The Integrative Psychiatric Research (iPSYCH) consortium has established a large Danish population-based Case-Cohort sample (iPSYCH2012) aimed at unravelling the genetic and environmental ...architecture of severe mental disorders. The iPSYCH2012 sample is nested within the entire Danish population born between 1981 and 2005, including 1 472 762 persons. This paper introduces the iPSYCH2012 sample and outlines key future research directions. Cases were identified as persons with schizophrenia (N=3540), autism (N=16 146), attention-deficit/hyperactivity disorder (N=18 726) and affective disorder (N=26 380), of which 1928 had bipolar affective disorder. Controls were randomly sampled individuals (N=30 000). Within the sample of 86 189 individuals, a total of 57 377 individuals had at least one major mental disorder. DNA was extracted from the neonatal dried blood spot samples obtained from the Danish Neonatal Screening Biobank and genotyped using the Illumina PsychChip. Genotyping was successful for 90% of the sample. The assessments of exome sequencing, methylation profiling, metabolome profiling, vitamin-D, inflammatory and neurotrophic factors are in progress. For each individual, the iPSYCH2012 sample also includes longitudinal information on health, prescribed medicine, social and socioeconomic information, and analogous information among relatives. To the best of our knowledge, the iPSYCH2012 sample is the largest and most comprehensive data source for the combined study of genetic and environmental aetiologies of severe mental disorders.
Nisin is a bacteriocin widely utilized in more than 50 countries as a safe and natural antibacterial food preservative. It is the most extensively studied bacteriocin, having undergone decades of ...bioengineering with a view to improving function and physicochemical properties. The discovery of novel nisin variants with enhanced activity against clinical and foodborne pathogens has recently been described. We screened a randomized bank of nisin A producers and identified a variant with a serine to glycine change at position 29 (S29G), with enhanced efficacy against S. aureus SA113. Using a site-saturation mutagenesis approach we generated three more derivatives (S29A, S29D and S29E) with enhanced activity against a range of Gram positive drug resistant clinical, veterinary and food pathogens. In addition, a number of the nisin S29 derivatives displayed superior antimicrobial activity to nisin A when assessed against a range of Gram negative food-associated pathogens, including E. coli, Salmonella enterica serovar Typhimurium and Cronobacter sakazakii. This is the first report of derivatives of nisin, or indeed any lantibiotic, with enhanced antimicrobial activity against both Gram positive and Gram negative bacteria.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The integration of the child or young person (CYP) in conversations around advance care planning (ACP) is an important area of paediatric practice. These discussions provide CYP with the opportunity ...to voice their values, goals and preferences, enabling health‐care professionals to ensure they are aligned with their planned course of treatment. This process, often undertaken within the context of the child's family, empowers children to participate in decisions and experience the dignity of self‐determination. It also facilitates an increased understanding between the CYP and those involved in their care. The objectives of this paper are to highlight the importance of these conversations for paediatricians and identify barriers, both real and perceived, that may prevent them from engaging with a CYP about their preferences for future care including focusing more on discussion with the parents, and concern about or not having the skills to engage the child in such sensitive conversations. Triggers that can prompt clinicians to undertake ACP are also discussed. A further complexity is that after seeking their perspective, it may become apparent that the CYP may hold different views and perspectives to their parents and/or clinician. This review article will especially examine elements of end‐of‐life conversations that are critical to support the important goal of listening to the voice of the CYP. This includes considerations around timing, legal aspects, ethical tensions that arise when amplifying a child's voice, clinician/team‐member roles, clinical process considerations, and the use of specific interventions and ACP tools to facilitate these conversations with CYP.
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.
In complex disease studies, it is crucial to perform multipoint linkage analysis with many markers and to use robust nonparametric methods that take account of all pedigree information. Currently ...available methods fall short in both regards. In this paper, we describe how to extract complete multipoint inheritance information from general pedigrees of moderate size. This information is captured in the multipoint inheritance distribution, which provides a framework for a unified approach to both parametric and nonparametric methods of linkage analysis. Specifically, the approach includes the following: (1) Rapid exact computation of multipoint LOD scores involving dozens of highly polymorphic markers, even in the presence of loops and missing data. (2) Non-parametric linkage (NPL) analysis, a powerful new approach to pedigree analysis. We show that NPL is robust to uncertainty about mode of inheritance, is much more powerful than commonly used nonparametric methods, and loses little power relative to parametric linkage analysis. NPL thus appears to be the method of choice for pedigree studies of complex traits. (3) Information-content mapping, which measures the fraction of the total inheritance information extracted by the available marker data and points out the regions in which typing additional markers is most useful. (4) Maximum-likelihood reconstruction of many-marker haplotypes, even in pedigrees with missing data. We have implemented NPL analysis, LOD-score computation, information-content mapping, and haplotype reconstruction in a new computer package, GENEHUNTER. The package allows efficient multipoint analysis of pedigree data to be performed rapidly in a single user-friendly environment.
The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human ...genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Central African Plateau (CAP) covers a million square kilometers of African lithosphere absent of recent volcanism and intense seismicity. Treating the CAP erosion surface as a reference frame ...for measuring continental deformation reveals an active landscape of normal fault systems and crustal flexures. Free‐air gravity anomalies over the CAP reveal both a short‐wavelength (100–200 km) flexural and a longer‐wavelength (>500 km) mantle convective signature. Apatite fission track thermochronometry records the onset of regional cooling of the erosion surface below 60 °C between 38 and 22 Ma. The erosion surface was formed by the Latest Miocene and elevated to its present altitude (1,200 ± 50 m) in the Latest Miocene/Pliocene. High‐resolution Shuttle Radar Topography Mission‐ and LIDAR‐based digital elevation models of the erosion surface show active fault terraces and alluvial fan deformation associated with pre‐existing rift border faults. Flexural modeling of the footwall uplift of the Luangwa Rift border fault yields an effective elastic thickness of the CAP lithosphere of ~35 km. The rifting initiated in the Pliocene with, or soon after, elevation of the CAP. Subsequent Plio‐Pleistocene deformation of the CAP surface controls the Congo and Zambezi drainage systems and wetland locations. The CAP rifts link southwestward through the Zambezi, Kafue and Muchili Rifts to the Pleistocene aged Okavango and Eiseb Rifts of Botswana and Namibia, defining a propagating Southwestern Rift cutting the Nubian Plate. This active rift system developed along relatively thin (~150 km) lithosphere between the Congo and Kalahari cratons within crust inherited from Neoproterozoic collisional tectonics.
Key Points
The Late Cenozoic erosion surface of the Central African Plateau can be used as a datum to analyze the neotectonics of central Africa
Pliocene uplift and later rifting has resulted in flexure of the central African lithosphere that controls river basin and wetland location
The Plio‐Quaternary rifts of central Africa can be traced SW across Africa as a continuous Southwestern Rift and embryonic plate boundary
Objective
Childhood cancer can have short‐ and long‐term impacts on parents’ finances and employment. It is important to understand how families adjust to the financial and employment changes caused ...by childhood cancer, the ongoing impacts after treatment completion, and which families need more targeted support. Qualitative research is necessary to facilitate an in‐depth understanding of the employment and financial impacts on families and to capture parents’ complex and nuanced experiences and perspectives.
Methods
We interviewed 56 parents of childhood cancer survivors (M = 2.13 years after treatment completion; 89% mothers) using the vocational and financial impact section of the Psychosocial Adjustment to Illness Scale–Carer Interview Form. We analyzed interviews using content analysis.
Results
Parents reported multiple sources of financial toxicity including travel to and from the hospital and needing to reduce their working hours during their child's cancer treatment. Workplace flexibility was an important factor to protect against unwanted vocational changes. After treatment completion, families living in low socioeconomic areas commonly reported ongoing financial difficulties. Mothers, particularly those who were on maternity leave when their child was diagnosed with cancer, reported ongoing employment impacts including unemployment.
Conclusions
Clinical staff including social workers could more consistently assess families’ financial distress and refer to professional services who can offer guidance for financial decision‐making as standard care. Flexible workplace agreements appear important for parents of children with cancer. Our findings can assist organizations to understand that cancer‐related disruptions are likely to continue after treatment completion, and therefore should offer benefits to parents where possible.
Exercise is widely recommended to reduce osteoporosis, falls and related fragility fractures, but its effect on whole bone strength has remained inconclusive. The primary purpose of this systematic ...review and meta-analysis was to evaluate the effects of long-term supervised exercise (> or =6 months) on estimates of lower-extremity bone strength from childhood to older age.
We searched four databases (PubMed, Sport Discus, Physical Education Index, and Embase) up to October 2009 and included 10 randomised controlled trials (RCTs) that assessed the effects of exercise training on whole bone strength. We analysed the results by age groups (childhood, adolescence, and young and older adulthood) and compared the changes to habitually active or sedentary controls. To calculate standardized mean differences (SMD; effect size), we used the follow-up values of bone strength measures adjusted for baseline bone values. An inverse variance-weighted random-effects model was used to pool the results across studies.
Our quality analysis revealed that exercise regimens were heterogeneous; some trials were short in duration and small in sample size, and the weekly training doses varied considerably between trials. We found a small and significant exercise effect among pre- and early pubertal boys SMD, effect size, 0.17 (95% CI, 0.02-0.32), but not among pubertal girls -0.01 (-0.18 to 0.17), adolescent boys 0.10 (-0.75 to 0.95), adolescent girls 0.21 (-0.53 to 0.97), premenopausal women 0.00 (-0.43 to 0.44) or postmenopausal women 0.00 (-0.15 to 0.15). Evidence based on per-protocol analyses of individual trials in children and adolescents indicated that programmes incorporating regular weight-bearing exercise can result in 1% to 8% improvements in bone strength at the loaded skeletal sites. In premenopausal women with high exercise compliance, improvements ranging from 0.5% to 2.5% have been reported.
The findings from our meta-analysis of RCTs indicate that exercise can significantly enhance bone strength at loaded sites in children but not in adults. Since few RCTs were conducted to investigate exercise effects on bone strength, there is still a need for further well-designed, long-term RCTs with adequate sample sizes to quantify the effects of exercise on whole bone strength and its structural determinants throughout life.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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