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Major depressive disorder and neuroticism (Neu) share a large genetic basis. We sought to determine whether this shared basis could be decomposed to identify genetic factors that are specific to depression.
We analysed summary statistics from genome-wide association studies (GWAS) of depression (from the Psychiatric Genomics Consortium, 23andMe and UK Biobank) and compared them with GWAS of Neu (from UK Biobank). First, we used a pairwise GWAS analysis to classify variants as associated with only depression, with only Neu or with both. Second, we estimated partial genetic correlations to test whether the depression's genetic link with other phenotypes was explained by shared overlap with Neu.
We found evidence that most genomic regions (25/37) associated with depression are likely to be shared with Neu. The overlapping common genetic variance of depression and Neu was genetically correlated primarily with psychiatric disorders. We found that the genetic contributions to depression, that were not shared with Neu, were positively correlated with metabolic phenotypes and cardiovascular disease, and negatively correlated with the personality trait conscientiousness. After removing shared genetic overlap with Neu, depression still had a specific association with schizophrenia, bipolar disorder, coronary artery disease and age of first birth. Independent of depression, Neu had specific genetic correlates in ulcerative colitis, pubertal growth, anorexia and education.
Our findings demonstrate that, while genetic risk factors for depression are largely shared with Neu, there are also non-Neu-related features of depression that may be useful for further patient or phenotypic stratification.
Most research on the causes of women's underrepresentation examines one of two stages of the political pipeline: the development of nascent political ambition or specific aspects of the campaign and election process. In this article, we make a different kind of contribution. We build on the growing literature on gender, psychology, and representation to provide an analysis of what kinds of men and women make it through the political pipeline at each stage. This allows us to draw some conclusions about the ways in which the overall process is similar and different for women and men. Using surveys of the general U.S. population (N = 1,939) and elected municipal officials such as mayors and city councilors (N = 2,354) that measure the distribution of Big Five personality traits, we find that roughly the same types of men and women have nascent political ambition; there is just an intercept shift for sex. In contrast, male and female elected officials have different personality profiles. These differences do not reflect underlying distributions in the general population or the population of political aspirants. In short, our data suggest that socialization into political ambition is similar for men and women, but campaign and election processes are not.
To determine the effect of three psycholinguistic variables—lexical frequency, age of acquisition (AoA), and neighborhood density (ND)—on lexical-semantic processing in individuals with non-fluent (nfvPPA), logopenic (lvPPA), and semantic primary progressive aphasia (svPPA). Identifying the scope and independence of these features can provide valuable information about the organization of words in our mind and brain.
We administered a lexical decision task—with words carefully selected to permit distinguishing lexical frequency, AoA, and orthographic ND effects—to 41 individuals with PPA (13 nfvPPA, 14 lvPPA, 14 svPPA) and 25 controls.
Of the psycholinguistic variables studied, lexical frequency had the largest influence on lexical-semantic processing, but AoA and ND also played an independent role. The results reflect a brain-language relationship with different proportional effects of frequency, AoA, and ND in the PPA variants, in a pattern that is consistent with the organization of the mental lexicon. Individuals with nfvPPA and lvPPA experienced an ND effect consistent with the role of inferior frontal and temporoparietal regions in lexical analysis and word form processing. By contrast, individuals with svPPA experienced an AoA effect consistent with the role of the anterior temporal lobe in semantic processing.
The findings are in line with a hierarchical mental lexicon structure with a conceptual (semantic) and a lexeme (word-form) level, such that a selective deficit at one of these levels of the mental lexicon manifests differently in lexical-semantic processing performance, consistent with the affected language-specific brain region in each PPA variant.
The SCN5A gene is implicated in many arrhythmogenic and cardiomyopathic processes. We identified a novel SCN5A variant in a family with significant segregation in individuals affected with progressive sinus and atrioventricular nodal disease, atrial arrhythmia, dilated cardiomyopathy, and early sudden cardiac arrest.
A patient pedigree was created following the clinical evaluation of three affected individuals, two monozygotic twins and a paternal half-brother, which lead to the evaluation of a paternal half-sister (four siblings with the same father and three mothers) all of whom experienced varying degrees of atrial arrhythmias, conduction disease, and dilated cardiomyopathy in addition to a paternal history of unexplained death in his 50s with similar autopsy findings. The index male underwent sequencing of 58 genes associated with cardiomyopathies. Sanger sequencing was used to provide data for bases with insufficient coverage and for bases in some known regions of genomic segmental duplications. All clinically significant and novel variants were confirmed by independent Sanger sequencing.
All relatives tested were shown to have the same SCN5A variant of unknown significance (p. Asp197His) and the monozygotic twins shared a co-occurring NEXN (p. Glu575*). Segregation analysis demonstrates likely pathogenic trait for the SCN5A variant with an additional possible role for the NEXN variant in combination.
There is compelling clinical evidence suggesting that the SCN5A variant p. Asp197His may be re-classified as likely pathogenic based on the segregation analysis of our family of interest. Molecular mechanism studies are pending.
The rocky shores of the north-east Atlantic have been long studied. Our focus is from Gibraltar to Norway plus the Azores and Iceland. Phylogeographic processes shape biogeographic patterns of biodiversity. Long-term and broadscale studies have shown the responses of biota to past climate fluctuations and more recent anthropogenic climate change. Inter- and intra-specific species interactions along sharp local environmental gradients shape distributions and community structure and hence ecosystem functioning. Shifts in domination by fucoids in shelter to barnacles/mussels in exposure are mediated by grazing by patellid limpets. Further south fucoids become increasingly rare, with species disappearing or restricted to estuarine refuges, caused by greater desiccation and grazing pressure. Mesoscale processes influence bottom-up nutrient forcing and larval supply, hence affecting species abundance and distribution, and can be proximate factors setting range edges (e.g., the English Channel, the Iberian Peninsula). Impacts of invasive non-native species are reviewed. Knowledge gaps such as the work on rockpools and host–parasite dynamics are also outlined.
As demonstrated by neuroimaging data, the human brain contains systems that control responses to threat. The revised Reinforcement Sensitivity Theory of personality predicts that individual differences in the reactivity of these brain systems produce anxiety and fear-related personality traits. Here we discuss some of the challenges in testing this theory and, as an example, present a pilot study that aimed to dissociate brain activity during pursuit by threat and goal conflict. We did this by translating the Mouse Defense Test Battery for human fMRI use. In this version, dubbed the Joystick Operated Runway Task (JORT), we repeatedly exposed 24 participants to pursuit and goal conflict, with and without threat of electric shock. The runway design of JORT allowed the effect of threat distance on brain activation to be evaluated independently of context. Goal conflict plus threat of electric shock caused deactivation in a network of brain areas that included the fusiform and middle temporal gyri, as well as the default mode network core, including medial frontal regions, precuneus and posterior cingulate gyrus, and laterally the inferior parietal and angular gyri. Consistent with earlier research, we also found that imminent threat activated the midbrain and that this effect was significantly stronger during the simple pursuit condition than during goal conflict. Also consistent with earlier research, we found significantly greater hippocampal activation during goal conflict than pursuit by imminent threat. In conclusion, our results contribute knowledge to theories linking anxiety disorders to altered functioning in defensive brain systems and also highlight challenges in this research domain.
Substantial clinical heterogeneity of major depressive disorder (MDD) suggests it may group together individuals with diverse aetiologies. Identifying distinct subtypes should lead to more effective diagnosis and treatment, while providing more useful targets for further research. Genetic and clinical overlap between MDD and schizophrenia (SCZ) suggests an MDD subtype may share underlying mechanisms with SCZ.
The present study investigated whether a neurobiologically distinct subtype of MDD could be identified by SCZ polygenic risk score (PRS). We explored interactive effects between SCZ PRS and MDD case/control status on a range of cortical, subcortical and white matter metrics among 2370 male and 2574 female UK Biobank participants.
There was a significant SCZ PRS by MDD interaction for rostral anterior cingulate cortex (RACC) thickness (β = 0.191, q = 0.043). This was driven by a positive association between SCZ PRS and RACC thickness among MDD cases (β = 0.098, p = 0.026), compared to a negative association among controls (β = −0.087, p = 0.002). MDD cases with low SCZ PRS showed thinner RACC, although the opposite difference for high-SCZ-PRS cases was not significant. There were nominal interactions for other brain metrics, but none remained significant after correcting for multiple comparisons.
Our significant results indicate that MDD case-control differences in RACC thickness vary as a function of SCZ PRS. Although this was not the case for most other brain measures assessed, our specific findings still provide some further evidence that MDD in the presence of high genetic risk for SCZ is subtly neurobiologically distinct from MDD in general.
Item 9 of the Patient Health Questionnaire-9 (PHQ-9) queries about thoughts of death and self-harm, but not suicidality. Although it is sometimes used to assess suicide risk, most positive responses are not associated with suicidality. The PHQ-8, which omits Item 9, is thus increasingly used in research. We assessed equivalency of total score correlations and the diagnostic accuracy to detect major depression of the PHQ-8 and PHQ-9.
We conducted an individual patient data meta-analysis. We fit bivariate random-effects models to assess diagnostic accuracy.
16 742 participants (2097 major depression cases) from 54 studies were included. The correlation between PHQ-8 and PHQ-9 scores was 0.996 (95% confidence interval 0.996 to 0.996). The standard cutoff score of 10 for the PHQ-9 maximized sensitivity + specificity for the PHQ-8 among studies that used a semi-structured diagnostic interview reference standard (N = 27). At cutoff 10, the PHQ-8 was less sensitive by 0.02 (−0.06 to 0.00) and more specific by 0.01 (0.00 to 0.01) among those studies (N = 27), with similar results for studies that used other types of interviews (N = 27). For all 54 primary studies combined, across all cutoffs, the PHQ-8 was less sensitive than the PHQ-9 by 0.00 to 0.05 (0.03 at cutoff 10), and specificity was within 0.01 for all cutoffs (0.00 to 0.01).
PHQ-8 and PHQ-9 total scores were similar. Sensitivity may be minimally reduced with the PHQ-8, but specificity is similar.
Shiga toxin-producing Escherichia coli (STEC) infection can cause serious illness including haemolytic uraemic syndrome. The role of socio-economic status (SES) in differential clinical presentation and exposure to potential risk factors amongst STEC cases has not previously been reported in England. We conducted an observational study using a dataset of all STEC cases identified in England, 2010–2015. Odds ratios for clinical characteristics of cases and foodborne, waterborne and environmental risk factors were estimated using logistic regression, stratified by SES, adjusting for baseline demographic factors. Incidence was higher in the highest SES group compared to the lowest (RR 1.54, 95% CI 1.19–2.00). Odds of Accident and Emergency attendance (OR 1.35, 95% CI 1.10–1.75) and hospitalisation (OR 1.71, 95% CI 1.36–2.15) because of illness were higher in the most disadvantaged compared to the least, suggesting potential lower ascertainment of milder cases or delayed care-seeking behaviour in disadvantaged groups. Advantaged individuals were significantly more likely to report salad/fruit/vegetable/herb consumption (OR 1.59, 95% CI 1.16–2.17), non-UK or UK travel (OR 1.76, 95% CI 1.40–2.27; OR 1.85, 95% CI 1.35–2.56) and environmental exposures (walking in a paddock, OR 1.82, 95% CI 1.22–2.70; soil contact, OR 1.52, 95% CI 2.13–1.09) suggesting other unmeasured risks, such as person-to-person transmission, could be more important in the most disadvantaged group.
Background: Hereditary transthyretin-mediated (hATTR) amyloidosis a hereditary, multi-systemic and life-threatening disease resulting in neuropathy and cardiomyopathy. In the APOLLO study, patisiran, an investigational RNAi therapeutic targeting hepatic TTR production resulted in significant improvement in neuropathy and QoL compared to placebo and was generally well tolerated. Methods: APOLLO, a Phase 3 study of patisiran vs. placebo (NCT01960348) prespecified a cardiac subpopulation (n=126 of 225 total) that included patients with baseline left ventricular (LV) wall thickness ≥ 13mm and no medical history of aortic valve disease or hypertension. Cardiac measures included structure and function by electrocardiography, changes in NT-proBNP and 10-MWT gait speed. Results: At 18 months, patisiran treatment resulted in a mean reduction in LV wall thickness of 1 mm (p=0.017) compared to baseline, which was associated with significant improvements relative to placebo in LV end diastolic volume (+8.31 mL, p=0.036), global longitudinal strain (-1.37%, p=0.015) and NT-proBNP (55% reduction, p=7.7 x 10-8) (Figure 1). Gait speed was also improved relative to placebo (+0.35 m/sec, p=7.4 x 10-9). Rate of death or hospitalization was lower with patisiran. mNIS+7 results in the cardiac subpopulation will also be presented. Conclusions: These data suggest patisiran has the potential to halt or reverse cardiac manifestations of hATTR amyloidosis.
Background: Hereditary transthyretin-mediated (hATTR) amyloidosis is a multi-systemic, heterogenous, life-threatening disease. Patisiran resulted in significant improvement in neuropathy and QoL at 18-months compared to placebo, and was generally well-tolerated in the Phase 3 APOLLO study. Methods: Multi-center, OLE study to evaluate the efficacy and safety of long-term patisiran dosing for ≤ 5 years in hATTR amyloidosis patients with polyneuropathy who have completed the APOLLO study (NCT02510261). Endpoints include safety, tolerability and long-term efficacy of patisiran. Measures of clinical benefit are the same endpoints used in APOLLO including changes in mNIS+7 composite neuropathy impairment score and QoL (Norfolk QoL-DN) Results: As of December 2017, 184 of 186 (99%) patients who completed APOLLO and 25 patients from the Ph 2 OLE study enrolled in the Global OLE study. Baseline data for 211(APOLLO/placebo, n=49; APOLLO/patisiran, n=137 and patisiran Ph 2 OLE, n=25) patients included: median age 61 years (26-84); 74% males; 46% V30M. Interim safety data and 12-month efficacy results will be presented. Conclusions: The global OLE study includes a diverse population of hATTR amyloidosis patients. Interim data will include the long-term safety and maintenance of effect in patients continuing on patisiran, as well as the impact of treatment with patisiran on patients previously treated with placebo.
Experiments were initiated to characterize a waterhemp population (CHR) discovered in a central Illinois corn field after it was not controlled by the 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor topramezone. Field experiments conducted during 2014–2015 indicated that acetolactate synthase (ALS)-, protoporphyrinogen oxidase (PPO)-, photosystem II (PSII)-, and HPPD-inhibiting herbicides and the synthetic auxin 2,4-D did not control the CHR population. Laboratory experiments confirmed target site–based resistance mechanisms to ALS- and PPO-inhibiting herbicides. Herbicide doses required to reduce dry biomass 50% (GR50) were determined in greenhouse dose–response experiments, and indicated 16-fold resistance to the HPPD inhibitor mesotrione, 9.5-fold resistance to the synthetic auxin 2,4-D, and 252-fold resistance to the PSII inhibitor atrazine. Complementary results from field, laboratory, and greenhouse investigations indicate that the CHR population has evolved resistance to herbicides from five sites of action (SOAs): ALS-, PPO-, PSII-, and HPPD-inhibiting herbicides and 2,4-D. Herbicide use history for the field in which CHR was discovered indicates no previous use of 2,4-D.
Analyzing audiovisual communication is challenging because its content is highly symbolic and less rule-governed than verbal material. But audiovisual messages are important to understand: they amplify, enrich, and complicate the meaning of textual information. We describe a fully-reproducible approach to analyzing video content using minimally—but systematically—trained online workers. By aggregating the work of multiple coders, we achieve reliability, validity, and costs that equal those of traditional, intensively trained research assistants, with much greater speed, transparency, and replicability. We argue that measurement strategies relying on the “wisdom of the crowd” provide unique advantages for researchers analyzing complex and intricate audiovisual political content.
Objectives: Insomnia is associated with neuropsychological dysfunction. Evidence points to the role of nocturnal light exposure in disrupted sleep patterns, particularly blue light emitted through smartphones and computers used before bedtime. This study aimed to test whether blocking nocturnal blue light improves neuropsychological function in individuals with insomnia symptoms. Methods: This study used a randomized, placebo-controlled crossover design. Participants were randomly assigned to a 1-week intervention with amber lenses worn in wrap-around frames (to block blue light) or a 1-week intervention with clear lenses (control) and switched conditions after a 4-week washout period. Neuropsychological function was evaluated with tests from the NIH Toolbox Cognition Battery at three time points: (1) baseline (BL), (2) following the amber lenses intervention, and (3) following the clear lenses intervention. Within-subjects general linear models contrasted neuropsychological test performance following the amber lenses and clear lenses conditions with BL performance. Results: Fourteen participants (mean(standard deviation, SD): age = 46.5(11.4)) with symptoms of insomnia completed the protocol. Compared with BL, individuals performed better on the List Sorting Working Memory task after the amber lenses intervention, but similarly after the clear lenses intervention (F = 5.16; p = .014; η2 = 0.301). A similar pattern emerged on the Pattern Comparison Processing Speed test (F = 7.65; p = 0.002; η2 = 0.370). Consideration of intellectual ability indicated that treatment with amber lenses “normalized” performance on each test from approximately 1 SD below expected performance to expected performance. Conclusions: Using a randomized, placebo-controlled crossover design, we demonstrated improvement in processing speed and working memory with a nocturnal blue light blocking intervention among individuals with insomnia symptoms. (JINS, 2019, 25, 668–677)
The use of particle-induced X-ray emission (PIXE) analysis as a standard analytical tool in the study of trace elements is well known. In the present investigation, an attempt is made to correlate human diseases with the presence or absence of trace elements and/or the changes in their concentration in healthy and diseased tissues. If such correlations do actually exist, trace element analysis could certainly be used as a diagnostic tool for the early detection of diseases and there is considerable interest in such information.
Ion-implantation has many applications in the fabrication and processing of microelectronic devices from semiconductors, but thermal treatments are required to remove defects produced by the implant and to electrically activate dopants. Recently, pulsed laser annealing has been used to activate surface layers of GaAs that have been heavily doped with 28Si+ by ion implantation, and carrier concentrations of > 1 x 1019 cm-3 have been achieved (Ref. 1). Double-crystal x-ray diffraction techniques are very sensitive to strains and defects in single crystals and provide a means for characterizing and quantifying the damage produced by ion-implantation and the subsequent relief of damage by pulsed laser annealing.
Poor compliance of prescription medication is an ongoing public health crisis. Nearly half of patients do not take their medication as prescribed, harming their own health while also increasing public health care costs. Despite these detrimental consequences, prior research has struggled to establish cost-effective and scalable interventions to improve adherence rates. We suggest that one reason for the limited success of prior interventions is that they make the personal health costs of non-adherence insufficiently prominent, while a higher saliency of these costs may motivate patients to adhere more. In the current research, we test whether an intervention that makes the personal health costs of non-compliance more salient for patients will increase their medication adherence. To do so, we conducted a randomized controlled trial with 16,191 patients across 278 UK pharmacies over a 9-month time period and manipulated the perceived consequences of medication non-adherence. We find that patients who received a treatment highlighting the personal health costs of non-compliance were significantly more likely to adhere to their medication than three comparison groups (odds ratio = 1.84, 95% confidence interval = 1.37–2.47). Shifting patients’ focus to the personal health costs of non-compliance may thus offer a potentially cost-effective and scalable approach to improving medication adherence.
We sought to define the prevalence of echocardiographic abnormalities in long-term survivors of paediatric hematopoietic stem cell transplantation and determine the utility of screening in asymptomatic patients. We analysed echocardiograms performed on survivors who underwent hematopoietic stem cell transplantation from 1982 to 2006. A total of 389 patients were alive in 2017, with 114 having an echocardiogram obtained ⩾5 years post-infusion. A total of 95 patients had echocardiogram performed for routine surveillance. The mean time post-hematopoietic stem cell transplantation was 13 years. Of 95 patients, 77 (82.1%) had ejection fraction measured, and 10/77 (13.0%) had ejection fraction z-scores ⩽−2.0, which is abnormally low. Those patients with abnormal ejection fraction were significantly more likely to have been exposed to anthracyclines or total body irradiation. Among individuals who received neither anthracyclines nor total body irradiation, only 1/31 (3.2%) was found to have an abnormal ejection fraction of 51.4%, z-score −2.73. In the cohort of 77 patients, the negative predictive value of having a normal ejection fraction given no exposure to total body irradiation or anthracyclines was 96.7% at 95% confidence interval (83.3–99.8%). Systolic dysfunction is relatively common in long-term survivors of paediatric hematopoietic stem cell transplantation who have received anthracyclines or total body irradiation. Survivors who are asymptomatic and did not receive radiation or anthracyclines likely do not require surveillance echocardiograms, unless otherwise indicated.