Blessed are those who weep : gratia lacrymarum in thirteenth-century hagiographies

Hagiographies and canonisation processes from the thirteenth century are frequently saturated with descriptions of tears. The tears of holy men and women were both the means to, and apex of, spiritual perfection. Using hagiographical sources from the new Mendicant Orders emerging in Italy, France and the Low Countries, but drawing on other important examples when appropriate, this thesis demonstrates the complexity and importance of tears in thirteenth-century religious life. It makes significant contributions to understanding the construction of sainthood and the history of emotions during this critical period. Case studies of the beguine Marie d’Oignies (d.1213), and the founder of the preaching friars Dominic of Caleruega (d.1221), developed in chapters one and two allow for the meaning of tears to be explored fully and contextualised within the broader themes of devotional piety, gender, medicine and physiology, and the cult of saints. The hypotheses raised in these case studies are tested in chapter three using an extensive sample of vitae to demonstrate the importance of tears. In order to navigate the sea of tears, the study offers a bipartite conceptual framework that takes into account both a charismatic experience of tears (often known as gratia lacrymarum) and a progressive, transformative journey through tears. Building on Piroska Nagy’s seminal work Le Don des Larmes, this thesis presents a comprehensive analysis of tears in thirteenth-century hagiographies. It argues that they were not devalued in light of other forms of bodily piety nor did they become mere virtues in light of their proliferation; on the contrary, tears were highly valued and saturated religious life, traversing boundaries of what was to be imitated and admired

Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis.

BACKGROUND: Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. METHODS: We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. FINDINGS: A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity. INTERPRETATION: This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. FUNDING: UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR