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Around 30% of individuals with schizophrenia remain symptomatic and significantly impaired despite antipsychotic treatment and are considered to be treatment resistant. Clinicians are currently unable to predict which patients are at higher risk of treatment resistance.
To determine whether genetic liability for schizophrenia and/or clinical characteristics measurable at illness onset can prospectively indicate a higher risk of treatment-resistant psychosis (TRP).
In 1070 individuals with schizophrenia or related psychotic disorders, schizophrenia polygenic risk scores (PRS) and large copy number variations (CNVs) were assessed for enrichment in TRP. Regression and machine-learning approaches were used to investigate the association of phenotypes related to demographics, family history, premorbid factors and illness onset with TRP.
Younger age at onset (odds ratio 0.94, P = 7.79 × 10−13) and poor premorbid social adjustment (odds ratio 1.64, P = 2.41 × 10−4) increased risk of TRP in univariate regression analyses. These factors remained associated in multivariate regression analyses, which also found lower premorbid IQ (odds ratio 0.98, P = 7.76 × 10−3), younger father's age at birth (odds ratio 0.97, P = 0.015) and cannabis use (odds ratio 1.60, P = 0.025) increased the risk of TRP. Machine-learning approaches found age at onset to be the most important predictor and also identified premorbid IQ and poor social adjustment as predictors of TRP, mirroring findings from regression analyses. Genetic liability for schizophrenia was not associated with TRP.
People with an earlier age at onset of psychosis and poor premorbid functioning are more likely to be treatment resistant. The genetic architecture of susceptibility to schizophrenia may be distinct from that of treatment outcomes.
The ‘Portus Project’ investigates the social and economic contexts of the maritime port of Imperial Rome. This article presents the results of analysis of plant, animal and human remains from the site, and evaluates their significance for the reconstruction of the diets and geographic origins of its inhabitants between the second and sixth centuries AD. Integrating this evidence with other material from the recent excavations, including ceramic data, the authors identify clear diachronic shifts in imported foods and diet that relate to the commercial and political changes following the breakdown of Roman control of the Mediterranean.
Bessel-beam launchers are promising and established technologies for focusing applications at microwaves. Their use in time-domain leads to the definition of a new class of devices, namely, the X-wave launchers. In this work, we discuss the focusing features of such devices with a specific interest at millimeter waves. The spatial resolutions of such systems are described under a rigorous mathematical framework to derive novel operating conditions for designing X-wave launchers. These criteria might be particularly appealing for specific millimeter-wave applications. In particular, it is shown that an electrically large aperture is not strictly required, as it seemed from previous works. However, the use of an electrically small aperture would demand a considerably wideband capability. The various discussions presented here provide useful information for the design of X-wave launchers. This aspect is finally shown with reference to the practical design of two different X-wave launchers.
Childhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age.
Within the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer.
CM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions.
Severity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.
Rare copy number variants (CNVs) are associated with risk of neurodevelopmental disorders characterised by varying degrees of cognitive impairment, including schizophrenia, autism spectrum disorder and intellectual disability. However, the effects of many individual CNVs in carriers without neurodevelopmental disorders are not yet fully understood, and little is known about the effects of reciprocal copy number changes of known pathogenic loci.
We aimed to analyse the effect of CNV carrier status on cognitive performance and measures of occupational and social outcomes in unaffected individuals from the UK Biobank.
We called CNVs in the full UK Biobank sample and analysed data from 420 247 individuals who passed CNV quality control, reported White British or Irish ancestry and were not diagnosed with neurodevelopmental disorders. We analysed 33 pathogenic CNVs, including their reciprocal deletions/duplications, for association with seven cognitive tests and four general measures of functioning: academic qualifications, occupation, household income and Townsend Deprivation Index.
Most CNVs (24 out of 33) were associated with reduced performance on at least one cognitive test or measure of functioning. The changes on the cognitive tests were modest (average reduction of 0.13 s.d.) but varied markedly between CNVs. All 12 schizophrenia-associated CNVs were associated with significant impairments on measures of functioning.
CNVs implicated in neurodevelopmental disorders, including schizophrenia, are associated with cognitive deficits, even among unaffected individuals. These deficits may be subtle but CNV carriers have significant disadvantages in educational attainment and ability to earn income in adult life.
To assess the reliability and validity of body weight (BW) and body image (BI) perception reported by parents (in children) and by adolescents in a South American population.
Cross-sectional study. BW perception was evaluated by the question, ‘Do you think you/your child are/is: severely wasted, wasted, normal weight, overweight, obese?’ BI perception was evaluated using the Gardner scale. To evaluate reliability, BW and BI perceptions were reported twice, two weeks apart. To evaluate validity, the BW and BI perceptions were compared with WHO BMI Z-scores. Kappa and Kendall’s tau-c coefficients were obtained.
Public and private schools and high schools from six countries of South America (Argentina, Peru, Colombia, Uruguay, Chile, Brazil).
Children aged 3–10 years (n 635) and adolescents aged 11–17 years (n 400).
Reliability of BW perception was fair in children’s parents (κ=0·337) and substantial in adolescents (κ=0·709). Validity of BW perception was slight in children’s parents (κ=0·176) and fair in adolescents (κ=0·268). When evaluating BI, most children were perceived by parents as having lower weight. Reliability of BI perception was slight in children’s parents (κ=0·124) and moderate in adolescents (κ=0·599). Validity of BI perception was poor in children’s parents (κ=−0·018) and slight in adolescents (κ=0·023).
Reliability of BW and BI perceptions was higher in adolescents than in children’s parents. Validity of BW perception was good among the parents of the children and adolescents with underweight and normal weight.
In their recent paper ‘On-farm trials for development impact? The organization of research and the scaling of agricultural technologies’, de Roo, Andersson and Krupnik report on three case studies, each undertaken by one of the authors, of projects conducting on-farm research. They reach conclusions on the limitations of the projects themselves and the effects of ‘donor dependency’, and propose a strategy to overcome these issues. However, the description of the philosophy, strategies and conduct of the projects reviewed in the southern African case study is incomplete and misleading, and shows that the case study author did not understand or overlooked important project components. Due to this the conclusions reached, insofar as this case study is concerned, are largely either invalid or already contemplated in the project activities. Here, we describe more fully the philosophy and strategies followed by the series of projects on which the case study was conducted, which were designed to facilitate, through the upscaling of project methodologies, the eventual outscaling and widespread adoption of more sustainable farming systems by smallholder farmers in eastern and southern Africa. We propose these methodologies as a valid comprehensive approach to the organization of agricultural research for development for the successful development, scaling-up and scaling-out of agricultural technologies.
The consumption of nitrate-rich vegetables can acutely lower blood pressure and improve mediators shown to optimise vascular health. However, we do not yet understand the impact of long-term habitual dietary nitrate intake and its association with CVD. Therefore, the aim of this investigation was to examine the relationship between habitual dietary nitrate intakes and risk of CHD in women from the Nurses’ Health Study. We prospectively followed 62 535 women who were free from diabetes, CVD and cancer at baseline in 1986. Information on diet was updated every 4 years with validated FFQ. The main outcome was CHD defined by the occurrence of non-fatal myocardial infarction or fatal CHD. Cox proportional hazard regression models were used to estimate the relative risks (RR) and 95 % CI. During 26 years of follow-up, 2257 cases of CHD were identified. When comparing the highest quintile of nitrate intake with the lowest quintile, in aged-adjusted analysis there was a protective association for CHD (RR=0·77, 95 % CI 0·68, 0·97; P=0·0002) which dissipated after further adjustment for smoking, physical activity, BMI and race (RR=0·91; 95 % CI 0·80, 1·04; P=0·27). This magnitude of association was further attenuated once we adjusted for the Alternative Healthy Eating Index excluding vegetable and fruit consumption (RR=1·04, 95 % CI 0·91, 1·20; P=0·34). Dietary nitrate intake was not related to the risk of CHD after adjustment for other lifestyle and non-vegetable dietary factors in a large group of US women.
Getting a fix on Estonians’ state of mind was difficult in the years before and after September 1991. The runup and aftermath of independence produced what an observer in Estonian Life called a “psychic rollercoaster”—euphoric hopes, long periods of boredom, and moments of sheer terror as Soviet agents struck hard at Baltic independence. Earlier years of collective obedience training had produced the effect of psychic numbing. In the 1990s Estonians dared to think and feel.
Walter C. Clemens, Jr. Negotiating a New Life: Burdens of Empire and Independence—the Case of the Baltics
The Soviet Union disappeared in 1991 but, dying, gave birth to many new shoots of life, each struggling to survive and flourish despite great difficulties. Devolution of empire rarely proceeds without pain; it often causes, or results from, great violence. The first year of independent life for the successor states of the USSR witnessed much less violence than attended the demise of other great empires in this century. None had to fight for liberation as did Algeria and Angola. The fighting over Nagorno-Karabakh and South Ossetia does not approach the violence seen in the breakup of India, the attempted secessions of Katanga and Biafra, or the Croatian-Serbian war.
Empire depends not only upon the strength of the center but upon compliant behavior in the periphery, and the nature of interactions between center and periphery. Each of these three variables is changing rapidly in the former Soviet empire.
Most studies underline the contribution of heritable factors for psychiatric disorders. However, heritability estimates depend on the population under study, diagnostic instruments, and study designs that each has its inherent assumptions, strengths, and biases. We aim to test the homogeneity in heritability estimates between two powerful, and state of the art study designs for eight psychiatric disorders.
We assessed heritability based on data of Swedish siblings (N = 4 408 646 full and maternal half-siblings), and based on summary data of eight samples with measured genotypes (N = 125 533 cases and 208 215 controls). All data were based on standard diagnostic criteria. Eight psychiatric disorders were studied: (1) alcohol dependence (AD), (2) anorexia nervosa, (3) attention deficit/hyperactivity disorder (ADHD), (4) autism spectrum disorder, (5) bipolar disorder, (6) major depressive disorder, (7) obsessive-compulsive disorder (OCD), and (8) schizophrenia.
Heritability estimates from sibling data varied from 0.30 for Major Depression to 0.80 for ADHD. The estimates based on the measured genotypes were lower, ranging from 0.10 for AD to 0.28 for OCD, but were significant, and correlated positively (0.19) with national sibling-based estimates. When removing OCD from the data the correlation increased to 0.50.
Given the unique character of each study design, the convergent findings for these eight psychiatric conditions suggest that heritability estimates are robust across different methods. The findings also highlight large differences in genetic and environmental influences between psychiatric disorders, providing future directions for etiological psychiatric research.
There is evidence for the cost-effectiveness of health visitor (HV) training to assess postnatal depression (PND) and deliver psychological approaches to women at risk of depression. Whether this approach is cost-effective for lower-risk women is unknown. There is a need to know the cost of HV-delivered universal provision, and how much it might cost to improve health-related quality of life for postnatal women. A sub-study of a cluster-randomised controlled trial in the former Trent region (England) previously investigated the effectiveness of PoNDER HV training in mothers at lower risk of PND. We conducted a parallel cost-effectiveness analysis at 6-months postnatal for all mothers with lower-risk status attributed to an Edinburgh Postnatal Depression Scale (EPDS) score <12 at 6-weeks postnatal.
Intervention HVs were trained in assessment and cognitive behavioural or person-centred psychological support techniques to prevent depression. Outcomes examined: quality-adjusted life-year (QALY) gains over the period between 6 weeks and 6 months derived from SF-6D (from SF-36); risk-of-depression at 6 months (dichotomising 6-month EPDS scores into lower risk (<12) and at-risk (⩾12).
In lower-risk women, 1474 intervention (63 clusters) and 767 control participants (37 clusters) had valid 6-week and 6-month EPDS scores. Costs and outcomes data were available for 1459 participants. 6-month adjusted costs were £82 lower in intervention than control groups, with 0.002 additional QALY gained. The probability of cost-effectiveness at £20 000 was very high (99%).
PoNDER HV training was highly cost-effective in preventing symptoms of PND in a population of lower-risk women and cost-reducing over 6 months.
The study of cultural stability requires a knowledge of cultural development over a reasonably long span of time. The definition of this time perspective is one of the major contributions of archaeology to the study of culture. The archaeologist therefore should be in a position to make a significant contribution to the appraisal of the stability problem itself. However, the lack of a commonly accepted anthropological definition of the concept of cultural stability imposes semantic difficulties which hinder the determination of practical limits for the stability- instability problem area. Moreover, the nature of the data available to the archaeologist conditions the kind of contribution he can make.
OBJECTIVES/SPECIFIC AIMS: We sought to investigate the role of the host microbiome during severe, acute respiratory infection (ARI) to understand the drivers of both acute clinical pathogenesis. METHODS/STUDY POPULATION: Nasopharyngeal swabs comprised of mixed cell populations at the active site of infection were collected from 192 hospitalized pediatric patients with ARI. We combined comprehensive respiratory virus detection and virus genome sequencing with 16S rRNA gene sequencing to evaluate the microbial content of the airway during ARI. This data was coupled with 11 clinical parameters, which were compiled to create a clinical severity score. The microbiome profiles were assessed to determine if clinical severity of infection, and/or specific virus was associated with increased clinical severity. RESULTS/ANTICIPATED RESULTS: We identified 8 major microbiome profiles classified by dominant bacterial genus, Moraxella, Corynebacterium, Staphylococcus, Haemophilus, Streptococcus, Alloiococcus, Schlegelella, and Diverse. Increased clinical severity was significantly associated with microbiome profiles dominated by Haemophilus, Streptococcus, and Schlegelella, whereas Corynebacterium and Alloiococcus were more prevalent in children with less severe disease. Independent of the microbial community, more than 60% of patients with the highest clinical severity were infected with either respiratory syncytial virus or rhinovirus. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results indicate that individually and in combination, both virus and microbial composition may drive clinical severity during acute respiratory viral infections. It is still unclear how the complex interplay between virus, bacterial community, and the host response influence long-term respiratory impacts, such as the development of asthma. Nonetheless, during ARIs therapeutic interventions such as antibiotics and probiotics may be warranted in a subset of patients that are identified to have both a virus and microbiome profile that is associated with increased pathogenesis to limit both acute and long-term phenotypes.
There is strong evidence that people born in winter and in spring have a small increased risk of schizophrenia. As this ‘season of birth’ effect underpins some of the most influential hypotheses concerning potentially modifiable risk exposures, it is important to exclude other possible explanations for the phenomenon.
Here we sought to determine whether the season of birth effect reflects gene-environment confounding rather than a pathogenic process indexing environmental exposure. We directly measured, in 136 538 participants from the UK Biobank (UKBB), the burdens of common schizophrenia risk alleles and of copy number variants known to increase the risk for the disorder, and tested whether these were correlated with a season of birth.
Neither genetic measure was associated with season or month of birth within the UKBB sample.
As our study was highly powered to detect small effects, we conclude that the season of birth effect in schizophrenia reflects a true pathogenic effect of environmental exposure.
To identify predominant dietary patterns in four African populations and examine their association with obesity.
We used data from the Africa/Harvard School of Public Health Partnership for Cohort Research and Training (PaCT) pilot study established to investigate the feasibility of a multi-country longitudinal study of non-communicable chronic disease in sub-Saharan Africa. We applied principal component analysis to dietary intake data collected from an FFQ developed for PaCT to ascertain dietary patterns in Tanzania, South Africa, and peri-urban and rural Uganda. The sample consisted of 444 women and 294 men.
We identified two dietary patterns: the Mixed Diet pattern characterized by high intakes of unprocessed foods such as vegetables and fresh fish, but also cold cuts and refined grains; and the Processed Diet pattern characterized by high intakes of salad dressing, cold cuts and sweets. Women in the highest tertile of the Processed Diet pattern score were 3·00 times more likely to be overweight (95 % CI 1·66, 5·45; prevalence=74 %) and 4·24 times more likely to be obese (95 % CI 2·23, 8·05; prevalence=44 %) than women in this pattern’s lowest tertile (both P<0·0001; prevalence=47 and 14 %, respectively). We found similarly strong associations in men. There was no association between the Mixed Diet pattern and overweight or obesity.
We identified two major dietary patterns in several African populations, a Mixed Diet pattern and a Processed Diet pattern. The Processed Diet pattern was associated with obesity.
Little is known about the association of cortical Aβ with depression and anxiety among cognitively normal (CN) elderly persons.
We conducted a cross-sectional study derived from the population-based Mayo Clinic Study of Aging in Olmsted County, Minnesota; involving CN persons aged ≥ 60 years that underwent PiB-PET scans and completed Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory (BAI). Cognitive diagnosis was made by an expert consensus panel. Participants were classified as having abnormal (≥1.4; PiB+) or normal PiB-PET (<1.4; PiB−) using a global cortical to cerebellar ratio. Multi-variable logistic regression analyses were performed to calculate odds ratios (OR) and 95% confidence intervals (95% CI) after adjusting for age and sex.
Of 1,038 CN participants (53.1% males), 379 were PiB+. Each one point symptom increase in the BDI (OR = 1.03; 1.00–1.06) and BAI (OR = 1.04; 1.01–1.08) was associated with increased odds of PiB-PET+. The number of participants with BDI > 13 (clinical depression) was greater in the PiB-PET+ than PiB-PET- group but the difference was not significant (OR = 1.42; 0.83–2.43). Similarly, the number of participants with BAI > 10 (clinical anxiety) was greater in the PiB-PET+ than PiB-PET− group but the difference was not significant (OR = 1.77; 0.97–3.22).
As expected, depression and anxiety levels were low in this community-dwelling sample, which likely reduced our statistical power. However, we observed an informative albeit weak association between increased BDI and BAI scores and elevated cortical amyloid deposition. This observation needs to be tested in a longitudinal cohort study.