Edward Hofer of The Lennox Independent

In 1913 a 14-year-old South Dakota native walked into the local weekly newspaper office and applied for the position of printer\u27s devil. The teenager was hired. Edward Hofer\u27s career, which has spanned more than 70 years, touched four southeastern South Dakota communities and included the responsibilities of editor/publisher at The Lennox Independent for more than 50 years. The journalist worked through two world wars, the 1930s depression, periods of prosperity, and great changes and advances in technology. The focus of this paper will be on a journalist/businessman supplying a community service--newspaper and job printing--for more than half a century in the same community. This thesis should give a better understanding of the role of a South Dakota weekly newspaper editor in the 20th century. The story of Hofer\u27s life and work in the field of printing and journalism is representative of a small-town editor\u27s struggle to exist and succeed. His story shows the work of one editor maintaining the only formal channel of communication in the area and keeping a community informed about news and events for more than a half century. Thomas F. Barnhart described a typical weekly editor in his 1936 book, Weekly Newspaper Management. The description could have been Hofer. He concerns himself primarily with the constructive side of commun1ty activities, reporting significant and insignificant news reliably, fairly, and interestingly. His paper thrives because of the curiosity of its readers which may be explained as a desire to know more about the lives of neighbors and friends. Hofer was a publisher recording news when South Dakota was entering its 35th year of statehood. As South Dakota approached the centennial mark of statehood, Hofer was still active in the printing and news business. The study of Hofer\u27s career will provide an historical overview of printing and journalism in rural mid-America. Hofer\u27s story spans nearly three-fourths of a century. The paper will also provide the author with a better understanding of journalism in her hometown and will provide the historians in Lennox and Lincoln County with a carefully researched biography of a long-time resident and newspaper editor. This paper will provide a summary of the history of The Lennox Independent and a biography of Edward Hofer. The paper will examine Hofer\u27s efforts to make the newspaper a profitable business through the supplement of income from the commercial printing business, especially the commercial carnival job business. The paper will also record how Edward Hofer used The Lennox Independent to promote the Lennox Municipal Band

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts.

BackgroundWith the onset of prevention trials for individuals at high risk for Alzheimer disease, there is increasing need for accurate risk prediction to inform study design and enrollment, but available risk estimates are limited. We developed risk estimates for the incidence of mild cognitive impairment (MCI) or dementia among cognitively unimpaired individuals by APOE-e4 dose for the genetic disclosure process of the Alzheimer's Prevention Initiative Generation Study, a prevention trial in cognitively unimpaired APOE-e4/e4 homozygote individuals.Methods and findingsWe included cognitively unimpaired individuals aged 60-75 y, consistent with Generation Study eligibility criteria, from the National Alzheimer's Coordinating Center (NACC) (n = 5,073, 158 APOE-e4/e4), the Rotterdam Study (n = 6,399, 156 APOE-e4/e4), the Framingham Heart Study (n = 4,078, 67 APOE-e4/e4), and the Sacramento Area Latino Study on Aging (SALSA) (n = 1,294, 11 APOE-e4/e4). We computed stratified cumulative incidence curves by age (60-64, 65-69, 70-75 y) and APOE-e4 dose, adjusting for the competing risk of mortality, and determined risk of MCI and/or dementia by genotype and baseline age. We also used subdistribution hazard regression to model relative hazard based on age, APOE genotype, sex, education, family history of dementia, vascular risk, subjective memory concerns, and baseline cognitive performance. The four cohorts varied considerably in age, education, ethnicity/race, and APOE-e4 allele frequency. Overall, cumulative incidence was uniformly higher in NACC than in the population-based cohorts. Among APOE-e4/e4 individuals, 5-y cumulative incidence was as follows: in the 60-64-y age stratum, it ranged from 0% to 5.88% in the three population-based cohorts versus 23.06% in NACC; in the 65-69-y age stratum, from 9.42% to 10.39% versus 34.62%; and in the 70-75-y age stratum, from 18.64% to 33.33% versus 38.34%. Five-year incidence of dementia was negligible except for APOE-e4/e4 individuals and those over 70 y. Lifetime incidence (to age 80-85 y) of MCI or dementia for the APOE-e4/e4 individuals in the long-term Framingham and Rotterdam cohorts was 34.69%-38.45% at age 60-64 y, 30.76%-40.26% at 65-69 y, and 33.3%-35.17% at 70-75 y. Confidence limits for these estimates are often wide, particularly for APOE-e4/e4 individuals and for the dementia outcome at 5 y. In regression models, APOE-e4 dose and age both consistently increased risk, as did lower education, subjective memory concerns, poorer baseline cognitive performance, and family history of dementia. We discuss several limitations of the study, including the small numbers of APOE-e4/e4 individuals, missing data and differential dropout, limited ethnic and racial diversity, and differences in definitions of exposure and outcome variables.ConclusionsEstimates of the absolute risk of MCI or dementia, particularly over short time intervals, are sensitive to sampling and a variety of methodological factors. Nonetheless, such estimates were fairly consistent across the population-based cohorts, and lower than those from a convenience cohort and those estimated in prior studies-with implications for informed consent and design for clinical trials targeting high-risk individuals

Excessive iron storage in captive omnivores? The case of the coati (Nasua spp.)

We collated necropsy reports for 13 coatis (Nasua spp.), revealing four cases of moderate and six cases of massive iron deposition in liver tissue. This survey corroborates an earlier report that noted a high frequency of iron deposits in coatis at necropsy. A comparison of the reported natural diet of coatis and the usually fed captive diets revealed that whereas vertebrate products (dog/cat food, prey items) represent the staple diet items for captive individuals, free-ranging coatis only rarely consume vertebrate prey; their natural diet is dominated by wild fruits and invertebrates. This discrepancy should be reflected in high levels of readily available heme iron in captive diets, with little or no heme iron in the natural diets. Therefore, it could be hypothesized that the use of vertebrate products in animals not adapted to such high levels of readily available heme iron could be a cause for dietary iron overload. Further studies on the relevance of excessive iron storage in omnivores/insectivores, and their etiopathology, are indicated

Cumulative incidence curves, adjusting for competing risk of mortality, for dementia by baseline age and <i>APOE</i>-e4 dose.

<p>Note that the strata shown are not independent for the Rotterdam and Framingham cohorts (see text). NACC, National Alzheimer’s Coordinating Center; RS, Rotterdam Study; SALSA, Sacramento Area Latino Study on Aging.</p

Lifetime (to age 80–85 y) cumulative incidence of dementia by baseline age and <i>APOE</i>-e4 dose.

<p>Lifetime (to age 80–85 y) cumulative incidence of dementia by baseline age and <i>APOE</i>-e4 dose.</p

Lifetime (to age 80–85 y) cumulative incidence curves, adjusting for competing risk of mortality, for dementia by baseline age and <i>APOE</i>-e4 dose.

<p>Note that the strata shown are not independent (see text).</p

Five-year cumulative incidence of mild cognitive impairment/dementia by baseline age and <i>APOE</i>-e4 dose.

<p>Five-year cumulative incidence of mild cognitive impairment/dementia by baseline age and <i>APOE</i>-e4 dose.</p