaire et de la distance centre à centre des macrofibrilles du cheveu; et des filaments intermédiaires dans la laine et les cheveux. Dans les cheveux ondulés, la permanente à base de SNS a provoqué à la fois un gonflement et une inclinaison des filaments intermédiaires des macrofibrilles hélicoïdales, entraînant une légère contraction longitudinale des macrofibrilles. Au total, le gonflement et l'inclinaison étaient plus importants dans les macrofibrilles hélicoïdales des cellules corticales de type B situées principalement dans la moitié convexe de la fibre. La présence d'un pourcentage plus élevé de macrofibrilles hélicoïdales dans la moitié convexe par rapport à la moitié concave de la fibre a entraîné une contraction différentielle entre les deux moitiés qui a entraîné le redressement de la fibre courbée. Un modèle mécanique a été proposé pour expliquer comment la permanente à base de SNS lissait les cheveux bouclés. CONCLUSION: Les effets de la permanente conventionnelle et à base de SNS sur les composants morphologiques et ultrastructuraux des cheveux japonais ondulés et des fibres de laine très frisés de mérinos ont permis de mieux comprendre le mécanisme du changement de courbure des fibres.

Disease epidemic and a marine heat wave are associated with the continental-scale collapse of a pivotal predator (Pycnopodia helianthoides).

Multihost infectious disease outbreaks have endangered wildlife, causing extinction of frogs and endemic birds, and widespread declines of bats, corals, and abalone. Since 2013, a sea star wasting disease has affected >20 sea star species from Mexico to Alaska. The common, predatory sunflower star (Pycnopodia helianthoides), shown to be highly susceptible to sea star wasting disease, has been extirpated across most of its range. Diver surveys conducted in shallow nearshore waters (n = 10,956; 2006-2017) from California to Alaska and deep offshore (55 to 1280 m) trawl surveys from California to Washington (n = 8968; 2004-2016) reveal 80 to 100% declines across a ~3000-km range. Furthermore, timing of peak declines in nearshore waters coincided with anomalously warm sea surface temperatures. The rapid, widespread decline of this pivotal subtidal predator threatens its persistence and may have large ecosystem-level consequences.

Three steroid-binding globulins, their localization in the brain and nose, and what they might be doing there.

Steroid-binding globulins (SBGs) such as sex hormone binding globulin, corticosteroid binding globulin, and vitamin-D binding protein are receiving increasing notice as being actively involved in steroid actions. This paper reviews data of all three of these SBGs, focusing on their presence and possible activity in the brain and nose. We have found all three proteins in the brain in limbic areas such as the paraventricular (PVN) and supraoptic nuclei (SON) as well as other areas of the hypothalamus, hippocampus, and medial preoptic area. There is also evidence that all three are made in the PVN and SON, in conjunction with the neuropeptides oxytocin and vasopressin. The localization of these three SBGs is more variable within areas of the main olfactory area and the vomeronasal organ. However, all three are found in the mucus of these areas, suggesting that one of their functions is to sequester aerosol steroids, such as pheromones, and deliver them to sensory cells and then to deeper sensory areas. In this manuscript, we present multiple models of SBG action including: A) SBG binding to a membrane receptor, B) this SBG receptor being associated with a larger protein complex including cytoplasmic steroid receptors, C) when the SBGs binds to their SBG receptors, second messengers within the cells respond, D) after SBG binding to its receptor, it releases its associated steroid into the membrane's lipid bilayer, from which it gains access into the cell only when bound by an internal protein, E) the SBG, possibly with its bound SBG receptor, is internalized into the cell from which it can gain access to numerous organelles and possibly the cell's nucleus or F) associate with intracellular steroid receptors, G) SBGs produced in target cells are released from those cells upon specific stimulation, and H) according to the Free Steroid Hypothesis steroids released from the extracellular SBG passively diffuse across the plasma membrane of the cell. These models move the area of steroid endocrinology forward by providing important paths of steroid activity within many steroid target cells.

Effects of endophyte-infected tall fescue seed and red clover isoflavones on rumen microbial populations and physiological parameters of beef cattle.

Lolium arundinaceum [(Darbyshire) tall fescue] toxicosis is responsible for substantial beef production losses in the United States, due to its negative effects on reproduction, growth, and feed efficiency. These effects are consequences of toxic alkaloids within tall fescue. Interseeding legumes, such as Trifolium pratense (red clover), into pastures has been shown to mitigate a portion of these effects. Clovers contain isoflavones, which may play a role in tall fescue toxicosis mitigation. The present study utilized 36 Angus steers to determine the effects of daily supplementation with a red clover-isolated isoflavone feed additive on physiological symptoms of tall fescue toxicosis and the rumen microbial environment over a 21-d period. Angus steers were initially stratified based upon their single nucleotide polymorphism genotype at the DRD2 receptor. Treatments were then randomly assigned in a 2 × 2 factorial arrangement within a completely randomized design, where treatment factors consisted of tall fescue seed type (endophyte-infected tall fescue seed vs. endophyte-free tall fescue seed) supplemented with and without the isoflavone additive. Steers that consumed endophyte-infected tall fescue seed had lower serum prolactin concentrations (P = 0.0007), average daily gain (ADG; P = 0.003), final body weight (BW; P = 0.004), and feed efficiency (P = 0.018) when compared with steers that consumed endophyte-free tall fescue seed. Serum insulin-like growth factor-1 (IGF-1) tended to be reduced with supplementation of isoflavones (P = 0.06) but was unaffected by seed type (P ≥ 0.10) and seed by treatment interaction (P ≥ 0.10). Isoflavones reduced serum glucose levels (P = 0.023), but neither seed type, isoflavones, or their interaction affected serum urea nitrogen (SUN), nonesterified fatty acids (NEFA), or insulin (P ≥ 0.10). Volatile fatty acid concentrations, dry matter intake (DMI), ruminal pH, and overall feeding behaviors were also unaffected by seed type or isoflavone treatments (P ≥ 0.10). Twenty-eight ruminal bacteria taxa shifted as a result of seed type or isoflavone treatment (P < 0.05). In this experiment, feeding isoflavones to Angus cattle did not completely mitigate all symptoms of fescue toxicosis. However, dose-response trials may aid future research to determine if dietary supplementation with isoflavones alleviates fescue toxicosis symptoms and promotes livestock growth and performance.

Fatigue and its management in the workplace.

Fatigue and workplace sleepiness are consequences of modern industrial society. Fatigue is a complex biological phenomenon that occurs as a function of time awake, time-of-day, workload, health, and off-duty lifestyle. Fatigue is a function of two major biological factors - the homeostatic drive for sleep and circadian rhythm of sleepiness. The greatest cause of fatigue is insufficient or disrupted sleep. Excessive sleepiness in the workplace and on highways is a serious safety hazard, and insufficient or disrupted sleep results in numerous accidents and adverse mental and physical health outcomes. Evidence-based strategies that promote better sleep and optimize work/rest schedules can mitigate the impact of fatigue and sleep loss. Proper nap and sleep scheduling, work breaks, modeling and monitoring tools, fatigue detection technologies, and pharmacological countermeasures can be implemented at home and/or in the workplace to reduce performance and safety hazards. Education about obtaining adequate sleep, the dangers of fatigue in terms of both health and cognitive consequences, and the availability of scientifically-proven sleep-enhancement and alertness-management strategies is essential.

Reconfigurable infrared hyperbolic metasurfaces using phase change materials.

Metasurfaces control light propagation at the nanoscale for applications in both free-space and surface-confined geometries. However, dynamically changing the properties of metasurfaces can be a major challenge. Here we demonstrate a reconfigurable hyperbolic metasurface comprised of a heterostructure of isotopically enriched hexagonal boron nitride (hBN) in direct contact with the phase-change material (PCM) single-crystal vanadium dioxide (VO2). Metallic and dielectric domains in VO2 provide spatially localized changes in the local dielectric environment, enabling launching, reflection, and transmission of hyperbolic phonon polaritons (HPhPs) at the PCM domain boundaries, and tuning the wavelength of HPhPs propagating in hBN over these domains by a factor of 1.6. We show that this system supports in-plane HPhP refraction, thus providing a prototype for a class of planar refractive optics. This approach offers reconfigurable control of in-plane HPhP propagation and exemplifies a generalizable framework based on combining hyperbolic media and PCMs to design optical functionality.

Behavioral changes in group-housed dairy calves infected with Mannheimia haemolytica.

Monitoring sickness behavior may improve identification, management, and welfare of sick animals. The objective of this study was to characterize components of sickness behavior in group-housed dairy calves, using an experimental disease challenge model with Mannheimia haemolytica (MH). Holstein bull calves (aged 3-7 weeks; 58.0 ± 12.0 kg of body weight) were group-housed based on age and body weight in sand-bedded pens (6 calves/pen, 6.6 m2/calf) and provided pasteurized waste milk (8 L/d) 2×/d and grain concentrate ad libitum. Within group, calves were randomly assigned to 1 of 2 treatments: (1) inoculation at the tracheal bifurcation with 3 × 109 cfu of MH suspended in 5 mL of sterile phosphate buffered saline (PBS) followed by a 120 mL wash PBS (MH; n = 12, 3/pen), or (2) inoculation with 5 mL + 120 mL of sterile PBS only (control; n = 12, 3/pen). Rectal temperature and health scores were collected from d 0 to +6 of the challenge. A range of behaviors, including feeding patterns and social interactions, were recorded from video from d 0 to +2. The challenge model resulted in calves experiencing a mild disease state: rectal temperatures of MH calves were elevated throughout the challenge compared with control calves, peaking at 12 h postinoculation (39.2 vs. 38.9°C; standard error = 0.14). Many behavioral responses were subject to treatment by day effects, with calves generally becoming less active following inoculation with MH and then returning to baseline. Affected behaviors surrounding feeding included milk feeding time, frequency of competitive displacements, and concentrate feeding time. Lying time was similarly subject to treatment by day effects, and MH calves also spent more time lying on their left side compared with their right (604 vs. 471 min/h; standard error = 32), whereas control calves expressed no laterality. Duration of social lying did not differ, but frequency of social lying bouts decreased in MH calves following inoculation (0.44 vs. 0.75 bouts/h; standard error = 0.04). Social grooming was initiated less by MH calves (0.78 vs. 1.96 min/h; standard error = 0.38), but they tended to receive more social grooming for a greater duration of time (1.59 vs. 1.25 min/h; standard error = 0.13). Overall, we found that infected calves exhibited reduced grooming, feeding, and social interactions, suggesting that these behavioral changes may be useful indicators of early stages of respiratory disease.

Validation of an algorithm to reveal the U wave in atrial fibrillation.

Major cardiac organisations recommend U wave abnormalities should be reported during ECG interpretation. However, U waves cannot be measured in patients with atrial fibrillation (AF) due to the obscuring fibrillatory wave. The aim was to validate a U wave measurement algorithm for AF patients. Multi-beat averaging was applied to ECGs of 25 patients during paroxysms of AF and the presence of U waves compared to those from the same patients during sinus rhythm (SR). In a further database of 10 long-term AF recordings, the number of beats for effective U wave extraction by the algorithm was calculated. U waves were revealed in all AF recordings and there was no significant difference between the presence of U waves in AF and SR (p = 0.88). U wave amplitude was significantly increased in AF (mean (s.d.) amplitude 55 (39) AF vs 37 (28) µV SR, p = 0.005). The presence of U waves could easily be discerned when as few as 10 beats were used in the algorithm. The study demonstrates the validity of the algorithm to reveal U waves in AF recordings. The algorithm offers the potential to detect U wave abnormalities in patients with AF.

Lower cutaneous microvascular reactivity in adult cancer patients receiving chemotherapy.

Cancer patients with a history of anticancer chemotherapy are at an increased cardiovascular disease risk compared with cancer-free populations. Therefore, we tested the hypothesis that cancer patients receiving adjuvant chemotherapy would have a lower cutaneous microvascular reactivity and lower endothelium-dependent flow-mediated dilation (FMD) of the brachial artery compared with matched cancer-free control subjects. To test this hypothesis, we performed a case control study with seven cancer patients receiving adjuvant chemotherapy and seven matched healthy reference control subjects. Red blood cell flux was measured as an index of cutaneous blood flow via laser Doppler flowmetry. Acetylcholine (ACh)-mediated vasodilation was determined by iontophoresis. Data were expressed as percent increase in cutaneous vascular conductance. Endothelium-dependent FMD of the brachial artery via ultrasonography was determined as an index of macrovessel endothelial function. Cutaneous microvascular reactivity was attenuated in cancer patients compared with control subjects [cancer: 959.9 ± 187.3%, control: 1,556.8 ± 222.2%; P = 0.03, effect size (ES) = 1.1]. Additionally, cancer patients demonstrated a significantly lower area under the curve response to ACh iontophoresis compared with healthy control subjects. Brachial artery FMD was also significantly lower in cancer patients compared with control subjects (cancer: 2.2 ± 0.6%, control: 6.6 ± 1.4%; P = 0.006, ES = 1.6), which was significantly associated with measurements of microvascular reactivity. These findings suggest that decreases in vascular reactivity can occur during cancer chemotherapy, which may have implications for the long-term risk of cardiovascular disease morbidity and mortality. NEW & NOTEWORTHY Cancer survivors treated with chemotherapy experience an increased risk of cardiovascular events, linked to both cardiac and vascular toxicity. The major finding of this study is that microvascular reactivity and macrovascular endothelium-dependent flow-mediated dilation are lower in cancer patients currently receiving adjuvant chemotherapy compared with healthy counterparts.