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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.
The existence of a shared constraint hierarchy is one of the criteria that defines and delimits speech communities. In particular, women and men are thought to differ only in their rates of variable usage, not in the constraints governing their variation; that is, women and men are typically considered to belong to the same speech community. We find that in early twentieth century Southland, New Zealand, women and men had different constraint hierarchies for rhoticity, with a community grammar of rhoticity only developing later. These results may be a product of a particular set of sociohistorical facts thatare not peculiar to Southland. We suggest that further research in other geographical locations may indeed reveal that men and women have different constraint hierarchies for other variables. Speech communities may thus be delimited along social lines in ways that have not been previously considered.
Centrally located early-stage non-small cell lung cancer in patients who are unfit for surgery are treated with fractionated radiotherapy. We present the outcomes of a moderately hypofractionated accelerated dose regimen of 50 Gy in 15 fractions from a single centre in the UK.
Materials and methods:
Electronic case notes and radiotherapy records of lung cancer patients treated between January 2014 and December 2016 were retrospectively reviewed. Adult Comorbidity Evaluation-27 score was used to evaluate comorbidities. Mean lung doses and percentage of lung receiving more than 20 Gy were calculated for all patients. Survival outcomes were estimated using Kaplan–Meier curves.
Fifty-three patients were included in the study; the median follow-up was 20.2 months. 87% of patients had stage I disease. There was no 30-day post-treatment mortality. Ninety-day mortality rate after radiotherapy was 3.8%. Grade 2 pneumonitis was seen in five patients while no grade 3 or 4 pneumonitis was observed. The median progression-free survival (PFS) and overall survival (OS) were 18.5 months and 28.2 months, respectively. The estimated 1 and 2 years PFS were 62.3% and 41.3%, respectively, and OS were 77.4% and 56.6%, respectively. Worsening performance status was associated with worse survival on cox regression analysis. Disease relapsed in 36% of patients. 7.5% of patients with relapsed disease had infield recurrence.
50 Gy in 15 fractions radiotherapy for central early-stage lung cancer is a feasible choice that requires further randomised trials.
Catheter ablation is a safe and effective therapy for the treatment of supraventricular tachycardia in children. Current improvements in technology have allowed progressive reduction in radiation exposure associated with the procedure. To assess the impact of three-dimensional mapping, we compared acute procedural results collected from the Catheter Ablation with Reduction or Elimination of Fluoroscopy registry to published results from the Prospective Assessment after Pediatric Cardiac Ablation study.
Inclusion and exclusion criteria from the Prospective Assessment after Pediatric Cardiac Ablation study were used as guidelines to select patient data from the Catheter Ablation with Reduction or Elimination of Fluoroscopy registry to compare acute procedural outcomes between cohorts. Outcomes assessed include procedural and fluoroscopy exposure times, success rates of procedure, and complications.
In 786 ablation procedures, targeting 498 accessory pathways and 288 atrioventricular nodal reentrant tachycardia substrates, average procedural time (156.5 versus 206.7 minutes, p < 0.01), and fluoroscopy time (1.2 versus 38.3 minutes, p < 0.01) were significantly shorter in the study group. Success rates for the various substrates were similar except for manifest accessory pathways which had a significantly higher success rate in the study group (96.4% versus 93.0%, p < 0.01). Major complication rates were significantly lower in the study group (0.3% versus 1.6%, p < 0.01).
In a large, multicentre study, three-dimensional systems show favourable improvements in clinical outcomes in children undergoing catheter ablation of supraventricular tachycardia compared to the traditional fluoroscopic approach. Further improvements are anticipated as technology advances.
The Promontory caves (Utah) and Franktown Cave (Colorado) contain high-fidelity records of short-term occupations by groups with material culture connections to the Subarctic/Northern Plains. This research uses Promontory and Franktown bison dung, hair, hide, and bone collagen to establish local baseline carbon isotopic variability and identify leather from a distant source. The ankle wrap of one Promontory Cave 1 moccasin had a δ13C value that indicates a substantial C4 component to the animal's diet, unlike the C3 diets inferred from 171 other Promontory and northern Utah bison samples. We draw on a unique combination of multitissue isotopic analysis, carbon isoscapes, ancient DNA (species and sex identification), tissue turnover rates, archaeological contexts, and bison ecology to show that the high δ13C value was not likely a result of local plant consumption, bison mobility, or trade. Instead, the bison hide was likely acquired via long-distance travel to/from an area of abundant C4 grasses far to the south or east. Expansive landscape knowledge gained through long-distance associations would have allowed Promontory caves inhabitants to make well-informed decisions about directions and routes of movement for a territorial shift, which seems to have occurred in the late thirteenth century.
Hysteroscopy is safe and effective and can greatly reduce morbidity and enhance recovery compared with conventional open procedures. Furthermore, it can minimise the inherent risks of general anaesthesia and hospital admissions because many hysteroscopic procedures can now be delivered in non-anaesthetised women in an outpatient setting. The overall complication rate of hysteroscopic intervention is estimated to be less than 1% [1, 2], of which half is due to serious complications, namely fluid overload, uterine perforation and upper genital tract haemorrhage. Complications occur during access and entry into the uterine cavity or during the diagnostic or operative procedure. Complication rates are higher with operative hysteroscopy (0.95%) compared with purely diagnostic procedures (0.13%) . These risks are highest with more complex hysteroscopic surgery such as myomectomy and adhesiolysis and lowest with purely diagnostic procedures.
Researchers employing qualitative comparative analysis (QCA) and its variants use two-element Boolean algebra to compare cases and identify putative causal conditions. I show that the two-element Boolean algebra constrains research in three important ways: it restricts what we can say about sets and the interactions between sets, it embodies a logical language that is too weak to capture modern social science theories, and it restricts our analysis of causation to necessity and sufficiency accounts and does not allow for counterfactuals. Modern quantitative analysis suffers none of these restrictions and provides a much richer way to understand the social world.
Emerging cybertechnologies, such as social digibots, bend epistemological conventions of life and culture already complicated by human and animal relationships. Virtually-augmented niches of machines and organic life promise new free-energy-governed selection of intelligent digital life. These provocative eco-evolutionary contexts demand a theory of (natural and artificial) minds to characterize and validate the immersive social phenomena universally-shaping cultural affordances.
Emergency physicians play an important role in providing care at the end-of-life as well as identifying patients who may benefit from a palliative approach. Several studies have shown that emergency medicine (EM) residents desire further training in palliative care. We performed a national cross-sectional survey of EM program directors. Our primary objective was to describe the number of Canadian postgraduate EM training programs with palliative and end-of-life care curricula.
A 15-question survey in English and French was sent by email to all program directors of both the Canadian College of Family Physicians emergency medicine (CCFP(EM)) and the Royal College of Physicians and Surgeons of Canada emergency medicine (RCPSC-EM) postgraduate training programs countrywide using FluidSurveys™ with a modified Dillman approach.
We received a total of 26 responses from the 36 (response rate = 72.2%) EM postgraduate programs in Canada. Ten out of 26 (38.5%) programs had a structured educational program pertaining to palliative and end-of-life care. Lectures or seminars were the exclusive choice to teach content. Clinical palliative medicine rotations were mandatory in one out of 26 (3.8%) programs. The top two barriers to implementation of palliative and end-of-life care curricula were lack of time (84.6%) and curriculum development concerns (80.8%).
Palliative and end-of-life care training within EM has been identified as an area of need. This cross-sectional survey demonstrates that a minority of Canadian EM programs have palliative and end-of-life care curricula. It will be important for all EM training programs, RCPSC-EM and CCFP(EM), in Canada, to develop an agreed upon set of competencies and to structure their curricula around them.
Some neurotropic enteroviruses hijack Trojan horse/raft commensal gut bacteria to render devastating biomimicking cryptic attacks on human/animal hosts. Such virus-microbe interactions manipulate hosts’ gut-brain axes with accompanying infection-cycle-optimizing central nervous system (CNS) disturbances, including severe neurodevelopmental, neuromotor, and neuropsychiatric conditions. Co-opted bacteria thus indirectly influence host health, development, behavior, and mind as possible “fair-weather-friend” symbionts, switching from commensal to context-dependent pathogen-like strategies benefiting gut-bacteria fitness.
Foraging for nutritional sustenance represents common significant learned/heritable survival strategies evolved for phylum-diverse cellular life on Earth. Unicellular aneural to multicellular neural foragers display conserved rational or irrational decision making depending on outcome predictions for noise-susceptible real/illusory homeodynamic and ambient dietary cues. Such context-dependent heuristic-guided foraging enables optimal, suboptimal, or fallacious decisions that drive organismal adaptation, health, longevity, and life history.
Technoscientific ambitions for perfecting human-like machines, by advancing state-of-the-art neuromorphic architectures and cognitive computing, may end in ironic regret without pondering the humanness of fallible artificial non-normative personalities. Self-organizing artificial personalities individualize machine performance and identity through fuzzy conscientiousness, emotionality, extraversion/introversion, and other traits, rendering insights into technology-assisted human evolution, robot ethology/pedagogy, and best practices against unwanted autonomous machine behavior.
The effect of conditioning on an additional covariate on confounding bias depends, in part, on covariates that are unobserved. We characterize the conditions under which the interaction between a covariate that is available for conditioning and one that is not can affect bias. When the confounding effects of two covariates, one of which is observed, are countervailing (in opposite directions), conditioning on the observed covariate can increase bias. We demonstrate this possibility analytically, and then show that these conditions are not rare in actual data. We also consider whether balance tests or sensitivity analysis can be used to justify the inclusion of an additional covariate. Our results indicate that neither provide protection against overadjustment.
This paper examines the phonological leveling and diffusion of variants of /t/ in Liverpool, northwest England, and two localities in its hinterland. We show that lenited realizations of /t/, thought to be historically restricted to Liverpool, are increasing over time and spreading over geographical space. We explore Labov's (2007) claims that linguistic changes that progress via transmission, within a speech community, are reproduced in all their structural complexity, whereas changes that spread across speech communities, via diffusion, are “simplified” en route. We find support for these hypotheses. Using a comparative sociolinguistic methodology, we show that the linguistic constraints operating on the realization of /t/ as [h] in Liverpool have remained stable over time, while those in a nearby town—Skelmersdale—seem to have simplified. However, we show that not all speakers from Skelmersdale share the same constraints on this variable form, and we connect this with speakers' positive or negative attitudes toward Skelmersdale or Liverpool.
The public health burden of alcohol is unevenly distributed across the life course, with levels of use, abuse, and dependence increasing across adolescence and peaking in early adulthood. Here, we leverage this temporal patterning to search for common genetic variants predicting developmental trajectories of alcohol consumption. Comparable psychiatric evaluations measuring alcohol consumption were collected in three longitudinal community samples (N = 2,126, obs = 12,166). Consumption-repeated measurements spanning adolescence and early adulthood were analyzed using linear mixed models, estimating individual consumption trajectories, which were then tested for association with Illumina 660W-Quad genotype data (866,099 SNPs after imputation and QC). Association results were combined across samples using standard meta-analysis methods. Four meta-analysis associations satisfied our pre-determined genome-wide significance criterion (FDR < 0.1) and six others met our ‘suggestive’ criterion (FDR <0.2). Genome-wide significant associations were highly biological plausible, including associations within GABA transporter 1, SLC6A1 (solute carrier family 6, member 1), and exonic hits in LOC100129340 (mitofusin-1-like). Pathway analyses elaborated single marker results, indicating significant enriched associations to intuitive biological mechanisms, including neurotransmission, xenobiotic pharmacodynamics, and nuclear hormone receptors (NHR). These findings underscore the value of combining longitudinal behavioral data and genome-wide genotype information in order to study developmental patterns and improve statistical power in genomic studies.
Finch trichomonosis, caused by Trichomonas gallinae, emerged in the Canadian Maritime provinces in 2007 and has since caused ongoing mortality in regional purple finch (Carpodacus purpureus) and American goldfinch (Carduelis tristis) populations. Trichomonas gallinae was isolated from (1) finches and rock pigeons (Columbia livia) submitted for post-mortem or live-captured at bird feeding sites experiencing trichomonosis mortality; (2) bird seed at these same sites; and (3) rock pigeons live-captured at known roosts or humanely killed. Isolates were characterized using internal transcribed spacer (ITS) region and iron hydrogenase (Fe-hyd) gene sequences. Two distinct ITS types were found. Type A was identical to the UK finch epidemic strain and was isolated from finches and a rock pigeon with trichomonosis; apparently healthy rock pigeons and finches; and bird seed at an outbreak site. Type B was obtained from apparently healthy rock pigeons. Fe-hyd sequencing revealed six distinct subtypes. The predominant subtype in both finches and the rock pigeon with trichomonosis was identical to the UK finch epidemic strain A1. Single nucleotide polymorphisms in Fe-hyd sequences suggest there is fine-scale variation amongst isolates and that finch trichomonosis emergence in this region may not have been caused by a single spill-over event.