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Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
Recent well-powered genome-wide association studies have enhanced prediction of substance use outcomes via polygenic scores (PGSs). Here, we test (1) whether these scores contribute to prediction over-and-above family history, (2) the extent to which PGS prediction reflects inherited genetic variation v. demography (population stratification and assortative mating) and indirect genetic effects of parents (genetic nurture), and (3) whether PGS prediction is mediated by behavioral disinhibition prior to substance use onset.
PGSs for alcohol, cannabis, and nicotine use/use disorder were calculated for Minnesota Twin Family Study participants (N = 2483, 1565 monozygotic/918 dizygotic). Twins' parents were assessed for histories of substance use disorder. Twins were assessed for behavioral disinhibition at age 11 and substance use from ages 14 to 24. PGS prediction of substance use was examined using linear mixed-effects, within-twin pair, and structural equation models.
Nearly all PGS measures were associated with multiple types of substance use independently of family history. However, most within-pair PGS prediction estimates were substantially smaller than the corresponding between-pair estimates, suggesting that prediction is driven in part by demography and indirect genetic effects of parents. Path analyses indicated the effects of both PGSs and family history on substance use were mediated via disinhibition in preadolescence.
PGSs capturing risk of substance use and use disorder can be combined with family history measures to augment prediction of substance use outcomes. Results highlight indirect sources of genetic associations and preadolescent elevations in behavioral disinhibition as two routes through which these scores may relate to substance use.
This chapter comprises the following sections: names, taxonomy, subspecies and distribution, descriptive notes, habitat, movements and home range, activity patterns, feeding ecology, reproduction and growth, behavior, parasites and diseases, status in the wild, and status in captivity.
We focus here on the resilience and sustainability of the Greek language in southern Albania, looking at it from the perspective of both economics and the ecology of language. Greek is a minority language in the region, spoken by as many as 100,000 speakers in a number of small villages and small urban centers. We chronicle here the ways in which the language has survived despite a near-perfect storm of factors working against it, and we provide an economic-theory rationale. A parallel is drawn to the fate of Turkish in Bulgaria.
To identify risk factors for surgical site infections (SSIs) after spine operations.
Case-control study of SSIs among patients undergoing spine operations.
An academic health center.
We studied patients undergoing spinal fusions or laminectomies at the University of Iowa Hospitals and Clinics from January 1, 2007, through June 30, 2009. We included patients who acquired SSIs meeting the National Healthcare Safety Network definition. We randomly selected controls among patients who had spine operations during the study period and did not meet the SSI definition.
In total, 54 patients acquired SSIs after 2,309 spine operations (2.3 per 100 procedures). SSIs were identified a median of 20 days after spinal fusions and 17 days after laminectomies; 90.7% were identified after discharge and 72.2% were deep incisional or organ-space infections. Staphylococcus aureus caused 53.7% of SSIs. Of patients with SSIs, 64.9% (fusion) and 70.6% (laminectomy) were readmitted and 59.5% (fusion) and 64.7% (laminectomy) underwent reoperation. By multivariable analysis, increased body mass index, Surgical Department A, fusion of 4–8 vertebrae, and operation at a thoracic or lumbar/sacral level were significant risk factors for SSIs after spinal fusions. Lack of private insurance and hypertension were significant risk factors for SSIs after laminectomies. Surgeons from Department A were more likely to use nafcillin or vancomycin for perioperative prophylaxis and to do more multilevel fusions than surgeons from Department B.
SSIs after spine operations significantly increase utilization of healthcare resources. Possible remediable risk factors include obesity, hypertension, and perioperative antimicrobial prophylaxis.
The correspondences between the names in the Scylding genealogy at the beginning of Beowulf and three names in the upper reaches of the genealogy of Æthelwulf in the Anglo-Saxon Chronicle, Beaw, Sceldwa and Sceaf, frequently appear in arguments for a late dating of Beowulf. But these arguments overlook many aspects of Æthelwulf's genealogy that disrupt their case for a late dating. As H. Munro Chadwick pointed out over a century ago, the forms Sceldwa and Beaw found in the Chronicle for Scyld and Beow are not West Saxon spellings, and the -wa suffix of Sceldwa and Tætwa suggests that these forms may be archaic. Thus spelling alone indicates that these names were probably copied from an older, non-West Saxon text. Furthermore, the very presence of these names in the royal pedigree is puzzling. On one level the presence of Scyld is easy to explain: Scyld and the Scyldings were famous in heroic legend, and his inclusion in Æthelwulf's pedigree provides reflected glory for the West Saxon dynasty and implies genealogical, political and cultural connections between the West Saxons and the Danes that could be useful for Alfred and his heirs to foster. But on another level his inclusion is rather surprising: according to genealogical conventions, the presence of Scyld implies that the West Saxon royal family is a cadet branch of the Scylding dynasty, and is thus potentially subordinate to Scandinavian rulers in England claiming direct descent from Scyld.
Since the date of the Beowulf manuscript is widely agreed upon, the very question which prompts this volume (and the conference it derives from, and even the 1980 conference with its 1981 proceedings volume) must assume that the date of the poem may not be the same as the date of the manuscript. It is certain that there must have been a moment of first inscription for the poem, and that the time and place of that moment remains a central point of interest for students of the poem. In this essay, I will bring new evidence to bear on this venerable question, and my argument shall be that Beowulf is metrically conservative according to a variety of independent metrical criteria. Further, I will suggest that that conservatism is so varied and consistent as to strongly indicate that the original version of Beowulf must be placed among the very earliest of the longer narrative Old English poems that survive, probably in the eighth century.
Of course, it remains true, I believe, that the moment of inscription is only one of the moments of interest which might engage modern scholars of the poem. As I argued in Authors, Audiences, and Old English Verse, our focus on authorship (and on moments of authorship) may sometimes cause us to lose sight of what can be gained by also considering audience, and I proposed there two later audiences for Beowulf, one located at Alfred's Wessex court in the late ninth century, and another, sometime around the turn of the eleventh century, perhaps in Canterbury, represented most clearly by the author of Maldon.
As the introduction to this collection makes clear, the various forms of linguistic and metrical evidence bearing on the dating of Beowulf point to a date of composition fairly early in the Anglo-Saxon period. In his article for The Dating of Beowulf in 1980, Thomas Cable proposed a rough guide to the metrical dating of poems using the incidence of type C, D, and E verses, which decline in frequency over the Anglo-Saxon period. Cable's criterion places Beowulf toward the beginning of a relative chronology. Since then, much additional metrical and linguistic evidence has been gathered that places Beowulf in the early to mid-eighth century. R.D. Fulk's A History of Old English Meter is the most substantial work of this kind, for it examines the presence of archaic metrical features through-out the corpus of Old English poetry and finds that Beowulf is by far the most archaic poem. Since that work, other scholars have written articles on individual metrical or linguistic features of the poetic corpus, which have corroborated the conclusions that Fulk so carefully reached.
Some scholars, however, remain dubious about the reliability of this type of evidence. At this point, the force of linguistic scholarship is too formidable to be undermined by the doubts raised by E.G. Stanley, who urged that the poem should not be dated by means of sundry linguistic oddities that could well be scribal error or just a few bad lines.
From the publication of the poem's editio princeps in 1815 to the emergence of the present collection two centuries later, few topics in Anglo-Saxon studies have generated as much speculation and scholarship as the dating of Beowulf. Marshaling disparate forms of evidence and argumentation, scholars have assigned dates to Beowulf that range from the seventh to the eleventh century. Various individuals have been unpersuasively identified as the author of Beowulf and dozens of kings, clerics, and contexts have been associated with the poem's genesis. Scholarship on the dating of Beowulf is markedly uneven in quality: alongside sober and thoughtful argumentation, there has been a great deal of improbable hypothesizing about the author of the poem or the milieu in which it was composed. Awareness of the qualitative differences in the scholarly literature is tacitly registered in the relative frequency with which publications are cited, but these differences have rarely received explicit discussion. This introduction to the dating of Beowulf controversy examines the changing standards of evidence, methodology, and argumentation that have attended this topic, particularly in the past thirty years. The dating of Beowulf has not been a static or monolithic subject, but has undergone considerable change in the disputes it connotes and the practices it encompasses. In the following account, emphasis will be given to the reasons for prevailing opinions rather than to the multiplicity of opinions as such.
Arguments about the date of Beowulf are more impassioned than the question seems to merit. Even so, the controversy has its uses. Beowulf is a great work, all agree, but it constitutes only a sliver of the poetic canon and is doubtless more important to Anglo-Saxon culture now than it was a thousand years ago. For all its glory, Beowulf provides no better an index to Anglo-Saxon poetry than Hamlet to Renaissance drama, which is to say that one can know both works well without knowing much about the corpus to which either belongs. It is to welcome and good effect, then, that several chapters in this volume link the date of Beowulf to the date of everything else, which, for purposes of this discussion, is the rest of Old English poetry.
At the Harvard conference, R.D. Fulk argued that the date of the poem's composition is less significant than the means used to hypothesize the date. The introduction to Fulk's Chapter 1 in this volume sums up an extended discussion regarding probability, proof, and linguistic evidence drawn from his History of Old English Meter. Fulk observes that the criteria for dating verse are not uniformly rigorous and that they have not been subjected to uniformly rigorous testing. Words can be counted and their forms analyzed, so that exceptions to linguistic and metrical criteria emerge quickly; in these cases, the relative probability of competing hypotheses can be readily gauged.