APOBEC mutagenesis is a common process in normal human small intestine

APOBEC mutational signatures SBS2 and SBS13 are common in many human cancer types. However, there is an incomplete understanding of its stimulus, when it occurs in the progression from normal to cancer cell and the APOBEC enzymes responsible. Here we whole-genome sequenced 342 microdissected normal epithelial crypts from the small intestines of 39 individuals and found that SBS2/SBS13 mutations were present in 17% of crypts, more frequent than most other normal tissues. Crypts with SBS2/SBS13 often had immediate crypt neighbors without SBS2/SBS13, suggesting that the underlying cause of SBS2/SBS13 is cell-intrinsic. APOBEC mutagenesis occurred in an episodic manner throughout the human lifespan, including in young children. APOBEC1 mRNA levels were very high in the small intestine epithelium, but low in the large intestine epithelium and other tissues. The results suggest that the high levels of SBS2/SBS13 in the small intestine are collateral damage from APOBEC1 fulfilling its physiological function of editing APOB mRNA. Whole-genome sequencing of healthy human epithelial crypts from the small intestines of 39 individuals highlights APOBEC enzymes as a common contributor to the overall mutational burden in this tissue.Peer reviewe

Pregnancy-related anxiety: Re-examining its distinctiveness

Objective Pregnancy‐related anxiety has been identified as a distinct anxiety associated with adverse outcomes. This partial replication of the seminal study which demonstrated pregnancy‐related anxiety and measures of state/trait anxiety and depression shared little variance, provides additional empirical support for this anxiety type. In addition, the Perinatal Anxiety Screening Scale (PASS) was examined together with the contributing role of neuroticism. Method Pregnant women were recruited online (n = 202, M age = 25.0, SD = 4.9), and completed the Pregnancy‐Related Anxiety Questionnaire‐Revised (PRAQ‐R2), PASS, Edinburgh Depression Scale, State Trait Anxiety Inventory, and the International Personality Item Pool Neuroticism scale. Results There were small to very large correlations between all main variables. Large correlations between the predictors (anxiety, depression, neuroticism) indicated multicollinearity resulting in the exclusion of neuroticism. Multiple regression confirmed that the PRAQ‐R2 shared little variance with measures of anxiety and depression. By contrast, the PASS shared large proportions of variance with measures of anxiety. Conclusions The findings in relation to the PRAQ‐R2 support the proposition that pregnancy‐related anxiety is a distinct anxiety type. However, given the significant proportion of variance the PASS shares with anxiety/depression, the PASS is better suited for screening anxiety disorder symptomology but less suitable as a measure of pregnancy‐related anxiety. Limitations included a sample size that was not sufficient to enable stratification. Further, given that the PRAQ‐R2 assesses only some of the core pregnancy‐related anxieties, use of a more comprehensive scale of pregnancy‐related anxiety is needed for an accurate assessment. Clinical implications include the possibility that some women with elevated pregnancy‐related anxiety may be overlooked using existing measures. Given the reported prevalence and adverse outcomes, a psychometrically sound measure for pregnancy‐related anxiety may afford valuable intervention opportunities

Paternal pregnancy-related anxiety : Systematic review of men's concerns and experiences during their partners' pregnancies

Background Up to 25 % of expectant parents experience anxiety symptoms. Pregnancy-related anxiety is characterised by concerns and worries specific to pregnancy, childbirth, and the transition to parenthood. While pregnancy-related anxiety is well-researched in women, the exact nature of this construct in men is unclear. The purpose of the current review was to examine men's concerns, worries, and fears during pregnancy and gain an understanding of their experiences during pregnancy. Methods An integrative review design was adopted, using thematic content analysis to synthesise findings from quantitative and qualitative studies. Quality appraisal of the quantitative studies used the AXIS appraisal tool. The Critical Appraisal Skills Program (CASP) checklist was used for the qualitative studies. Results A comprehensive search of nine databases led to inclusion of 14 quantitative and 41 qualitative studies. Ten dimensions of paternal pregnancy-related anxiety were identified: childbirth concerns, attitudes towards childbirth, baby concerns, acceptance of pregnancy, partner concerns, relationship concerns, worry about self, transition to parenthood, attitudes towards health care professionals, and practical and financial concerns. The pregnancy transition was characterised by mixed emotions and conflicted experiences for fathers. Limitations Generalizability of review findings was limited by poor reporting of demographic information by many included studies, exclusion of studies not published in English, and focus on heterosexual relationships. Conclusions Expectant fathers may experience anxiety symptoms characterised by excessive worry across multiple domains of pregnancy-related concerns. Clinicians play an important role in identifying and supporting fathers with pregnancy-related anxiety and addressing the sense of exclusion often experienced by them

The initial development of the Pregnancy-related Anxiety Scale

Problem/background Pregnancy-related anxiety is a distinct anxiety characterised by pregnancy-specific concerns. This anxiety is consistently associated with adverse birth outcomes, and obstetric and paediatric risk factors, associations generally not seen with other anxieties. The need exists for a psychometrically sound scale for this anxiety type. This study, therefore, reports on the initial development of the Pregnancy-related Anxiety Scale. Methods The item pool was developed following a literature review and the formulation of a definition for pregnancy-related anxiety. An Expert Review Panel reviewed the definition, item pool and test specifications. Pregnant women were recruited online (N = 671). Results Using a subsample (N = 262, M = 27.94, SD = 4.99), fourteen factors were extracted using Principal Components Analysis accounting for 63.18% of the variance. Further refinement resulted in 11 distinct factors. Confirmatory Factor Analysis further tested the model with a second subsample (N = 369, M = 26.59, SD = 4.76). After additional refinement, the resulting model was a good fit with nine factors (childbirth, appearance, attitudes towards childbirth, motherhood, acceptance, anxiety, medical, avoidance, and baby concerns). Internal consistency reliability was good with the majority of subscales exceeding α = .80. Conclusions The Pregnancy-related Anxiety Scale is easy to administer with higher scores indicative of greater pregnancy-related anxiety. The inclusion of reverse-scored items is a potential limitation with poorer reliability evident for these factors. Although still in its development stage, the Pregnancy-related Anxiety Scale will eventually be useful both clinically (affording early intervention) and in research settings

The pregnancy-related anxiety scale: A validity examination using Rasch analysis

Background Pregnancy-related anxiety is increasingly recognised as a common condition that is associated with many deleterious outcomes for both the mother and infant (e.g., preterm birth, postnatal depression). Limitations in the psychometric properties and/or breadth of existing scales for pregnancy-related anxiety highlight the need for a psychometrically sound measure to facilitate effective screening and possible early interventions. The recently developed Pregnancy-related Anxiety Scale (PrAS) was evaluated using Rasch analysis to explore how the scale's psychometric properties could be fine-tuned. Method A sample of 497 pregnant women completed the PrAS. Data were subjected to Rasch analysis, and the resulting scale structure examined using Confirmatory Factor Analysis. Results After minor modifications, the Rasch model with 33-items and 8-factors demonstrated good fit, unidimensionality and excellent targeting and internal consistency. Confirmatory Factor Analysis confirmed the final structure, and Cronbach's alpha demonstrated excellent reliability. Limitations The use of the same sample for all analyses was a potential limitation due to the possibility of sample-specific influences. Conclusions The Rasch analysis further supports the internal construct validity of the PrAS. Ordinal to interval score conversions provide added precision to the analysis of the PrAS scores. The Rasch results, together with previous validation evidence, point to the PrAS as a comprehensive and psychometrically sound screening scale for pregnancy-related anxiety. The PrAS offers clinicians the ability to screen for pregnancy-related anxiety. The subscales provide additional insights into a woman's pregnancy-related anxiety and her specific areas of concern, enabling more targeted interventions

APOBEC mutagenesis is a common process in normal human small intestine.

APOBEC mutational signatures SBS2 and SBS13 are common in many human cancer types. However, there is an incomplete understanding of its stimulus, when it occurs in the progression from normal to cancer cell and the APOBEC enzymes responsible. Here we whole-genome sequenced 342 microdissected normal epithelial crypts from the small intestines of 39 individuals and found that SBS2/SBS13 mutations were present in 17% of crypts, more frequent than most other normal tissues. Crypts with SBS2/SBS13 often had immediate crypt neighbors without SBS2/SBS13, suggesting that the underlying cause of SBS2/SBS13 is cell-intrinsic. APOBEC mutagenesis occurred in an episodic manner throughout the human lifespan, including in young children. APOBEC1 mRNA levels were very high in the small intestine epithelium, but low in the large intestine epithelium and other tissues. The results suggest that the high levels of SBS2/SBS13 in the small intestine are collateral damage from APOBEC1 fulfilling its physiological function of editing APOB mRNA

APOBEC mutagenesis is a common process in normal human small intestine.

Funder: Core funding from the Wellcome Sanger Institute (Wellcome Trust, No. 206194).Funder: Wellcome PhD Studentship (Wellcome Trust, No. 206194)Funder: Wellcome Clinical PhD fellowship (Wellcome Trust, No. 206194)Funder: Pathological Society of Great Britain and Ireland; doi: https://doi.org/10.13039/501100000672Funder: Jean Shank/Pathological Society of Great Britain and Ireland Intermediate Clinical Fellowship(JSPS IF 2019 01)Funder: Finnish Center of Excellence Program 2018–2025, No. 312041Funder: NIHR Cambridge Biomedical Research CentreFunder: Core funding from The Pharsalia Trust.APOBEC mutational signatures SBS2 and SBS13 are common in many human cancer types. However, there is an incomplete understanding of its stimulus, when it occurs in the progression from normal to cancer cell and the APOBEC enzymes responsible. Here we whole-genome sequenced 342 microdissected normal epithelial crypts from the small intestines of 39 individuals and found that SBS2/SBS13 mutations were present in 17% of crypts, more frequent than most other normal tissues. Crypts with SBS2/SBS13 often had immediate crypt neighbors without SBS2/SBS13, suggesting that the underlying cause of SBS2/SBS13 is cell-intrinsic. APOBEC mutagenesis occurred in an episodic manner throughout the human lifespan, including in young children. APOBEC1 mRNA levels were very high in the small intestine epithelium, but low in the large intestine epithelium and other tissues. The results suggest that the high levels of SBS2/SBS13 in the small intestine are collateral damage from APOBEC1 fulfilling its physiological function of editing APOB mRNA