High COVID-19 Attack Rate Among Attendees at Events at a Church - Arkansas, March 2020.

On March 16, 2020, the day that national social distancing guidelines were released (1), the Arkansas Department of Health (ADH) was notified of two cases of coronavirus disease 2019 (COVID-19) from a rural county of approximately 25,000 persons; these cases were the first identified in this county. The two cases occurred in a husband and wife; the husband is the pastor at a local church (church A). The couple (the index cases) attended church-related events during March 6-8, and developed nonspecific respiratory symptoms and fever on March 10 (wife) and 11 (husband). Before his symptoms had developed, the husband attended a Bible study group on March 11. Including the index cases, 35 confirmed COVID-19 cases occurred among 92 (38%) persons who attended events held at church A during March 6-11; three patients died. The age-specific attack rates among persons aged ≤18 years, 19-64 years, and ≥65 years were 6.3%, 59.4%, and 50.0%, respectively. During contact tracing, at least 26 additional persons with confirmed COVID-19 cases were identified among community members who reported contact with church A attendees and likely were infected by them; one of the additional persons was hospitalized and subsequently died. This outbreak highlights the potential for widespread transmission of SARS-CoV-2, the virus that causes COVID-19, both at group gatherings during church events and within the broader community. These findings underscore the opportunity for faith-based organizations to prevent COVID-19 by following local authorities' guidance and the U.S. Government's Guidelines: Opening Up America Again (2) regarding modification of activities to prevent virus transmission during the COVID-19 pandemic.

Role of TLR4 in the Modulation of Central Amygdala GABA Transmission by CRF Following Restraint Stress.

AIMS: Stress induces neuroimmune responses via Toll-like receptor 4 (TLR4) activation. Here, we investigated the role of TLR4 in the effects of the stress peptide corticotropin-releasing factor (CRF) on GABAergic transmission in the central nucleus of the amygdala (CeA) following restraint stress. METHODS: Tlr4 knock out (KO) and wild-type rats were exposed to no stress (naïve), a single restraint stress (1 h) or repeated restraint stress (1 h per day for 3 consecutive days). After 1 h recovery from the final stress session, whole-cell patch-clamp electrophysiology was used to investigate the effects of CRF (200 nM) on CeA GABAA-mediated spontaneous inhibitory postsynaptic currents (sIPSCs). RESULTS: TLR4 does not regulate baseline GABAergic transmission in the CeA of naive and stress-treated animals. However, CRF significantly increased the mean sIPSC frequencies (indicating enhanced GABA release) across all genotypes and stress treatments, except for the Tlr4 KO rats that experienced repeated restraint stress. CONCLUSIONS: Overall, our results suggest a limited role for TLR4 in CRF's modulation of CeA GABAergic synapses in naïve and single stress rats, though TLR4-deficient rats that experienced repeated psychological stress exhibit a blunted CRF cellular response. SHORT SUMMARY: TLR4 has a limited role in CRF's activation of the CeA under basal conditions, but interacts with the CRF system to regulate GABAergic synapse function in animals that experience repeated psychological stress.

Association between latent toxoplasmosis and cognition in adults: a cross-sectional study.

Latent infection from Toxoplasma gondii (T. gondii) is widespread worldwide and has been associated with cognitive deficits in some but not all animal models and in humans. We tested the hypothesis that latent toxoplasmosis is associated with decreased cognitive function in a large cross-sectional dataset, the National Health and Nutrition Examination Survey (NHANES). There were 4178 participants aged 20-59 years, of whom 19.1% had IgG antibodies against T. gondii. Two ordinary least squares (OLS) regression models adjusted for the NHANES complex sampling design and weighted to represent the US population were estimated for simple reaction time, processing speed and short-term memory or attention. The first model included only main effects of latent toxoplasmosis and demographic control variables, and the second added interaction terms between latent toxoplasmosis and the poverty-to-income ratio (PIR), educational attainment and race-ethnicity. We also used multivariate models to assess all three cognitive outcomes in the same model. Although the models evaluating main effects only demonstrated no association between latent toxoplasmosis and the cognitive outcomes, significant interactions between latent toxoplasmosis and the PIR, between latent toxoplasmosis and educational attainment, and between latent toxoplasmosis and race-ethnicity indicated that latent toxoplasmosis may adversely affect cognitive function in certain groups.

Copy number variation in pediatric multiple sclerosis.

BACKGROUND: Pediatric onset multiple sclerosis (MS) accounts for 2-4% of all MS. It is unknown whether the disease shares the same underlying pathophysiology found in adult patients or an extreme early onset phenotype triggered by distinct biological mechanisms. It has been hypothesized that copy number variations (CNVs) may result in extreme early onset diseases because CNVs can have major effects on many genes in large genomic regions. OBJECTIVES AND METHODS: The objective of the current research was to identify CNVs, with a specific focus on de novo CNVs, potentially causing early onset MS by competitively hybridizing 30 white non-Hispanic pediatric MS patients with each of their parents via comparative genomic hybridization (CGH) analysis on the Agilent 1M CGH array. RESULTS AND DISCUSSION: We identified 10 CNVs not overlapping with any CNV regions currently reported in the Database of Genomic Variants (DGV). Fifty-five putatively de novo CNVs were also identified: all but one common in the DGV. We found the single rare CNV was a private variation harboring the SACS gene. SACS mutations cause autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) disease. Additional clinical review revealed that the patient with the SACS gene CNV shared some features of both MS and ARSACS. CONCLUSIONS: This is the first reported study analyzing pediatric MS CNVs. While not yielding causal variation in our initial pediatric dataset, our approach confirmed diagnosis of an ARSACS-like disease in addition to MS in the affected individual, which led to a more complete understanding of the patient's disease course and prognosis.

The influence of body mass index, age and gender on current illness: a cross-sectional study.

CONTEXT: Obesity poses a significant health risk, but health risk is not equivalent to actual health status. Further, age and gender might alter the effect of body weight on physical health. OBJECTIVE: To determine the relationship between body mass index (BMI), age, gender and current health status. DESIGN: Data from the 1988-1994, 2003-2004 and 2005-2006 National Health & Nutrition Examination Surveys were weighted to represent the US population. BMI, age, gender and current medication use were analyzed in a sample-adjusted 9071 women and 8880 men. MAIN OUTCOME MEASURES: The percentage of participants taking medication and the total number of medications taken. RESULTS: In both the 1988-1994 and 2003-2006 data sets, with few exceptions, medication loads did not increase significantly in overweight compared with normal-weight people. Medication loads increased significantly in obese compared with normal-weight people aged 40+, but only marginally at 25-39 years. Medication loads were higher in women than men, but significantly less so in people aged 55-70. CONCLUSIONS: First, medication loads, a measure of current health status, were increased in obese compared with the normal-weight people, but the effect was mainly at ages over 40 years. In addition, BMI category contributed less to medication loads at ages 25-39 than in older groups. Second, there was little difference in current health status in normal-weight versus overweight people at all ages. Finally, higher medication loads in women than men are more apparent in younger than older people. Although obesity does not substantially affect current health in young people, it is likely that the increased medication loads in obese compared with normal-weight older people originates at least in part from an increased BMI starting at a younger age. Thus, age, gender and onset of high BMI all require consideration when using BMI to assess current health status.

Contributions of biogenic material to the atmospheric ice-nucleating particle population in North Western Europe.

A minute fraction of atmospheric particles exert a disproportionate effect on the phase of mixed-phase clouds by acting as ice-nucleating particles (INPs). To understand the effects of these particles on weather and climate, both now and into the future, we must first develop a quantitative understanding of the major INP sources worldwide. Previous work has demonstrated that aerosols such as desert dusts are globally important INPs, but the role of biogenic INPs is unclear, with conflicting evidence for their importance. Here, we show that at a temperate site all INPs active above -18 °C at concentrations >0.1 L-1 are destroyed on heating, consistent with these INPs being of biological origin. Furthermore, we show that a global model of desert dust INPs dramatically underestimates the measured INP concentrations, but is consistent with the thermally-stable component. Notably, the heat sensitive INPs are active at temperatures where shallow cloud layers in Northern Europe are frequently observed to glaciate. Hence, we suggest that biogenic material is important for primary ice production in this region. The prevalence of heat sensitive, most likely biogenic, INPs in this region highlights that, as a community, we need to quantify the sources and transport of these particles as well as determine their atmospheric abundance across the globe and at cloud altitudes.

CAT8, a new zinc cluster-encoding gene necessary for derepression of gluconeogenic enzymes in the yeast Saccharomyces cerevisiae.

The expression of gluconeogenic fructose-1,6-bisphosphatase (encoded by the FBP1 gene) depends on the carbon source. Analysis of the FBP1 promoter revealed two upstream activating elements, UAS1FBP1 and UAS2FBP1, which confer carbon source-dependent regulation on a heterologous reporter gene. On glucose media neither element was activated, whereas after transfer to ethanol a 100-fold derepression was observed. This gene activation depended on the previously identified derepression genes CAT1 (SNF1) (encoding a protein kinase) and CAT3 (SNF4) (probably encoding a subunit of Cat1p [Snf1p]). Screening for mutations specifically involved in UAS1FBP1 derepression revealed the new recessive derepression mutation cat8. The cat8 mutants also failed to derepress UAS2FBP1, and these mutants were unable to grow on nonfermentable carbon sources. The CAT8 gene encodes a zinc cluster protein related to Saccharomyces cerevisiae Gal4p. Deletion of CAT8 caused a defect in glucose derepression which affected all key gluconeogenic enzymes. Derepression of glucose-repressible invertase and maltase was still normally regulated. A CAT8-lacZ promoter fusion revealed that the CAT8 gene itself is repressed by Cat4p (Mig1p). These results suggest that gluconeogenic genes are derepressed upon binding of Cat8p, whose synthesis depends on the release of Cat4p (Mig1p) from the CAT8 promoter. However, gluconeogenic promoters are still glucose repressed in cat4 mutants, which indicates that in addition to its transcription, the Cat8p protein needs further activation. The observation that multicopy expression of CAT8 reverses the inability of cat1 and cat3 mutants to grow on ethanol indicates that Cat8p might be the substrate of the Cat1p/Cat3p protein kinase.

Inviting instability: Transposable elements, double-strand breaks, and the maintenance of genome integrity.

The ubiquity of mobile elements in mammalian genomes poses considerable challenges for the maintenance of genome integrity. The predisposition of mobile elements towards participation in genomic rearrangements is largely a consequence of their interspersed homologous nature. As tracts of nonallelic sequence homology, they have the potential to interact in a disruptive manner during both meiotic recombination and DNA repair processes, resulting in genomic alterations ranging from deletions and duplications to large-scale chromosomal rearrangements. Although the deleterious effects of transposable element (TE) insertion events have been extensively documented, it is arguably through post-insertion genomic instability that they pose the greatest hazard to their host genomes. Despite the periodic generation of important evolutionary innovations, genomic alterations involving TE sequences are far more frequently neutral or deleterious in nature. The potentially negative consequences of this instability are perhaps best illustrated by the >25 human genetic diseases that are attributable to TE-mediated rearrangements. Some of these rearrangements, such as those involving the MLL locus in leukemia and the LDL receptor in familial hypercholesterolemia, represent recurrent mutations that have independently arisen multiple times in human populations. While TE-instability has been a potent force in shaping eukaryotic genomes and a significant source of genetic disease, much concerning the mechanisms governing the frequency and variety of these events remains to be clarified. Here we survey the current state of knowledge regarding the mechanisms underlying mobile element-based genetic instability in mammals. Compared to simpler eukaryotic systems, mammalian cells appear to have several modifications to their DNA-repair ensemble that allow them to better cope with the large amount of interspersed homology that has been generated by TEs. In addition to the disruptive potential of nonallelic sequence homology, we also consider recent evidence suggesting that the endonuclease products of TEs may also play a key role in instigating mammalian genomic instability.

The Alu Yc1 subfamily: sorting the wheat from the chaff.

Members of the Alu Yc1 subfamily are distinguished from the older Alu Y subfamily by a signature G-->A substitution at base 148 of their 281-bp consensus sequence. Members of the much older and larger Alu Y subfamily could have by chance accumulated this signature G-->A substitution and be misclassified as belonging to the Alu Yc1 subfamily. Using a Mahanalobis classification method, it was estimated that the "authentic" Alu Yc1 subfamily consists of approximately 262 members in the human genome. PCR amplification and further analysis was successfully completed on 225 of the Yc1 Alu family members. One hundred and seventy-seven Yc1 Alu elements were determined to be monomorphic (fixed for presence) in a panel of diverse human genomes. Forty-eight of the Yc1 Alu elements were polymorphic for insertion presence/absence in diverse human genomes. The insertion polymorphism rate of 21% in the human genome is similar to rates reported previously for other "young" Alu subfamilies. The polymorphic Yc1 Alu elements will be useful genetic loci for the study of human population genetics.

Identification of novel genes in late-onset Alzheimer's disease.

Four genes affecting Alzheimer's Disease (AD)(AP, PS1, PS2, and APOE) have been identified and a fifth potential gene localized to chromosome 12. Collectively, these genes explain at most half of the genetic effect in AD. Understanding the genetics of AD is critical to developing new treatments. The quest to find the remaining AD genes led us to undertake a large genomic screen using over 466 families (730 affected sibpairs) in late-onset AD. In conjunction with this increase in power, we initiated several novel approaches to identify potential AD-related genes. This included stratification of the data into an autopsy-confirmed subset of 199 AD families. Each of these targeted analyses resulted in the identification of novel regions containing potential AD genetic risk factors. Our most significant finding was on chromosome 9 in the autopsy-confirmed subset where we obtained an MLS of 4.31. These approaches, together with new methodologies such as conditional linkage analysis, generalized family-based association tests (PDT), and a new generation of genetic markers (SNPs), opens the door for additional AD gene discovery. Such strategies are necessary if we are to understand the subtle and complex threads that, woven together, create the intricate tapestry of AD.

De novo partial duplication of chromosome 7p in a male with autistic disorder.

We describe a de novo partial duplication of 7p in a 25-year-old male with autistic disorder (AD). High-resolution chromosome analysis revealed an extra segment added to the proximal short arm of chromosome 7. The G-band pattern was consistent with an inverted duplication of 7p11.2-p14.1. Fluorescent in situ hybridization (FISH), using a whole chromosome 7 DNA probe (Cytocell, Inc., UK), confirmed that the extra chromosome material is derived from chromosome 7, indicating that the patient is partially trisomic for a region of the short arm of chromosome 7. Partial duplication of the short arm of chromosome 7 is uncommon with little more than 30 cases in the literature. This is the first report of an individual with a 7p duplication who also has AD.

Efficacy, safety, and tolerability of venlafaxine extended release and buspirone in outpatients with generalized anxiety disorder.

BACKGROUND: The objective of this randomized, double-blind study was to compare the efficacy and safety of venlafaxine extended release (XR) and buspirone in outpatients with generalized anxiety disorder (GAD) but without concomitant major depressive disorder. METHOD: Male and female outpatients at least 18 years old who met the DSM-IV criteria for GAD and had scores of 18 or higher on the Hamilton Rating Scale for Anxiety (HAM-A) were randomly assigned to treatment with either venlafaxine XR (75 or 150 mg/day), buspirone (30 mg/day in 3 divided doses), or placebo for 8 weeks. The primary efficacy variables were changes in anxiety as determined by final on-therapy HAM-A total and psychic anxiety scores and Clinical Global Impressions scale (CGI) scores. Other key efficacy variables were HAM-A anxious mood and tension scores and the anxiety subscale scores of the patient-rated Hospital Anxiety and Depression scale (HAD). RESULTS: The efficacy analysis included 365 patients and the safety analysis, 405. At week 8, adjusted mean HAM-A psychic anxiety, anxious mood, and tension scores were significantly lower for venlafaxine XR-treated patients than for placebo-treated patients. On the HAD anxiety subscale, venlafaxine XR, 75 or 150 mg/day, was significantly more efficacious than placebo at all time points except weeks 1 (both dosages) and 2 (150-mg/day dosage only) and significantly more efficacious than buspirone at all time points except week 1. On the CGI-Improvement scale, scores for venlafaxine XR (both dosages) and buspirone were numerically superior to those for placebo at all time points, and statistical significance was observed at weeks 3, 4, 6, and 8 for venlafaxine XR and at weeks 6 and 8 for buspirone. The adverse events were not essentially different between treatment groups. CONCLUSION: Venlafaxine XR is an effective, safe, and well-tolerated once-daily anxiolytic agent in patients with GAD without comorbid major depressive disorder. This agent was significantly superior to buspirone on the HAD anxiety subscale. Buspirone demonstrated statistical significance versus placebo on a measure of anxiolytic response.

Factors affecting return of symptoms 1 year after treatment in a 62-week controlled study of fluoxetine in major depression.

BACKGROUND: In spite of impressive results in acute studies, the long-term treatment of major depression remains problematic. To explore the return of depressive symptoms and their interaction with social factors on long-term outcome, we assessed 55 patients whose depression had been treated during a 62-week, fluoxetine maintenance study, 1 year after the study's termination. METHOD: During the year following the study termination, patients were free to select treatment options. Assessments at the 1-year follow-up included measures of depressive symptoms (using the Hamilton Rating Scale for Depression [HAM-D]), social and marital impairment (using the Weissman Social Adjustment Scale [SAS]), personal stressors (using the Holmes Social Readjustment Rating Scale), and history of treatment during the past year. RESULTS: At the time of the naturalistic follow-up, 53% of patients sustained their improvement in mood. Factors associated with return of depressive symptoms included personal stresses, marital maladjustment, personal decision to discontinue antidepressants, and medication failure. Psychosocial variables were associated with poor outcome in over 90% of impaired subjects. Development of subsyndromal symptoms during the 50-week double-blind phase was predictive of poorer outcome at the long-term follow-up. CONCLUSION: The study demonstrates that no matter how effective initial pharmacologic therapy may be, without ongoing clinical monitoring and support, particularly in dealing with issues such as marriage and handling significant life stresses, and compliance with medications, it will not be successful in the long-term treatment for a significant portion of patients with depression.

Safety of aerosol tobramycin administration for 3 months to patients with cystic fibrosis.

To determine the potential toxicity of prolonged aerosol tobramycin administration, 22 patients with cystic fibrosis were monitored while receiving inhaled tobramycin three times a day for 12 weeks. Prior to, four times during administration and approximately 6 weeks after discontinuation of treatment, we assessed pulmonary function, weight, height, body temperature, eighth cranial nerve function, serum creatinine, blood urea nitrogen, urinary creatinine clearance, plasma iothalamate clearance, urinary beta-2 microglobulin concentration, and Pseudomonas aeruginosa density in sputum. There was no detectable laboratory evidence of nephrotoxicity. Neither a decrease in auditory acuity (range 250-20,000 Hz) nor vestibular dysfunction was detected. Pulmonary function tests significantly improved during the first month in all subjects (P less than 0.05) but returned to enrollment values by the end of the 12th week of administration of tobramycin aerosol. Sputum P. aeruginosa density initially decreased from a mean of 10(7) cfu/gm to a mean of 10(4) cfu/gm after 2 weeks of aerosol tobramycin administration and remained significantly below the enrollment value throughout. Coincident with the reduced bacterial density, a reduction in cough frequency and sputum production, as well as a weight gain was observed. Seventy-three percent of the patients with sputum P. aeruginosa isolates susceptible to tobramycin on enrollment yielded resistant organisms during aerosol administration. However, 1 year later all sputum P. aeruginosa isolates obtained from patients were susceptible to tobramycin. We conclude that thrice daily aerosol tobramycin administration for 3 months is not associated with detectable eighth cranial nerve or renal toxicity. Transient emergence of tobramycin resistant P. aeruginosa may occur.

Adaptation level as an explanation of the peak shift in generalization with movement stimuli.

Two experiments examine the value of adaptation level theory as an explanation of the peak shift phenomenon in stimulus generalization using linear arm movements. The first experiment manipulates the differences in adaptation levels during training by varying the frequency of experience of the training stimulus. Significant shifts in the peaks of generalization gradients were subsequently identified. The peak shifts were in the direction predicted by adaptation level theory. The second experiment manipulates testing adaptation levels by biasing the generalization test movements. Three groups of subjects performed differentially weighted test sequences in which the relative number of short, medium, or long movements was manipulated. Significant peak shifts of generalization gradients were observed in the direction predicted by adaptation level theory.

Stimulus generalization and the peak shift with movement stimuli.

Stimulus generalization is suggested as an alternative method for examination of the "novelty" problem in motor learning. These experiments demonstrated that stimulus generalization occurs using simple movements as stimuli. The phenomenon of the "peak shift" in post-discrimination generalization gradients was also examined. The first experiment demonstrated that a peak shift occurred using linear movements as stimuli and that the magnitude of the peak shift increased as the difference between the training stimuli decreased. The second experiment showed similar results when the stimuli consisted of a range of movements rather than single movement length. The final experiment provided evidence that perception of movement length is influenced by the magnitude of an immediately preceding movement. The relevance of these studies to current motor-learning theory is discussed.

Effects of bodyweight and PMS administration on reproduction rate in Merino ewes.

Data are presented on the effects of the use of pregnant mare serum gonadotrophin (PMS) and of increased liverweight on the number of lambs born, or in utero, in mature fine-woolled Merino ewes. The primary effect of increased bodyweight was to reduce the number of barren ewes whereas the main effect of PMS treatment was to increase the level of twinning among those ewes which conceived. The 2 effects appeared to be additive but it is pointed out that the survival rate of the lambs will be an important consideration in assessing the relative merits of the 2 treatments.

Education in end-of-life care: bridging disciplinary and institutional boundaries.

This paper describes the development of an interdisciplinary, interinstitutional seminar in palliative care for South Dakota students in medicine, nursing, pharmacy, chaplaincy, and social work. Student outcomes from six seminars conducted during 2001-2004 are reported, and recommendations for future educational efforts are outlined.