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There is an increasing number of policy and guidance documents on the use and acceptability of real-world evidence (RWE) to support regulatory and health technology assessment (HTA) decision-making. The Innovative Health Initiative Integration of Heterogeneous Data and Evidence towards Regulatory and HTA Acceptance (IDERHA) partnership is undertaking a global landscape review of these documents to understand where there is consensus and divergence, and where further policy development is needed.
Methods
A literature search of the MEDLINE and Embase databases was performed, in addition to handsearching the websites of specific HTA and regulatory organizations. All policies, standards, frameworks, and guidance documents on requirements for acceptable RWE data use published from 2017 were included. Two reviewers independently extracted data using a standard data extraction form that was pilot tested before use. Any discrepancies between the reviewers were resolved by consensus. Extracted data are currently being analyzed by researchers with regulatory or HTA expertise. A workshop held in October 2023 sought input from experts on analysis plans.
Results
The initial literature search yielded 3,184 results. After screening against the inclusion criteria, a total of 87 documents were selected for full-text review (21 HTA and 62 regulatory documents). Of these, 32 were identified as key documents and prioritized for initial review. Key themes in the documents, including transparency, data collection, study design, and data quality, were identified and validated in a workshop with five regulatory or HTA experts. Data extraction is ongoing for the remaining documents and any further themes identified will be added. Any gaps and areas of divergence will be identified, so they can be addressed by future IDERHA work.
Conclusions
This review assessed the increasingly complex global landscape of regulatory and HTA policies and guidance on the use of RWE. Through the exploration of similarities, differences, and gaps in these policies, this work will extend the current understanding of best practice and identify areas that need development of further guidance.
We present new data from the debris-rich basal ice layers of the NEEM ice core (NW Greenland). Using mineralogical observations, SEM imagery, geochemical data from silicates (meteoric 10Be, εNd, 87Sr/86Sr) and organic material (C/N, δ13C), we characterize the source material, succession of previous glaciations and deglaciations and the paleoecological conditions during ice-free episodes. Meteoric 10Be data and grain features indicate that the ice sheet interacted with paleosols and eroded fresh bedrock, leading to mixing in these debris-rich ice layers. Our analysis also identifies four successive stages in NW Greenland: (1) initial preglacial conditions, (2) glacial advance 1, (3) glacial retreat and interglacial conditions and (4) glacial advance 2 (current ice-sheet development). C/N and δ13C data suggest that deglacial environments favored the development of tundra and taiga ecosystems. These two successive glacial fluctuations observed at NEEM are consistent with those identified from the Camp Century core basal sediments over the last 3 Ma. Further inland, GRIP and GISP2 summit sites have remained glaciated more continuously than the western margin, with less intense ice-substratum interactions than those observed at NEEM.
OBJECTIVES/GOALS: We adapted the Serious Illness Care Program (SICP), an evidence-based intervention designed to promote early serious illness conversation, to be delivered via telehealth for older patients with acute myeloid leukemia and myelodysplastic syndromes. The purpose of this study is to assess the feasibility and usability of the adapted intervention. METHODS/STUDY POPULATION: We are conducting a single-arm pilot study of an adapted SICP that is delivered via telehealth for older patients with AML or MDS (>=60 years) and their caregivers (if available). The adapted SICP includes: 1) Patient preparation pamphlet: sent to patient prior the visit with their clinician, 2) Geriatric assessment: completed by study team and provided to clinician prior to their visit with the patient, 3) A 30-60 minute telehealth visit with their primary oncologist or oncology advance practitioner, 4) Serious Illness Conversation Guide (SICG): used by the clinician during the visit to elicit patient values, 5) Family guide: provided to patient following their visit to help patient’s share their values with their family, 6) Electronic medical record note template for clinicians to document their visit the patient. RESULTS/ANTICIPATED RESULTS: We hypothesize that the adapted SICP intervention will be feasible and usable. We will assess feasibility based on retention rate (percent of patients who consent and complete the visit); >80% is considered feasible. Usability will be assessed using the telehealth usability questionnaire; an average score of >5 is considered usable. Other measures include psychological health, advance care planning engagement, quality of life, and disease understanding. We plan to enroll 20 patients in this study. To date, 11 patients have consented to participate, 10 patients have scheduled SICP visits, 9 patients have completed their visits, 7 patients have completed post-intervention qualitative interviews, and 4 patients have completed post-intervention surveys. DISCUSSION/SIGNIFICANCE: The adapted telehealth-based SICP may promote early serious illness conversation, patient-reported outcomes, and end-of-life experience for older patients with AML and MDS. Results from this study will be used to inform development of clinical trials testing the impact of the adapted SICP on patient- and caregiver-reported outcomes.
Both undergraduate students and faculty members face a challenging job market that requires innovative approaches to skill development and research products. Moreover, entrenched approaches to research and education reinforce traditional hierarchies, exclusionary norms, and exploitative practices. This article describes a lab-based pedagogical framework designed to support faculty research goals and student learning and, simultaneously, to attenuate patterns of historical exclusion. This approach leverages evidence-based best practices from experiential education, team-based workflows, an understanding of servant leadership, and “whole-person”–style mentorship models. We find that these tools advance faculty research goals (in terms of both quality and productivity), support student learning in ways beyond traditional undergraduate coursework, and disrupt patterns of historical exclusion. We provide qualitative evidence to support our model and discuss the hurdles and challenges still to be overcome.
OBJECTIVES/GOALS: Neonatal endotracheal tubes (ETTs) are usually uncuffed to avoid subglottic stenosis and other complications, but cuffed ETTs allow better ventilation. Our goal was to detect and control pressure in the cuff below the limit of occluding venous flow to minimize the risk of subglottic stenosis. METHODS/STUDY POPULATION: We designed a pressure sensor to fit on a 2.5 ETT for prototype testing in 8 age adult female rabbits. Eight uncuffed age- and sex- matched rabbits served as control. Study duration was 2 hours during which pressure in the cuff was limited by novel sensor (intervention) or auscultation (control). Anesthesia was maintained with sevoflurane. Ventilation was provided mechanically. Subsequently the tracheae were removed, sectioned crosswise, and compared histologically for mucosal damage. RESULTS/ANTICIPATED RESULTS: Preliminary data demonstrated an almost 30% greater amount of intact mucosa in the intervention group. The sensor also provided data on heart rate and respiratory rate, although this signal was not optimal. After filing an invention disclosure and provisional patent, we are refining our device to include multiple compartments for local control of cuff pressure and applying for a STTR Phase I/II application. DISCUSSION/SIGNIFICANCE: Ventilation in neonates with uncuffed ETTs can be suboptimal due to leak around the tube, but cuffed ETTs pose the threat of subglottic stenosis and other complications. We have designed a prototype cuffed ETT with a sensor to maintain low cuff pressure while preventing leaks and largely avoiding damage to the tracheal mucosa.
OBJECTIVES/GOALS: Neonatal endotracheal tubes (ETTs) are usually uncuffed to avoid subglottic stenosis and other complications, but cuffed ETTs allow better ventilation. Our goal was to detect and control pressure in the cuff below the limit of occluding venous flow to minimize the risk of subglottic stenosis. METHODS/STUDY POPULATION: We designed a pressure sensor to fit on a 2.5 ETT for prototype testing in 8 age adult female rabbits. Eight uncuffed age- and sex- matched rabbits served as control. Study duration was 2 hours during which pressure in the cuff was limited by novel sensor (intervention) or auscultation (control). Anesthesia was maintained with sevoflurane. Ventilation was provided mechanically. Subsequently the tracheae were removed, sectioned crosswise, and compared histologically for mucosal damage. RESULTS/ANTICIPATED RESULTS: Preliminary data demonstrated an almost 30% greater amount of intact mucosa in the intervention group. The sensor also provided data on heart rate and respiratory rate, although this signal was not optimal. After filing an invention disclosure and provisional patent, we are refining our device to include multiple compartments for local control of cuff pressure and applying for a STTR Phase I/II application. DISCUSSION/SIGNIFICANCE: Ventilation in neonates with uncuffed ETTs can be suboptimal due to leak around the tube, but cuffed ETTs pose the threat of subglottic stenosis and other complications. We have designed a prototype cuffed ETT with a sensor to maintain low cuff pressure while preventing leaks and largely avoiding damage to the tracheal mucosa.
Subglacial hydrological systems require innovative technological solutions to access and observe. Wireless sensor platforms can be used to collect and return data, but their performance in deep and fast-moving ice requires quantification. We report experimental results from Cryoegg: a spherical probe that can be deployed into a borehole or moulin and transit through the subglacial hydrological system. The probe measures temperature, pressure and electrical conductivity in situ and returns all data wirelessly via a radio link. We demonstrate Cryoegg's utility in studying englacial channels and moulins, including in situ salt dilution gauging. Cryoegg uses VHF radio to transmit data to a surface receiving array. We demonstrate transmission through up to 1.3 km of cold ice – a significant improvement on the previous design. The wireless transmission uses Wireless M-Bus on 169 MHz; we present a simple radio link budget model for its performance in cold ice and experimentally confirm its validity. Cryoegg has also been tested successfully in temperate ice. The battery capacity should allow measurements to be made every 2 h for more than a year. Future iterations of the radio system will enable Cryoegg to transmit data through up to 2.5 km of ice.
The aim of this study was to investigate the ethical dilemma of prioritising financial resources to expensive biological therapies. For this purpose, the four principles of biomedical ethics formulated by ethicists Tom Beauchamp and James Childress were used as a theoretical framework. Based on arguments of justice, Beauchamp and Childress advocate for a health care system organised in line with the Danish system. Notably, our study was carried out in a Danish setting.
The COVID-19 pandemic has created a high demand on personal protective equipment, including disposable N95 masks. Given the need for mask reuse, we tested the feasibility of vaporized hydrogen peroxide (VHP), ultraviolet light (UV), and ethanol decontamination strategies on N95 mask integrity and the ability to remove the infectious potential of SARS-CoV-2.
Methods:
Disposable N95 masks, including medical grade (1860, 1870+) and industrial grade (8511) masks, were treated by VHP, UV, and ethanol decontamination. Mask degradation was tested using a quantitative respirator fit testing. Pooled clinical samples of SARS-CoV-2 were applied to mask samples, treated, and then either sent immediately for real-time reverse transcriptase–polymerase chain reaction (RT-PCR) or incubated with Vero E6 cells to assess for virucidal effect.
Results:
Both ethanol and UV decontamination showed functional degradation to different degrees while VHP treatment showed no significant change after two treatments. We also report a single SARS-CoV-2 virucidal experiment using Vero E6 cell infection in which only ethanol treatment eliminated detectable SARS-CoV-2 RNA.
Conclusions:
We hope our data will guide further research for evidenced-based decisions for disposable N95 mask reuse and help protect caregivers from SARS-CoV-2 and other pathogens.
The typical onset of schizophrenia coincides with the maturational peak in cognition; however, for a significant proportion of patients the onset is before age 18 and after age 30 years. While cognitive deficits are considered core features of schizophrenia, few studies have directly examined the impact of age of illness onset on cognition.
Methods
The aim of the study was to examine if the effects of age on cognition differ between healthy controls (HCs) and patients with schizophrenia at illness onset. We examined 156 first-episode antipsychotic-naïve patients across a wide age span (12–43 years), and 161 age- and sex-matched HCs. Diagnoses were made according to ICD-10 criteria. Cognition was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS), and IQ was estimated using subtests from the Wechsler adult- or child-intelligence scales. Multivariate analysis of covariance (MANCOVA) was used to examine linear and quadratic effects of age on cognitive scores and interactions by group, including sex and parental socioeconomic status as covariates.
Results
There was a significant overall effect of age on BACS and IQ (p < 0.001). Significant group-by-age interactions for verbal memory (for age-squared, p = 0.009), and digit sequencing (for age, p = 0.01; age-squared, p < 0.001), indicated differential age-related trajectories between patients and HCs.
Conclusions
Cognitive functions showing protracted maturation into adulthood, such as verbal memory and verbal working memory, may be particularly impaired in both early- and late-schizophrenia onset. Our findings indicate a potential interaction between the timing of neurodevelopmental maturation and a possible premature age effect in late-onset schizophrenia.
In January of 2010, North Carolina (NC) USA implemented state-wide Trauma Triage Destination Plans (TTDPs) to provide standardized guidelines for Emergency Medical Services (EMS) decision making. No study exists to evaluate whether triage behavior has changed for geriatric trauma patients.
Hypothesis/Problem:
The impact of the NC TTDPs was investigated on EMS triage of geriatric trauma patients meeting physiologic criteria of serious injury, primarily based on whether these patients were transported to a trauma center.
Methods:
This is a retrospective cohort study of geriatric trauma patients transported by EMS from March 1, 2009 through September 30, 2009 (pre-TTDP) and March 1, 2010 through September 30, 2010 (post-TTDP) meeting the following inclusion criteria: (1) age 50 years or older; (2) transported to a hospital by NC EMS; (3) experienced an injury; and (4) meeting one or more of the NC TTDP’s physiologic criteria for trauma (n = 5,345). Data were obtained from the Prehospital Medical Information System (PreMIS). Data collected included proportions of patients transported to a trauma center categorized by specific physiologic criteria, age category, and distance from a trauma center.
Results:
The proportion of patients transported to a trauma center pre-TTDP (24.4% [95% CI 22.7%-26.1%]; n = 604) was similar to the proportion post-TTDP (24.4% [95% CI 22.9%-26.0%]; n = 700). For patients meeting specific physiologic triage criteria, the proportions of patients transported to a trauma center were also similar pre- and post-TTDP: systolic blood pressure <90 mmHg (22.5% versus 23.5%); respiratory rate <10 or >29 (23.2% versus 22.6%); and Glascow Coma Scale (GCS) score <13 (26.0% versus 26.4%). Patients aged 80 years or older were less likely to be transported to a trauma center than younger patients in both the pre- and post-TTDP periods.
Conclusions:
State-wide implementation of a TTDP had no discernible effect on the proportion of patients 50 years and older transported to a trauma center. Under-triage remained common and became increasingly prevalent among the oldest adults. Research to understand the uptake of guidelines and protocols into EMS practice is critical to improving care for older adults in the prehospital environment.
Experiments with a weakly damped monopile, either fixed or free to oscillate, exposed to irregular waves in deep water, obtain the wave-exciting moment and motion response. The nonlinearity and peak wavenumber cover the ranges: $\unicode[STIX]{x1D716}_{P}\sim 0.10{-}0.14$ and $k_{P}r\sim 0.09{-}0.14$ where $\unicode[STIX]{x1D716}_{P}=0.5H_{S}k_{P}$ is an estimate of the spectral wave slope, $H_{S}$ the significant wave height, $k_{P}$ the peak wavenumber and $r$ the cylinder radius. The response and its statistics, expressed in terms of the exceedance probability, are discussed as a function of the resonance frequency, $\unicode[STIX]{x1D714}_{0}$ in the range $\unicode[STIX]{x1D714}_{0}\sim 3{-}5$ times the spectral peak frequency, $\unicode[STIX]{x1D714}_{P}$. For small wave slope, long waves and $\unicode[STIX]{x1D714}_{0}/\unicode[STIX]{x1D714}_{P}=3$, the nonlinear response deviates only very little from its linear counterpart. However, the nonlinearity becomes important for increasing wave slope, wavenumber and resonance frequency ratio. The extreme response events are found in a region where the Keulegan–Carpenter number exceeds $KC>5$, indicating the importance of possible flow separation effects. A similar region is also covered by a Froude number exceeding $Fr>0.4$, pointing to surface gravity wave effects at the scale of the cylinder diameter. Regarding contributions to the higher harmonic forces, different wave load mechanisms are identified, including: (i) wave-exciting inertia forces, a function of the fluid acceleration; (ii) wave slamming due to both non-breaking and breaking wave events; (iii) a secondary load cycle; and (iv) possible drag forces, a function of the fluid velocity. Also, history effects due to the inertia of the moving pile, contribute to the large response events. The ensemble means of the third, fourth and fifth harmonic wave-exciting force components extracted from the irregular wave results are compared to the third harmonic FNV (Faltinsen, Newman and Vinje) theory as well as other available experiments and calculations. The present irregular wave measurements generalize results obtained in deep water regular waves.
In 785 mother–child (50% male) pairs from a longitudinal epidemiological birth cohort, we investigated associations between inflammation-related epigenetic polygenic risk scores (i-ePGS), environmental exposures, cognitive function, and child and adolescent internalizing and externalizing problems. We examined prenatal and postnatal effects. For externalizing problems, one prenatal effect was found: i-ePGS at birth associated with higher externalizing problems (ages 7–15) indirectly through lower cognitive function (age 7). For internalizing problems, we identified two effects. For a prenatal effect, i-ePGS at birth associated with higher internalizing symptoms via continuity in i-ePGS at age 7. For a postnatal effect, higher postnatal adversity exposure (birth through age 7) associated with higher internalizing problems (ages 7–15) via higher i-ePGS (age 7). Hence, externalizing problems were related mainly to prenatal effects involving lower cognitive function, whereas internalizing problems appeared related to both prenatal and postnatal effects. The present study supports a link between i-ePGS and child and adolescent mental health.
Laboratory experiments with a bottom hinged surface-piercing cylinder, exposed to irregular deep water waves, are used to investigate high-frequency forcing. The focus is on the secondary load cycle, a strongly nonlinear phenomenon regarding the wave load on a vertical cylinder, first identified by Grue et al. (1993 Preprint Series. Mechanics and Applied Mathematics, pp. 1–30. University of Oslo, available at http://urn.nb.no/URN:NBN:no-52740; 1994 Ninth International Workshop on Water Waves and Floating Bodies (ed. M. Ohkusu), pp. 77–81, available at http://iwwwfb.org). For a total of 2166 single wave events, the force above $3\unicode[STIX]{x1D714}$ (where $\unicode[STIX]{x1D714}$ is the governing wave frequency) is used to identify and split the strongly nonlinear forces into two peaks: a high-frequency peak closely correlated in time with the wave crest when the total load is positive and a high-frequency peak defining the secondary load cycle which occurs close in time to the wave zero downcrossing when the total load is negative. The two peaks are studied by regression analysis as a function of either the Keulegan–Carpenter number ($KC$) or the Froude number ($Fr$). Regarding the secondary load cycle, the best correlation is found with $Fr$. The speed of the travelling edge of the undisturbed wave approximates the fluid velocity. A threshold value separating between small and large forces is found for $KC\sim 4$–5, indicating effects of flow separation. Alternatively, the threshold occurs for $Fr\sim 0.3$–0.4, indicating local wave effects at the scale of the cylinder diameter. The findings suggest that both effects are present and important.
Engabreen is an outlet glacier of the Svartisen Ice Cap located in Northern Norway. It is a unique glacier due to the Svartisen Subglacial Laboratory which allows direct access to the glacier bed. In this study, we combine both sub- and supraglacial observations with ice-flow modelling in order to investigate conditions at the bed of Engabreen both spatially and temporally. We use the full-Stokes model Elmer/Ice and satellite-based surface-velocity maps from 2010 and 2014 to infer patterns of basal friction. Direct measurements of basal sliding and deformation of lower layers of the ice are used to adjust the ice viscosity and provide essential input to the setup of our model and influence the interpretation of the results. We find a clear seasonal cycle in the subglacial conditions at the higher elevation region of the study area and discuss this in relation to the subglacial hydrological system. Our results also reveal an area with an overdeepening where basal friction is significantly lower than elsewhere on the glacier all year round. We attribute this to either water pooling at the base, or saturated sediments and increased strain heating at this location which softens the ice further.
This chapter adopts new theoretical insights from cognitive science and dynamic systems theory and employs the notion of “metaphoricity” to explore how metaphor in discourse can be understood more adequately. Relating the ecological turn in cognitive science to metaphor studies and insisting on a unified bio-social perspective, it argues that metaphoricity – if conceptualized within an ecological framework – can offer an alternative to viewing metaphor as primarily social or cognitive. In-depth analyses of two real-life examples analyze metaphoricity as the act of doing metaphor within an interpersonal ecology established by the ongoing and dynamic presence of other people, physical artifacts and sociocultural constraints. Rather than treated as a product of individual minds, metaphor is thus shown to emerge from the dynamics of human dialogue viewed as a complex living system. The chapter focuses especially on how metaphoricity works as a gradable, interactively negotiated phenomenon that is intertwined with affective behaviors and situational affordances.
Smooth brome and Kentucky bluegrass are introduced cool-season perennial grasses known to invade grasslands throughout North America. During the fall of 2005 and spring of 2006, we implemented a restoration study at six native prairie sites in eastern South Dakota that have been invaded by smooth brome and Kentucky bluegrass. Treatments included five herbicide combinations, a fall prescribed burn, and an untreated control to determine the potential of each for renovation of invaded native grasslands. Herbicide treatments tested were sulfosulfuron, imazapyr, imazapic + sulfosulfuron, and imazapyr + imazapic, and were applied in late September 2005 and mid-May 2006. Untreated control plots averaged 64% (± 3.1) smooth brome cover and 38% (± 5.5) Kentucky bluegrass cover after the third growing season. Smooth brome cover in herbicide treated plots ranged from 6 to 23% and Kentucky bluegrass cover ranged from 15 to 35% after the third growing season. Smooth brome cover was 20% (± 2.9) and Kentucky bluegrass cover was 19% (± 4.0) in burned plots after the third growing season. Spring and fall treatments had similar native plant cover after three growing seasons. Spring and fall application of 0.33 kg ai ha−1 imazapyr and 0.10 kg ai ha−1 imazapic + 0.16 kg ai ha−1 imazapyr had ≤ 10% smooth brome cover and increased native species cover after three growing seasons. Herbicides were effective at reducing cover of smooth brome and Kentucky bluegrass, and can be incorporated with other management strategies to restore prairie remnants.
Smooth brome (Bromus inermis) is an introduced, cool-season perennial, sod-forming grass that has been shown to invade both native cool-and warm-season grasslands throughout North America. During the fall of 2005 through spring 2007, we implemented a smooth brome removal study at five sites in eastern South Dakota. Sites were selected to represent a range of soil and environmental conditions. Seven fall herbicide treatments, five spring herbicide treatments, an untreated plot that was planted with a native seed mix, and an untreated control that received no herbicide or seed addition were applied at each location in fall 2005/spring 2006 and fall 2006/spring 2007. Based upon first-year results, three fall herbicide treatments and two spring herbicide treatments were added in fall 2006/spring 2007. Sites were seeded with a native plant mix within 2 wk following spring herbicide treatment. Smooth brome cover in untreated plots ranged from 73 to 99% at the conclusion of the study. Smooth brome cover on herbicide-treated plots ranged from 0 to 84% on 2005/2006 plots and 0 to 98% on 2006/2007 plots after three growing seasons. Native plant response varied by site and treatment, possibly due to competition from exotic weeds. Although several herbicides show promise for control of smooth brome, future response of native plants will be important in determining the proper timing and herbicide combination.