Portfolio Vol. I N 2

Wiley, Thomas R. In the Cathedral, Mexico City . Picture. 2. Whitehead, Richard Jr. Izzy was a Lady, After All . Prose. 3. Beckham, Adela. Rain on a March morning . Poem. 6. Beckham, Adela. Heaven . Poem. 6. Deane, Dorothy. Temptation . Poem. 6. Kellogg, Elizabeth. Gruess Dich Gott . Prose. 7. Nadel, Norman. The Duchess . Poem. 8. Dick, Pewilla. The Sligo Fisherman . Prose. 9. Deane, Dorothy. Against the Winter . Poem 12. Flory, Doris Jean. A problem . Poem 12. Travis, Paul Bough. My First View of the Congo Forest . Picture. 13. Bellows, George. Stag at Sharkey\u27s . Picture. 13. B.C.W. Aspiration . Poem. 14. Stewart, John. On Record . Prose 14. Sweitzer, Harry J. Playing Around . Prose. 15. Ellsberg, Edward. Book Parade: Hell on Ice . Prose. 15. B.C.W. End of Winter . Poem. 16. Wiley, Thomas R. End of Winter . Picture. 16. Deeter, Robert. Television, How, Where, and When . Prose. 17. Brush, Jane. Love A La Mode . Poem. 20. Brush, Jane. Radio! . Poem. 20. Brush, Jane. Backward Glance . Poem. 20. Brush, Jane. Homo Paradoxus . Poem. 20. Brush, Jane. The Sardonic Slant . Poem. 20. Brush, Jane. Baths . Prose. 20. Wilson, Gordon. Brushword . Cartoon. 20

Parental Height Differences Predict the Need for an Emergency Caesarean Section

More than 30% of all pregnancies in the UK require some form of assistance at delivery, with one of the more severe forms of assistance being an emergency Caesarean section (ECS). Previously it has been shown that the likelihood of a delivery via ECS is positively associated with the birth weight and size of the newborn and negatively with maternal height. Paternal height affects skeletal growth and mass of the fetus, and thus might also affect pregnancy outcomes. We hypothesized that the effect of newborn birth weight on the risk of ECS would decrease with increasing maternal height. Similarly, we predicted that there would be an increase in ECS risk as a function of paternal height, but that this effect would be relative to maternal height (i.e., parental height differences). We used data from the Millennium Cohort Study: a large-scale survey (N = 18,819 births) with data on babies born and their parents from the United Kingdom surveyed 9 to 12-months after birth. We found that in primiparous women, both maternal height and parental height differences interacted with birth weight and predicted the likelihood of an ECS. When carrying a heavy newborn, the risk of ECS was more than doubled for short women (46.3%) compared to tall women (21.7%), in agreement with earlier findings. For women of average height carrying a heavy newborn while having a relatively short compared to tall partner reduced the risk by 6.7%. In conclusion, the size of the baby, the height of the mother and parental height differences affect the likelihood of an ECS in primiparous women

TLR9-induced interferon β is associated with protection from gammaherpesvirus-induced exacerbation of lung fibrosis

Abstract Background We have shown previously that murine gammaherpesvirus 68 (γHV68) infection exacerbates established pulmonary fibrosis. Because Toll-like receptor (TLR)-9 may be important in controlling the immune response to γHV68 infection, we examined how TLR-9 signaling effects exacerbation of fibrosis in response to viral infection, using models of bleomycin- and fluorescein isothiocyanate-induced pulmonary fibrosis in wild-type (Balb/c) and TLR-9-/- mice. Results We found that in the absence of TLR-9 signaling, there was a significant increase in collagen deposition following viral exacerbation of fibrosis. This was not associated with increased viral load in TLR-9-/- mice or with major alterations in T helper (Th)1 and Th2 cytokines. We examined alveolar epithelial-cell apoptosis in both strains, but this could not explain the altered fibrotic outcomes. As expected, TLR-9-/- mice had a defect in the production of interferon (IFN)-β after viral infection. Balb/c fibroblasts infected with γHV68 in vitro produced more IFN-β than did infected TLR-9-/- fibroblasts. Accordingly, in vitro infection of Balb/c fibroblasts resulted in reduced proliferation rates whereas infection of TLR-9-/- fibroblasts did not. Finally, therapeutic administration of CpG oligodeoxynucleotides ameliorated bleomycin-induced fibrosis in wild-type mice. Conclusions These results show a protective role for TLR-9 signaling in murine models of lung fibrosis, and highlight differences in the biology of TLR-9 between mice and humans.http://deepblue.lib.umich.edu/bitstream/2027.42/112877/1/13069_2011_Article_57.pd

Is the Kaiser Permanente model superior in terms of clinical integration?: a comparative study of Kaiser Permanente, Northern California and the Danish healthcare system

<p>Abstract</p> <p>Background</p> <p>Integration of medical care across clinicians and settings could enhance the quality of care for patients. To date, there is limited data on the levels of integration in practice. Our objective was to compare primary care clinicians' perceptions of clinical integration and three sub-aspects in two healthcare systems: Kaiser Permanente, Northern California (KPNC) and the Danish healthcare system (DHS). Further, we examined the associations between specific organizational factors and clinical integration within each system.</p> <p>Methods</p> <p>Comparable questionnaires were sent to a random sample of primary care clinicians in KPNC (n = 1103) and general practitioners in DHS (n = 700). Data were analysed using multiple logistic regression models.</p> <p>Results</p> <p>More clinicians in KPNC perceived to be part of a clinical integrated environment than did general practitioners in the DHS (OR = 3.06, 95% CI: 2.28, 4.12). Further, more KPNC clinicians reported timeliness of information transfer (OR = 2.25, 95% CI: 1.62, 3.13), agreement on roles and responsibilities (OR = 1.79, 95% CI: 1.30, 2.47) and established coordination mechanisms in place to ensure effective handoffs (OR = 6.80, 95% CI: 4.60, 10.06). None of the considered organizational factors in the sub-country analysis explained a substantial proportion of the variation in clinical integration.</p> <p>Conclusions</p> <p>More primary care clinicians in KPNC reported clinical integration than did general practitioners in the DHS. Focused measures of clinical integration are needed to develop the field of clinical integration and to create the scientific foundation to guide managers searching for evidence based approaches.</p

Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, Pmeta = 2.5 × 10−9, OR[T] = 0.81) and 17q21.32 (rs72823592, Pmeta = 9.3 × 10−9, OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, Pmeta = 9.1 × 10−9, OR[T] = 0.68) and at 1q43 for JME (rs12059546, Pmeta = 4.1 × 10−8, OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, Pmeta = 4.0 × 10−6) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndrome

Association of ultra-rare coding variants with genetic generalized epilepsy: A case\u2013control whole exome sequencing study

Objective: We aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large cohorts enriched with individuals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE. Methods: We performed a case\u2013control whole exome sequencing study in unrelated individuals of European descent diagnosed with GGE (previously recruited and sequenced through multiple international collaborations) and ancestry-matched controls. The association of ultra-rare variants (URVs; in 18&nbsp;834 protein-coding genes) with epilepsy was examined in 1928 individuals with GGE (vs. 8578 controls), then separately in 945 individuals with familial GGE (vs. 8626 controls), and finally in 1005 individuals with sporadic GGE (vs. 8621 controls). We additionally examined the association of URVs with familial and sporadic GGE in two gene sets important for inhibitory signaling (19&nbsp;genes encoding \u3b3-aminobutyric acid type A [GABAA] receptors, 113&nbsp;genes representing the GABAergic pathway). Results: GABRG2 was associated with GGE (p&nbsp;=&nbsp;1.8&nbsp; 7&nbsp;10 125), approaching study-wide significance in familial GGE (p&nbsp;=&nbsp;3.0&nbsp; 7&nbsp;10 126), whereas no gene approached a significant association with sporadic GGE. Deleterious URVs in the most intolerant subgenic regions in genes encoding GABAA receptors were associated with familial GGE (odds ratio [OR]&nbsp;=&nbsp;3.9, 95% confidence interval [CI]&nbsp;=&nbsp;1.9\u20137.8, false discovery rate [FDR]-adjusted p&nbsp;=.0024), whereas their association with sporadic GGE had marginally lower odds (OR&nbsp;=&nbsp;3.1, 95% CI&nbsp;=&nbsp;1.3\u20136.7, FDR-adjusted p&nbsp;=.022). URVs in GABAergic pathway genes were associated with familial GGE (OR&nbsp;=&nbsp;1.8, 95% CI&nbsp;=&nbsp;1.3\u20132.5, FDR-adjusted p&nbsp;=.0024) but not with sporadic GGE (OR&nbsp;=&nbsp;1.3, 95% CI&nbsp;=.9\u20131.9, FDR-adjusted p&nbsp;=.19). Significance: URVs in GABRG2 are likely an important risk factor for familial GGE. The association of gene sets of GABAergic signaling with familial GGE is more prominent than with sporadic GGE

Ultra-rare genetic variation in common epilepsies: a case-control sequencing study

BACKGROUND:Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies. METHODS:We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies. FINDINGS:We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2·3, 95% CI 1·7-3·2, p=9·1 × 10-8; familial non-acquired focal epilepsy 3·6, 2·7-4·9, p=1·1 × 10-17). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5·8 × 10-8) that were lower than expected from a random sampling of genes. INTERPRETATION:We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future. FUNDING:National Institute of Neurological Disorders and Stroke (NINDS), and Epilepsy Research UK

Endogenous (In)Formal Institutions.

Despite the huge evidence documenting the relevance of inclusive political institutions and a culture of cooperation, we still lack a framework that identifies their origins and interaction. In a model in which an elite and a citizenry try to cooperate in consumption risk-sharing and investment, we show that a rise in the investment value encourages the elite to introduce more inclusive political institutions to convince the citizenry that a sufficient part of the returns on joint investments will be shared. In addition, accumulation of culture rises with the severity of consumption risk if this is not too large and thus cheating is not too appealing. Finally, the citizenry may over-accumulate culture to credibly commit to cooperate in investment when its value falls and so inclusive political institutions are at risk. These predictions are consistent with the evolution of activity-specific geographic factors, monasticism, and political institutions in a panel of 90 European regions spanning the 1000-1600 period. Evidence from several identification strategies suggests that the relationships we uncover are causal