What’s All the Fizz About? A Teaching Case Study on the Use of Coca-Cola® Freestyle® Machines in Quick-Service Restaurants

This case focuses on the issues surrounding whether the Coca-Cola® Freestyle® machine should be installed at specific quick-service restaurants (QSR). The case explores how to quantify the service performance of the Freestyle® compared to traditional fountain drink dispensers. Also, the nature of specific QSR processes (ordering, food preparation and delivery) could impact whether a Freestyle® is appropriate. The case is designed for use in upper-division undergraduate courses in operations, consumer behavior and strategy. As part of the case, a link to a simulation has been provide: HERE or visit https://drive.google.com/open?id=0B9gWLxcVUszrYmFjd3JQTW9tRFU. Students will use the simulation to answer case question

Biallelic CPAMD8 Variants Are a Frequent Cause of Childhood and Juvenile Open-Angle Glaucoma

© 2020 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND licensePurpose Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. Design Retrospective, multicenter case series. Participants A total of 268 probands and their relatives with a diagnosis of childhood or juvenile open-angle glaucoma. Purpose Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. Methods Patients underwent a comprehensive ophthalmic assessment, with DNA from patients and their relatives subjected to genome, exome, or capillary sequencing. CPAMD8 RNA expression analysis was performed on tissues dissected from cadaveric human eyes. Main Outcome Measures Diagnostic yield within a cohort of childhood and juvenile open-angle glaucoma, prevalence and risk of ophthalmic phenotypes, and relative expression of CPAMD8 in the human eye. Results We identified rare (allele frequency < 4×10−5) biallelic CPAMD8 variants in 5.7% (5/88) of probands with childhood glaucoma and 2.1% (2/96) of probands with juvenile open-angle glaucoma. When including family members, we identified 11 individuals with biallelic variants in CPAMD8 from 7 unrelated families. Nine of these individuals were diagnosed with glaucoma (9/11, 81.8%), with a mean age at diagnosis of 9.22±14.89 years, and all individuals with glaucoma required 1 or more incisional procedures to control high intraocular pressure. Iris abnormalities were observed in 9 of 11 individuals, cataract was observed in 8 of 11 individuals (72.7%), and retinal detachment was observed in 3 of 11 individuals (27.3%). CPAMD8 expression was highest in neural crest–derived tissues of the adult anterior segment, suggesting that CPAMD8 variation may cause malformation or obstruction of key drainage structures. Conclusions Biallelic CPAMD8 variation was associated with a highly heterogeneous phenotype and in our cohorts was the second most common inherited cause of childhood glaucoma after CYP1B1 and juvenile open-angle glaucoma after MYOC. CPAMD8 sequencing should be considered in the investigation of both childhood and juvenile open-angle glaucoma, particularly when associated with iris abnormalities, cataract, or retinal detachment

CYP1B1 copy number variation is not a major contributor to primary congenital glaucoma

This article is published under a Creative Commons Attribution-NonCommercial-NoDerivatives License 3.0, or CC BY-NC-ND 3.0 (see http://creativecommons.org/licenses/by-nc-nd/3.0/ for license terms). The authors retain copyright and grant Molecular Vision an irrevocable, royalty-free, perpetual license to publish and distribute the article, in all formats now known or later developed, and to identify Molecular Vision as the original publisher.Purpose: To evaluate the prevalence and the diagnostic utility of testing for CYP1B1 copy number variation (CNV) in primary congenital glaucoma (PCG) cases unexplained by CYP1B1 point mutations in The Australian and New Zealand Registry of Advanced Glaucoma. Methods: In total, 50 PCG cases either heterozygous for disease-causing variants or with no CYP1B1 sequence variants were included in the study. CYP1B1 CNV was analyzed by Multiplex Ligation-dependent Probe Amplification (MLPA). Results: No deletions or duplications were found in any of the cases. Conclusion: This is the first study to report on CYP1B1 CNV in PCG cases. Our findings show that this mechanism is not a major contributor to the phenotype and is of limited diagnostic utility

Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression

Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 × 10). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups

On the Perception of Newcomers: Toward an Evolved Psychology of Intergenerational Coalitions

Human coalitions frequently persist through multiple, overlapping membership generations, requiring new members to cooperate and coordinate with veteran members. Does the mind contain psychological adaptations for interacting within these intergenerational coalitions? In this paper, we examine whether the mind spontaneously treats newcomers as a motivationally privileged category. Newcomers—though capable of benefiting coalitions—may also impose considerable costs (e.g., they may free ride on other members, they may be poor at completing group tasks). In three experiments we show (1) that the mind categorizes coalition members by tenure, including newcomers; (2) that tenure categorization persists in the presence of orthogonal and salient social dimensions; and (3) that newcomers elicit a pattern of impressions consistent with their probable ancestral costs. These results provide preliminary evidence for a specialized component of human coalitional psychology: an evolved concept of newcomer

Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma

Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways - “response to fluid shear stress” and “abnormal retina morphology” - in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a highly heritable disease (h2 = 0.42 ± 0.09). Siblings of POAG cases have a ten-fold increase risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG ris

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Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. CORRECTION: Please note a corrigendum has been published by teh authors on 12 Oct 2017, and appears below.Variation in FOXC1 and PITX2 is associated with Axenfeld-Rieger syndrome, characterised by structural defects of the anterior chamber of the eye and a range of systemic features. Approximately half of all affected individuals will develop glaucoma, but the age at diagnosis and the phenotypic spectrum have not been well defined. As phenotypic heterogeneity is common, we aimed to delineate the age-related penetrance and the full phenotypic spectrum of glaucoma in FOXC1 or PITX2 carriers recruited through a national disease registry. All coding exons of FOXC1 and PITX2 were directly sequenced and multiplex ligation-dependent probe amplification was performed to detect copy number variation. The cohort included 53 individuals from 24 families with disease-associated FOXC1 or PITX2 variants, including one individual diagnosed with primary congenital glaucoma and five with primary open-angle glaucoma. The overall prevalence of glaucoma was 58.5% and was similar for both genes (53.3% for FOXC1 vs 60.9% for PITX2, P=0.59), however, the median age at glaucoma diagnosis was significantly lower in FOXC1 (6.0±13.0 years) compared with PITX2 carriers (18.0±10.6 years, P=0.04). The penetrance at 10 years old was significantly lower in PITX2 than FOXC1 carriers (13.0% vs 42.9%, P=0.03) but became comparable at 25 years old (71.4% vs 57.7%, P=0.38). These findings have important implications for the genetic counselling of families affected by Axenfeld-Rieger syndrome, and also suggest that FOXC1 and PITX2 contribute to the genetic architecture of primary glaucoma subtypes

Nano-Resolved Current-Induced Insulator-Metal Transition in the Mott Insulator Ca_{2}RuO_{4}

The Mott insulator Ca_{2}RuO_{4} is the subject of much recent attention following reports of emergent nonequilibrium steady states driven by applied electric fields or currents. In this paper, we carry out infrared nano-imaging and optical-microscopy measurements on bulk single crystal Ca_{2}RuO_{4} under conditions of steady current flow to obtain insight into the current-driven insulator-to-metal transition. We observe macroscopic growth of the current-induced metallic phase, with nucleation regions for metal and insulator phases determined by the polarity of the current flow. A remarkable metal-insulator-metal microstripe pattern is observed at the phase front separating metal and insulator phases. The microstripes have orientations tied uniquely to the crystallographic axes, implying a strong coupling of the electronic transition to lattice degrees of freedom. Theoretical modeling further illustrates the importance of the current density and confirms a submicron-thick surface metallic layer at the phase front of the bulk metallic phase. Our work confirms that the electrically induced metallic phase is nonfilamentary and is not driven by Joule heating, revealing remarkable new characteristics of electrically induced insulator-metal transitions occurring in functional correlated oxides