Bringing platform trials closer to reality by enabling with digital research environment (DRE) connectivity.

Platform trials are generally regarded as an innovative approach to address clinical valuation of early stage candidates, regardless of modality as the evidence evolves. As a type of randomized clinical trial (RCT) design construct in which multiple interventions are evaluated concurrently against a common control group allowing new interventions to be added and the control group to be updated throughout the trial, they provide a dynamic and efficient mechanism to compare and potentially discriminate new treatment candidates. Their recent use in the evaluation of new therapies for COVID-19 has spurred new interest in the approach. The paucity of platform trials is less influenced by the novelty and operational requirements as opposed to concerns regarding the sharing of intellectual property (IP) and the lack of infrastructure to operationalize the conduct in the context of IP and data sharing. We provide a mechanism how this can be accomplished through the use of a digital research environment (DRE) providing a safe and secure platform for clinical researchers, quantitative and physician scientists to analyze and develop tools (e.g., models) on sensitive data with the confidence that the data and models developed are protected. A DRE, in this context, expands on the concept of a trusted research environment (TRE) by providing remote access to data alongside tools for analysis in a securely controlled workspace, while allowing data and tools to be findable, accessible, interoperable, and reusable (FAIR), version-controlled, and dynamically grow in size or quality as a result of each treatment evaluated in the trial.

That's out! How expert umpires make leg-before-wicket judgements in cricket.

Despite evidence that elite-level cricket umpires are highly accurate in making leg-before-wicket (LBW) judgements, there is limited understanding as to how they make these judgements. In this study, we explored the explicit LBW decision-making expertise of elite-level cricket umpires (N = 10) via 10 individual semi-structured interviews. Using thematic analysis, we aimed to identify the sources of information that umpires incorporate into their decision-making process. Results indicated that umpires engage in intentional pre-delivery information-gathering to guide their expectations, and to set context-specific parameters as to what would constitute an LBW dismissal. Not only do umpires use information about the ball trajectory, but they also use additional information about the condition of the pitch, the action-capabilities and susceptibilities of players, and the unique requirements of different match formats. Umpires reported employing a gaze-anchor strategy when gathering information for each delivery and described the process of this information as initially intuitive, before engaging in deeper post-hoc reasoning. Findings highlight the importance of including contextual information when exploring officials' decisions and may inform future training interventions for cricket umpires.

Dialect identification, intelligibility ratings, and acceptability ratings of dysarthric speech in two American English dialects.

The current study explored the intelligibility and acceptability ratings of dysarthric speakers with African American English (AAE) and General American English (GAE) dialects by listeners who identify as GAE or AAE speakers, as well as listener ability to identify dialect in dysarthric speech. Eighty-six listeners rated the intelligibility and acceptability of sentences extracted from a passage read by speakers with dysarthria. Samples were used from the Atlanta Motor Speech Disorders Corpus and ratings were collected via self-report. The listeners identified speaker dialect in a forced-choice format. Listeners self-reported their dialect and exposure to AAE. AAE dialect was accurately identified in 63.43% of the the opportunities; GAE dialect was accurately identified in 70.35% of the opportunities. Listeners identifying as AAE speakers rated GAE speech as more acceptable, whereas, listeners identifying as GAE speakers rated AAE speech as more acceptable. Neither group of listeners demonstrated a difference in intelligibility ratings. Exposure to AAE had no effect on intelligibility or acceptability ratings. Listeners can identify dialect (AAE and GAE) with a better than chance degree of accuracy. One's dialect may have an effect on intelligibility and acceptability ratings. Exposure to a dialect did not affect listener ratings of intelligibility or acceptability.

Does the method of telehealth delivery affect the physiotherapy management of adults with bleeding disorders? A comparison of audioconferencing and videoconferencing.

AIM: To determine whether the method of telehealth delivery (audioconferencing or videoconferencing) affects the physiotherapy management of adults with inherited bleeding disorders. METHODS: A cross-sectional observational study was utilised involving 40 physiotherapy consultations (23 initial consultations and 17 follow-up consultations) of adults (>18) with a diagnosed bleeding disorder. Each consultation involved an initial audioconferencing component followed immediately by a separate videoconferencing component. Following each component, the physiotherapist utilised the clinical information gathered to formulate and record a management plan, and additionally recorded their confidence in this plan. Differences between the management plans and clinician confidence were recorded, including where applicable the visual information prompting a change in management plans. RESULTS: Audioconferencing and videoconferencing management plans differed in 40% of all consultations, including 52.0% of initial consultations and 23.5% of follow-up consultations. Among consultations where management plans differed, this was prompted by visual information related to the anatomic location of symptoms (31.3%), the absence/presence of swelling (31.3%), joint range of movement (25.0%), and general appearance (12.5%). Median self-reported clinician confidence of management plans increased significantly from 70.0% following audioconferencing to 93.0% following videoconferencing. CONCLUSION: When utilizing telehealth, the choice between audioconferencing or videoconferencing may affect physiotherapy management of adults with bleeding disorders, particularly with initial consultations. Videoconferencing potentially leads to more appropriate management plans, clinician confidence and utilization of healthcare resources. Further high-quality studies are required to confirm the findings of this study.

The roles of a novel CDKB/KRP/FB3 cell cycle core complex in rice gametes and initiation of embryogenesis.

The cell cycle controls division and proliferation of all eukaryotic cells and is tightly regulated at multiple checkpoints by complexes of core cell cycle proteins. Due to the difficulty in accessing female gametes and zygotes of flowering plants, little is known about the molecular mechanisms underlying embryogenesis initiation despite the crucial importance of this process for seed crops. In this study, we reveal three levels of factors involved in rice zygotic cell cycle control and characterize their functions and regulation. Protein-protein interaction studies, including within zygote cells, and in vitro biochemical analyses delineate a model of the zygotic cell cycle core complex for rice. In this model, CDKB1, a major regulator of plant mitosis, is a cyclin (CYCD5)-dependent kinase; its activity is coordinately inhibited by two cell cycle inhibitors, KRP4 and KRP5; and both KRPs are regulated via F-box protein 3 (FB3)-mediated proteolysis. Supporting their critical roles in controlling the rice zygotic cell cycle, mutations in KRP4, KRP5 and FB3 result in the compromised function of sperm cells and abnormal organization of female germ units, embryo and endosperm, thus significantly reducing seed-set rate. This work helps reveal regulatory mechanisms controlling the zygotic cell cycle toward seed formation in angiosperms.

The future of rare disease drug development: the rare disease cures accelerator data analytics platform (RDCA-DAP).

Rare disease drug development is wrought with challenges not the least of which is access to the limited data currently available throughout the rare disease ecosystem where sharing of the available data is not guaranteed. Most pharmaceutical sponsors seeking to develop agents to treat rare diseases will initiate data landscaping efforts to identify various data sources that might be informative with respect to disease prevalence, patient selection and identification, disease progression and any data projecting likelihood of patient response to therapy including any genetic data. Such data are often difficult to come by for highly prevalent, mainstream disease populations let alone for the 8000 rare disease that make up the pooled patient population of rare disease patients. The future of rare disease drug development will hopefully rely on increased data sharing and collaboration among the entire rare disease ecosystem. One path to achieving this outcome has been the development of the rare disease cures accelerator, data analytics platform (RDCA-DAP) funded by the US FDA and operationalized by the Critical Path Institute. FDA intentions were clearly focused on improving the quality of rare disease regulatory applications by sponsors seeking to develop treatment options for various rare disease populations. As this initiative moves into its second year of operations it is envisioned that the increased connectivity to new and diverse data streams and tools will result in solutions that benefit the entire rare disease ecosystem and that the platform becomes a Collaboratory for engagement of this ecosystem that also includes patients and caregivers.

Digital Research Environment(DRE)-enabled Artificial Intelligence (AI) to facilitate early stage drug development.

Early-stage drug discovery is highly dependent upon drug target evaluation, understanding of disease progression and identification of patient characteristics linked to disease progression overlaid upon chemical libraries of potential drug candidates. Artificial intelligence (AI) has become a credible approach towards dealing with the diversity and volume of data in the modern drug development phase. There are a growing number of services and solutions available to pharmaceutical sponsors though most prefer to constrain their own data to closed solutions given the intellectual property considerations. Newer platforms offer an alternative, outsourced solution leveraging sponsors data with other, external open-source data to anchor predictions (often proprietary algorithms) which are refined given data indexed upon the sponsor's own chemical libraries. Digital research environments (DREs) provide a mechanism to ingest, curate, integrate and otherwise manage the diverse data types relevant for drug discovery activities and also provide workspace services from which target sharing and collaboration can occur providing yet another alternative with sponsors being in control of the platform, data and predictive algorithms. Regulatory engagement will be essential in the operationalizing of the various solutions and alternatives; current treatment of drug discovery data may not be adequate with respect to both quality and useability in the future. More sophisticated AI/ML algorithms are likely based on current performance metrics and diverse data types (e.g., imaging and genomic data) will certainly be a more consistent part of the myriad of data types that fuel future AI-based algorithms. This favors a dynamic DRE-enabled environment to support drug discovery.

Resetting of the 24-nt siRNA landscape in rice zygotes.

The zygote, a totipotent stem cell, is crucial to the life cycle of sexually reproducing organisms. It is produced by the fusion of two differentiated cells-the egg and sperm, which in plants have radically different siRNA transcriptomes from each other and from multicellular embryos. Owing to technical challenges, the epigenetic changes that accompany the transition from differentiated gametes to totipotent zygote are poorly understood. Because siRNAs serve as both regulators and outputs of the epigenome, we characterized small RNA transcriptomes of zygotes from rice. Zygote small RNAs exhibit extensive maternal carryover and an apparent lack of paternal contribution, indicated by absence of sperm signature siRNAs. Zygote formation is accompanied by widespread redistribution of 24-nt siRNAs relative to gametes, such that ∼70% of the zygote siRNA loci do not overlap any egg cell siRNA loci. Newly detected siRNA loci in zygote are gene-proximal and not associated with centromeric heterochromatin, similar to canonical siRNAs, in sharp contrast to gametic siRNA loci that are gene-distal and heterochromatic. In addition, zygote but not egg siRNA loci are associated with high DNA methylation in the mature embryo. Thus, the zygote begins transitioning before the first embryonic division to an siRNA profile that is associated with future RdDM in embryogenesis. These findings indicate that, in addition to changes in gene expression, the transition to totipotency in the plant zygote is accompanied by resetting of the epigenetic reprogramming that occurred during gamete formation.

Clinical considerations in providing intravenous sedation with midazolam for obese patients in dentistry.

The widespread prevalence of obesity continues to rise. Obesity and dental disease share common risk factors and so the demand for dental care for obese patients is escalating. For some of these patients, there is a corresponding need to be able to provide intravenous sedation safely when it is necessary and appropriate to do so. However, obesity often presents with multiple comorbidities and airway complexities, leading to more challenging management and potentially increased risk. The risk assessment process as well as patient monitoring and management strategies will be explored in this article. By reviewing the literature from dentistry and other medical specialties, we also aim to establish the potential benefit in administering supplemental oxygen and the use of capnography in monitoring this cohort of patients.

An exploratory study of student, speech-language pathologist and emergency worker impressions of speakers with dysarthria.

PURPOSE: To explore the influence of listener profession on impressions of speakers with dysarthria with varying intelligibility using semantic differential scales. Method: Three listener groups (undergraduate students, emergency workers, speech-language pathologists (SLPs); n = 38) rated non-speech attributes of six adults with dysarthria that ranged from low to high speech intelligibility. Participants rated 22 bipolar adjective pairs and listening effort on visual analogue scales. Following factor analysis of the semantic differential scales, listener impression and effort ratings were compared across listening groups and speaker intelligibility. RESULT: Repeated measures ANOVA revealed that neither impressions nor effort ratings differed across listener groups. However, impressions significantly decreased and listening effort significantly increased with reduced intelligibility. Analysis of the semantic differential scale items revealed two factors (Capability, Personality) that predicted 52% of the variance. Listener impressions were significantly higher for Personality than Capability. Conclusion: Preliminary findings suggest that speakers with dysarthria with reduced intelligibility are at risk to be negatively judged, particularly on their physical and mental capability. This study demonstrates the promise of employing semantic differential scales to investigate listener impressions and therefore the daily communication experiences of speakers with dysarthria. SLPs should consider patient experience of negative impressions when designing treatment.

Genome-wide redistribution of 24-nt siRNAs in rice gametes.

Gametes constitute a critical stage of the plant life cycle during which the genome undergoes reprogramming in preparation for embryogenesis. Here, we examined genome-wide distributions of small RNAs in the sperm and egg cells of rice. We found that 24-nt siRNAs, which are a hallmark of RNA-directed DNA methylation (RdDM) in plants, were depleted from heterochromatin boundaries in both gametes relative to vegetative tissues, reminiscent of siRNA patterns in DDM1-type nucleosome remodeler mutants. In sperm cells, 24-nt siRNAs were spread across heterochromatic regions, while in egg cells, 24-nt siRNAs were concentrated at a smaller number of heterochromatic loci throughout the genome, especially at loci which also produced siRNAs in other tissues. In both gametes, patterns of CHH methylation, typically a strong indicator of RdDM, were similar to vegetative tissues, although lower in magnitude. These findings indicate that the small RNA transcriptome undergoes large-scale redistribution in both male and female gametes, which is not correlated with recruitment of DNA methyltransferases in gametes and suggestive of unexplored regulatory activities of gamete small RNAs.

Step-by-step protocols for rice gamete isolation.

KEY MESSAGE: A detailed, step-by-step protocol for isolation of rice gametes for transcriptional profiling, with a general workflow that includes controls for RNA contamination from surrounding cells and tissues is presented. Characterization of the transcriptome and other -omics studies of flowering plant gametes are challenging as a consequence of the small sizes and relative inaccessibility of these cells. Collecting such poorly represented cells is also complicated by potential contamination from surrounding sporophytic, adjacent gametophytic tissues and difficulties in extracting high-quality intact cells. Here we present detailed, step-by-step procedures for collecting intact, unfixed rice (Oryza sativa) egg cells and sperm cells without enzymatic treatments. In addition, we also present a general workflow for assessing sample purity by RT-PCR, using primers specific for marker genes preferentially expressed in surrounding cells and tissues. These protocols should facilitate future studies of genome-scale characterization of gametes in this important model crop.

Understanding the Constipation Conundrum: Predictors of Obtaining an Abdominal Radiograph During the Emergency Department Evaluation of Pediatric Constipation.

OBJECTIVES: Many children with constipation who are evaluated in emergency departments (EDs) receive an abdominal radiograph (AR) despite evidence-based guidelines discouraging imaging. The objectives of this study were to identify predictors associated with obtaining an AR and to determine if ARs were associated with a longer length of stay (LOS) among children with constipation evaluated in the ED. METHODS: A review of billing and electronic health records was conducted in an academic pediatric ED for children ages 0 to 17 years who had a primary discharge diagnosis of constipation from July 2013 to June 2014. Logistic regression was used to identify predictors for obtaining an AR. Differences in mean LOS were analyzed using linear regression. RESULTS: In total, 326 children met inclusion criteria, and 60% of the children received an AR. In logistic regression, significant predictors included age (odds ratio [OR] = 1.1/year of age, P = 0.004), presenting with abdominal pain as chief complaint compared with constipation (OR = 4.4, P < 0.0001), and history of emesis (OR = 2.8, P = 0.001) after controlling for provider type and previous constipation medication use. In linear regression, the adjusted mean LOS for those with an AR was 163 minutes compared with 117 minutes for those without after controlling for age, provider type, and history of constipation medication use (P < 0.0001). CONCLUSIONS: Abdominal radiographs were used frequently in the ED diagnosis and management of constipation, particularly in older children and those with abdominal pain and emesis. Abdominal radiographs were associated with increased LOS.

Identification of Affective State Change in Adults With Aphasia Using Speech Acoustics.

Purpose: The current study aimed to identify objective acoustic measures related to affective state change in the speech of adults with post-stroke aphasia. Method: The speech of 20 post-stroke adults with aphasia was recorded during picture description and administration of the Western Aphasia Battery-Revised (Kertesz, 2006). In addition, participants completed the Self-Assessment Manikin (Bradley & Lang, 1994) and the Stress Scale (Tobii Dynavox, 1981-2016) before and after the language tasks. Speech from each participant was used to detect a change in affective state test scores between the beginning and ending speech. Results: Machine learning revealed moderate success in classifying depression, minimal success in predicting depression and stress numeric scores, and minimal success in classifying changes in affective state class between the beginning and ending speech. Conclusions: The results suggest the existence of objectively measurable aspects of speech that may be used to identify changes in acute affect from adults with aphasia. This work is exploratory and hypothesis-generating; more work will be needed to make conclusive claims. Further work in this area could lead to automated tools to assist clinicians with their diagnoses of stress, depression, and other forms of affect in adults with aphasia.

The Zygotic Transition Is Initiated in Unicellular Plant Zygotes with Asymmetric Activation of Parental Genomes.

The zygotic transition, from a fertilized egg to an embryo, is central to animal and plant reproduction. Animal embryos depend upon maternally provided factors until zygotic genome activation (ZGA). In plants, the timing and parental genome contributions to ZGA are unresolved. Here, we use the flowering plant Oryza sativa (rice) to characterize transcriptomes of time-staged isogenic and hybrid zygotes following fertilization. Large-scale transcriptomic changes were observed in unicellular zygotes, including upregulation of S-phase genes, a characteristic of ZGA. The parental contributions to ZGA were highly asymmetric. Zygotic transcription was primarily from the maternal genome and included genes for basic cellular processes. Transcription of the paternal genome was highly restricted but unexpectedly included genes encoding putative pluripotency factors expressed at the onset of ZGA. Thus, distinct transcriptional activities are exhibited by the parental genomes during the initiation of embryogenesis, which presumptively derive from divergent pre-zygotic transcriptional states established in the gametes.

Isolation of Rice Sperm Cells for Transcriptional Profiling.

The male germline of flowering plants displays unexpectedly divergent transcriptional profiles compared to other cell types and tissues of plants. As these are among the smallest cells, and are harbored within pollen, isolating a pure collection of germline RNA presents unusual challenges. The sperm cells of rice represent a particularly challenging subject for study as the pollen are unusually short lived upon release from the anther, and the marker gene sequences that make FACS possible in Arabidopsis have not yet been introduced into rice. The purity of the germline samples requires careful collection because of the limited amount of material available and potential contamination by other nearby tissues, pollen, and RNases. A discontinuous Percoll density gradient centrifuge was developed to isolate and obtain enough rice sperm cells for RNA-seq or microarray analysis.

The GmFWL1 (FW2-2-like) nodulation gene encodes a plasma membrane microdomain-associated protein.

The soybean gene GmFWL1 (FW2-2-like1) belongs to a plant-specific family that includes the tomato FW2-2 and the maize CNR1 genes, two regulators of plant development. In soybean, GmFWL1 is specifically expressed in root hair cells in response to rhizobia and in nodules. Silencing of GmFWL1 expression significantly reduced nodule numbers supporting its role during soybean nodulation. While the biological role of GmFWL1 has been described, its molecular function and, more generally, the molecular function of plant FW2-2-like proteins is unknown. In this study, we characterized the role of GmFWL1 as a membrane microdomain-associated protein. Specifically, using biochemical, molecular and cellular methods, our data show that GmFWL1 interacts with various proteins associated with membrane microdomains such as remorin, prohibitins and flotillins. Additionally, comparative genomics revealed that GmFWL1 interacts with GmFLOT2/4 (FLOTILLIN2/4), the soybean ortholog to Medicago truncatula FLOTILLIN4, a major regulator of the M. truncatula nodulation process. We also observed that, similarly to MtFLOT4 and GmFLOT2/4, GmFWL1 was localized at the tip of the soybean root hair cells in response to rhizobial inoculation supporting the early function of GmFWL1 in the rhizobium infection process.

Stress and depression scales in aphasia: relation between the aphasia depression rating scale, stroke aphasia depression questionnaire-10, and the perceived stress scale.

BACKGROUND: Assessment and diagnosis of post-stroke depression (PSD) among patients with aphasia presents unique challenges. A gold standard assessment of PSD among this population has yet to be identified. OBJECTIVES: The first aim was to investigate the association between two depression scales developed for assessing depressive symptoms among patients with aphasia. The second aim was to evaluate the relation between these scales and a measure of perceived stress. METHOD: Twenty-five (16 male; 9 female) individuals with history of left hemisphere cerebrovascular accident (CVA) were assessed for depression and perceived stress using the Stroke Aphasic Depression Questionnaire-10 (SADQ-10), the Aphasia Depression Rating Scale (ADRS), and the Perceived Stress Scale (PSS). RESULTS: SADQ-10 and ADRS ratings were strongly correlated with each other (r = 0.708, p < 0.001). SADQ-10 ratings were strongly correlated with PSS ratings (r = 0.620, p = 0.003), while ADRS ratings were moderately correlated (r = 0.492, p = 0.027). Item analysis of each scale identified items which increased both inter-scale correlation and intra-scale consistency when excluded. CONCLUSIONS: The SADQ-10 and ADRS appear to be acceptable measures of depressive symptoms in aphasia patients. Measurements of perceived stress may also be an important factor in assessment of depressive symptoms.

The Atlanta Motor Speech Disorders Corpus: Motivation, Development, and Utility.

BACKGROUND/AIMS: This paper describes the design and collection of a comprehensive spoken language dataset from speakers with motor speech disorders in Atlanta, Ga., USA. This collaborative project aimed to gather a spoken database consisting of nonmainstream American English speakers residing in the Southeastern US in order to provide a more diverse perspective of motor speech disorders. METHODS: Ninety-nine adults with an acquired neurogenic disorder resulting in a motor speech disorder were recruited. Stimuli include isolated vowels, single words, sentences with contrastive focus, sentences with emotional content and prosody, sentences with acoustic and perceptual sensitivity to motor speech disorders, as well as 'The Caterpillar' and 'The Grandfather' passages. RESULTS: Utility of this data in understanding the potential interplay of dialect and dysarthria was demonstrated with a subset of the speech samples existing in the database. CONCLUSION: The Atlanta Motor Speech Disorders Corpus will enrich our understanding of motor speech disorders through the examination of speech from a diverse group of speakers.

A Prospective, Single Arm, Multi-site, Clinical Evaluation of a Nonradioactive Surgical Guidance Technology for the Location of Nonpalpable Breast Lesions during Excision.

OBJECTIVES: This study was a multicenter evaluation of the SAVI SCOUT(®) breast localization and surgical guidance system using micro-impulse radar technology for the removal of nonpalpable breast lesions. The study was designed to validate the results of a recent 50-patient pilot study in a larger multi-institution trial. The primary endpoints were the rates of successful reflector placement, localization, and removal. METHODS: This multicenter, prospective trial enrolled patients scheduled to have excisional biopsy or breast-conserving surgery of a nonpalpable breast lesion. From March to November 2015, 154 patients were consented and evaluated by 20 radiologists and 16 surgeons at 11 participating centers. Patients had SCOUT(®) reflectors placed up to 7 days before surgery, and placement was confirmed by mammography or ultrasonography. Implanted reflectors were detected by the SCOUT(®) handpiece and console. Presence of the reflector in the excised surgical specimen was confirmed radiographically, and specimens were sent for routine pathology. RESULTS: SCOUT(®) reflectors were successfully placed in 153 of 154 patients. In one case, the reflector was placed at a distance from the target that required a wire to be placed. All 154 lesions and reflectors were successfully removed during surgery. For 101 patients with a preoperative diagnosis of cancer, 86 (85.1 %) had clear margins, and 17 (16.8 %) patients required margin reexcision. CONCLUSIONS: SCOUT(®) provides a reliable and effective alternative method for the localization and surgical excision of nonpalpable breast lesions using no wires or radioactive materials, with excellent patient, radiologist, and surgeon acceptance.