Editors' Note

Editors' Note for the Proceedings of the 2020 Annual Meeting on Phonology (AMP 2020), held at the University of California, Santa Cruz in September 2020

Understanding foot-and-mouth disease virus transmission biology: identification of the indicators of infectiousness

The control of foot-and-mouth disease virus (FMDV) outbreaks in non-endemic countries relies on the rapid detection and removal of infected animals. In this paper we use the observed relationship between the onset of clinical signs and direct contact transmission of FMDV to identify predictors for the onset of clinical signs and identify possible approaches to preclinical screening in the field. Threshold levels for various virological and immunological variables were determined using Receiver Operating Characteristic (ROC) curve analysis and then tested using generalized linear mixed models to determine their ability to predict the onset of clinical signs. In addition, concordance statistics between qualitative real time PCR test results and virus isolation results were evaluated. For the majority of animals (71%), the onset of clinical signs occurred 3–4 days post infection. The onset of clinical signs was associated with high levels of virus in the blood, oropharyngeal fluid and nasal fluid. Virus is first detectable in the oropharyngeal fluid, but detection of virus in the blood and nasal fluid may also be good candidates for preclinical indicators. Detection of virus in the air was also significantly associated with transmission. This study is the first to identify statistically significant indicators of infectiousness for FMDV at defined time periods during disease progression in a natural host species. Identifying factors associated with infectiousness will advance our understanding of transmission mechanisms and refine intra-herd and inter-herd disease transmission models

Maternal serum retinol and B-carotene concentrations and neonatal bone mineralisation: Results from the Southampton Women's Survey cohort

Background: studies in older adults and animals have suggested contrasting relations between bone health and different vitamin A compounds. To our knowledge, the associations between maternal vitamin A status and offspring bone development have not previously been elucidated.Objective: we examined the associations between maternal serum retinol and ?-carotene concentrations during late pregnancy and offspring bone mineralization assessed at birth with the use of dual-energy X-ray absorptiometry.Design: in the Southampton Women’s Survey mother-offspring birth cohort, maternal health, lifestyle, and diet were assessed prepregnancy and at 11 and 34 wk of gestation. In late pregnancy, maternal serum retinol and ?-carotene concentrations were measured. Offspring total body bone mineral density (BMD), bone mineral content (BMC), and bone area (BA) were measured within 2 wk after birth.Results: in total, 520 and 446 mother-offspring pairs had measurements of maternal serum retinol and ?-carotene, respectively. Higher maternal serum retinol in late pregnancy was associated with lower offspring total body BMC (? = ?0.10 SD/SD; 95% CI: ?0.19, ?0.02; P = 0.020) and BA (? = ?0.12 SD/SD; 95% CI: ?0.20, ?0.03; P = 0.009) but not BMD. Conversely, higher maternal serum ?-carotene concentrations in late pregnancy were associated with greater total body BMC (? = 0.12 SD/SD; 95% CI: 0.02, 0.21; P = 0.016) and BA (? = 0.12 SD/SD; 95% CI: 0.03, 0.22; P = 0.010) but not BMD.Conclusions: maternal serum retinol and ?-carotene concentrations had differing associations with offspring bone size and growth at birth: retinol was negatively associated with these measurements, whereas ?-carotene was positively associated. These findings highlight the need for further investigation of the effects of maternal retinol and carotenoid status on offspring bone developmen

Case study of a performance-active changing trans* male singing voice

A professional classical singer of more than 25 years (AZ) in his early 50s requested this voice researcher’s consultation and assistance in early 2014. He was about to start living full time as a trans* man. Despite his intention to be included in the low start/gradual increase testosterone option of the Trans* Male (previously, “FTM”) Singing Voice Program, the request contained a rather unconventional aspect: AZ would continue to sing while his voice was changing. The above request was integral with his singing history. After the introduction of safeguards and his informed consent, AZ was accepted onto the Program. Due to the highly individual circumstances, his participation was recorded as a case study. The study has aimed to replicate the particulars of the slow hormonal changes and continuing singing ability found in certain cisgender male adolescent voices. Despite dealing with an adult trans* male individual, the progress has been comparable. This has been achieved by carefully monitoring AZ’s low start/gradual increase testosterone administration in communication with the medical practitioner. The participant’s vocal health remained safeguarded and promoted by carefully individualized vocal tuition. This article will discuss the collective results of the case study, including the recordings and the data analysis

Targeting Hepatitis B Virus with Zinc Finger Nucleases

Despite an existing effective vaccine, hepatitis B virus (HBV) remains a major public health concern. There are effective suppressive therapies for HBV, but they remain expensive and inaccessible to many, and not all patients respond well. Furthermore, HBV can persist as genomic covalently closed circular DNA (cccDNA) that remains in hepatocytes even during otherwise effective therapy and facilitates rebound in patients after treatment has stopped. Therefore, the need for an effective treatment that targets active and persistent HBV infections remains. As a novel approach to treat HBV, we have targeted the HBV genome for disruption to prevent viral reactivation and replication. We generated 3 zinc finger nucleases (ZFNs) that target sequences within the HBV polymerase, core and X genes. Upon the formation of ZFN-induced DNA double strand breaks (DSB), imprecise repair by non-homologous end joining leads to mutations that inactivate HBV genes. We delivered HBV-specific ZFNs using self-complementary adeno-associated virus (scAAV) vectors and tested their anti-HBV activity in HepAD38 cells. HBV-ZFNs efficiently disrupted HBV target sites by inducing site-specific mutations. Cytotoxicity was seen with one of the ZFNs. scAAV-mediated delivery of a ZFN targeting HBV polymerase resulted in complete inhibition of HBV DNA replication and production of infectious HBV virions in HepAD38 cells. This effect was sustained for at least 2 weeks following only a single treatment. Furthermore, high specificity was observed for all ZFNs, as negligible off-target cleavage was seen via high-throughput sequencing of 7 closely matched potential off-target sites. These results show that HBV-targeted ZFNs can efficiently inhibit active HBV replication and suppress the cellular template for HBV persistence, making them promising candidates for eradication therapy

Vitamin d status predicts 30 day mortality in hospitalised cats

Vitamin D insufficiency, defined as low serum concentrations of the major circulating form of vitamin D, 25 hydroxyvitamin D (25(OH)D), has been associated with the development of numerous infectious, inflammatory, and neoplastic disorders in humans. In addition, vitamin D insufficiency has been found to be predictive of mortality for many disorders. However, interpretation of human studies is difficult since vitamin D status is influenced by many factors, including diet, season, latitude, and exposure to UV radiation. In contrast, domesticated cats do not produce vitamin D cutaneously, and most cats are fed a commercial diet containing a relatively standard amount of vitamin D. Consequently, domesticated cats are an attractive model system in which to examine the relationship between serum 25(OH)D and health outcomes. The hypothesis of this study was that vitamin D status would predict short term, all-cause mortality in domesticated cats. Serum concentrations of 25(OH)D, together with a wide range of other clinical, hematological, and biochemical parameters, were measured in 99 consecutively hospitalised cats. Cats which died within 30 days of initial assessment had significantly lower serum 25(OH)D concentrations than cats which survived. In a linear regression model including 12 clinical variables, serum 25(OH)D concentration in the lower tertile was significantly predictive of mortality. The odds ratio of mortality within 30 days was 8.27 (95% confidence interval 2.54-31.52) for cats with a serum 25(OH)D concentration in the lower tertile. In conclusion, this study demonstrates that low serum 25(OH)D concentration status is an independent predictor of short term mortality in cats

Vitamin D insufficiency in COVID-19 and influenza A, and critical illness survivors: a cross-sectional study

Objectives: The steroid hormone vitamin D has roles in immunomodulation and bone health. Insufficiency is associated with susceptibility to respiratory infections. We report 25-hydroxy vitamin D (25(OH)D) measurements in hospitalised people with COVID-19 and influenza A and in survivors of critical illness to test the hypotheses that vitamin D insufficiency scales with illness severity and persists in survivors. Design: Cross-sectional study. Setting and participants: Plasma was obtained from 295 hospitalised people with COVID-19 (International Severe Acute Respiratory and emerging Infections Consortium (ISARIC)/WHO Clinical Characterization Protocol for Severe Emerging Infections UK study), 93 with influenza A (Mechanisms of Severe Acute Influenza Consortium (MOSAIC) study, during the 2009–2010 H1N1 pandemic) and 139 survivors of non-selected critical illness (prior to the COVID-19 pandemic). Total 25(OH)D was measured by liquid chromatography-tandem mass spectrometry. Free 25(OH)D was measured by ELISA in COVID-19 samples. Outcome measures: Receipt of invasive mechanical ventilation (IMV) and in-hospital mortality. Results: Vitamin D insufficiency (total 25(OH)D 25–50 nmol/L) and deficiency (<25 nmol/L) were prevalent in COVID-19 (29.3% and 44.4%, respectively), influenza A (47.3% and 37.6%) and critical illness survivors (30.2% and 56.8%). In COVID-19 and influenza A, total 25(OH)D measured early in illness was lower in patients who received IMV (19.6 vs 31.9 nmol/L (p<0.0001) and 22.9 vs 31.1 nmol/L (p=0.0009), respectively). In COVID-19, biologically active free 25(OH)D correlated with total 25(OH)D and was lower in patients who received IMV, but was not associated with selected circulating inflammatory mediators. Conclusions: Vitamin D deficiency/insufficiency was present in majority of hospitalised patients with COVID-19 or influenza A and correlated with severity and persisted in critical illness survivors at concentrations expected to disrupt bone metabolism. These findings support early supplementation trials to determine if insufficiency is causal in progression to severe disease, and investigation of longer-term bone health outcomes

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

The Sound of Silence: Investigations of Implicit Prosody

This dissertation is about implicit prosody, the prosodic structure that readers assign during silent reading. The dissertation has several goals: determining which reading tasks are appropriate for studying implicit prosody, establishing how grammatical principles could guide incremental assignment of prosodic structure, and investigating how implicit prosody interacts with other properties such as focus in order to influence syntactic parsing and interpretation. On the methodological side, this dissertation demonstrates that the Maze task is suitable for studying implicit prosody by replicating several major findings on metrical and phrasal prosody in both the Maze task and in self-paced reading. In addition to showing that the Maze is sensitive to implicit prosody, the methodological comparison confirms previously reported advantages of the Maze over self-paced reading, such as more localized and larger effects. On the theoretical side, the dissertation lays the groundwork for developing an incremental model of prosodic parsing. I provide an overview of the major grammatical constraints that govern the syntax-prosody interface, drawing on work from the theoretical phonology literature. I discuss how and when these grammatical constraints, which are typically invoked to model the final phrasing for a complete sentence structure, could be deployed by an incremental parser that assigns a prosodic structure word-by-word. Using a toy model of an incremental parser, I also show how the parser’s first pass implicit prosody may differ from the final prosody, arguing that future work in this area should more closely consider these potential differences. The final set of experiments investigates both the timing of implicit prosodic assignment and how prosodic structure and information structure affect attachment decisions. Based on the results of these experiments, I propose the Visibility First Hypothesis, according to which attachment decisions are determined primarily by prosodic visibility, while other factors such as focus only exert an influence when two potential attachment sites are equally visible. I then outline several experiments to test the Visibility First Hypothesis in future work