Assessing safety and efficacy of a novel glucose-free amino acid oral rehydration solution for watery diarrhea management in children: a randomized, controlled, phase III trial.

Background: Diarrhoeal disease poses a significant global health challenge, especially in children under three years old. Despite the effectiveness of oral rehydration therapy (ORT), its adoption remains low. Glucose-based ORS (GORS) is the standard, but novel formulations like glucose-free amino acid-based VS002A have emerged as potential alternatives. This study aimed to compare the safety and efficacy of VS002A against the standard WHO-ORS in treating non-cholera acute watery diarrhoea in children. Methods: A triple-blind, randomized trial enrolled 310 male infants and children aged 6-36 months, who were assigned to receive WHO-ORS or VS002A over a 16-month period, from June 2021 to September 2022. Both groups received standard of care, including zinc supplementation. The Primary study outcome measured was the duration of diarrhoea. Secondary outcomes included stool output, treatment failure and adverse events. Exploratory endpoints included urinary output, body weight changes, blood biochemistry, stool microbiology and gut health biomarkers. Findings: Both VS002A and WHO-ORS were well-tolerated with a low adverse event rate. While not different statistically (p = 0.10), duration of diarrhoea was shorter in children treated with VS002A vs. WHO-ORS (65.4 h vs. 72.6 h). Similarly, stool output was also lower vs. WHO-ORS in children treated with VS002A, though not statistically different (p = 0.40). Serum citrulline levels, an indicator of gut health, were higher in the VS002A group at 24 h suggesting a potential protective effect (p = 0.06). Interpretation: The findings of this study support the non-inferiority of VS002A, a glucose-free amino acid-based ORS compared to the WHO-ORS standard of care. VS002A was shown to be safe and effective in treating non-cholera acute watery diarrhoea in young children. VS002A may offer advantages in pathogen-driven diarrhoea, supported by trends toward a lower duration of diarrhoea and stool output within the per protocol group. Furthermore, individuals with prolonged diarrhoea, severe malnutrition, environmental enteric dysfunction or have issues with obesity or insulin resistance, could benefit from a glucose-free ORS. This research contributes to addressing the persistent challenge of childhood diarrhoea by presenting an alternative glucose-free ORS formulation with potential advantages in select scenarios, offering a promising avenue for improving paediatric diarrhoea management worldwide. Funding: The study was funded by Entrinsic Bioscience, LLC., Norwood, MA, USA.

Long COVID Clinical Severity Types Based on Symptoms and Functional Disability: A Longitudinal Evaluation.

Background: Long COVID (LC) is a multisystem clinical syndrome with functional disability and compromised overall health. Information on LC clinical severity types is emerging in cross-sectional studies. This study explored the pattern and consistency of long COVID (LC) clinical severity types over time in a prospective sample. Methods: Participants with LC completed the condition-specific outcome measure C19-YRSm (Yorkshire Rehabilitation Scale modified version) at two assessment time points. A cluster analysis for clinical severity types was undertaken at both time points using the k-means partition method. Results: The study included cross-sectional data for 759 patients with a mean age of 46.8 years (SD = 12.7), 69.4% females, and a duration of symptoms of 360 days (IQR 217 to 703 days). The cluster analysis at first assessment revealed three distinct clinical severity type clusters: mild (n = 96), moderate (n = 422), and severe (n = 241). Longitudinal data on 356 patients revealed that the pattern of three clinical severity types remained consistent over time between the two assessments, with 51% of patients switching clinical severity types between the assessments. Conclusions: This study is the first of its kind to demonstrate that the pattern of three clinical severity types is consistent over time, with patients also switching between severity types, indicating the fluctuating nature of LC.

The humanistic and economic burden of work-related musculoskeletal pain: a cross-sectional survey of workers in the United Kingdom.

OBJECTIVE: The aim of this study was to evaluate the impact of work-related musculoskeletal (MSK) lower body pain on health-related quality of life (HRQoL) and work productivity in a large sample of workers in the United Kingdom, as well as evaluating the potential economic impact of MSK pain. METHODS: Participants with self-reported work-related MSK pain were recruited from an online panel maintained by a third party (Qualtrics LLC). Participants completed three validated instruments online: the Brief Pain Inventory (BPI), the Assessment of Quality of Life Instrument (AQoL-4D), and the 6-item Work Productivity and Activity Impairment Questionnaire (WPAI). Sociodemographic details, work patterns and healthcare resource utilisation were also reported. One-way analysis of variance (ANOVA) and t-tests were used to explore differences between variables. Linear regression was applied to determine the impact of work-related MSK pain on HRQoL. RESULTS: All 1035 recruited participants completed the survey (57.4% female; mean age 43.4 years). Participants reported spending all (25.2%) or most (53%) of their time at work on their feet. Mean pain severity was 4.63 (standard deviation: 2.07); mean pain interference was 4.37 (2.49). There was a linear relationship between length of shift, time on feet and pain. Mean AQoL-4D scores were 0.609 (0.254). A mean of 4.12 h was lost per week due to pain. Absenteeism (last 7 days) was 9.5% (20.7%), and presenteeism 33.3% (24.9%). An average 1.55 visits were made to family practitioners (total cost: £19,866) and 1 hospital visit (£37,320) due to work-related MSK pain. CONCLUSION: This study demonstrated that work-related lower body pain has a significant impact in terms of individual HRQoL and as an economic societal burden.

I-PreFer Study: A Discrete Choice Experiment to Explore Patient, Caregiver and Pulmonologist Preferences of Idiopathic Pulmonary Fibrosis Pharmacological Treatment Options.

Purpose: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and ultimately fatal lung disease that, while rare, has seen incidence rise over time. There is no cure for IPF other than a lung transplant, though two antifibrotic (AF) drugs do exist to slow disease progression. While these drugs are efficacious, they are both associated with differing profiles of adverse events. This study aimed to elicit patient, caregiver and pulmonologist preferences on the treatment profiles of AFs via a discrete choice experiment (DCE). Patients and Methods: The DCE and associated survey were distributed across 7 European countries, and bespoke DCEs were developed for patients/caregivers and pulmonologists. After collaboration with European Pulmonary Fibrosis & Related Disorders Federation (EU-PFF) and expert pulmonologists, respectively, a patient/caregiver DCE with 5 attributes and a pulmonologist DCE with 6 attributes were finalized. The DCEs had a blocked approach to reduce participant burden and were distributed on an online survey platform. Preferences were estimated through conditional multinomial logit regression analysis. Results: Ninety-five patients, 22 caregivers and 115 pulmonologists fully completed their respective DCEs. Overall, patients and caregivers preferred management of treatment-related adverse events over both survival benefits and disease progression. Nearly all preference levels were found to be significantly different from their reference level. In contrast, pulmonologists showed a greater preference for control of lung function and exacerbations over adverse events. Although there were relative differences between the univariate subgroups in terms of the preference weights, most of these were not statistically significant. Conclusion: The outcomes from this study suggest that while patients and caregivers had similar preferences for characteristics of IPF treatments, pulmonologists did not share those same preferences. Patients and caregivers preferred safety, while pulmonologists preferred efficacy. These differences should be considered by clinicians to better involve the patient in treatment decision-making for IPF.

I-PreFer Study: A Questionnaire to Explore Patient, Caregiver and Pulmonologist Preferences of Idiopathic Pulmonary Fibrosis Treatment Options.

Introduction: Idiopathic Pulmonary Fibrosis (IPF) is a rare disease that causes shortness of breath, dry cough, and tiredness. While there is no cure for IPF, current therapeutic treatments aim to slow lung degeneration while managing side effects. There is little known about patient experience and attitude with regards to their disease and medication. Purpose: To understand the perceptions, behaviors and drivers of treatment decision-making among patients, caregivers and pulmonologists in IPF. Patients and Methods: Online surveys to patients with IPF, caregivers and pulmonologists were developed and administered in Belgium, Finland, France, Greece (pulmonologists only), the Netherlands, Ireland and the United Kingdom between November 2021 and January 2022. Results: A total of 111 patients, 22 caregivers and 140 pulmonologists participated. Half (47%) of patients rated their disease as "severe", while pulmonologists reported that a quarter of their patients had a low Forced Vital Capacity (FVC) (below 50% of the predicted value). Between 21% and 42% of the patients do not take an IPF medication (patients' perception) or antifibrotic (physicians' perception). Pulmonologists reported that a total of 58% of their patients were receiving antifibrotic medication, any IPF medication, while around 53%, 55%, 35% and 73% of the patients limited their exposure (sometimes or often) to the sun due to IPF, considered taking medication against diarrhea, nausea/vomiting and heartburn, respectively. Treatment adherence was relatively high (81%), in line with the caregivers' view and the pulmonologists' expectations. Overall, cultural, clinical or socio-demographic factors impacted patients' perceptions or behaviors. Conclusion: This study shows there is a significant proportion of IPF patients who remain untreated, a misalignment of disease severity between patients and their physicians and patient background impacts behavior. Overall, more in-depth patient-physician communication is needed to improve treatment experience.

Beyond the usual climate? Factors determining flowering and fruiting phenology across a genus over 117 years.

PREMISE: Although changes in plant phenology are largely attributed to changes in climate, the roles of other factors such as genetic constraints, competition, and self-compatibility are underexplored. METHODS: We compiled >900 herbarium records spanning 117 years for all eight nominal species of the winter-annual genus Leavenworthia (Brassicaceae). We used linear regression to determine the rate of phenological change across years and phenological sensitivity to climate. Using a variance partitioning analysis, we assessed the relative influence of climatic and nonclimatic factors (self-compatibility, range overlap, latitude, and year) on Leavenworthia reproductive phenology. RESULTS: Flowering advanced by ~2.0 days and fruiting by ~1.3 days per decade. For every 1°C increase in spring temperature, flowering advanced ~2.3 days and fruiting ~3.3 days. For every 100 mm decrease in spring precipitation, each advanced ~6-7 days. The best models explained 35.4% of flowering variance and 33.9% of fruiting. Spring precipitation accounted for 51.3% of explained variance in flowering date and 44.6% in fruiting. Mean spring temperature accounted for 10.6% and 19.3%, respectively. Year accounted for 16.6% of flowering variance and 5.4% of fruiting, and latitude for 2.3% and 15.1%, respectively. Nonclimatic variables combined accounted for <11% of the variance across phenophases. CONCLUSIONS: Spring precipitation and other climate-related factors were dominant predictors of phenological variance. Our results emphasize the strong effect of precipitation on phenology, especially in the moisture-limited habitats preferred by Leavenworthia. Among the many factors that determine phenology, climate is the dominant influence, indicating that the effects of climate change on phenology are expected to increase.

The effects of greater frequency of two most prevalent bothersome acute respiratory symptoms on health-related quality of life in the 2020 US general population.

PURPOSE: Upper respiratory tract infections (URTI) and related symptoms are widespread and a common reason for visiting primary care with cough and sore throat being most prevalent. Despite their impact on daily activities, no studies have explored the impact on health-related quality of life (HRQOL) in representative general populations. We aimed to understand the short-term impact of the two most prevalent URTI symptoms on HRQOL. METHODS: Online 2020 surveys including acute (≤ 4 weeks) respiratory symptoms (sore throat and cough) and SF-36® health survey (all with 4-week recall) were analysed using analysis of covariance (ANCOVA) in comparison with adult US population norms. Linear T-score transformation of SF-6D utility (ranging from 0 to 1) enabled direct comparisons with SF-36. RESULTS: In total, 7563 US adults responded (average age: 52 years; range: 18-100 years). Sore throat and cough lasting at least several days were experienced by 14% and 22% participants, respectively. Chronic respiratory conditions were reported by 22% of the sample. A clear and consistent pattern of group HRQOL means declining significantly (p < 0.001) for acute cough and sore throat symptom presence and severity. Declines were observed on SF-36 physical (PCS) and mental component (MCS) and health utility (SF-6D) scores controlling for covariates. Those reporting respiratory symptoms 'most days' declined ≥ 0.5 standard deviation (minimal important difference [MID]) worse with averages at the 19th and 34th centiles for cough on the PCS and MCS, and 21st to 26th centile for sore throat. CONCLUSION: Declines in HRQOL with acute cough and sore throat symptoms consistently exceeded MID standards and should not be ignored as self-limiting without intervention. Future studies on early self-care for symptom relief and its implications on HRQOL and health economics would be valuable to understand the benefits on healthcare burden and need for updating treatment guidelines.

Effectiveness of an amino acid beverage formulation in diarrhea-predominant irritable bowel syndrome: A pragmatic real-world study.

BACKGROUND: Amino-acid based medical foods have shown promise in alleviating symptoms of drug induced gastrointestinal side effects; particularly, diarrhea-predominant symptoms. Irritable bowel syndrome (IBS) is a gastrointestinal disorder that affects up to 9% of people globally, with diarrhea predominant IBS (IBS-D) being the most prevalent subtype. Further trials are needed to explore potential added benefits when integrated into standard care for IBS-D. AIM: To assess the effectiveness of an amino acid-based medical food as an adjunct to standard of care for adults with IBS-D. METHODS: This is a pragmatic, real world, open label, single arm study comparing a 2-week baseline assessment to a 2-week intervention period. One hundred adults, aged 18 to 65 years, with IBS-D, according to Rome IV criteria, were enrolled after completing a 2-week baseline assessment period and received a 2-week supply of an amino acid based medical food which was consumed at home twice daily on top of their standard of care. The primary outcome was an assessment of tolerability after 2-weeks of consumption, while secondary outcomes included changes in stool consistency (Bristol Stool Form Scale), severity of abdominal pain & discomfort, symptoms of urgency, Global Improvement Survey (GIS), and the IBS severity scoring system (IBS-SSS). RESULTS: The test product was well-tolerated as each participant successfully completed the full 14-day trial, and there were no instances of dropouts or discontinuation of the study product reported. Forty percent of participants achieved a 50% or more reduction in the number of days with type 6-7 bowel movements (IBS-D stool consistency responders). Fifty-three percent of participants achieved a clinically meaningful reduction of 30% in mean weekly pain scores, and 55% experienced the same for mean weekly discomfort scores (IBS-D pain and discomfort responders). Participants experienced a mean -109.4 (95% confidence interval: -130.1, -88.8) point reduction on the IBS-SSS and 52% experienced a minimally clinically important difference of > 95 points. An IBS-SSS category shift from severe to moderate or mild occurred in 69% of participants. For functional symptoms, 76% of participants reported symptom relief on the GIS. CONCLUSION: The amino acid-based medical food was well-tolerated, when added to the standard of care, and demonstrated improvements in both overall IBS symptom severity and IBS-D symptoms within just 2 wk.

The Distinctive Forehead Cleft of the Risso's Dolphin (Grampus griseus) Hardly Affects Biosonar Beam Formation.

The Risso's dolphin (Grampus griseus) has a distinctive vertical crease (or cleft) along the anterior surface of the forehead. Previous studies have speculated that the cleft may contribute to biosonar beam formation. To explore this, we constructed 2D finite element models based on computer tomography data of the head of a naturally deceased Risso's dolphin. The simulated acoustic near-field signals, far-field signals, and transmission beam patterns were compared to corresponding measurements from a live, echolocating Risso's dolphin. To investigate the effect of the cleft, we filled the cleft with neighboring soft tissues in our model, creating a hypothetical "cleftless" forehead, as found in other odontocetes. We compared the acoustic pressure field and the beam pattern between the clefted and cleftless cases. Our results suggest that the cleft plays an insignificant role in forehead biosonar sound propagation and far-field beam formation. Furthermore, the cleft was not responsible for the bimodal click spectrum recorded and reported from this species.

Climate change is associated with increased allocation to potential outcrossing in a common mixed mating species.

PREMISE: Although the balance between cross- and self-fertilization is driven by the environment, no long-term study has documented whether anthropogenic climate change is affecting reproductive strategy allocation in species with mixed mating systems. Here, we test whether the common blue violet (Viola sororia; Violaceae) has altered relative allocation to the production of potentially outcrossing flowers as the climate has changed throughout the 20th century. METHODS: Using herbarium records spanning from 1875 to 2015 from the central United States, we quantified production of obligately selfing cleistogamous (CL) flowers and potentially outcrossing chasmogamous (CH) flowers by V. sororia, coupled these records with historic temperature and precipitation data, and tested whether changes to the proportion of CL flowers correlate with temporal climate trends. RESULTS: We find that V. sororia progressively produced lower proportions of CL flowers across the past century and in environments with lower mean annual temperature and higher total annual precipitation. We also find that both CL and CH flower phenology has advanced across this time period. CONCLUSIONS: Our results suggest that V. sororia has responded to lower temperatures and greater water availability by shifting reproductive strategy allocation away from selfing and toward potential outcrossing. This provides the first long-term study of how climate change may affect relative allocation to potential outcrossing in species with mixed mating systems. By revealing that CL flowering is associated with low water availability and high temperature, our results suggest the production of obligately selfing flowers is favored in water limited environments.

A Discrete Choice Experiment to Derive Health Utilities for Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency in France.

PURPOSE: Cost-effectiveness evaluations of interventions require health utility data. However, in medical conditions, such as aromatic L-amino acid decarboxylase (AADC) deficiency, this presents problems due to the rarity of the disease. The study aim therefore was to employ a discrete choice experiment (DCE) to generate health utilities for AADC deficiency. METHODS: A previous literature review, clinician and parent interviews had identified six key AADC deficiency attributes: mobility, muscle weakness, oculogyric crises (OCG), feeding ability, cognitive impairment and screaming. A representative sample of the French general population was recruited. Participants rated 5 health state vignettes describing AADC deficiency using time-trade-off (TTO) and standard gamble (SG). Additionally, participants rated the worst health state using the Health Utility Index version 3 (HUI3). Subsequently, participants completed DCE 11 choice sets. Indirect DCE part-worth utilities were converted to health utilities using the anchors from the TTO, SG and HUI3. RESULTS: The DCE was completed online by 1001 participants (50.9% female; mean age 45.7 years). Most participants (596, 59.5%) provided consistent responses to the repeated choice task. Five models were evaluated, and one preference reversal ("head control"/"sitting unaided") was identified in all models. The rescaled utilities ranged from 0.3891 to 0.5577 (difference of 0.17 utilities) for TTO anchors corresponding to the worst (633233) and best (111111) health states. Health utilities ranged from 0.5534 to 0.7093 for the SG anchors. The disutility associated with a transition from "no problems walking" to "bedridden" was -0.0533, whereas disutility of moving from "constant screaming" relative to "no screaming" was -0.0248. The disutility associated with daily OCG was -0.0167. Disutilities for the other attributes were small although there were exceptions. CONCLUSION: A DCE was used to derive health utilities for AADC deficiency. These health utilities will subsequently be used in an economic model evaluating an AADC deficiency intervention.

Development of an observer-reported outcome measure to capture the signs and impact of fever distress symptoms in infants and young children.

PURPOSE: This qualitative study aimed to construct an observer-reported outcome measure (ObsRO) to evaluate fever distress in young children. METHODS: A literature review was conducted to identify fever-related concepts. Clinical experts were interviewed for feedback on these concepts. Parents of young children were interviewed to identify behaviours the child exhibited during a recent fever episode. Fever sign and behaviour concepts endorsed by ≥ 20% parents were used to create items for the draft ObsRO. Parents of young children who recently had fever completed the ObsRO and gave feedback during two successive rounds of cognitive interviews. RESULTS: Twenty-five parents participated in the concept elicitation. Mean child age was 2.7 years (range: 0.6-5.8 years). Fever sign and behaviour concepts endorsed by ≥ 20% participants were high temperature (80%), skin hot to touch (32%), skin redness/flushing (32%), reduced appetite/drink (96%), needy/clingy/irritable (48-92%), less active/interactive (68-84%) and lethargic (64-88%). Eighteen items, four in the Fever Signs Module and 14 in the Fever Behaviours Module, were developed for the draft ObsRO. Chosen recall period was 24 h. Thirty participants (Round 1: n = 17; Round 2: n = 13), participated in cognitive interviews. Mean child age was 2.4 years (range 0.3-5.8). Round 1 feedback resulted in two Fever Signs items being combined. Three Fever Behaviour items were deleted, six revised and four unchanged. No changes were made following Round 2 feedback. Most participants understood all aspects of the ObsRO and found it user-friendly. CONCLUSION: The ObsRO will undergo further development in validation studies testing measurement properties of each item.

Eliciting health state utilities for Aromatic L-amino Acid Decarboxylase (AADC) deficiency: a UK vignette study.

PURPOSE: The aim of this study was to generate health state utilities for aromatic L-amino acid decarboxylase (AADC) deficiency, a rare genetic, lifelong neurogenerative condition predominantly manifesting in young infants. METHODS: Participants were presented with health state vignettes. These had been previously developed based on published literature, clinician input, interviews with parents of AADC deficiency patients and expert opinion. A total of 5 health state vignettes were presented: bedridden, head control, sitting unsupported, standing with assistance and walking with assistance. Health state utilities (HSU) were elicited using time-trade off (TTO; 10-year time horizon) and the standard gamble (SG). The vignettes were completed online by panel participants drawn from a representative sample of the United Kingdom residential population. RESULTS: A total of 1598 participants completed the vignettes. Around 21% had incongruent responses (higher utilities for the bedridden compared to walking health states). Incongruent responses were associated with shorter task completion times, gender and parental status. These responses were removed from the analysis. Health state utilities (HSU) increased correspondingly as health states improved for both the TTO and SG. The mean HSU (standard deviation) for the TTO task were: bedridden state 0.49 (0.34); head control 0.54 (0.33), sitting unsupported 0.63 (0.31); standing with assistance 0.68 (0.31); and walking with assistance 0.73 (0.31). For the SG, mean health state utilities were: 0.56 (0.28), 0.57 (0.27), 0.67 (0.24), 0.70 (0.24), and 0.75 (0.25), respectively. CONCLUSION: Health state utilities were derived for AADC deficiency through a vignette study. These will be used for a cost-effectiveness model of an AADC deficiency treatment.

A Survey to Identify Determinants That Influence Self-Perceived Sensitive Skin in a British Population: Clues to Developing a Reliable Screening Tool for Sensitive Skin.

BACKGROUND: Skin sensitivity characteristics and triggers have been identified in populations in previous studies. However, few have compared these characteristics among self-reported sensitive skin. OBJECTIVE: The aim of the study was to evaluate and compare specific intrinsic and extrinsic triggers of skin sensitivity between individuals with self-reported sensitive skin and non-sensitive skin. METHODS: A systematic literature review was undertaken to identify intrinsic and extrinsic factors associated with sensitive skin. A 167-item survey was developed on the basis of the literature review. The survey was completed online by a sample of adult participants drawn from the general United Kingdom population. Participants also completed sociodemographic and self-reported health questions. RESULTS: A total of 3050 surveys were completed: 1526 participants with self-reported skin sensitivity and 1524 participants not reporting skin sensitivity. There was a decrease in self-reported skin sensitivity with increasing age (p<0.05), and proportionally more women reported sensitive skin. Smoking also led to a higher frequency of sensitive skin. All signs and symptoms of sensitive skin, such as itch, dryness/flakiness, roughness and flushing/blushing were more commonly reported by those with self-reported sensitive skin. These were frequently reported in association with external factors (cold/windy weather, clothes and fabrics), as well as internal factors such as pre-existing skin conditions and atopy. CONCLUSION: The study evaluated self-reported sensitive skin against a non-sensitive skin in order to identify common inherent and external triggers to distinguish between these groups in a large general population study in the United Kingdom. The key symptoms and signs of this syndrome identified in the literature were confirmed to be reported significantly more when compared with those without sensitive skin. However, no correlation or pattern of symptomology could be identified, reinforcing the complexity of this condition. Given the strong differentiation from the non-sensitive group, the results of this research could be utilised for the development of a clinically meaningful screening tool.

Eliciting Health State Utilities for Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency: A Vignette Study in France.

PURPOSE: Health-related quality of life (HRQoL) is difficult to measure in rare diseases, especially in paediatric populations, yet capturing HRQoL is critical to evaluating treatment, including the cost-effectiveness of treatments. Given the ultra-rare nature of AADC deficiency indirect elicitation of HRQoL data through proxy caregiver/parent ratings is not feasible. In these circumstances, HRQoL data may be derived through vignette studies using the general population. The aim of the study was to generate health utility values specific for France for AADC deficiency using vignettes. METHODS: The study was completed online by panel participants from a French representative sample. Five health state vignettes, reflecting key milestones in the eladocagene exuparvovec clinical trials and economic model, were presented to the participants: "bedridden", "head control", "sitting unsupported", "standing with assistance" and "walking with assistance". The vignettes had been previously developed with input from parents of patients with AADC deficiency, patients and expert opinion. Participants also completed the Health Utilities Index-3 for the "bedridden" health state. RESULTS: A total of 1001 participants (51% females; mean age 46 years) completed the vignettes. Utilities increased linearly as the health state improved for both the time trade-off (TTO): 0.47 (standard deviation, SD 0.36) to 0.54 (SD 0.36) and standard gamble (SG): 0.61 (SD 0.29) to 0.67 (SD 0.27). A significant minority had incongruent responses (high utilities for the bedridden compared to walking health states) for the vignette (27%). When these were removed, the TTO health utilities (N=729) ranged from 0.39 (SD 0.36) to 0.56 (SD 0.38) and 0.61 (SD 0.30) to 0.69 (SD 0.27) for the SG. CONCLUSION: Health utilities were derived for AADC deficiency which will be used for a cost-effectiveness model of an AADC deficiency treatment.

The phylogeographic history of a range disjunction in eastern North America: the role of post-glacial expansion into newly suitable habitat.

PREMISE: A disjunct distribution, where a species' geographic range is discontinuous, can occur through vicariance or long-distance dispersal. Approximately 75 North American plant species exhibit a ~650 km disjunction between the Ozark and Appalachian regions. This disjunction is attributed to biogeographic forces including: (1) Eocene-Oligocene vicariance by the formation of the Mississippi embayment; (2) Pleistocene vicariance from interglacial flooding; (3) post-Pleistocene northward colonization from separate glacial refugia; (4) Hypsithermal vicariance due to climate fluctuations; and (5) recent long-distance dispersal. We investigated which of these pathways most likely gave rise to the Appalachian-Ozark disjunction in Delphinium exaltatum. METHODS: We genotyped populations of D. exaltatum from five Ozark and seven Appalachian localities, analyzed genetic structure, tested the order and timing of divergences using DIYABC, and conducted niche reconstructions up to 21,000 years before present (YBP). RESULTS: Populations fell into five main genetic clusters, i.e., a group in the central Appalachians, and four "lowland" groups. DIYABC analyses showed the central Appalachian and lowland lineages diverging 11,300 to17,000 YBP, and the lowland groups diverging 6800 to 10,900 YBP. Niche reconstructions showed that suitable climate for the central Appalachian lineage experienced large spatial discontinuity starting 14,000 YBP, such that divergence and persistence before this period is less plausible than divergence thereafter. CONCLUSIONS: Our results did not fully support any of the original hypotheses. Rather, the oldest divergence likely occurred after 13,500 YBP through expansion into newly opened habitat in the Appalachians. The Appalachian-Ozark disjunction likely resulted from northward dispersal of the lowland lineage as climate warmed during the Holocene.

A Discrete Choice Experiment to Derive Health Utilities for Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency.

PURPOSE: Deriving health utilities for rare medical conditions such as aromatic L-amino acid decarboxylase (AADC) deficiency poses challenges. The rarity of AADC deficiency and the fact that this genetic condition often presents in very young children means that robust utility values cannot be derived from the child or their parent/caregiver. Alternative approaches, eg, discrete choice experiments (DCE), are required in order to provide health utilities. The aim of the study was to generate health utilities for AADC deficiency using a DCE. METHODS: The DCE was completed online by panel participants from a UK representative sample. The DCE comprised 6 AADC deficiency attributes (2-6 levels): mobility, muscle weakness, oculogyric crises, feeding ability, cognitive impairment and screaming. These were identified from published literature, clinician input, parent interviews and expert opinion. Participants were presented with 10 choice sets specified using an orthogonal design, including a repeat task to evaluate choice consistency. Participants were presented with 5 health state vignettes prior to the DCE. These were used to elicit time trade-off (TTO) utilities. Multinomial logit models were estimated for the DCE data. The TTO utilities for the worst/best health states were used as anchors to convert indirect DCE part-worth utilities to health utilities. RESULTS: A total of 1596 participants completed the DCE. The majority (70.7%) gave consistent responses to the repeated choice task; only 1.7% (27) always chose the same alternative for every choice set. Five models were evaluated. There was one preference reversal ("sitting unaided"/"standing with assistance") occurring in all models; these two mobility level coefficients were set to be equal in the final model. Rescaled utilities ranged from 0.494 to 0.7279, corresponding to the worst (633233) and best (111111) health states. CONCLUSION: Health utilities were derived for AADC deficiency through a DCE. These will be used for a cost-effectiveness model of an AADC deficiency treatment.

Deriving Vignettes for the Rare Disease AADC Deficiency Using Parent, Caregiver and Clinician Interviews to Evaluate the Impact on Health-Related Quality of Life.

PURPOSE: Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare genetic condition, characterised by movement disorder, and speech and cognitive functioning impairment. To enable economic evaluation of treatments, health-related quality of life or utilities need to be derived. These are currently lacking in the literature. This is challenging, where patient numbers are small, particularly in paediatric populations. This study outlines the 5-stage development of vignettes describing AADC, for use in a subsequent health-state utility elicitation study, with an emphasis on caregiver and clinician engagement. METHODS: To align with the economic model, 5 vignettes describing 5 AADC deficiency motor milestones were developed, ranging from "bedridden" to "walking with assistance". Stage 1 comprised identification of symptoms/impairments from the literature and AADC deficiency charity websites. Stage 2 comprised group discussion with 3 caregivers. A symptoms matrix was developed, followed by draft vignettes (Stage 3). Eight clinicians reviewed these, alongside the same 3 caregivers via a survey (Stage 4). The vignettes were revised at stage 5. RESULTS: There was high consensus regarding symptoms at Stages 1 and 2, although the literature highlighted behavioural and autonomic symptoms, which caregivers did not. The symptoms were grouped into neuromuscular, autonomic, cognitive, behavioural and functional impairments. Clinician and caregiver vignette feedback highlighted the idiopathic nature of AADC. Despite this, clinicians suggested only 2 additional symptoms. Similarly, caregivers suggested 4 symptoms and a change to the wording used for the cognitive symptoms. Not all changes were included. CONCLUSION: The differing focus of caregivers, clinicians and the literature reinforces the importance of patient/caregiver engagement. The vignettes need to comprehensively capture what it is like to live with AADC deficiency, in order for the subsequent utilities to be robust. A focus on evidence triangulation, especially for idiopathic conditions, and how engagement is sought from caregivers are important future avenues of research.

Toothed whale auditory brainstem responses measured with a non-invasive, on-animal tag.

Empirical measurements of odontocete hearing are limited to captive individuals, constituting a fraction of species across the suborder. Data from more species could be available if such measurements were collected from unrestrained animals in the wild. This study investigated whether electrophysiological hearing data could be recorded from a trained harbor porpoise (Phocoena phocoena) using a non-invasive, animal-attached tag. The results demonstrate that auditory brainstem responses to external and self-generated stimuli can be measured from a stationary odontocete using an animal-attached recorder. With additional development, tag-based electrophysiological platforms may facilitate the collection of hearing data from freely swimming odontocetes in the wild.