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.

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.

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.

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.

Impact of shear rate pattern on post-occlusive near-infrared spectroscopy microvascular reactivity.

The primary aim of the present study was to determine the impact of acute changes in shear rate patterns, in particular retrograde shear rate, on microvascular function in 15 healthy, young men and women as determined via the post-occlusive near-infrared spectroscopy (NIRS) microvascular reactivity response. Microvascular reactivity, via NIRS-derived measurements of post-occlusion tissue saturation index (TSI%) and total microvascular hemoglobin+myoglobin concentration ([Hb]total), were assessed in each participant before and immediately after exposure to a 30min retrograde shear treatment. Retrograde shear was achieved via a blood pressure cuff placed below the knee inflated to 75mmHg. One leg was exposed to the retrograde shear (Treatment leg) and the contralateral leg served as a non-treatment control. In the Treatment leg, significant increases in retrograde shear rate occurred during the retrograde intervention. Following the intervention, the area under the TSI% post-occlusion response curve, which represents the total microvascular reactivity response, and the absolute peak TSI% response were significantly increased compared to pre-intervention in the Treatment leg, but not the Control leg. The absolute peak [Hb]total response was significantly increased post-intervention in both legs. These results are in contrast to our hypothesis that 75mmHg cuff inflation, designed to increase retrograde shear rate in the femoral artery would negatively affect post-occlusive microvascular reactivity. These data suggest that the current method of increasing retrograde shear rate in the intact human does not adversely impact NIRS derived measurements of microvascular reactivity.

Esophageal IgG4 levels correlate with histopathologic and transcriptomic features in eosinophilic esophagitis.

BACKGROUND: Recent data associate eosinophilic esophagitis (EoE) with IgG4 rather than IgE, but its significance and function have not been determined. Our aims were to measure esophageal IgG4 levels and to determine functional correlations as assessed by histologic and transcriptome analyses. METHODS: This case-control study included pediatric subjects with EoE (≥15 eosinophils/HPF) and non-EoE controls. Protein lysates were analyzed for IgA, IgM, and IgG1-IgG4 using the Luminex 100 system; IgE was quantified by ELISA. Esophageal biopsies were scored using the EoE histology scoring system. Transcripts were probed by the EoE diagnostic panel, designed to examine the expression of 96 esophageal transcripts. RESULTS: Esophageal IgG subclasses, IgA, and IgM, but not IgE, were increased in subjects with EoE relative to controls. The greatest change between groups was seen in IgG4 (4.2 mg/g protein [interquartile range: 1.0-13.1 mg/g protein] vs 0.2 mg/g protein [0.1-0.9]; P < .0001). Tissue IgG4 levels correlated with esophageal eosinophil counts (P = .0006); histologic grade (P = .0011) and stage (P = .0112) scores; and IL4, IL10, IL13, but not TGFB1, expression and had strong associations with a subset of the EoE transcriptome. Esophageal IgG4 transcript expression was increased and correlated with IgG4 protein levels and IL10 expression. CONCLUSION: These findings extend prior studies on IgG4 in adult EoE to the pediatric population and provide deeper understanding of the potential significance and regulation of IgG4, demonstrating that IgG4 is a relevant feature of the disease; is closely related to esophageal eosinophil levels, type 2 immunity and T regulatory cytokines; and is likely produced locally.

One or more bound planets per Milky Way star from microlensing observations.

Most known extrasolar planets (exoplanets) have been discovered using the radial velocity or transit methods. Both are biased towards planets that are relatively close to their parent stars, and studies find that around 17-30% (refs 4, 5) of solar-like stars host a planet. Gravitational microlensing, on the other hand, probes planets that are further away from their stars. Recently, a population of planets that are unbound or very far from their stars was discovered by microlensing. These planets are at least as numerous as the stars in the Milky Way. Here we report a statistical analysis of microlensing data (gathered in 2002-07) that reveals the fraction of bound planets 0.5-10 AU (Sun-Earth distance) from their stars. We find that 17(+6)(-9)% of stars host Jupiter-mass planets (0.3-10 M(J), where M(J) = 318 M(⊕) and M(⊕) is Earth's mass). Cool Neptunes (10-30 M(⊕)) and super-Earths (5-10 M(⊕)) are even more common: their respective abundances per star are 52(+22)(-29)% and 62(+35)(-37)%. We conclude that stars are orbited by planets as a rule, rather than the exception.

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.

Safety of orally administered, USP-compliant levothyroxine sodium tablets in dogs.

The safety of synthetic levothyroxine sodium tablets (Thyro-Tabs® Canine; LLOYD, Inc.) in dogs was evaluated in a randomized, sham-dose controlled, parallel-group study. Young, healthy, euthyroid Beagle dogs were randomized into four groups (four females and four males per group) and received single daily doses of 0×, 2× (0.044 mg/kg), 6× (0.132 mg/kg), or 10× (0.22 mg/kg) the labeled starting dose of 0.022 mg kg-1  day-1 for 182 days. Every 2 weeks, physical examinations, electrocardiology examinations, and sample collections for thyroid panel, hematology, serum biochemistry, coagulation panel, and urinalysis were performed. At the end of the study, the dogs were euthanized and full necropsies performed. The most overt finding was the expected dose-dependent increase in serum concentrations of total and free thyroxine with dose-dependent suppression of the hypothalamic-pituitary-thyroid axis as evidenced by decreased serum thyroid-stimulating hormone concentrations, decreased thyroid+parathyroid/body weight ratios, and a trend for decreased pituitary weight/brain weight ratios. Clinical signs of thyrotoxicosis (excitation, tachypnea, tachycardia) in the treated dogs were sporadic with no dose-response relationship. Other findings statistically associated with levothyroxine treatment were generally mild and not clinically important. In summary, doses of levothyroxine sodium up to 10× the labeled starting dose were well tolerated in healthy dogs.

Neural dysregulation during a working memory task in human immunodeficiency virus-seropositive and hepatitis C coinfected individuals.

Cognitive and functional neural correlates of human immunodeficiency virus (HIV) are only partially understood at present. Variability in neural response, which has been noted in the literature, may relate to clinical factors associated with HIV, including time since HIV diagnosis, CD4 count and nadir, HIV viral load, and comorbid infectious processes, especially hepatitis C. The present investigation evaluated working memory-related functional neural activation in 26 HIV+ participants, 28 demographically matched HIV-seronegative individuals, and 8 HIV+ individuals with hepatitis C coinfection. Analyses examined impact of HIV infection duration, CD4 count and nadir, HIV viral load, and hepatitis C serostatus. Results showed that HIV-seronegative participants had fastest reaction times, and during the working memory task, HIV+ participants with hepatitis C coinfection showed strongest bias toward commission errors; however, signal detection (i.e., overall task performance) was equivalent across groups. Functional magnetic resonance imaging (fMRI) results showed HIV-related greater activation to an easier vigilance task and HIV-related lower activation to a more difficult working memory task, consistent with reduced cognitive reserve. Hepatitis C coinfection related to diffuse neural dysregulation. Correlational analyses suggested relationships of increasingly severe disease with poorer functioning in brain regions linked to error monitoring and attention regulation.

Targeting the wee1 kinase for treatment of pediatric Down syndrome acute myeloid leukemia.

BACKGROUND: Most Down syndrome children with acute myeloid leukemia (DS-AML) have an overall excellent prognosis, however, patients who suffer an induction failure or relapse, have an extremely poor prognosis. Hence, new therapies need to be developed for this subgroup of DS-AML patients. One new therapeutic approach is preventing cell cycle checkpoint activation by inhibiting the upstream kinase wee1 with the first-in-class inhibitor MK-1775 in combination with the standard genotoxic agent cytarabine (AraC). PROCEDURE: Using the clinically relevant DS-AML cell lines CMK and CMY, as well as ex vivo primary DS-AML patient samples, the ability of MK-1775 to enhance the cytotoxicity of AraC was investigated with MTT assays. The mechanism by which MK-1775 enhanced AraC cytotoxicity was investigated in the cell lines using Western blots to probe CDK1 and H2AX phosphorylation and flow cytometry to determine apoptosis, cell cycle arrest, DNA damage, and aberrant mitotic entry. RESULTS: MK-1775 alone had modest single-agent activity, however, MK-1775 was able to synergize with AraC in causing proliferation arrest in both cell lines and primary patient samples, and enhance AraC-induced apoptosis. MK-1775 was able to decrease inhibitory CDK1(Y15) phosphorylation at the relatively low concentration of 100 nM after only 4 hours. Furthermore, it was able to enhance DNA damage induced by AraC and partially abrogate cell cycle arrest. Importantly, the DNA damage enhancement appeared in early S-phase. CONCLUSIONS: MK-1775 is able to enhance the cytotoxicity of AraC in DS-AML cells and presents a promising new treatment approach for DS-AML.

An active role for steroid-binding globulins: an update.

It has been 7 years (can it really be that long?) since we co-edited a volume (#38) of Hormone and Metabolic Research that focused on evidence that steroid-binding globulins play an active role in the actions of steroids. There has been considerable progress in identifying the location, the physiological actions, and of determining the role of binding globulins in the actions of steroids and identifying a membrane-associated receptor for a binding protein since then and this review will discuss this progress.

Colocalization of p450 aromatase and oxytocin immunostaining in the rat hypothalamus.

With combined immunoperoxidase and immunofluorescence, we observed colocalization of cytochrome P450 aromatase with the posterior lobe peptide oxytocin and its associated neurophysin 1 in adult male rats. P450 was most abundant in the anterior hypothalamus. Colocalization of OT with P450 was observed in the preoptic region, the periventricular nucleus of the hypothalamus, the lateral subcommissural nucleus, and in the zona incerta. Magnocellular perikarya in the supraoptic and in the paraventricular nuclei contained only occasionally both antigens. P450 immunostaining overlapped to a great extent with known estrogen target regions. Oxytocinergic functions are controlled by estradiol while androgen receptors are mostly absent in neuroendocrine hypothalamic nuclei. Our findings suggest that systemic androgens may be aromatized to estrogens in male oxytocinergic neurons linked to the limbic system.

Bilayer graphene grown on 4H-SiC (0001) step-free mesas.

We demonstrate the first successful growth of large-area (200 × 200 µm(2)) bilayer, Bernal stacked, epitaxial graphene (EG) on atomically flat, 4H-SiC (0001) step-free mesas (SFMs) . The use of SFMs for the growth of graphene resulted in the complete elimination of surface step-bunching typically found after EG growth on conventional nominally on-axis SiC (0001) substrates. As a result heights of EG surface features are reduced by at least a factor of 50 from the heights found on conventional substrates. Evaluation of the EG across the SFM using the Raman 2D mode indicates Bernal stacking with low and uniform compressive lattice strain of only 0.05%. The uniformity of this strain is significantly improved, which is about 13-fold decrease of strain found for EG grown on conventional nominally on-axis substrates. The magnitude of the strain approaches values for stress-free exfoliated graphene flakes. Hall transport measurements on large area bilayer samples taken as a function of temperature from 4.3 to 300 K revealed an n-type carrier mobility that increased from 1170 to 1730 cm(2) V(-1) s(-1), and a corresponding sheet carrier density that decreased from 5.0 × 10(12) cm(-2) to 3.26 × 10(12) cm(-2). The transport is believed to occur predominantly through the top EG layer with the bottom layer screening the top layer from the substrate. These results demonstrate that EG synthesized on large area, perfectly flat on-axis mesa surfaces can be used to produce Bernal-stacked bilayer EG having excellent uniformity and reduced strain and provides the perfect opportunity for significant advancement of epitaxial graphene electronics technology.

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.

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.

Heart failure, diastolic dysfunction and atrial fibrillation; mechanistic insight of a complex inter-relationship.

Atrial fibrillation (AF) and heart failure (HF) commonly coexist, and their co-presence is associated with adverse outcomes relating to thromboembolic events, HF progression, hospitalisation and death. Diastolic dysfunction (DD) is also frequently present in patients with HF and is an independent predictor of hospitalisation and mortality. The presence of DD is a strong predictor of incident AF in patients with HF. In this review, we provide mechanistic insight into pathophysiological processes that frequently promote the occurrence of AF, HF and DD and outline the yin-yang relationship between AF, DD and HF. More recently, invasive studies have also shown that asymptomatic paroxysmal atrial fibrillation (PAF) is a common phenomenon in HF patients. We examine complex inter-relationships between PAF, HF and DD and speculate upon the possible clinical influence of undiagnosed PAF in HF patients.

Pitch-dependent resonances and near-field coupling in infrared nanoantenna arrays.

We investigate coupling in arrays of nanoparticles resonating as half-wave antennas on both silicon and sapphire, and find a universal behavior when scaled by antenna length and substrate index. Three distinct coupling regimes are identified and characterized by rigorous finite-difference time domain simulations. As interparticle pitch is reduced below the oft-described radiative to evanescent transition, resonances blue shift and narrow and exhibit an asymmetric band consistent with a Fano lineshape. Upon further pitch reduction, a transition to a third regime, termed here as near-field coupling, is observed in which the resonance shifts red, becomes more symmetric, and broadens dramatically. This latter regime occurs when the extension of the resonant mode beyond the physical antenna end overlaps that of its neighbor. Simulations identify a clear rearrangement of field intensity accompanying this regime, illustrating that longitudinal modal fields localize in the air gap rather than in the higher index substrate at a pitch consistent with the experimentally observed transition.

Sex-related differences in the relationship between acceleromyographic adductor pollicis train-of-four ratio and clinical manifestations of residual neuromuscular block: a study in healthy volunteers during near steady-state infusion of mivacurium.

BACKGROUND: Studies in volunteers suggest that train-of-four (TOF) ratios >0.9 are needed to retain normal function of muscles involved in upper airway patency, swallowing, and vital capacity breathing. We determined if sex-related differences exist in the relationship between adductor pollicis (AP) TOF ratio and measures of neuromuscular function commonly used to assess recovery from neuromuscular block. METHODS: In 10 males and 10 females, three steady-state levels of neuromuscular block were achieved with mivacurium infusions. TOF ratio was measured with acceleromyography at the AP. Hand grip strength and the ability to clench the teeth, raise the head >5 s, swallow, protrude the tongue, and open the eyes were tested at each stable block level and reconciled to uncorrected and normalized (pre-paralysis values) TOF measures. These relationships were compared between sexes. RESULTS: The ability to clench teeth and head raise >5 s was lost at a significantly greater TOF ratio in males than females. The percentage decrease in handgrip strength with decreasing TOF ratio was proportionally greater in males than females. Forty per cent of the males were unable to clench the teeth at an uncorrected TOF ratio >0.9. When TOF ratios were normalized, clinical functions showed no decrement at TOF ratio >0.9 in any volunteer. CONCLUSIONS: Sex-related differences exist in the relationship between AP TOF ratio and clinical measures of muscle function used to assess recovery from neuromuscular block. Normalization of AP TOF ratios is recommended because a non-normalized TOF ratio of 0.9 does not guarantee adequate reversal of neuromuscular block.