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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.
Metabolites produced by microbial fermentation in the human intestine, especially short-chain fatty acids (SCFAs), are known to play important roles in colonic and systemic health. Our aim here was to advance our understanding of how and why their concentrations and proportions vary between individuals. We have analysed faecal concentrations of microbial fermentation acids from 10 human volunteer studies, involving 163 subjects, conducted at the Rowett Institute, Aberdeen, UK over a 7-year period. In baseline samples, the % butyrate was significantly higher, whilst % iso-butyrate and % iso-valerate were significantly lower, with increasing total SCFA concentration. The decreasing proportions of iso-butyrate and iso-valerate, derived from amino acid fermentation, suggest that fibre intake was mainly responsible for increased SCFA concentrations. We propose that the increase in % butyrate among faecal SCFA is largely driven by a decrease in colonic pH resulting from higher SCFA concentrations. Consistent with this, both total SCFA and % butyrate increased significantly with decreasing pH across five studies for which faecal pH measurements were available. Colonic pH influences butyrate production through altering the stoichiometry of butyrate formation by butyrate-producing species, resulting in increased acetate uptake and butyrate formation, and facilitating increased relative abundance of butyrate-producing species (notably Roseburia and Eubacterium rectale).
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
To stop transmission of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in association with myocardial perfusion imaging (MPI) at a cardiology clinic.
Outbreak investigation and quasispecies analysis of HCV hypervariable region 1 genome.
Outpatient cardiology clinic.
Patients undergoing MPI.
Case patients met definitions for HBV or HCV infection. Cases were identified through surveillance registry cross-matching against clinic records and serological screening. Observations of clinic practices were performed.
During 2012–2014, 7 cases of HCV and 4 cases of HBV occurred in 4 distinct clusters among patients at a cardiology clinic. Among 3 case patients with HCV infection who had MPI on June 25, 2014, 2 had 98.48% genetic identity of HCV RNA. Among 4 case patients with HCV infection who had MPI on March 13, 2014, 3 had 96.96%–99.24% molecular identity of HCV RNA. Also, 2 clusters of 2 patients each with HBV infection had MPI on March 7, 2012, and December 4, 2014. Clinic staff reused saline vials for >1 patient. No infection control breaches were identified at the compounding pharmacy that supplied the clinic. Patients seen in clinic through March 27, 2015, were encouraged to seek testing for HBV, HCV, and human immunodeficiency virus. The clinic switched to all single-dose medications and single-use intravenous flushes on March 27, 2015, and no further cases were identified.
This prolonged healthcare-associated outbreak of HBV and HCV was most likely related to breaches in injection safety. Providers should follow injection safety guidelines in all practice settings.
The realist novel can be understood to bear witness to a changed understanding of history, ushered in with the modern era. This chapter argues that the French realist novel grew out of the historical novel, insofar as it attempted to offer a history of the present. However, a history of the present is challenging if not impossible to write because of the difficulty, and even the impossibility, of achieving a sufficiently distanced vantage point. French realist novels, consequently, aim to represent present reality but indirectly suggest the impossibility of any such representation. The chapter goes on to show that the French realist novels of the 1830s draw attention to the changeable nature of the present, partly because of the unstable social and political contexts of nineteenth-century France, and partly because of a shift in the way that people conceived of present reality. In at least two broad and closely interconnected senses, therefore, the early French realist novel is profoundly historical in its ambitions: it aims to offer a history of the present, however flawed that attempted history necessarily is, and it reveals the historical, or mutable, qualities of the present that it attempts to capture.
Major depressive disorder (MDD) is characterised by a recurrent course and high comorbidity rates. A lifespan perspective may therefore provide important information regarding health outcomes. The aim of the present study is to examine mental disorders that preceded 12-month MDD diagnosis and the impact of these disorders on depression outcomes.
Data came from 29 cross-sectional community epidemiological surveys of adults in 27 countries (n = 80 190). The Composite International Diagnostic Interview (CIDI) was used to assess 12-month MDD and lifetime DSM-IV disorders with onset prior to the respondent's age at interview. Disorders were grouped into depressive distress disorders, non-depressive
distress disorders, fear disorders and externalising disorders. Depression outcomes included 12-month suicidality, days out of role and impairment in role functioning.
Among respondents with 12-month MDD, 94.9% (s.e. = 0.4) had at least one prior disorder (including previous MDD), and 64.6% (s.e. = 0.9) had at least one prior, non-MDD disorder. Previous non-depressive distress, fear and externalising disorders, but not depressive distress disorders, predicted higher impairment (OR = 1.4–1.6) and suicidality (OR = 1.5–2.5), after adjustment for sociodemographic variables. Further adjustment for MDD characteristics weakened, but did not eliminate, these associations. Associations were largely driven by current comorbidities, but both remitted and current externalising disorders predicted suicidality among respondents with 12-month MDD.
These results illustrate the importance of careful psychiatric history taking regarding current anxiety disorders and lifetime externalising disorders in individuals with MDD.
Depressive and anxiety disorders are highly comorbid, which has been theorized to be due to an underlying internalizing vulnerability. We aimed to identify groups of participants with differing vulnerabilities by examining the course of internalizing psychopathology up to age 45.
We used data from 24158 participants (aged 45+) in 23 population-based cross-sectional World Mental Health Surveys. Internalizing disorders were assessed with the Composite International Diagnostic Interview (CIDI). We applied latent class growth analysis (LCGA) and investigated the characteristics of identified classes using logistic or linear regression.
The best-fitting LCGA solution identified eight classes: a healthy class (81.9%), three childhood-onset classes with mild (3.7%), moderate (2.0%), or severe (1.1%) internalizing comorbidity, two puberty-onset classes with mild (4.0%) or moderate (1.4%) comorbidity, and two adult-onset classes with mild comorbidity (2.7% and 3.2%). The childhood-onset severe class had particularly unfavorable sociodemographic outcomes compared to the healthy class, with increased risks of being never or previously married (OR = 2.2 and 2.0, p < 0.001), not being employed (OR = 3.5, p < 0.001), and having a low/low-average income (OR = 2.2, p < 0.001). Moderate or severe (v. mild) comorbidity was associated with 12-month internalizing disorders (OR = 1.9 and 4.8, p < 0.001), disability (B = 1.1–2.3, p < 0.001), and suicidal ideation (OR = 4.2, p < 0.001 for severe comorbidity only). Adult (v. childhood) onset was associated with lower rates of 12-month internalizing disorders (OR = 0.2, p < 0.001).
We identified eight transdiagnostic trajectories of internalizing psychopathology. Unfavorable outcomes were concentrated in the 1% of participants with childhood onset and severe comorbidity. Early identification of this group may offer opportunities for preventive interventions.
Major depressive disorder (MDD) is a leading cause of morbidity and mortality. Shortfalls in treatment quantity and quality are well-established, but the specific gaps in pharmacotherapy and psychotherapy are poorly understood. This paper analyzes the gap in treatment coverage for MDD and identifies critical bottlenecks.
Seventeen surveys were conducted across 15 countries by the World Health Organization-World Mental Health Surveys Initiative. Of 35 012 respondents, 3341 met DSM-IV criteria for 12-month MDD. The following components of effective treatment coverage were analyzed: (a) any mental health service utilization; (b) adequate pharmacotherapy; (c) adequate psychotherapy; and (d) adequate severity-specific combination of both.
MDD prevalence was 4.8% (s.e., 0.2). A total of 41.8% (s.e., 1.1) received any mental health services, 23.2% (s.e., 1.5) of which was deemed effective. This 90% gap in effective treatment is due to lack of utilization (58%) and inadequate quality or adherence (32%). Critical bottlenecks are underutilization of psychotherapy (26 percentage-points reduction in coverage), underutilization of psychopharmacology (13-point reduction), inadequate physician monitoring (13-point reduction), and inadequate drug-type (10-point reduction). High-income countries double low-income countries in any mental health service utilization, adequate pharmacotherapy, adequate psychotherapy, and adequate combination of both. Severe cases are more likely than mild-moderate cases to receive either adequate pharmacotherapy or psychotherapy, but less likely to receive an adequate combination.
Decision-makers need to increase the utilization and quality of pharmacotherapy and psychotherapy. Innovations such as telehealth for training and supervision plus non-specialist or community resources to deliver pharmacotherapy and psychotherapy could address these bottlenecks.
While the idea that fictional works have ethical value dates back to Aristotle at least, the recent empirical evidence, outlined in our first chapter, that they nurture empathy and social understanding seems likely to be welcome news for the literary scholar. Teachers of literature, including teachers of literature in a foreign language, like myself, are often required by their managers, and more generally by the laws of the market, to package what they do in the language of employability and transferable skills, so scientific evidence for the quantifiable benefits of studying novels must surely be welcome. However, while it is true that various literary specialists have, in recent years, contributed meaningfully to the debate about whether engagement with literature can improve the empathy of readers, there is not yet much local evidence that university departments of English and modern languages are rewriting their prospectuses or projected learning outcomes to incorporate the new evidence that engagement with literary fiction can enhance the empathic capabilities and social cognition of their students. What explains this apparent modesty?
At first glance, reticence seems an odd attitude. The novel has, after all, been closely associated with the cultivation of sympathy, a forerunner and occasional near-synonym of empathy, for a very long time. George Eliot wrote, for example, that ‘the greatest benefit we owe the artist, whether painter, poet or novelist, is the extension of our sympathies’. For Eliot, art (including novels) offers ‘a mode of amplifying experience and extending our contact with our fellow-men beyond the bounds of our personal lot’. It is nonetheless true that literary scholars do not generally embrace the argument that reading novels makes us more empathetic. This reluctance can be caricatured as intellectual snobbery; it has been argued for example by one prominent commentator that literary scholars consider the idea of ‘the reading of fiction as an empathy expander and a force toward humanitarian progress’ to be ‘too middlebrow, too therapeutic, too kitsch, too sentimental, too Oprah’. Let us analyse this alleged phobia of the middlebrow and the sentimental on the part of literary scholars.
Firstly, every student and specialist in the field of literary studies knows that the very first rule of being a good reader is the maintenance of a degree of critical distance.
This book set out to see whether a close reading of literary texts could yield insights into the question of how, and possibly why, fiction engages affective sharing and mind-reading skills. On the basis of recent work in psychology and cognitive studies, the first chapter proposed an idea that, to my knowledge, has not been explored in those fields but that is likely to find fairly ready acceptance among literary scholars, at least once the terms of the argument are shifted from affective sharing and mind-reading to seduction and suspicion. This new but not new idea is that the closely connected skills of affective sharing and mind-reading are regularly brought into creative conflict by fictional texts, both at the thematic level and at the level of reception. In order to make its case, this book proposed, in its third chapter, that literary texts can thematise their own reception in the representation of responses inspired by a stranger figure who is closely associated with fiction. Close readings of three novels were subsequently proposed by way of illustration. This concluding chapter will outline a couple of general conclusions about the fiction–empathy relationship that might tentatively but plausibly be drawn from this book's close readings of fictional responses to fictional stranger figures. It will also ask, in closing, what specific contributions this study might be considered to make to the wider cross-disciplinary conversation on the subject of the relationship between fiction and empathy.
The Limits of Mind-Reading
As discussed in the chapter on La Fille aux yeux d’or, the realist novel appears to promise total legibility of character, and of the social world more generally. However, the more or less realist fictions selected for study here show us on an explicit, thematic level that characters, and by extension people, can be other than they seem, and resistant to mindreading. Whether or not Henri finally succeeds in deciphering the truth of Paquita's desire is a moot point. Julien's motivations for shooting Madame de Rênal remain opaque at the end of Le Rouge et le Noir, not least to himself. Even the generous nature of Ralph's intentions towards Indiana is at least partially thrown into doubt by elements in his self-presentation.
This book studies recent psychological findings which suggest that reading fiction cultivates empathy, encouraging us to be critically reflective, suspicious readers as well as participatory, 'naïve' readers.
In one of Balzac's novels, he personifies the nineteenth century as a questing surgeon or archaeologist:
There played out in La Baudraye one of those long and monotonous conjugal tragedies that would remain unknown for all eternity if the avid scalpel of the nineteenth century, driven by the need to find the new, did not go searching in the darkest corners of the heart or, if you prefer, those parts that the discretion of previous centuries had respected.
As this passage indirectly suggests, Balzac's century was a time of accelerated scientific discovery: it saw revolutionary advances in the medical understanding of disease, for example, and in the fields of archaeology and palaeontology. It is no coincidence that hieroglyphs are referenced so frequently in Balzac's novels: the author was a contemporary of Jean-François Champollion, who in the 1820s effectively completed the decryption of the Rosetta Stone, thereby unlocking the secrets of hieroglyphic script. Indeed, Balzac considered his own role as a writer to be one of quasi-scientific exploration; he compared his novelistic project to the investigations undertaken by his older contemporary, the French zoologist Geoffroy Saint-Hilaire, and used the metaphor of the scalpel, tacitly in the above passage and more explicitly elsewhere, to describe the observational skills of the novelist.
Balzac's writerly scalpel was just as avid and as lacking in discretion as the one he attributes to the nineteenth century in the passage quoted above. Not only are his novels driven by a desire for knowledge, they also appeal very shrewdly to the reader's own curiosity. Barthes has written about the operation of what he calls the hermeneutic code in the classic (and, as it happens, Balzacian) novel: this is the set of textual elements that both construct a question and then lead towards– and present obstacles to– its answer. Balzac's novels characteristically present enigmas, which they then proceed to solve, thereby following the basic structure of a detective novel (not coincidentally an invention of the nineteenth century) or, as Barthes puts it, a striptease (which also, as it happens, has its origins in the nineteenth century).
Stendhal, who as well as being a novelist, literary critic and would-be playwright, wrote extensively about the visual arts and enthusiastically about music, placed emotional experience at the heart of the aesthetic encounter. On the one hand, he gave emotion a fundamental role in artistic creation. Stendhal described passion as ‘the possibility and the subject of the fine arts’. On the other hand, emotion played a key role in aesthetic reception for this author. In one of his autobiographical works, the author compares the novel to a bow designed to produce music by acting upon the soul of its reader. When one views the work of Michelangelo, he claims, ‘the soul is agitated by sensations that it is not used to receiving through the eyes’. Stendhal famously believed that some people were more open than others to the experience of being moved, whether by a novel, a piece of music, a play or a painting: these sensitive souls, he suggests in various places, are ‘the Happy Few’. He argues for example that ‘an eye that knows how to see and a soul that knows how to feel’ are necessary in order truly to see what Michelangelo achieved on the Sistine Chapel ceiling. To be under forty years old was a distinct advantage in this respect, but a passionate disposition was decisive: ‘A passionate man who submits to the effect of the fine arts finds everything in his heart.’
For Stendhal, encounters with works of art tended to take the form of a sharing of emotion, which he associated with the phenomenon of ‘sympathie’, defined by him as ‘the ability to identify with another person’. Even the success of works that do not primarily appeal to sympathy could depend upon this faculty, to the extent that attendance at a theatre or concert could produce a ‘nervous sympathy’ or ‘reciprocal sympathy’ felt with other people in the room. Novel-reading lacked this collective dimension, but could nevertheless itself be a rich source of sympathetic communication. For example, Stendhal included fictional characters, whether on the stage or on the page, among those to whom a reader's sympathy might be extended:
If the [stage] character appears in the slightest way to think about his style, mistrust emerges, sympathy flees, and pleasure in the drama disappears.
Of all of George Sand's novels, only one– her first as a solo author– can be considered predominantly realist in its style, even if it is true that aspects of this first novel also undermine its realism. From its first chapter, Indiana presents a world that is, ostensibly at least, legible in its every detail, not least because it is mediated by a narrator who adopts the recognisably all-knowing and seductive tone of the Balzacian omniscient narrator. Both narrator and characters regularly decipher facial expressions and the messages conveyed by glances or bodily movement, and in fact the performance of, and obstacles to, mind-reading are central to the novel's plot. The novel also makes a theme of narrative seduction, in its depiction of the charming but duplicitous Raymon de Ramière. This chapter will argue that Indiana both suggests that narrative seduction is to be resisted and highlights the limits of mind-reading.
There are two very obvious figures of the stranger in Indiana: both the eponymous heroine and Noun, her childhood companion and maid, are designated as ‘créoles’ (creoles) from Île Bourbon (now Réunion). Indiana is of European origin, her father having moved from Spain to the French colony, while there are numerous suggestions that Noun is of African origin. In Sand's representation, both heroines are perceived by other characters as foreign to different degrees. These figures will not be the main focus of study in this chapter, however, because there are two other stranger figures who are more closely associated in the novel with pretence, and who might therefore serve as more appropriate figures of fiction in the text.
The ability to seduce others is particularly closely linked, in this novel, to the ability to arouse the sympathy of others. One male protagonist has no difficulties in attracting either erotic partners or friends, while the other is defined by his lack of erotic charm as well as by his inability to inspire any feelings of sympathy in those around him. This chapter will begin by arguing that the character of Raymon, in Indiana, is one of two fiction-connoted figures of the stranger in the novel, and that he embodies the dangerous seductions of fiction. Indiana and Noun both fall for him; only the former survives the encounter, due at least in part to a capacity for resistance that appears to be innate.