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Extracellular vesicles (EVs), or exosomes, play important roles in physiological and pathological cellular communication and have gained substantial traction as biological drug carriers. EVs contain both short and long non-coding RNAs that regulate gene expression and epigenetic processes. To fully capitalize on the potential of EVs as drug carriers, it is important to study and understand the intricacies of EV function and EV RNA-based communication. Here we developed a genetically encodable RNA-based biomaterial, termed EXO-Probe, for tracking EV RNAs. The EXO-Probe comprises an EV-loading RNA sequence (EXO-Code), fused to a fluorogenic RNA Mango aptamer for RNA imaging. This fusion construct allowed the visualization and tracking of EV RNA and colocalization with markers of multivesicular bodies; imaging RNA within EVs, and non-destructive quantification of EVs. Overall, the new RNA-based biomaterial provides a useful and versatile means to interrogate the role of EVs in cellular communication via RNA trafficking to EVs and to study cellular sorting decisions. The system will also help lay the foundation to further improve the therapeutic efficacy of EVs as drug carriers.

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Most firearm related homicides involve the deceased being forensically examined within a day or two, however, there are times when bodies have been examined and the fired components removed several days or weeks after death, when the body is in an active or advanced state of decomposition. In these cases, ballistic investigation has been found to be complicated due to the damage to the bullets, however the extent of this is not yet known. To date, there have been no studies investigating the effect of human decomposition and the subsequent analysis of bullets lodged in the body in an Australian context. Herein, seven fired copper jacketed bullets were manually inserted into three specific tissue types; lungs, abdomen and leg muscle (twenty-one bullets in total), of human donors in both cool and warm conditions at the Australian Facility for Taphonomic Experimental Research (AFTER). Bullets were removed every three days for a period of twenty-one days, and each bullet underwent manual microscopic examinations by firearms examiners across Australia. Results have indicated that the bullets corrode quickly in warm conditions, compared to bullets exposed to decomposition in cooler conditions. The results of this study will inform investigators and pathologists of the need to remove and examine fired bullets from decomposed bodies as soon as possible, especially in warm conditions to provide firearms examiners with the best opportunity to link fired bullets to a common source.

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Forensic toolmark examiners compare marks between those observed on an item/surface and those made by a reference implement, such as a particular tool or weapon, to provide an opinion of the likelihood of common origin. It is widely accepted that such comparison opinions need to be underpinned by empirical research, and this study aimed to add to the knowledge base relied upon when developing and comparing saw marks in bone, a substrate encountered in body dismemberment cases. Porcine bones were used as a human proxy; they were either fresh with residual soft tissue and bodily fluids present ('wet') to replicate dismembered bones shortly post-mortem, or processed to remove soft tissue and moisture content ('dry') to represent cases of dismemberment after an extended period of decomposition and exposure. The bones were cut using one implement of each of five classes: hand saw, mitre saw, reciprocating saw, oscillating saw, and serrated knife. They were cut, either completely through (except for serrated knife), giving two surfaces per cut to examine, or to a depth up to 3 mm (false starts). Five replicates per combination of bone condition, saw, and cut type gave 130 bone samples. These were then cleaned and cast using Isomark Silicone Polymer Compound or Mikrosil, giving 260 cast samples. All bone and cast samples were photographed, examined for various class characteristic markers, and specific markers measured. No significant differences between Isomark and Mikrosil casts were observed when compared side-by-side, demonstrating suitability of both materials for casting of saw marks on bone. Although saw marks presented more class characteristic markers on dry than wet bones, calculations of tooth distances and measurements of kerf width (KW) from marks did not significantly differ between bone conditions, with exception of the reciprocating saw that produced false start marks with significantly larger minimum KW on wet than dry samples. Further analysis supported that tooth distances on marks made by hand and oscillating saws are sufficiently accurate for the determination of saw teeth per inch (TPI). However, one tooth distance on marks made by reciprocating saws did not accurately represent TPI. Finally, examination of presence or absence of class characteristic markers on each saw mark demonstrated consistent variation between saw classes. These results enabled the development of exclusion-based decision trees, and a reference database (available on request), for use by toolmark examiners in their evaluation of saw types based on class characteristic markers observed in cut bone.

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INTRODUCTION: Problems that worry patients throughout hospitalization are complex and varied, but they fall within the scope of safe, effective, patient-centered care. To our knowledge, there is no evidence describing the problems that worry patients in inpatient psychiatric units. AIM: The purpose of this quality improvement project was to describe common themes of worry experienced by individuals in psychiatric inpatient units in order to improve patient experience. METHOD: This project took place at an urban, safety net hospital at an academic medical center in the northeastern United States between March and December 2019. All patients across five inpatient psychiatric units were offered the Combined Assessment of Psychiatric Environments (CAPE) survey as they approached the end of their stay. RESULTS: A total of 1,800 patients took the survey. Of these patients, 36% (650/1,800) patients responded never/sometimes to "During my hospitalization, I found solutions to problems that worried me," and 46% (297/650) patients provided a response to the follow-up question "What are the problems that worry you the most?" Common themes of worry for inpatient behavioral health patients include (a) life in the hospital, (b) self, and (c) outside life. CONCLUSIONS: Each of these worry themes that emerged from this thematic analysis has implications for behavioral health staff who are preparing the psychiatric/behavioral health inpatient for discharge. These themes can also be used to focus on a variety of quality improvement initiatives to improve the patients experience while in an inpatient psychiatric/behavioral health unit.

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OBJECTIVE: In this work, we systematically evaluated the reserved alarm sounds of the IEC 60601-1-8 international medical alarm standard to determine when and how they can be totally and partially masked. BACKGROUND: IEC 60601-1-8 gives engineers instruction for creating human-perceivable auditory medical alarms. This includes reserved alarm sounds: common types of alarms where each is a tonal melody. Even when this standard is honored, practitioners still fail to hear alarms, causing practitioner nonresponse and, thus, potential patient harm. Simultaneous masking, a condition where one or more alarms is imperceptible in the presence of other concurrently sounding alarms due to limitations of the human sensory system, is partially responsible for this. METHODS: In this research, we use automated proof techniques to determine if masking can occur in a modeled configuration of medical alarms. This allows us to determine when and how reserved alarm sound can mask other reserved alarms and to explore parameters to address discovered problems. RESULTS: We report the minimum number of other alarm sounds it takes to both totally and partially mask each of the high-, medium-, and low-priority alarm sounds from the standard. CONCLUSIONS: Significant masking problems were found for both the total and partial masking of high-, medium-, and low-priority reserved alarm sounds. APPLICATION: We show that discovered problems can be mitigated by setting alarm volumes to standard values based on priority level and by randomizing the timing of alarm tones.

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Stress hyperglycemia (SH) is a manifestation of altered glucose metabolism in acutely ill patients which worsens outcomes and may represent a risk factor for diabetes. Continuity of care can assess this risk, which depends on quality of hospital clinical documentation. We aimed to determine the incidence of SH and documentation tendencies in hospital discharge summaries and continuity notes. We retrospectively examined diagnoses during a 12-months period. A 3-months representative sample of discharge summaries and continuity clinic notes underwent manual abstraction. Over 12-months, 495 admissions had ≥ 2 blood glucose measurements ≥ 10 mmol/L (180 mg/dL), which provided a SH incidence of 3.3%. Considering other glucose states suggestive of SH, records showing ≥ 4 blood glucose measurements ≥ 7.8 mmol/L (140 mg/dL) totaled 521 admissions. The entire 3-months subset of 124 records lacked the diagnosis SH documentation in discharge summaries. Only two (1.6%) records documented SH in the narrative of hospital summaries. Documentation or assessment of SH was absent in all ambulatory continuity notes. Lack of documentation of SH contributes to lack of follow-up after discharge, representing a disruptor of optimal care. Activities focused on improving quality of hospital documentation need to be integral to the education and competency of providers within accountable health systems.

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INTRODUCTION: Innovative approaches are needed to design robust clinical decision support (CDS) to optimize hospital glycemic management. We piloted an electronic medical record (EMR), evidence-based algorithmic CDS tool in an academic center to alert clinicians in real time about gaps in care related to inpatient glucose control and insulin utilization, and to provide management recommendations. RESEARCH DESIGN AND METHODS: The tool was designed to identify clinical situations in need for action: (1) severe or recurrent hyperglycemia in patients with diabetes: blood glucose (BG) ≥13.88 mmol/L (250 mg/dL) at least once or BG ≥10.0 mmol/L (180 mg/dL) at least twice, respectively; (2) recurrent hyperglycemia in patients with stress hyperglycemia: BG ≥10.0 mmol/L (180 mg/dL) at least twice; (3) impending or established hypoglycemia: BG 3.9-4.4 mmol/L (70-80 mg/dL) or ≤3.9 mmol/L (70 mg/dL); and (4) inappropriate sliding scale insulin (SSI) monotherapy in recurrent hyperglycemia, or anytime in patients with type 1 diabetes. The EMR CDS was active (ON) for 6 months for all adult hospital patients and inactive (OFF) for 6 months. We prospectively identified and compared gaps in care between ON and OFF periods. RESULTS: When active, the hospital CDS tool significantly reduced events of recurrent hyperglycemia in patients with type 1 and type 2 diabetes (3342 vs 3701, OR=0.88, p=0.050) and in patients with stress hyperglycemia (288 vs 506, OR=0.60, p<0.001). Hypoglycemia or impending hypoglycemia (1548 vs 1349, OR=1.15, p=0.050) were unrelated to the CDS tool on subsequent analysis. Inappropriate use of SSI monotherapy in type 1 diabetes (10 vs 22, OR=0.36, p=0.073), inappropriate use of SSI monotherapy in type 2 diabetes (2519 vs 2748, OR=0.97, p=0.632), and in stress hyperglycemia subjects (1617 vs 1488, OR=1.30, p<0.001) were recognized. CONCLUSION: EMR CDS was successful in reducing hyperglycemic events among hospitalized patients with dysglycemia and diabetes, and inappropriate insulin use in patients with type 1 diabetes.

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Background: Inhaled corticosteroids (ICS) produce local effects on upper airway dilators that could increase the risk of developing obstructive sleep apnea (OSA). Given that the particle size of ICS changes their distribution, the particle size of ICS may impact the risk of developing OSA. Objectives: In this large retrospective study, we explore the relationship of ICS use and OSA in patients with asthma. In addition, we seek to determine if this relationship is affected by the particle size of ICS. Methods: Using electronic health records, we established a cohort of 29,816 asthmatics aged 12 and older with a diagnosis of asthma documented by ICD-9 or ICD-10 codes between January 2011 and August 2016. We performed analyses of variance and multivariate logistic regression analysis to determine the effects ICS on the diagnosis of OSA with sub-analysis by particle size of ICS. Results: Uncontrolled asthmatics showed increased odds of receiving a diagnosis of OSA whether when looking at ACT scores (adjusted odds ratio (aOR) 1.60, 95% CI 1.32-1.94) or PFT results (aOR 1.45, 95% CI 1.19-1.77). Users of ICS also had increased odds of OSA independent of asthma control (aOR 1.58, 95% CI 1.47-1.70). Notably, users of extra-fine particle ICS did not have significantly increased odds of having OSA compared to non-users of ICS (aOR 1.11, 95% CI 0.78-1.58). Conclusions: Use of ICS appears to be an independent risk factor for OSA. Notably, extra-fine particle size ICS do not appear to be associated with an increased risk of OSA.

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It is widely recognized that public health interventions benefit from community engagement and leadership, yet there are challenges to evaluating complex, community-led interventions assuming hierarchies of evidence derived from laboratory experimentation and clinical trials. Particular challenges include, first, the inconsistency of the intervention across sites and, second, the absence of researcher control over the sampling frame and methodology. This report highlights these challenges as they played out in the evaluation of a community-organized health project in South London. The project aimed to benefit maternal mental health, health literacy, and social capital, and especially to engage local populations known to have reduced contact with statutory services. We evaluated the project using two studies with different designs, sampling frames, and methodologies. In one, the sampling frame and methodology were under community control, permitting a comparison of change in outcomes before and after participation in the project. In the other, the sampling frame and methodology were under researcher control, permitting a case-control design. The two evaluations led to different results, however: participants in the community-controlled study showed benefits, while participants in the researcher-controlled study did not. The principal conclusions are that while there are severe challenges to evaluating a community-led health intervention using a controlled design, the measurement of pre-/post-participation changes in well-defined health outcomes should typically be a minimum evaluation requirement, and confidence in attributing causation of any positive changes to participation can be increased by use of interventions in the project and in the engagement process itself that have a credible theoretical and empirical basis.

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Social adversity can significantly influence the wellbeing of mothers and their children. Maternal health may be improved through strengthened support networks and better health literacy. Health improvement at the population level requires optimizing of the collaboration between statutory health services, civic organizations (e.g., churches, schools), as well as community groups and parents. Two key elements in improving community engagement are co-production and community control. This study evaluated a co-produced and community-led project, PACT (Parents and Communities Together), for mothers in a deprived south London borough. The project offered social support and health education. Intended effects were improvements in mental health, health literacy, and social support, assessed by standardized measures in a pre-post design. Sixty-one mothers consented to take part in the evaluation. Significant improvements were found in mental health measures, in health literacy, for those with low literacy at baseline, and in overall and some specific aspects of social support. Satisfaction with the project was high. We found that the project engaged local populations that access statutory health services relatively less. We conclude that community-organized and community-led interventions in collaboration with statutory health services can increase accessibility and can improve mothers' mental health and other health-related outcomes.

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OBJECTIVE: This research investigated whether the psychoacoustics of simultaneous masking, which are integral to a model-checking-based method, previously developed for detecting perceivability problems in alarm configurations, could predict when IEC 60601-1-8-compliant medical alarm sounds are audible. BACKGROUND: The tonal nature of sounds prescribed by IEC 60601-1-8 makes them potentially susceptible to simultaneous masking: where concurrent sounds render one or more inaudible due to human sensory limitations. No work has experimentally assessed whether the psychoacoustics of simultaneous masking accurately predict IEC 60601-1-8 alarm perceivability. METHOD: In two signal detection experiments, 28 nursing students judged whether alarm sounds were present in collections of concurrently sounding standard-compliant tones. The first experiment used alarm sounds with single-frequency (primary harmonic) tones. The second experiment's sounds included the additional, standard-required frequencies (often called subharmonics). T tests compared miss, false alarm, sensitivity, and bias measures between masking and nonmasking conditions and between the two experiments. RESULTS: Miss rates were significantly higher and sensitivity was significantly lower for the masking condition than for the nonmasking one. There were no significant differences between the measures of the two experiments. CONCLUSION: These results validate the predictions of the psychoacoustics of simultaneous masking for medical alarms and the masking detection capabilities of our method that relies on them. The results also show that masking of an alarm's primary harmonic is sufficient to make an alarm sound indistinguishable. APPLICATION: Findings have profound implications for medical alarm design, the international standard, and masking detection methods.

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This paper discusses the process of retrieval and updating legacy data to allow on-line discovery and delivery. There are many pitfalls of institutional and non-institutional ecological data conservation over the long term. Interruptions to custodianship, old media, lost knowledge and the continuous evolution of species names makes resurrection of old data challenging. We caution against technological arrogance and emphasise the importance of international standards. We use a case study of a compiled set of continent-wide vegetation survey data for which, although the analyses had been published, the raw data had not. In the original study, publications containing plot data collected from the 1880s onwards had been collected, interpreted, digitised and integrated for the classification of vegetation and analysis of its conservation status across Australia. These compiled data are an extremely valuable national collection that demanded publishing in open, readily accessible online repositories, such as the Terrestrial Ecosystem Research Network (http://www.tern.org.au) and the Atlas of Living Australia (ALA: http://www.ala.org.au), the Australian node of the Global Biodiversity Information Facility (GBIF: http://www.gbif.org). It is hoped that the lessons learnt from this project may trigger a sober review of the value of endangered data, the cost of retrieval and the importance of suitable and timely archiving through the vicissitudes of technological change, so the initial unique collection investment enables multiple re-use in perpetuity.

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BACKGROUND: Type 2 diabetes mellitus (T2DM) and obesity are syndemic and will have a significant impact on affected individuals and healthcare services worldwide. Evidence shows that T2DM remission can be achieved with significant weight loss in those who are younger with early diabetes and requiring fewer medications for glycaemic control. DIADEM-I aims to examine the impact of an intensive lifestyle intervention (ILI) using a low-energy diet (LED) meal replacement approach combined with physical activity in younger individuals with early T2DM. METHODS: The planned study is an ongoing, non-blinded, pragmatic, randomised controlled, parallel-group trial examining the impact of an LED-based ILI on body weight and diabetes remission in younger (18-50 years) T2DM individuals with early diabetes (≤ 3-year duration). The ILI will be compared to usual medical care (UMC). The primary outcome will be weight loss at 12 months. Other key outcomes of interest include diabetes remission, glycaemic control, diabetes complications, cardiovascular health, physical activity, mental health, and quality of life. It is planned for the study to include 138 subjects for assessment of the primary outcome. Safety will be assessed throughout. DISCUSSION: If DIADEM-I demonstrates a clinically significant effect for younger individuals with early T2DM, it will inform clinical guidelines and services of the future for management of T2DM. TRIAL REGISTRATION: ISRCTN: ISRCTN20754766 (date assigned: 7 June 2017); ClinicalTrials.gov, ID: NCT03225339 Registered on 26 June 2017.

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The failure of humans to respond to auditory medical alarms has resulted in numerous patient injuries and deaths and is thus a major safety concern. A relatively understudied source of response failures has to do with simultaneous masking, a condition where concurrent sounds interact in ways that make one or more of them imperceptible due to physical limitations of human perception. This paper presents a method, which builds on a previous implementation, that uses a novel combination of psychophysical modeling and formal verification with model checking to detect masking in a modeled configuration of medical alarms. Specifically, the new method discussed here improves the original method by adding the ability to detect additive masking while concurrently improving method usability and scalability. This paper describes how these additions to our method were realized. It then demonstrates the scalability and detection improvements via three different case studies. Results and future research are discussed.

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BACKGROUND: The importance of community engagement in health is widely recognized, and key themes in UK National Institute for Health and Clinical Excellence (NICE) recommendations for enhancing community engagement are co-production and community control. This study reports an innovative approach to community engagement using the community-organizing methodology, applied in an intervention of social support to increase social capital, reduce stress and improve well-being in mothers who were pregnant and/or with infants aged 0-2 years. METHODS: Professional community organizers in Citizens-UK worked with local member civic institutions in south London to facilitate social support to a group of 15 new mothers. Acceptability of the programme, adherence to principles of co-production and community control, and changes in the outcomes of interest were assessed quantitatively in a quasi-experimental design. RESULTS: The programme was found to be feasible and acceptable to participating mothers, and perceived by them to involve co-production and community control. There were no detected changes in subjective well-being, but there were important reductions in distress on a standard self-report measure (GHQ-12). There were increases in social capital of a circumscribed kind associated with the project. CONCLUSIONS: Community organizing provides a promising model and method of facilitating community engagement in health.

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Breakdowns in complex systems often occur as a result of system elements interacting in unanticipated ways. In systems with human operators, human-automation interaction associated with both normative and erroneous human behavior can contribute to such failures. Model-driven design and analysis techniques provide engineers with formal methods tools and techniques capable of evaluating how human behavior can contribute to system failures. This paper presents a novel method for automatically generating task analytic models encompassing both normative and erroneous human behavior from normative task models. The generated erroneous behavior is capable of replicating Hollnagel's zero-order phenotypes of erroneous action for omissions, jumps, repetitions, and intrusions. Multiple phenotypical acts can occur in sequence, thus allowing for the generation of higher order phenotypes. The task behavior model pattern capable of generating erroneous behavior can be integrated into a formal system model so that system safety properties can be formally verified with a model checker. This allows analysts to prove that a human-automation interactive system (as represented by the model) will or will not satisfy safety properties with both normative and generated erroneous human behavior. We present benchmarks related to the size of the statespace and verification time of models to show how the erroneous human behavior generation process scales. We demonstrate the method with a case study: the operation of a radiation therapy machine. A potential problem resulting from a generated erroneous human action is discovered. A design intervention is presented which prevents this problem from occurring. We discuss how our method could be used to evaluate larger applications and recommend future paths of development.

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Both the human factors engineering (HFE) and formal methods communities are concerned with improving the design of safety-critical systems. This work discusses a modeling effort that leveraged methods from both fields to perform formal verification of human-automation interaction with a programmable device. This effort utilizes a system architecture composed of independent models of the human mission, human task behavior, human-device interface, device automation, and operational environment. The goals of this architecture were to allow HFE practitioners to perform formal verifications of realistic systems that depend on human-automation interaction in a reasonable amount of time using representative models, intuitive modeling constructs, and decoupled models of system components that could be easily changed to support multiple analyses. This framework was instantiated using a patient controlled analgesia pump in a two phased process where models in each phase were verified using a common set of specifications. The first phase focused on the mission, human-device interface, and device automation; and included a simple, unconstrained human task behavior model. The second phase replaced the unconstrained task model with one representing normative pump programming behavior. Because models produced in the first phase were too large for the model checker to verify, a number of model revisions were undertaken that affected the goals of the effort. While the use of human task behavior models in the second phase helped mitigate model complexity, verification time increased. Additional modeling tools and technological developments are necessary for model checking to become a more usable technique for HFE.

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Breakdowns in complex systems often occur as a result of system elements interacting in ways unanticipated by analysts or designers. In systems with human operators, human-automation interaction associated with both normative and erroneous human behavior can contribute to such failures. This paper presents a method for automatically generating task analytic models encompassing both erroneous and normative human behavior from normative task models. The resulting model can be integrated into a formal system model so that system safety properties can be formally verified with a model checker. This allows analysts to prove that a human automation-interactive system (as represented by the model) will or will not satisfy safety properties with both normative and generated erroneous human behavior. This method is illustrated with a case study: the operation of a radiation therapy machine. In this example, a problem resulting from a generated erroneous human action is discovered. Future extensions of our method are discussed.

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Predicting failures in complex, human-interactive systems is difficult as they may occur under rare operational conditions and may be influenced by many factors including the system mission, the human operator's behavior, device automation, human-device interfaces, and the operational environment. This paper presents a method that integrates task analytic models of human behavior with formal models and model checking in order to formally verify properties of human-interactive systems. This method is illustrated with a case study: the programming of a patient controlled analgesia pump. Two specifications, one of which produces a counterexample, illustrate the analysis and visualization capabilities of the method.

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Spatial awareness is important in domains where safety hinges on human operators keeping track of the relative locations of objects in the environment. While a variety of subjective and judgment-based measures have been used to evaluate spatial awareness, none have probed all three of its levels: (1) identification of environmental objects, (2) their current locations relative to the operator, and (3) their relative positions over time. This work compares new judgment-based measures of spatial awareness that probe all three levels of spatial awareness to conventional subjective measures. In the evaluation of 14 configurations of Synthetic Vision Systems head down displays (seven terrain textures and two Geometric Fields of View (GFOVs)), 18 pilots made four types of judgments (relative angle, distance, height, and abeam time) regarding the location of terrain points displayed in 112 5-s, non-interactive simulations. They also provided subjective demand, awareness, clutter, SA-SWORD, and preferred GFOV measures. Correlation analyses revealed that displays that received higher awareness and SA-SWORD subjective ratings were associated with smaller errors in abeam time judgments and, for SA-SWORD, smaller errors in relative distance judgments. Thus SA-SWORD provides insight into level 2 spatial awareness and both SA-SWORD and awareness provide insight into level 3 spatial awareness. ANOVA and chi(2) analyses revealed comparable results between display configurations that produced the minimum error in judgments and those recommended by the awareness, SA-SWORD, and preferred GFOV measures.

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