Browsing by Author "King C"

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    Developmental and epileptic encephalopathy: Personal utility of a genetic diagnosis for families
    (Wiley Periodicals LLC on behalf of International League Against Epilepsy, 2021-03) Jeffrey JS; Leathem J; King C; Mefford HC; Ross K; Sadleir LG
    Objectives Identifying genetic pathogenic variants improves clinical outcomes for children with developmental and epileptic encephalopathy (DEE) by directing therapy and enabling accurate reproductive and prognostic information for families. We aimed to explore the additional personal utility of receiving a genetic diagnosis for families. Methods Semi-structured interviews were conducted with fifteen families of children with a DEE who had received a genetic diagnosis. The interviews stimulated discussion focusing on the impact of receiving a genetic diagnosis for the family. Interview transcripts were analyzed using the six-step systematic process of interpretative phenomenological analysis (IPA). Results Three key themes were identified: “Importance of the label,” “Relief to end the diagnostic journey,” and “Factors that influence personal utility.” Families reported that receiving a genetic label improved their knowledge about the likely trajectory of the DEE, increased their hope for the future, and helped them communicate with others. The relief of finally having an answer for the cause of their child's DEE alleviated parental guilt and self-blame as well as helped families to process their grief and move forward. Delay in receipt of a genetic diagnosis diluted its psychological impact. Significance To date, the factors associated with the personal utility of a genetic diagnosis for DEEs have been under appreciated. This study demonstrates that identifying a genetic diagnosis for a child's DEE can be a psychological turning point for families. A genetic result has the potential to set these families on an adaptive path toward better quality of life through increased understanding, social connection, and support. Early access to genetic testing is important as it not only increases clinical utility, but also increases personal utility with early mitigation of family stress, trauma, and negative experiences.
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    Recurrent horizontal transfer identifies mitochondrial positive selection in a transmissible cancer.
    (Springer Nature Limited, 2020-06-16) Strakova A; Nicholls TJ; Baez-Ortega A; Ní Leathlobhair M; Sampson AT; Hughes K; Bolton IAG; Gori K; Wang J; Airikkala-Otter I; Allen JL; Allum KM; Arnold CL; Bansse-Issa L; Bhutia TN; Bisson JL; Blank K; Briceño C; Castillo Domracheva A; Corrigan AM; Cran HR; Crawford JT; Cutter SM; Davis E; de Castro KF; De Nardi AB; de Vos AP; Delgadillo Keenan L; Donelan EM; Espinoza Huerta AR; Faramade IA; Fazil M; Fotopoulou E; Fruean SN; Gallardo-Arrieta F; Glebova O; Gouletsou PG; Häfelin Manrique RF; Henriques JJGP; Horta RS; Ignatenko N; Kane Y; King C; Koenig D; Krupa A; Kruzeniski SJ; Lanza-Perea M; Lazyan M; Lopez Quintana AM; Losfelt T; Marino G; Martínez Castañeda S; Martínez-López MF; Masuruli BM; Meyer M; Migneco EJ; Nakanwagi B; Neal KB; Neunzig W; Nixon SJ; Ortega-Pacheco A; Pedraza-Ordoñez F; Peleteiro MC; Polak K; Pye RJ; Ramirez-Ante JC; Reece JF; Rojas Gutierrez J; Sadia H; Schmeling SK; Shamanova O; Sherlock AG; Steenland-Smit AE; Svitich A; Tapia Martínez LJ; Thoya Ngoka I; Torres CG; Tudor EM; van der Wel MG; Vițălaru BA; Vural SA; Walkinton O; Wehrle-Martinez AS; Widdowson SAE; Zvarich I; Chinnery PF; Falkenberg M; Gustafsson CM; Murchison EP
    Autonomous replication and segregation of mitochondrial DNA (mtDNA) creates the potential for evolutionary conflict driven by emergence of haplotypes under positive selection for 'selfish' traits, such as replicative advantage. However, few cases of this phenomenon arising within natural populations have been described. Here, we survey the frequency of mtDNA horizontal transfer within the canine transmissible venereal tumour (CTVT), a contagious cancer clone that occasionally acquires mtDNA from its hosts. Remarkably, one canine mtDNA haplotype, A1d1a, has repeatedly and recently colonised CTVT cells, recurrently replacing incumbent CTVT haplotypes. An A1d1a control region polymorphism predicted to influence transcription is fixed in the products of an A1d1a recombination event and occurs somatically on other CTVT mtDNA backgrounds. We present a model whereby 'selfish' positive selection acting on a regulatory variant drives repeated fixation of A1d1a within CTVT cells.
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    Retention of internal teat sealants over the dry period and their efficacy in reducing clinical and subclinical mastitis at calving
    (Elsevier Inc and the Federation of Animal Science Societies (Fass) Inc on behalf of the American Dairy Science Association, 2022-06) Bates AJ; King C; Dhar M; Fitzpatrick C; Laven RA
    Internal teat sealants (ITS) reduce the risk of new intramammary infections over the dry period by forming a physical barrier to pathogen ingress. As the first and last 2 wk of the dry period are high-risk periods for new infections, maintaining an effective barrier in this period is a key requirement. Few studies have systematically examined sealant retention and none have done so under New Zealand pastoral conditions, where cows frequently move to separate grazing for dry periods, typically 80 to 90 d long. This multi-herd study was a split-udder equivalence trial comparing 2 ITS formulations for retention and efficacy in preventing periparturient clinical and subclinical mastitis. Both ITS contained 65% (2.6 g) bismuth salts, which contribute to the barrier within the teat canal, emulsified in ≤1.4 g of mineral oil. However, one ITS additionally contained <10% amorphous silica. At dry-off, treatment was randomly allocated to diagonal teat-pairs within 409 cows on 4 farms. All cows met industry best practice criteria for ITS treatment alone. The study unit was quarter within cow and farm. Outcomes included clinical mastitis (CM) incidence for the last 7 d of the dry period and first 42 d of lactation, subclinical mastitis (SCM) incidence 96 h after calving, and quantity of residual after centrifuging 50 mL of colostrum collected from each quarter within 24 h of calving. Proportional outcomes were analyzed using Bayesian mixed models with a binomial distribution and logit link function, whereas the quantity of residual was analyzed using Bayesian finite mixture models and cluster bootstrapping. We set a region of probable equivalence (ROPE) of ±2.5% between proportions and ±0.2 g for residual weight. Records were available for 1,596 quarters (399 cows). We detected no meaningful difference in incidence of CM or SCM attributable to differences in sealant: the model predicted treatment differences of 0.00 with a 95% highest density interval (HDI) of ±1.00%. Across all cows and farms, the marginal difference in the percentage of quarters with CM was 0.11% (95% HDI: -2.11 to 2.49%), and for SCM 0.00 (95% HDI: -1.98 to 1.94%). Including the quantity of residual recovered at calving did not improve fit or predictive ability of the models predicting CM or SCM, and the coefficient spanned the null value. The distribution of the weight of material recovered at calving was multi-modal; for 25% of quarters, more residual was recovered than inserted. When the residual weight was less than or equal to the median residual weight (2.06 g; range: 0.19-6.03 g), there was a ≥90% probability that any treatment difference in residual was ≤0.2 g. When the residual weight was between the median and 75th percentile (4.40 g; 95% HDI: 4.00 to 4.75 g), there was no clear difference in residual between products. Above the 75th percentile, there was a 90% probability that the residual from quarters differed by product type (difference = 0.36 g, 90% HDI: 0.20 to 0.54 g). In conclusion, both products had equivalent efficacy for SCM and CM. As the quantity of residual increased, the difference in residual weight recovered increased but this may represent increases in debris rather than indicating a more effective barrier.