Autosomal Dominant Retinal Dystrophies Caused by a Founder Splice Site Mutation, c.828+3A>T, in PRPH2 and Protein Haplotypes in trans as Modifiers.

PurposeWe determined the phenotypic variation, disease progression, and potential modifiers of autosomal dominant retinal dystrophies caused by a splice site founder mutation, c.828+3A>T, in the PRPH2 gene.MethodsA total of 62 individuals (19 families) harboring the PRPH2 c.828+3A>T mutation, had phenotype analysis by fundus appearance, electrophysiology, and visual fields. The PRPH2 haplotypes in trans were sequenced for potential modifying variants and generalized estimating equations (GEE) used for statistical analysis.ResultsSeveral distinct phenotypes caused by the PRPH2 c.828+3A>T mutation were observed and fell into two clinical categories: Group I (N = 44) with mild pattern dystrophies (PD) and Group II (N = 18) with more severe cone-rod dystrophy (CRD), retinitis pigmentosa (RP), and central areolar chorioretinal dystrophy (CACD). The PRPH2 Gln304-Lys310-Asp338 protein haplotype in trans was found in Group I only (29.6% vs. 0%), whereas the Glu304-Lys310-Gly338 haplotype was predominant in Group II (94.4% vs. 70.4%). Generalized estimating equations analysis for PD versus the CRD/CACD/RP phenotypes in individuals over 43 years alone with the PRPH2 haplotypes in trans and age as predictors, adjusted for correlation within families, confirmed a significant effect of haplotype on severity (P = 0.03) with an estimated odds ratio of 7.16 (95% confidence interval [CI] = [2.8, 18.4]).ConclusionsThe PRPH2 c.828+3A>T mutation results in multiple distinct phenotypes likely modified by protein haplotypes in trans; the odds of having the CACD/RP-like phenotype (versus the PD phenotype) are 7.16 times greater with a Glu304-Lys310-Gly338 haplotype in trans. Further functional studies of the modifying haplotypes in trans and PRPH2 splice variants may offer therapeutic targets

Minimal, superficial DNA damage in human skin from filtered far-ultraviolet C

Funding: This study was funded in part by MR/P012248/1 to R.P.H. from the Medical Research Council.Publisher PDFPeer reviewe

Hoof lesions in partly housed pasture-based dairy cows

Lameness is a symptom of a painful disorder affecting the limbs, which impacts dairy cow welfare and productivity. Lameness is primarily caused by hoof lesions. The prevalence of different lesion types can differ depending on environmental conditions and farm management practices. The aims of this observational study were to establish the cow-level and herd-level lesion prevalence during both housing and grazing periods in a partly housed, pasture-based system, establish the prevalence of lesions always associated with pain (“alarm” lesion), identify the lesions associated with a higher lameness score, determine relationships between lesions, and identify risk factors for digital dermatitis. On 98 farms during the grazing period and on 74 of the same farms during the housing period, every cow was lameness scored (0–3 lameness scoring scale), and the hind hooves of lame cows (score 2 and 3) were examined (maximum 20 cows per visit) and the prevalence of each lesion type recorded. To gather data on potential predictors for the risk factor analysis, a questionnaire with the farmer was conducted on lameness management practices and infrastructure measurements were taken at each visit. Cow-level data were also collected (e.g., parity, breed, milk yield, and so on). Noninfectious lesions were found to be more prevalent than infectious lesions in this system type. The most prevalent lesion types during both grazing and housing periods were white line separation, sole hemorrhages and overgrown claws; all remaining lesions had a cow-level prevalence of less than 15%. The cow-level prevalence of alarm lesions was 19% during the grazing period and 25% during the housing period; the most prevalent alarm lesion was sole ulcers during both periods. We found significantly more foreign bodies within the hoof sole (grazing = 14%, housing = 7%) and overgrown claws (grazing = 71%, housing = 55%) during the grazing period compared with the housing period. Cows with foul of the foot, sole ulcer, white line abscess, toe necrosis or an amputated claw had higher odds of being more severely lame, compared with mildly lame. The strongest correlation between lesions were between toe necrosis and digital dermatitis (r = 0.40), overgrown claws and corkscrew claws (r = 0.33), and interdigital hyperplasia and digital dermatitis (r = 0.31) at herd level. At the cow level, the strongest correlation was between overgrown claws and corkscrew claws (r = 0.27), and digital dermatitis and heel erosion (r = 0.22). The farmers' perception of the presence of digital dermatitis (and lameness) was significantly correlated with the actual presence of digital dermatitis recorded. Additional risk factors for the presence of digital dermatitis were cow track and verge width near the collecting yard, and stone presence on the cow tracks. Results from this study help further our understanding of the causes of lameness in partly housed, pasture-based dairy cows, and can be used to guide prevention and treatment protocols

Cow- and herd-level risk factors for lameness in partly housed pasture-based dairy cows

Lameness in dairy cows is a major animal welfare concern and has substantial economic impact through reduced production and fertility. Previous risk factor analyses have focused on housed systems, rather than those where cows were grazed for the majority of the year and housed only for the winter period. Therefore, the aim of this observational study was to identify a robust set of cow-level and herd-level risk factors for lameness in a pasture-based system, based on predictors from the housing and grazing periods. Ninety-nine farms were visited during the grazing period (April 2019–September 2019), and 85 farms were revisited during the housing period (October 2019–February 2020). At each visit, all lactating cows were scored for lameness (0 = good mobility, 1 = imperfect mobility, 2 = impaired mobility, 3 = severely impaired mobility), and potential herd-level risk factors were recorded through questionnaires and infrastructure measurements. Routine cow-level management data were also collected. Important risk factors for lameness were derived though triangulation of results from elastic net regression, and from logistic regression model selection using modified Bayesian information criterion. Both selection methods were implemented using bootstrapping. This novel approach has not previously been used in a cow-level or herd-level risk factor analysis in dairy cows, to the authors' knowledge. The binary outcome variable was lameness status, whereby cows with a lameness score of 0 or 1 were classed as non-lame and cows with a score of 2 or 3 were classed as lame. Cow-level risk factors for increased lameness prevalence were age and genetic predicted transmitting ability for lameness. Herd-level risk factors included farm and herd size, stones in paddock gateways, slats on cow tracks near the collecting yard, a sharper turn at the parlor exit, presence of digital dermatitis on the farm, and the farmers' perception of whether lameness was a problem on the farm. This large-scale study identified the most important associations between risk factors and lameness, based on the entire year (grazing and housing periods), providing a focus for future randomized clinical trials

Control of oocyte release by progesterone receptor-regulated gene expression

The progesterone receptor (PGR) is a nuclear receptor transcription factor that is essential for female fertility, in part due to its control of oocyte release from the ovary, or ovulation. In all mammals studied to date, ovarian expression of PGR is restricted primarily to granulosa cells of follicles destined to ovulate. Granulosa cell expression of PGR is induced by the pituitary Luteinizing Hormone (LH) surge via mechanisms that are not entirely understood, but which involve activation of Protein Kinase A and modification of Sp1/Sp3 transcription factors on the PGR promoter. Null mutations for PGR or treatment with PGR antagonists block ovulation in all species analyzed, including humans. The cellular mechanisms by which PGR regulates ovulation are currently under investigation, with several downstream pathways having been identified as PGR-regulated and potentially involved in follicular rupture. Interestingly, none of these PGR-regulated genes has been demonstrated to be a direct transcriptional target of PGR. Rather, in ovarian granulosa cells, PGR may act as an inducible coregulator for constitutively bound Sp1/Sp3 transcription factors, which are key regulators for a discrete cohort of ovulatory genes

Test-beam and laboratory characterisation of the TORCH prototype detector

The TORCH time-of-flight (TOF) detector is being developed to provide particle identification up to a momentum of 10 GeV/c over a flight distance of 10 m. It has a DIRC-like construction with View the MathML source10mm thick synthetic amorphous fused-silica plates as a Cherenkov radiator. Photons propagate by total internal reflection to the plate periphery where they are focused onto an array of customised position-sensitive micro-channel plate (MCP) detectors. The goal is to achieve a 15 ps time-of-flight resolution per incident particle by combining arrival times from multiple photons. The MCPs have pixels of effective size 0.4 mm×6.6 mm2 in the vertical and horizontal directions, respectively, by incorporating a novel charge-sharing technique to improve the spatial resolution to better than the pitch of the readout anodes. Prototype photon detectors and readout electronics have been tested and calibrated in the laboratory. Preliminary results from testbeam measurements of a prototype TORCH detector are also presented

Neonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence

Comparison between groups of monozygotic (MZ) and dizygotic (DZ) twins enables an estimation of the relative contribution of genetic and shared and nonshared environmental factors to phenotypic variability. Using DNA methylation profiling of ∼20,000 CpG sites as a phenotype, we have examined discordance levels in three neonatal tissues from 22 MZ and 12 DZ twin pairs. MZ twins exhibit a wide range of within-pair differences at birth, but show discordance levels generally lower than DZ pairs. Within-pair methylation discordance was lowest in CpG islands in all twins and increased as a function of distance from islands. Variance component decomposition analysis of DNA methylation in MZ and DZ pairs revealed a low mean heritability across all tissues, although a wide range of heritabilities was detected for specific genomic CpG sites. The largest component of variation was attributed to the combined effects of nonshared intrauterine environment and stochastic factors. Regression analysis of methylation on birth weight revealed a general association between methylation of genes involved in metabolism and biosynthesis, providing further support for epigenetic change in the previously described link between low birth weight and increasing risk for cardiovascular, metabolic, and other complex diseases. Finally, comparison of our data with that of several older twins revealed little evidence for genome-wide epigenetic drift with increasing age. This is the first study to analyze DNA methylation on a genome scale in twins at birth, further highlighting the importance of the intrauterine environment on shaping the neonatal epigenome

Exploring Black and South Asian women's experiences of help-seeking and engagement in perinatal mental health services in the UK

Background and aims: In the United Kingdom (UK), Black and South Asian women are less likely than White British women to access support from perinatal mental health services, despite experiencing similar, or higher, levels of distress. This inequality needs to be understood and remedied. The aim of this study was to answer two questions: how do Black and South Asian women experience (1) access to perinatal mental health services and (2) care received from perinatal mental health services? Method: Semi-structured interviews were conducted with Black and South Asian women (n = 37), including four women who were interviewed with an interpreter. Interviews were recorded and transcribed line-by-line. Data were analyzed using framework analysis, by an ethnically diverse multidisciplinary team of clinicians, researchers and people with lived experience of perinatal mental illness. Results: Participants described a complex interplay of factors that impacted on seeking, and receiving help, and benefiting from services. Four themes emerged that captured the highly varied experiences of individuals: (1) Self-identity, social expectations and different attributions of distress deter help-seeking; (2) Hidden and disorganized services impede getting support; (3) The role of curiosity, kindness and flexibility in making women feel heard, accepted and supported by clinicians; (4) A shared cultural background may support or hinder trust and rapport. Conclusion: Women described a wide range of experiences and a complex interplay of factors impacting access to, and experience of, services. Women described services as giving them strength and also leaving them disappointed and confused about where to get help. The main barriers to access were attributions related to mental distress, stigma, mistrust and lack of visibility of services, and organizational gaps in the referral process. These findings describe that many women feel heard, and supported by services, reporting that services provide a high quality of care that was inclusive of diverse experiences and understandings of mental health problems. Transparency around what PMHS are, and what support is available would improve the accessibility of PMHS

Healthcare professionals' views on the accessibility and acceptability of perinatal mental health services for South Asian and Black women: a qualitative study

BACKGROUND: Perinatal mental illness affects one third of new and expectant mothers. Individuals from ethnic minority groups experience higher rates of mental health problems and higher suicide rates. Despite this, women from ethnic minorities-Black and South Asian women in particular-are less likely to receive support from mental health services in the perinatal period. Healthcare professionals (HCPs) who have contact with women during this period have a unique perspective, and their views may provide insights to understand and remedy this health inequality. This study aimed to identify healthcare professionals' views on the current accessibility and acceptability of perinatal mental health services, and ways of improving services by addressing the barriers for these women. METHODS: Semi-structured interviews were conducted with twenty-four healthcare professionals who work with patients in the perinatal period. Purposive sampling was used to select HCPs from a range of different professions (including mental health staff, midwifery, primary care, social care). The data were analysed using Framework Analysis. RESULTS: Three main themes were identified from the data: (1) lack of awareness and understanding of perinatal mental illness and service structure in both healthcare professionals and patients; (2) patients' relationships with family, friends and healthcare professionals can both hinder and facilitate access to services; (3) healthcare professionals encourage raising awareness, flexibility, developing shared understandings and questioning assumptions to improve the accessibility and acceptability of services. CONCLUSION: Key insights into explaining and remedying the health inequalities observed between ethnic groups were proposed by healthcare professionals. Recommendations included sharing information; taking steps to ensure each woman was considered as an individual in her relationship with her culture, ethnicity and childrearing practices; and healthcare professionals addressing their possible unconscious biases through engaging in personal reflexive practices. Reasons these are currently not being implemented deserve further research, and the potential of novel roles such as peer support workers in bridging the space between ideals and practice needs further investigation