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Once-daily dosing with dasotraline, a novel dopamine and norepinephrine reuptake inhibitor, achieves stable plasma concentrations over 24 hours. This phase 3 study evaluated the efficacy and safety of dasotraline in children with attention deficithyperactivity disorder (ADHD) throughout the day, in a laboratory classroom setting (NCT02734693).
Children (6–12 years) meeting DSM-5 criteria for ADHD were randomized to 2 weeks of dasotraline or placebo (dosed daily at home at approximately 8 PM). Following an abbreviated practice day, laboratory classroom evaluations took place at baseline and on Day 15. The primary endpoint was mean change from baseline at Day 15 in ADHD symptoms, as measured by the Swanson, Kotkin, Agler, M-Flynn, and Pelham Combined Score (SKAMP-CS), obtained from the average of 7 assessments collected across the 12-hour laboratory classroom day (12–24 hours post-dose). Secondary endpoints included SKAMP scores obtained throughout the day at individual timepoints from 8 AM through 8 PM (12–24 hours post-dose), and measures of safety and tolerability.
The ITT population comprised 112 patients. Mean age was 9.5 years, 68.8% were male; 92% completed the study. Dasotraline 4 mg/day significantly improved mean SKAMP-CS versus placebo (p<0.0001, effect size 0.85) with significant effects persisting throughout the day. Mean SKAMP subscores improved significantly versus placebo (Attention p<0.0001, effect size 0.81; Deportment p<0.001, effect size 0.70). Treatment-emergent adverse events were generally mild or moderate in severity; most frequent (with dasotraline 4 mg/day; placebo) included: insomnia (19.6%; 3.6%, all terms combined), decreased appetite (10.7%; 3.6%), headache (10.7%; 8.9%), affect lability (8.9%; 7.1%), irritability (5.4%; 3.6%), postural orthostatic tachycardia syndrome (5.4%; 0%), and perceptual disturbances (5.4%; 0%).
In this 2-week, randomized, double-blind, laboratory classroom study in children with ADHD, once-daily dasotraline significantly improved ADHD symptoms (including deportment and attention), compared with placebo, and demonstrated sustained efficacyup to 24 hours post-dose. The most common adverse events were insomnia, decreased appetite, and headache.
Once-daily dosing with dasotraline, a novel dopamine and norepinephrine reuptake inhibitor, achieves stable plasma concentrations over 24 hours with once-daily dosing. This study evaluated dasotraline in children aged 6–12 years (NCT02428088).
Patients were randomized 1:1:1 to 6 weeks of once-daily, fixed-dose dasotraline 2 or 4 mg/day, or placebo. The primary efficacy endpoint was change from baseline (CFB) at Week 6 in ADHD Rating Scale Version IV – Home Version (ADHD RS-IV HV) total score, using a mixed model for repeated measures (MMRM) in the intent-to-treat (ITT) population. Secondary endpoints included Clinical Global Impression-Severity (CGI-S) score and safety endpoints.
The mean age of 342 randomized patients was 9.1 [SD: 1.9] years; 66.7% were male. Overall, 79% of patients completed the study. In the ITT population (N=336), ADHD RS-IV HV total score improved significantly with dasotraline 4 mg/day vs placebo(least squares [LS] mean [SE] CFB at Week 6: –17.53 [±1.31] vs –11.36 [±1.29], respectively, p<0.001; effect size [ES]: 0.48). Inattentiveness and hyperactivity/impulsivity subscale scores significantly improved with 4 mg/day vs placebo at Week 6 (p=0.001, p=0.003, respectively). Improvement in CGI-S score was statistically significant with dasotraline 4 mg/day vs placebo(LS mean [SE] CFB at Week 6: –1.39 [±0.12] vs –1.04 [±0.12], respectively, p=0.040; ES: 0.29). No significant improvement was observed on the ADHD RS-IV HV total score and the CGI-S score for dasotraline 2 mg/day vs placebo. The most frequent treatment-emergent AEs (≥5% and higher than placebo) were (2 mg/day; 4 mg/day; placebo): insomnia (15.3%; 21.7%; 4.3%, all terms combined), decreased appetite (12.6%; 21.7%; 5.2%), weight loss (5.4%; 8.7%; 0%), irritability (3.6%; 7.0%; 6.0%), nasopharyngitis (0.9%; 5.2%; 0.9%), and nausea (0%; 5.2%; 2.6%).
Compared with placebo, dasotraline 4 mg/day significantly improved ADHD symptoms in children, as assessed by ADHD RS-IV HV total score and inattentiveness and hyperactivity/impulsivity subscale scores. Dasotraline was generally well tolerated; most common AEs were insomnia, decreased appetite, weight loss and irritability.
Binge eating disorder (BED) is the most common eating disorder in the US, with a lifetime prevalence of 2.8%. Disturbances in reward circuitry have been implicated in its pathogenesis. Dasotraline is a novel and potent dopamine and norepinephrine reuptake inhibitor with slow absorption and a long half-life resulting in stable plasma concentrations over 24 hours with once-daily dosing. This study evaluated the efficacy and safety of flexibly-dosed dasotraline (4, 6, and 8 mg/day) vs placebo in adults with moderate to severe BED over a 12-week period (NCT02564588).
Key inclusion criteria included moderate to severe BED based on a history of ≥2 binge eating days/week for ≥6 months prior to screening, and ≥3 binge eating days for each of2 weeks prior to randomization, as documented in participant’s binge eating diary. Patients were randomized 1:1 to flexibly-dosed dasotraline (4, 6, 8 mg/day) or placebo. Theprimary endpoint was change from baseline (CFB) in the number of binge eating days per week at Week 12. Key secondary endpoints were: CFB in Clinical Global Impression–Severity (CGI-S) Scale at Week 12; CFB in Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating (YBOCS-BE) at Week 12; and the percentage ofsubjects with a 4-week cessation from binge eating prior to Week 12 or end of treatment (EOT). Except for 4-week cessation, the other three variables were analyzed using amixed model for repeated measures (MMRM).
317 subjects (84% female) received ≥1 dose of study medication (mean age was 38.2 years; mean number of binge eating days per week, 4.25; mean CGI-S score, 4.5; mean BMI, 34.7). The MMRM analysis of CFB at Week 12 in the number of binge days/week yielded a significant mean difference of –0.99 (95% CI: –0.65 to –1.33; p<0.001) infavour of dasotraline (–3.74 in the dasotraline group vs –2.75 in the placebo group). All three key secondary endpoints were met at Week 12 or EOT: 46.5% of subjects in thedasotraline group achieved at least 4 consecutive weeks’ cessation from binge eating vs 20.6% in the placebo group (p<0.001); CFB in CGI-S and YBOCS-BE scores were also statistically significant in favour of dasotraline (p<0.001). The treatment-emergent adverse events (TEAEs) that occurred more frequently with dasotraline vs placebo at >2% incidence included: insomnia (44.6% vs 8.1%), dry mouth (27.4% vs 5.0%), decreased appetite (19.7% vs 6.9%), anxiety (17.8% vs 2.5%), nausea (12.7% vs 6.9%) and decreased body weight (12.1% vs 0%). Discontinuation due to AEs occurred in 11.5% of patients taking dasotraline vs 2.5% taking placebo.
In adults with moderate to severe BED, there were highly significant and clinically meaningful reductions with dasotraline vs placebo in the frequency of binge eating, global severity of illness, and obsessive-compulsive symptoms related to binge eating. These results suggest dasotraline may offer a novel, well-tolerated and efficacious treatmentfor BED.
The impact of mass and lattice difference on thermal boundary conductance is investigated using non-equilibrium molecular dynamics with the Lennard-Jones interatomic potential. Results show that the maximum thermal boundary conductance is achieved when the mass and the lattice of two dissimilar materials are matched, although the composite thermal conductance is not necessarily a maximum. It is observed that the small difference in mass and potential well depth has as significant an impact as large differences, and that the frequency mismatch is an important factor that affects thermal boundary conductance. It is, also, found that inelastic scattering begins to play a role at the interface as the temperature increases.
Selectively-absorbing nanofluids were synthesized and evaluated for spectrum splitting PV/T collector applications. Core-shell silver-silica (Ag-SiO2) nanodiscs and multi-walled carbon nanotubes (MWCNTs) were suspended in water at varying dilutions and then tested as an optical filter placed between a light source and silicon solar cell. A concentrated Ag-SiO2 solution diluted with an aqueous MWCNT solution yielded higher thermal efficiencies than when diluted by the same volume of water. However, AgSiO2-MWCNT mixtures yielded a lower electrical output than aqueous AgSiO2 dilutions due to the non-selective absorption of MWCNTs. The most concentrated Ag-SiO2 nanofluid (0.026wt%) yielded a peak thermal efficiency of 65%, to deliver the greatest combined efficiency of ∼72%.
I argue that authentic photography is not able to develop to the full as a communicative representational art. Photography is authentic when it is true to its self-image as the imprinting of images. For an image to be imprinted is for its content to be linked to the scene in which it originates by a chain of sufficient, mind-independent causes. Communicative representational art (in any medium: photography, painting, literature, music, etc.) is art that exploits the resources of representation to achieve artistically interesting communication of thought. The central resources of representation are content, vehicle properties, and the interplay between these two. Whereas painting and other representational arts are able to exploit all three to communicate thought, authentic photography can exploit interplay only to a very limited degree. However, the exploitation of interplay is the culmination of communicative representational art: the natural endpoint in its development.
Scholarly assessments of Chaucer's fabliaux seldom acknowledge that these tales are erotic as well as funny; even less frequently do such investigations delve into why fabliaux are a source of pleasure. As Tom Hanks and W. W. Allman note in their article ‘Rough Love: Notes toward an Erotics of The Canterbury Tales’, scholars seem ‘to have averted their gaze when Chaucer's characters leap into bed’. Allman and Hanks, as their title implies, study an erotics of violence, mostly of men doing violence to women, and they focus in particular on the Merchant's Tale and its ‘erotics of stabbing’. A more positive erotic reading of the Merchant's Tale appears in Andrew Taylor's 1996 essay ‘Reading the Dirty Bits’. Taylor notes the lingering gaze of another scholar, E. Talbot Donaldson, upon a description of young May's body:
Hir fresshe beautee and hir age tendre,
Hir myddel smal, hire armes longe and sklendre,
Hir wise governaunce, hir gentilesse,
Hir wommanly berynge, and hire sadnesse.
Donaldson writes, ‘the Spring of pretty young girls is a permanent thing, and that May in their personas will always warm the masculine heart’. Taylor suggests that pleasure taken in this description and in Donaldson's gloss of it is mimetic: ‘For the young college man to share Donaldson's and Chaucer's pleasure in May is to become, like them, a connoisseur of both good writing and pretty girls, a master of ironic detachment and well-modulated heterosexual desire’.
In the late fifteenth-century Squire of Low Degree, the incompetent protagonist woos a Hungarian princess in a way that seems to subject the romance genre to derivative, almost parodic, excess. This excess, however, offers particular insight into the representation of wooing in Middle English romance more broadly. While many romance heroines assume their suitors will display knightly prowess to win their love, this princess seems so aware of the Squire's shortcomings that she explains to him precisely what he must do, focusing on the rather boy-scout-like logistics of riding ‘Over hylles and dales, and hye mountaines, / In wethers wete, both hayle and raynes’, and lodging ‘under a tre, / Among the beastes wyld and tame’. Reminiscent here of how a Sir Thopas might understand chivalry, the text continues its overzealous attempt to ape romance when the princess exhaustively details the accoutrements that she expects from a suitor (203–30), and it is equally unable to find the right register when she offers to bankroll his required adventures (251–5). The envious steward's attempts to ruin the Squire by exposing his amorous inclinations are predictable enough; the results, however, have been seen as uncharacteristic of romance, since the king does not object to the Squire courting his daughter, but rather instructs the steward:
In her 2007 essay ‘“Wordy vnthur wede”: Clothing, Nakedness and the Erotic in some Romances of Medieval Britain’, Amanda Hopkins examines the interplay of clothing and nudity in creating erotic moments, noting the connection of eroticism with female aggression on the one hand, and the erotic link between female nudity and passivity on the other. Lancelot's encounter with Elaine at Corbyn in Malory's Morte Darthur is marked by erotic moments featuring female nudity that appear emblematic of the latter. The eroticism of the moment when Lancelot rescues the ‘dolerous lady’ (2.791) from the boiling water by taking her by the hand, ‘naked as a nedyll’ (2.792), depends both on her total nudity and her status as victim – that is to say that the moment is erotic not just because she is naked, but because that nudity is not of her own making. Later, when Elaine ‘skypped oute of her bedde all naked’ (2.795) and kneels at Lancelot's feet to beg for her life, both her nudity and her vulnerability work to produce an erotic effect. Certainly Lancelot quickly changes his mind and turns from threatening her to embracing her. Yet to view Elaine as completely passive is a mistake – at the least her passivity is manipulated and Lancelot's presence in her bed is the result of machinations in which Elaine plays a willing part.
George Ripley, in his apostrophic preface to God in the Compound of Alchemy, claims to have ‘renounced … fleshly lust’ and asks God to provide him (and, presumably, other worthy alchemists) with His ‘secret treasure’: ‘Shew us thy secrets and to us be bounteous’ (21.4). Throughout the Compound, Ripley guides readers away from worldly pleasures, urging them instead to focus their desires on God-granted alchemical secrets and ‘our stone of great delight’ (37.2). Likewise, Thomas Norton, in his prologue to the Ordinal of Alchemy, warns of avaricious would-be alchemists who ‘in fyre / Of brennyng couetise haue therto desire’ (27–8). Norton emphatically shuns ‘wordly werkis’ in favour of alchemical ‘connyng’, advising his reader to ‘sett fully his trust’ in God and ‘in connyng be fixid al his lust’ (509, 517, 535–6): ‘For above all erthlye thynge / I mooste desire & love connynge’ (2595–6). Desire or lust, in both the Compound and the Ordinal, is thus redirected from the physical body and material world toward the divinely inspired knowledge of the alchemical corpus. Moreover, as I will illustrate, Norton and Ripley both direct their reader to focus on the text's rhetorical structures in order to achieve desired alchemical objectives.
In her seminal 1980 essay Pouvoirs de l'horreur, Julia Kristeva identifies ‘the abject’ as the human reaction to a breakdown in meaning caused by the loss of distinction between the subject and the object, the interior and the exterior, or the self and the Other. Her classic example of a site of abjection is that of the human corpse, which although a continuation of the dead person's corporeal presence also becomes simultaneously a marker of his or her spiritual absence, and thus must be rejected or repressed, causing the subjective experience of ‘horror’. Kristeva argues that human rationality necessarily involves a series of such repressions, and that the association of the human with the unrepressed thus becomes a site of potential tension. ‘The abject confronts us’, she suggests, ‘with those fragile states where man strays on the territories of animal’. This borderland between the acceptable and the unacceptable thus becomes the site of the carnivalesque, the comedic and the socially transgressive, as attested by post-medieval writers from Rabelais to Bakhtin and beyond.
In the first decade of the sixteenth century, the abject was also a major concern for the poet William Dunbar, writing at the court of King James IV. Dunbar's poems are critically regarded as some of the most brilliant – and, frequently, the most offensive – writings produced in late medieval/ early modern Scotland. Many of his satirical pieces depict the court of James (who would later go on to lose his life at the disastrous Battle of Flodden) at play, simultaneously parodying and affirming the excesses of late medieval/Renaissance aristocratic culture.
Sir Thopas's resolution to forsake human women in order to seek out an elf-queen as his lover satirizes one of the most well-known romance motifs: the fairy mistress who offers herself to the human protagonist of the narrative. It is characteristic of this motif that, with relatively few exceptions, the fairy offers sexual intercourse to the hero without any demand for the commitment of marriage and without stipulating any directly connected negative consequences. The motif's origins are a good deal earlier than those of romance – it features in several early medieval Irish narratives – but it is with romance that the motif is most particularly associated. It is noticeable that this extramarital sex is generally not explicitly condemned in the romances. Of course, romance authors are not prone to sermonizing digressions, so this might be passed over as merely a reflex of the genre; however, condemnation need not be overtly stated to still be clear and, in this respect, romance differs markedly from fabliaux, the other genre which frequently portrays extra-marital sex.
As Roger Ascham famously observed, Malory's Morte Darthur is primarily concerned with ‘open manslaughter, and bold bawdry’. I would not disagree; in fact, I would say that these themes are not only dominant but are inextricably interwoven. Male sexuality, in Malory, is consistently portrayed as potentially violent and disruptive, dangerous not only to individuals but to the whole structure of society, and therefore in need of controlling measures. The medieval world did not, of course, often portray any form of sexuality positively. Sexual desire leads both men and women to sin: both directly in committing fornication, incest and adultery, and indirectly in committing treason or disregarding their duties. It could easily be assumed that this is a divide between the clergy on the one side, themselves compelled to live in celibacy and thus suspicious of sexual desire, and the more relaxed nobility and commons on the other, cheerfully ignoring the rules when it suited them. However, this is too simple a dichotomy. Malory himself, despite the bold bawdry, shares in the suspicion of unregulated desire, in his nostalgia for a chaster time,
nowadayes men can nat love sevennyght but they muste have all their desyres … But the olde love was nat so. for men and women coulde love togydirs seven yerys, and no lycoures lustis was betwyxte them, and than was love trouthe and faythefulnes.
It is often said that the past is a foreign country where they do things differently, and perhaps no type of "doing" is more fascinating than sexual desires and behaviours. Our modern view of medieval sexuality is characterised bya polarising dichotomy between the swooning love-struck knights and ladies of romance on one hand, and the darkly imagined and misogyny of an unenlightened "medieval" sexuality on the other. British medieval sexual culture also exhibits such dualities through the influential paradigms of sinner or saint, virgin or whore, and protector or defiler of women. However, such sexual identities are rarely coherent or stable, and it is in the grey areas, the interstices between normative modes of sexuality, that we find the most compelling instances of erotic frisson and sexual expression. This collection of essays brings together a wide-ranging discussion of the sexual possibilitiesand fantasies of medieval Britain as they manifest themselves in the literature of the period. Taking as their matter texts and authors as diverse as Chaucer, Gower, Dunbar, Malory, alchemical treatises, and romances, the contributions reveal a surprising variety of attitudes, strategies and sexual subject positions. Contributors: Aisling Byrne, Anna Caughey, Kristina Hildebrand, Amy S. Kaufman, Yvette Kisor, Megan G. Leitch, Cynthea Masson, Hannah Priest, Samantha J. Rayner, Robert Allen Rouse, Cory James Rushton, Amy N. Vines.
To assess management of epistaxis at a tertiary ENT referral hospital against a recently published standard of best practice.
Fifty consecutive cases of acute epistaxis that required admission to Guy's Hospital in 2009 were evaluated. Epistaxis education sessions were held to introduce our algorithm of best practice in tandem with an emphasis on emergency department care. Similar retrospective reviews were carried out in both 2010 and 2011 (on groups of 50 patients).
Results and conclusion:
The first audit cycle demonstrated that only 8 per cent of patients underwent a suitable nasal examination in the emergency department prior to transfer, with no documented attempts at nasal cautery. Surgical intervention procedures were performed on only 40 per cent of eligible patients. The audit cycles that followed the introduction of the epistaxis algorithm demonstrated continued improvement in initial evaluation and management of epistaxis. In select patients, sphenopalatine artery ligation can provide timely, definitive management of refractory epistaxis.