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Abstract Bronchopulmonary dysplasia (BPD) is a major complication in prematurely born infants. Pulmonary hypertension (PH) associated with BPD (BPD-PH) is characterized by alveolar diffusion impairment, abnormal vascular remodeling, and rarefication of pulmonary vessels (vascular growth arrest), which lead to increased pulmonary vascular resistance and right heart failure. About 25% of infants with moderate to severe BPD develop BPD-PH that is associated with high morbidity and mortality. The recent evolution of broader PH-targeted pharmacotherapy in adults has opened up new treatment options for infants with BPD-PH. Sildenafil became the mainstay of contemporary BPD-PH therapy. Additional medications, such as endothelin receptor antagonists and prostacyclin analogs/mimetics, are increasingly being investigated in infants with PH. However, pediatric data from prospective or randomized controlled trials are still sparse. We discuss comprehensive diagnostic and therapeutic strategies for BPD-PH and briefly review the relevant differential diagnoses of parenchymal and interstitial developmental lung diseases. In addition, we provide a practical framework for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH from the 2018 World Symposium on Pulmonary Hypertension, and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies. Finally, current gaps of knowledge and future research directions are discussed. Impact PH in BPD substantially increases mortality. Treatment of BPD-PH should be conducted by an interdisciplinary team and follow our new treatment algorithm while still kept tailored to the individual patient. We discuss recent developments in BPD-PH, make recommendations on diagnosis, monitoring and treatment of PH in BPD, and address current gaps of knowledge and potential research directions. We provide a practical framework, including a new treatment algorithm, for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH (2018 WSPH) and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies for BPD-PH.

Background Raregenetic variantscause pulmonary arterial hypertension, but the contribution of commongenetic variationto 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 usedgenotypesfrom 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals.Cross-validationof 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 ofsurvival.All-cause mortalitywas the primary endpoint in survival analyses. Findings A locus nearSOX17(rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10–15) and a second locus inHLA-DPA1andHLA-DPB1(collectively referred to asHLA-DPA1/DPB1here; rs2856830, 1·56 [1·42–1·71], p=7·65 × 10–20) within the class II MHC region were associated with pulmonary arterial hypertension. TheSOX17locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69 × 10–12; and rs10103692). Functional andepigenomicdata indicate that the risk variants nearSOX17altergene regulationvia anenhanceractive inendothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reducedSOX17expression. TheHLA-DPA1/DPB1rs2856830 genotype was strongly associated with survival. Median survival fromdiagnosisin 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 baselinedisease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer nearSOX17and inHLA-DPA1/DPB1is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by raremutationsinSOX17. Further studies are needed to confirm the association betweenHLA typingor rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improvesrisk stratificationin clinical practice or trials.

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.

PERSON MARKERS: FINITE CONJUNCT AND DISJUNCT VERB FORMS IN NEWARI. 95 1. THE PROBLEM 95 2. CONJUNCT, DISJUNCT AND THE TRUE INSTIGATOR 96 3. QUOTES, QUOTE FRAMES AND CO-REFERENTIAL ACTORS 97 4. QUESTIONS AND THE CO-REFERENCE RULE 98 5. TRUE QUESTIONS, RHETORICAL QUESTIONS AND THE FIRST PERSON 99 6. SUMMARY OF THE FINITE CONJUNCT-DISJUNCT PATTERNS 100Notes 102References 105

CASE AND ROLE IN NEWARI. 79 1. CASES 79 2. ACTOR COMPLEX 80 3. SITE COMPLEX 82 4. UNDERGOER COMPLEX 84Notes 90References 93

Surgical treatment for short bowel syndrome has been directed toward slowing intestinal transit or increasing the absorptive surface area of the bowel. In the present work, we attempted to enhance bowel absorption by increasing vascularity, using the omentum's unique ability to revascularize incorporated tissue. After a 90% resection of small bowel with primary anastomosis in 5 mongrel dogs, an omental flap based on the right gastroepiploic vessels was incorporated into a seromuscular incision on the antimesenteric border of the remnant small bowel. Five control dogs underwent a similar resection and seromuscular incision with an omentectomy. Serum d-xylose assays, hemoglobin, and total protein levels were measured preoperatively and at 3, 6, 9, and 12 weeks postoperatively. Weekly weights were followed. The mean percent d-xylose absorption in the experimental group increased from 96% of the baseline at 3 weeks to 136%, 163%, and 179% at 6, 9, and 12 weeks respectively (p < 0.5). The control group maintained absorption levels between 54% and 74%. Weight loss in the experimental group was significantly less than the controls at weeks 6 and 9, but by 12 weeks, weights were similar for the two groups. Small bowel absorption of d-xylose was significantly enhanced by incorporation of the omentum into the bowel remnant.

An amplified 16 channel dense wavelength division multiplexing (DWDM) array architecture is presented for interferometric fibre optic sensor array systems. This architecture employs a distributed Erbium doped fibre amplifier (EDFA) scheme to decrease the array insertion loss, and employs time division multiplexing (TDM) at each wavelength to increase the number of sensors that can be supported. The first experimental demonstration of this system is reported including results which show the potential for multiplexing and interrogating up to 4096 sensors using a single telemetry fibre pair with good system performance.

It is of great importance to develop gas sensing techniques which are selective, quantitative, fast-acting and not susceptible to poisoning. Spectroscopic optical gas sensors, especially those capable of remote sensing over optical fibres, are highly attractive for fast real-time detection and measurement of many gases [1]. One highly selective optical gas sensing method is correlation spectroscopy (CS) [2], in which a reference sample of target gas is held fixed within the interrogation system to act as a spectral reference, and is then compared with the spectrum of the test gas to obtain the measurement. We have suggested that a Photonic Bandgap Fibre (PBGF), filled with the target gas, provides a very effective and compact reference, with a clear advantage over traditional linear cells, which are bulky, intricate, fragile, difficult to align and expensive [3].

This paper describes recent experimental results on the detection of carbon dioxide and methane gases using the complementary source modulation (CoSM) method, the topology of which is shown in figure 1, and compares these with numerical simulations from data derived from the HITRAN database. There is a particular interest in sensors using optical fibres coupled to a passively coupled sensing head. CO have reasonably strong absorption bands in the 2.0 µm and 2.3 µm spectral regions respectively. That of methane in the 2.3 µm band is less suited for propagation over fibre lengths greater than a few metres, so the somewhat weaker absorption band at 1.6 µm is more suited to sensing over extended fibre networks. Analyses have been conducted for both of these gases and results will be presented for the prediction of modulation index, signal/noise ratio and detection sensitivity for these gases. Experimental results for these gases, using the CoSM method will be presented for the first time, and comparisons with simulations made.