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PurposeNeurite orientation dispersion and density imaging (NODDI) provides measures of neurite density and dispersion through computation of the neurite density index (NDI) and the orientation dispersion index (ODI). However, NODDI overestimates the cerebrospinal fluid water fraction in white matter (WM) and provides physiologically unrealistic high NDI values. Furthermore, derived NDI values are echo time (TE)-dependent. In this work, we propose a modification of NODDI, named constrained NODDI (C-NODDI), for NDI and ODI mapping in WM.MethodsUsing NODDI and C-NODDI, we investigated age-related alterations in WM in a cohort of 58 cognitively unimpaired adults. Further, NDI values derived using NODDI or C-NODDI were correlated with the neurofilament light chain (NfL) concentration levels, a plasma biomarker of axonal degeneration.ResultsODI derived values using both approaches were virtually identical. We confirm the previous finding that NDI estimation using NODDI is TE-dependent. In contrast, C-NODDI-NDI exhibit lower susceptibility to TE. Further, C-NODDI-NDI values were lower than NODDI-NDI. Further, our results indicate a quadratic relationship between NDI and age suggesting that axonal maturation continues until middle age followed by a decrease. This quadratic association was notably significant in several WM regions using C-NODDI, while limited to a few regions using NODDI. ODI exhibited overall constant trends with age. Finally, C-NODDI-NDI values exhibited a stronger correlation with NfL concentration levels as compared NODDI-NDI, with lower NDI values correspond to higher levels of NfL.ConclusionsC-NODDI provides a complementary method to NODDI for determination of NDI in white matter in normative aging.

The g‐ratio, defined as the inner‐to‐outer diameter of a myelinated axon, is associated with the speed of nerve impulse conduction, and represents an index of axonal myelination and integrity. It has been shown to be a sensitive and specific biomarker of neurodevelopment and neurodegeneration. However, there have been very few magnetic resonance imaging studies of the g‐ratio in the context of normative aging; characterizing regional and time‐dependent cerebral changes in g‐ratio in cognitively normal subjects will be a crucial step in differentiating normal from abnormal microstructural alterations. In the current study, we investigated age‐related differences in aggregate g‐ratio, that is, g‐ratio averaged over all fibers within regions of interest, in several white matter regions in a cohort of 52 cognitively unimpaired participants ranging in age from 21 to 84 years. We found a quadratic, U‐shaped, relationship between aggregate g‐ratio and age in most cerebral regions investigated, suggesting myelin maturation until middle age followed by a decrease at older ages. As expected, we observed that these age‐related differences vary across different brain regions, with the frontal lobes and parietal lobes exhibiting slightly earlier ages of minimum aggregate g‐ratio as compared to more posterior structures such as the occipital lobes and temporal lobes; this agrees with the retrogenesis paradigm. Our results provide evidence for a nonlinear association between age and aggregate g‐ratio in a sample of adults from a highly controlled population. Finally, sex differences in aggregate g‐ratio were observed in several cerebral regions, with women exhibiting overall lower values as compared to men; this likely reflects the greater myelin content in women's brain, in agreement with recent investigations., Using quantitative MRI, we investigated age‐related differences in aggregate g‐ratio in several white matter regions in a cohort of 52 cognitively unimpaired participants ranging in age from 21 to 84 years. We found a quadratic, U‐shaped, relationship between aggregate g‐ratio and age in most cerebral regions investigated. Sex differences were also observed in several cerebral regions.

To characterize the relationship between objective tympanogram values and patient-reported symptoms and associations with common comorbid conditions.Cross-sectional study with prospective data collection.Tertiary medical center.Patients undergoing routine audiometric evaluation between October 2018 and June 2019 were included. Participants with temporomandibular joint dysfunction, inner ear hydrops, and similar conditions were excluded. Symptoms were assessed with the 7-item Eustachian Tube Dysfunction Questionnaire. Demographics and medical comorbidities were recorded from the medical record. Analysis of tympanometric peak pressure (TPP), demographics, and comorbidities was performed to determine associations with clinically significant eustachian tube dysfunction (ETD) symptoms.A total of 250 patients were included with similar demographics: 101 (40.4%) in the asymptomatic group and 149 (59.6%) in the symptomatic group. The median (interquartile range) TPP was -10 (20) daPa and -25 (100) daPa in the asymptomatic and symptomatic groups, respectively. A diagnosis of rhinitis was more likely to be associated with significant ETD symptoms (adjusted odds ratio, 2.61; 95% CI, 1.23-5.63). A subgroup analysis revealed that symptomatic patients with normal TPP values were negatively skewed as compared with asymptomatic patients. This symptomatic group had a higher prevalence of rhinitis and chronic rhinosinusitis than the asymptomatic group.Patients with symptoms of ETD may have a TPP within a range typically considered normal per conventional standards. This suggests that the currently accepted interpretation of tympanometry findings may be insensitive for the diagnosis of less severe cases of ETD.

Chapter 2 focuses extensively on major events in the royal family’s early years in England (1603-1612) and Lennox’s involvement. His hand can be found in almost all that shaped their lives, participating in the coronation for James and Anne and the subsequent civic pageant honoring them. James immediately appointed Lennox to the Privy Council and made him head of the Gentlemen of the Bedchamber. The years 1610-1612 concentrate on Prince Henry beginning with his installation as Prince of Wales. In late 1612 Henry became ill and died on 6 of November. Lennox served as “chief supporter” to Prince Charles, the chief mourner in the funeral procession.

This chapter focuses on Lennox’s political activities, diplomatic missions, and participation in the arts. On several occasions King James dispatched Lennox back to Scotland to wrangle with the Scottish Parliament. Lennox was also sent as emissary to France to solidify relationships and engage in marriage negotiations for Charles. Lennox regularly entertained and intervened for foreign ambassadors in London. In 1613 James made Lennox Earl of Richmond, enabling him to sit in Parliament. He became Lord Steward of the Household in 1616, and in 1623 Duke of Richmond. Early on Lennox became patron of his own acting company; he arranged the first Jacobean court masque, and he performed in several masques.

The complex immunosuppressive nature of solid tumor microenvironments poses a significant challenge to generating efficacious and durable anticancer responses. Photoimmunotherapy is a cancer treatment strategy by which an antibody is conjugated with a non-toxic light-activatable dye. Following administration of the conjugate and binding to the target tumor, subsequent local laser illumination activates the dye, resulting in highly specific target cell membrane disruption. Here we demonstrate that photoimmunotherapy treatment elicited tumor necrosis, thus inducing immunogenic cell death characterized by the release of damage-associated molecular patterns (DAMPs). Photoimmunotherapy-killed tumor cells activated dendritic cells (DC), leading to the production of proinflammatory cytokines, T cell stimulation, priming antigen-specific T cells, and durable memory T cell responses, which led complete responder mice to effectively reject new tumors upon rechallenge. PD-1 blockade in combination with photoimmunotherapy enhanced overall anticancer efficacy, including against anti-PD-1-resistant tumors. The combination treatment also elicited abscopal anticancer activity, as observed by reduction of distal, non-illuminated tumors, further demonstrating the ability of photoimmunotherapy to harness local and peripheral T cell responses. With this work we therefore delineate the immune mechanisms of action for photoimmunotherapy and demonstrate the potential for cancer-targeted photoimmunotherapy to be combined with other immunotherapy approaches for augmented, durable anticancer efficacy. Moreover, we demonstrate responses utilizing various immunocompetent mouse models, as well as in vitro data from human cells, suggesting broad translational potential.

Chapter 3 begins with the preparations for and the celebration of Princess Elizabeth’s wedding to Prince Frederick of Germany on 14 February 1613, as the court moved away from Henry’s death. Lennox participated fully in all the activities associated with the wedding. Then, at James’s request, Lennox accompanied the princess on her journey to her new home in Germany. Lennox continued to execute numerous tasks given to him by the king. In1616, he was central in the events associated with Charles’s investiture as Prince of Wales. Lennox also skillfully negotiated his relationships with two of the king’s favourites: Robert Carr and George Villiers.

This chapter explores Lennox’s time from his arrival in Scotland as a 9-year-old boy from France in November 1583 until the departure for England in 1603. Having been invited to Scotland by his cousin King James VI, Lennox quickly developed skills that would enable him to serve the king, which he did faithfully. He overcame initial unfamiliarity with Scotland’s culture and politics. When James went to Denmark to marry Princess Anne in 1589, he put the 15-year-old Lennox in charge of the government, a task which he handled well, as he did many other offices. This chapter discusses Lennox’s two marriages, his siblings, who also arrived from France, and his relationships with the royal family. The king invited Lennox to go with him to England after Queen Elizabeth’s death.

This is the first biography of Ludovic Stuart, Duke of Lennox, who served King James VI of Scotland/ I of England from his arrival in 1583 in Scotland until his untimely death in February 1624. Lennox arrived as a 9-year-old boy from France, a cousin of the king. For the next 40 years Lennox served James faithfully and skillfully, becoming the quintessential courtier, James’s confidant, adviser, and friend. Shrewd politician, ambitious and sometimes ruthless, but also beloved by the royal family, Lennox carefully negotiated political and diplomatic minefields. He also participated in the arts as patron and performer, sponsoring his own acting company, attending drama performances and dancing in several court masques. This book explores his private life as well, his three marriages, his relationships with his siblings, his illegitimate son, and life with the royal family. This biography covers the politics and cultural life of the Jacobean court in Scotland and England and Lennox’s unparalleled importance, without whom our knowledge of King James is incomplete.

The Introduction establishes the essential argument of the book: that Lennox was the most important courtier in the Jacobean court from his arrival from France in 1583 until his death in 1624. This section sketches the evidence for this claim in his political, diplomatic, and personal life. The Introduction outlines the organization of the biography, chapter by chapter. It also discusses the research involved in the biography.

This final chapter has three parts: marriage, letters, death and funeral. Lennox married the widow Frances Howard in June 1621, just a few weeks after her former husband’s death. This seems to have been Lennox’s only successful marriage. Numerous personal letters receive attention; they open additional insights into Lennox. While asleep, Lennox died unexpectedly on 16 February 1624, shocking the nation. His death was a major blow to the king and Prince Charles. Numerous writers responded to his death with elegies and tributes. James postponed the opening of Parliament, and he arranged for an elaborate funeral on 19 April. Hundreds of noblemen, clergy and others joined the funeral procession as it made its way to Westminster Abbey at which Lennox received exceptional praise.

Voice is a risky and more challenging type of organizational citizenship behavior in that it is designed to bring about change. Using conservation of resources and social exchange theories, we investigate relationships between voice, perceptions of organizational politics, and perceived organizational support (POS). We also investigate the mediating role of POS in the politics–voice relationship to determine the extent to which POS can explain this relationship. Lagged survey data from supervisor–employee dyads ( N = 257) were collected 6 weeks apart. Results show that perceptions of organizational politics were negatively related to voice, while POS was positively related to voice. POS had a mediating effect on the relationship between perceptions of organizational politics and voice. Our results underscore the importance of contextual factors in encouraging or prohibiting voice and may help managers and organizations understand how best to encourage this important change-oriented workplace behavior.

The relationship between regional brain myelination and aging has been the subject of intense study, with magnetic resonance imaging perhaps the most effective modality for elucidating this. However, most of these studies have used nonspecific methods to probe myelin content, including diffusion tensor imaging, magnetization transfer ratio, and relaxation times. In the present study, we used the BMC-mcDESPOT analysis, a direct and specific method for imaging of myelin water fraction (MWF), a surrogate of myelin content. We investigated age-related differences in MWF in several brain regions in a large cohort of cognitively unimpaired participants, spanning a wide age range. Our results indicate a quadratic, inverted U-shape, relationship between MWF and age in all brain regions investigated, suggesting that myelination continues until middle age followed by decreases at older ages. We also observed that these age-related differences vary across different brain regions, as expected. Our results provide evidence for nonlinear associations between age and myelin in a large sample of well-characterized adults, using a direct myelin content imaging method.

Resume Contexte Il existe de plus en plus de preuves sur les roles et les impacts du pharmacien. Les decideurs, les gestionnaires en sante, les cliniciens et les patients ont besoin de preuves afin de soutenir une repartition appropriee des fonds aux differents modeles de pratique envisages. Objectifs L’objectif principal est de presenter un etat des lieux entourant les roles et les impacts de l’activite pharmaceutique dans la litterature internationale. Methodes Revue de litterature. Les articles relies aux roles et impacts du pharmacien ont ete selectionnes selon une strategie de recherche reproductible de 1990 a nos jours (francais/anglais avec description de l’intervention et des impacts, lorsqu’applicable) et un mode operatoire normalise. Les variables suivantes ont ete extraites : auteur, pays, devis, activites pharmaceutiques, programmes de soins, pathologies ciblees, impacts selon huit marqueurs (mortalite, morbidite, couts, evenements indesirables, erreurs medicamenteuses, observance, satisfaction, autres) et score de qualite. Seules des statistiques descriptives ont ete effectuees. Resultats Au 1er fevrier 2019, nous avons recense 2424 articles repartis en 100 sujets (41 activites pharmaceutiques, 30 pathologies, 29 programmes de soins). Les etudes proviennent notamment des Etats-Unis (46,66 %), de pays multiples (8,00 %), du Canada (7,67 %), de France (6,06 %), du Royaume-Uni (5,19 %), d’Australie (3,50 %) et d’autres pays (22,92 %). Les etudes sont de type transversale (47,55 %), retrospective (33,68 %) et prospective (17,87 %) ou non categorisee ( Conclusion Cette revue de litterature confirme les roles et les impacts de l’activite pharmaceutique pour differents milieux de pratique. Une majorite des interventions pharmaceutiques etudiees comportent des impacts positifs. Il est essentiel de considerer les preuves relatives aux roles et aux impacts de l’activite pharmaceutique pour profiter pleinement de l’expertise du pharmacien dans les soins de sante.