#WeAreNotWaiting DIY artificial pancreas systems and challenges for the law.

Commercial hybrid closed-loop systems are becoming more readily available, yet the number of DIY artificial pancreas system (DIY APS) users continues to rise. These DIY systems have not gone through the usual regulatory approvals processes, and, thus, present a number of legal difficulties for a number of actors, including clinicians, parents who build DIY APS for their children, and users themselves. These issues have so far received insufficient attention. Due to the complex constellation of actors involved in both development of DIY APSs and in its deployment, it is not currently clear who, and to what extent, different parties might (successfully) be held liable if something goes wrong. Despite this uncertainty, unless and until clearer guidance is issued by relevant bodies, or a case appears before the courts which clarifies the situation, existing legal principles apply. In this article, we examine some of these to shed light on how the law would likely be applied if harm were to result from the use of a DIY APS.

Beyond the control of the care home: A meta-ethnography of qualitative studies of Infection Prevention and Control in residential and nursing homes for older people.

OBJECTIVE: This study aimed to develop interpretive insights concerning Infection Prevention and Control (IPC) in care homes for older people. DESIGN: This study had a meta-ethnography design. DATA SOURCES: Six bibliographic databases were searched from inception to May 2020 to identify the relevant literature. REVIEW METHODS: A meta-ethnography was performed. RESULTS: Searches yielded 652 records; 15 were included. Findings were categorized into groups: The difficulties of enacting IPC measures in the care home environment; workload as an impediment to IPC practice; the tension between IPC and quality of life for care home residents; and problems dealing with medical services located outside the facility including diagnostics, general practice and pharmacy. Infection was revealed as something seen to lie 'outside' the control of the care home, whether according to origins or control measures. This could help explain the reported variability in IPC practice. Facilitators to IPC uptake involved repetitive training and professional development, although such opportunities can be constrained by the ways in which services are organized and delivered. CONCLUSIONS: Significant challenges were revealed in implementing IPC in care homes including staffing skills, education, workloads and work routines. These challenges cannot be properly addressed without resolving the tension between the objectives of maintaining resident quality of life while enacting IPC practice. Repetitive staff training and professional development with parallel organisational improvements have prospects to enhance IPC uptake in residential and nursing homes. PATIENT OR PUBLIC CONTRIBUTION: A carer of an older person joined study team meetings and was involved in writing a lay summary of the study findings.

Prescribing unapproved medical devices? The case of DIY artificial pancreas systems.

In response to slow progress regarding technological innovations to manage type 1 diabetes, some patients have created unregulated do-it-yourself artificial pancreas systems (DIY APS). Yet both in the United Kingdom (UK) and internationally, there is an almost complete lack of specific guidance - legal, regulatory, or ethical - for clinicians caring for DIY APS users. Uncertainty regarding their professional obligations has led to them being cautious about discussing DIY APS with patients, let alone recommending or prescribing them. In this article, we argue that this approach threatens to undermine trust and transparency. Analysing the professional guidance from the UK regulator - the General Medical Council - we demonstrate that nothing within it ought to be interpreted as precluding clinicians from initiating discussions about DIY APS. Moreover, in some circumstances, it may require that clinicians do so. We also argue that the guidance does not preclude clinicians from prescribing such unapproved medical devices.

Leaving Hospital: A Step too Far for Risk-Based Regulation?

Discharges from hospital are internationally recognised as a dangerous time in the care pathway of a patient, posing a risk to both their physical wellbeing and dignity. This article examines the effectiveness of risk-based regulation as a tool to address patient safety incidents linked to the hospital discharge process within the English National Health Service. It examines how the risk of this process is identified, conceptualised, and prioritised amongst the relevant statutory regulators, and argues that the risk is neither uniformly recognised by the statutory regulators within the English NHS, nor sufficiently addressed. Professional regulators in particular appear to have a poor awareness of the risk and their role in addressing it. Until these issues are resolved, patients leaving hospitals will continue to be exposed to patient safety incidents which should be avoidable.

Age-dependent cardiac function during experimental sepsis: effect of pharmacological activation of AMP-activated protein kinase by AICAR.

Age represents a major risk factor for multiple organ failure, including cardiac dysfunction, in patients with sepsis. AMP-activated protein kinase (AMPK) is a crucial regulator of energy homeostasis that controls mitochondrial biogenesis by activation of peroxisome proliferator-activated receptor-γ coactivator-1α and disposal of defective organelles by autophagy. We investigated whether AMPK dysregulation contributes to age-dependent cardiac injury in young (2-3 mo) and mature adult (11-13 mo) male mice subjected to sepsis by cecal ligation and puncture and whether AMPK activation by 5-amino-4-imidazole carboxamide riboside affords cardioprotective effects. Plasma proinflammatory cytokines and myokine follistatin were similarly elevated in vehicle-treated young and mature adult mice at 18 h after sepsis. However, despite equivalent troponin I and T levels compared with similarly treated young mice, vehicle-treated mature adult mice exhibited more severe cardiac damage by light and electron microscopy analyses with more marked intercellular edema, inflammatory cell infiltration, and mitochondrial derangement. Echocardiography revealed that vehicle-treated young mice exhibited left ventricular dysfunction after sepsis, whereas mature adult mice exhibited a reduction in stroke volume without apparent changes in load-dependent indexes of cardiac function. At molecular analysis, phosphorylation of the catalytic subunits AMPK-α1/α2 was associated with nuclear translocation of peroxisome proliferator-activated receptor-γ coactivator-1α in vehicle-treated young but not mature adult mice. Treatment with 5-amino-4-imidazole carboxamide riboside ameliorated cardiac architecture derangement in mice of both ages. These cardioprotective effects were associated with attenuation of the systemic inflammatory response and amelioration of cardiac dysfunction in young mice only, not in mature adult animals. NEW & NOTEWORTHY Our data suggest that sepsis-induced cardiac dysfunction manifests with age-dependent characteristics, which are associated with a distinct regulation of AMP-activated protein kinase-dependent metabolic pathways. Consistent with this age-related deterioration, pharmacological activation of AMP-activated protein kinase may afford cardioprotective effects allowing a partial recovery of cardiac function in young but not mature age.

Promoting activity, independence and stability in early dementia and mild cognitive impairment (PrAISED): development of an intervention for people with mild cognitive impairment and dementia.

This series of articles for rehabilitation in practice aims to cover a knowledge element of the rehabilitation medicine curriculum. Nevertheless, they are intended to be of interest to a multidisciplinary audience. The competency addressed in this article is an understanding of how to develop an intervention for people with mild cognitive impairment and dementia to promote their independence, stability, and physical activity. INTRODUCTION: Older adults with dementia are at a high risk of falls. Standard interventions have not been shown to be effective in this patient population potentially due to poor consideration of dementia-specific risk factors. An intervention is required that addresses the particular needs of older people with dementia in a community setting. METHODS: We followed guidelines for the development of an intervention, which recommend a structured approach considering theory, evidence and practical issues. The process used 15 information sources. Data from literature reviews, clinician workshops, expert opinion meetings, patient-relative interviews, focus groups with people with dementia and clinicians, a cross-sectional survey of risk factors, a pre-post intervention study and case studies were included. Data were synthesized using triangulation to produce an intervention suitable for feasibility testing. Practical consideration of how an intervention could be delivered and implemented were considered from the outset. RESULTS: Elements of the intervention included individually tailored, dementia-appropriate, balance, strength and dual-task exercises, functional training, and activities aimed at improving environmental access, delivered using a motivational approach to support adherence and long-term continuation of activity. We focussed on promoting safe activity rather than risk or prevention of falls. CONCLUSION: We used a systematic process to develop a dementia-specific intervention to promote activity and independence while reducing falls risk in older adults with mild dementia.

Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members.

We show that the antiapoptotic proteins BCL-2, BCL-XL, MCL-1, BFL-1, and BCL-w each bear a unique pattern of interaction with a panel of peptides derived from BH3 domains of BH3-only proteins. Cellular dependence on an antiapoptotic protein for survival can be decoded based on the pattern of mitochondrial sensitivity to this peptide panel, a strategy that we call BH3 profiling. Dependence on antiapoptotic proteins correlates with sequestration of activator BH3-only proteins like BID or BIM by antiapoptotic proteins. Sensitivity to the cell-permeable BCL-2 antagonist ABT-737 is also related to priming of BCL-2 by activator BH3-only molecules. Our data allow us to distinguish a cellular state we call "primed for death," which can be determined by BH3 profiling and which correlates with dependence on antiapoptotic family members for survival.

Assessment of Mitochondrial Oxygen Consumption Using a Plate Reader-based Fluorescent Assay.

Mitochondria serve many important functions, including cellular respiration, ATP production, controlling apoptosis, and acting as a central hub of metabolic pathways. Therefore, experimentally assessing mitochondrial functionality can provide insight into variations among different populations or disease states. Additionally, it is valuable to assess whether isolated mitochondria are healthy enough to proceed with experiments. One characteristic often used to compare mitochondrial function in different samples is the rate of oxygen consumption. Oxygen consumption and subsequent calculation of the respiratory control ratio in either intact cells or mitochondria isolated from tissue can serve all three purposes. Using mitochondria isolated from the livers of brush lizards in conjunction with a phosphorescent probe that is sensitive to the fluctuations in oxygen concentration of a solution, we measured oxygen consumption using a fluorescent plate reader. This method is not only quick and efficient but also can be conducted with a small amount of mitochondria and without the need for specialized equipment. The step-by-step protocol described here increases the accessibility of mitochondrial functional assessment to researchers.

Evolution of a self-renewing, participant-centered workshop series in BMB assessment.

We present as a case study the evolution of a series of participant-centered workshops designed to meet a need in the life sciences education community-the incorporation of best practices in the assessment of student learning. Initially, the ICABL (Inclusive Community for the Assessment of Biochemistry and Molecular Biology/BMB Learning) project arose from a grass-roots effort to develop material for a national exam in biochemistry and molecular biology. ICABL has since evolved into a community of practice in which participants themselves-through extensive peer review and reflection-become integral stakeholders in the workshops. To examine this evolution, this case study begins with a pilot workshop supported by seed funding and thoughtful programmatic assessment, the results of which informed evidence-based changes that, in turn, led to an improved experience for the community. Using participant response data, the case study also reveals critical features for successful workshops, including participant-centered activities and the value of frequent peer review of participants' products. Furthermore, we outline a train-the-trainer model for creating a self-renewing community by bringing new perspectives and voices into an existing core leadership team. This case study, then, offers a blueprint for building a thriving, evolving community of practice that not only serves the needs of individual scientist-educators as they seek to enhance student learning, but also provides a pathway for elevating members to positions of leadership.

HIV-1 Nef impairs heterotrimeric G-protein signaling by targeting Gα(i2) for degradation through ubiquitination.

The HIV Nef protein is an important pathogenic factor that modulates cell surface receptor trafficking and impairs cell motility, presumably by interfering at multiple steps with chemotactic receptor signaling. Here, we report that a dominant effect of Nef is to trigger AIP4 E3 ligase-mediated Gα(i2) ubiquitination, which leads to Gα(i2) endolysosomal sequestration and destruction. The loss of the Gα(i2) subunit was demonstrable in many cell types in the context of gene transfection, HIV infection, or Nef protein transduction. Nef directly interacts with Gα(i2) and ternary complexes containing AIP4, Nef, and Gα(i2) form. A substantial reversal of Gα(i2) loss and a partial recovery of impaired chemotaxis occurred following siRNA knockdown of AIP4 or NEDD4 or by inhibiting dynamin. The N-terminal myristoyl group, (62)EEEE(65) motif, and (72)PXXP(75) motif of Nef are critical for this effect to occur. Nef expression does not affect a Gq(i5) chimera where the five C-terminal residues of Gq are replaced with those of Gα(i2). Lysine at position 296 of Gα(i2) was identified as the critical determinant of Nef-induced degradation. By specifically degrading Gα(i2), Nef directly subverts leukocyte migration and homing. Impaired trafficking and homing of HIV Nef-expressing lymphocytes probably contributes to early immune dysfunction following HIV infection.

Variation in Melanin Content of Lizard Livers: Hybrids Turning to the Dark Side.

AbstractPigments such as melanin are most often associated with the surface of an organism, providing functions such as coloration and protection from UV radiation. However, the internal organs of some species also contain melanin. Internal melanin may also perform protective functions when cellular stress is experienced. We tested liver tissue of two tree lizard species that experienced introgression of their mitochondria to see whether melanin was present and whether it was at higher concentrations in the types of lizards thought to be under cellular stress. Previous work found that mitochondria from livers of hybrid tree lizards (those with introgressed mitochondrial DNA) had higher levels of ATP production at higher temperatures than both parental species and showed indications of dysfunction. Therefore, we predicted that if internal melanin functions to mediate the impact of damaging by-products of metabolism, such as excessive reactive oxygen species (ROS), melanin would be highest in livers of lizards with introgressed mitochondria. To test this, we used a melanin-specific stain on liver tissue sections and measured melanin concentration with spectrophotometry of heavy-membrane fractions from whole-liver homogenates of both parental species and their hybrids with introgressed mitochondria. Slides of liver sections treated with a melanin-specific stain revealed that hybrids contained melanin and had significantly higher levels of it than either parental species. Spectrophotometry gave the same result. This distribution of internal melanin matches the pattern expected if melanin functions as a compensatory mechanism to deal with higher ATP production and the subsequent high levels of ROS expected in these hybrid lizards. Future studies will examine this mechanistically.

The adult horn fly transcriptome and its complement of transcripts encoding cytochrome P450s, glutathione S-transferases, and esterases.

The horn fly, Haematobia irritans, is a blood-feeding parasitic fly with a global distribution that includes Europe, Africa, Asia, and the Americas. The fly has a major detrimental economic impact upon cattle production, with losses estimated at over $800 million annually in the United States and $2.5 billion in Brazil alone. Insecticide resistance in specific horn fly populations has been a problem for many years and there are several mechanisms whereby resistance develops. Little is known about the complement of metabolic enzymes encoded by the horn fly's genome that might provide the fly with detoxification or sequestration pathways to survive insecticide treatments. The cytochrome P450, glutathione S-transferase, and esterase enzyme families contain members that are capable of sequestering and/or detoxifying xenobiotic molecules such as insecticides. We sought to develop a comprehensive dataset of metabolic enzyme-encoding transcript sequences from the adult horn fly, as this is the life stage whose actions directly impose the economic costs to cattle producers. We used an Illumina paired-end read RNA-Seq approach to determine the adult horn fly transcriptomes from laboratory and field populations of horn flies with varying levels of pesticide resistance, including untreated and pyrethroid-treated newly eclosed adult flies. We followed with bioinformatic analyses to discern sequences putatively encoding cytochrome P450, esterase, and GST enzymes. We utilized read-mapping of RNA-Seq data and quantitative real-time polymerase chain reaction (qRT-PCR) to examine gene expression levels of specific P450 transcripts in several fly populations with varying degrees of pesticide resistance.

A population-based study of juvenile perpetrators of homicide in England and Wales.

This study aimed to describe the social, behavioural and offence characteristics of all convicted perpetrators of homicide aged 17 and under; to examine their previous contact with mental health services, and to discuss strategies for homicide prevention. An eight-year (1996-2004) sample of 363 juvenile homicide perpetrators in England and Wales was examined. The majority of perpetrators were male, used a sharp instrument, and most victims were acquaintances or strangers. Over half had previously offended. A history of alcohol and/or drug misuse was common, as was the prevalence of family dysfunction, abuse, educational difficulties or discipline problems. Previous contact with mental health services was rare. Earlier intervention targeting social and psychological adversity and substance misuse could help to reduce the level of risk for future violence, and may reduce homicide rates among juveniles. Strengthening engagement with young offenders and increasing resources to prevent recidivism may also be beneficial.

COVID-360: A Collaborative Effort to Develop a Multidisciplinary Set of Online Resources for Engaging Teaching on the COVID-19 Pandemic.

The COVID-19 pandemic has challenged undergraduate instructors and students in an unprecedented manner. Each has needed to find creative ways to continue the engaged teaching and learning process in an environment defined by physical separation and emotional anxiety and uncertainty. As a potential tool to meet this challenge, we developed a set of curricular materials that combined our respective life science teaching interests with the real-time scientific problem of the COVID-19 pandemic in progress. Discrete modules were designed that are engaging to students, implement active learning-based coursework in a variety of institutional and learning settings, and can be used either in person or remotely. The resulting interdisciplinary curriculum, dubbed "COVID-360," enables instructors to select from a menu of curricular options that best fit their course content, desired activities, and mode of class delivery. Here we describe how we devised the COVID-360 curriculum and how it represents our efforts to creatively and effectively respond to the instructional needs of diverse students in the face of an ongoing instructional crisis.

Development of a Certification Exam to Assess Undergraduate Students' Proficiency in Biochemistry and Molecular Biology Core Concepts.

With support from the American Society for Biochemistry and Molecular Biology (ASBMB), a community of biochemistry and molecular biology (BMB) scientist-educators has developed and administered an assessment instrument designed to evaluate student competence across four core concept and skill areas fundamental to BMB. The four areas encompass energy and metabolism; information storage and transfer; macromolecular structure, function, and assembly; and skills including analytical and quantitative reasoning. First offered in 2014, the exam has now been administered to nearly 4000 students in ASBMB-accredited programs at more than 70 colleges and universities. Here, we describe the development and continued maturation of the exam program, including the organic role of faculty volunteers as drivers and stewards of all facets: content and format selection, question development, and scoring.

Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737.

Antiapoptotic B cell leukemia/lymphoma 2 (BCL2) family proteins are expressed in many cancers, but the circumstances under which these proteins are necessary for tumor maintenance are poorly understood. We exploited a novel functional assay that uses BCL2 homology domain 3 (BH3) peptides to predict dependence on antiapoptotic proteins, a strategy we call BH3 profiling. BH3 profiling accurately predicts sensitivity to BCL2 antagonist ABT-737 in primary chronic lymphocytic leukemia (CLL) cells. BH3 profiling also accurately distinguishes myeloid cell leukemia sequence 1 (MCL1) from BCL2 dependence in myeloma cell lines. We show that the special sensitivity of CLL cells to BCL2 antagonism arises from the requirement that BCL2 tonically sequester proapoptotic BIM in CLL. ABT-737 displaced BIM from BCL2's BH3-binding pocket, allowing BIM to activate BAX, induce mitochondrial permeabilization, and rapidly commit the CLL cell to death. Our experiments demonstrate that BCL2 expression alone does not dictate sensitivity to ABT-737. Instead, BCL2 complexed to BIM is the critical target for ABT-737 in CLL. An important implication is that in cancer, BCL2 may not effectively buffer chemotherapy death signals if it is already sequestering proapoptotic BH3-only proteins. Indeed, activator BH3-only occupation of BCL2 may prime cancer cells for death, offering a potential explanation for the marked chemosensitivity of certain cancers that express abundant BCL2, such as CLL and follicular lymphoma.

Systematic scoping review of frameworks used to develop rehabilitation interventions for older adults.

OBJECTIVES: Rehabilitation interventions for older adults are complex as they involve a number of interacting components, have multiple outcomes of interest and are influenced by a number of contextual factors. The importance of rigorous intervention development prior to formal evaluation has been acknowledged and a number of frameworks have been developed. This review explored which frameworks have been used to guide the development of rehabilitation interventions for older adults. DESIGN: Systematic scoping review. SETTING: Studies were not limited for inclusion based on setting. PARTICIPANTS: Studies were included that featured older adults (>65 years of age). INTERVENTIONS: Studies were included that reported the development of a rehabilitation intervention. PRIMARY AND SECONDARY OUTCOME MEASURES: Data were extracted on study population, setting, type of intervention developed and frameworks used. The primary outcome of interest was the type of intervention development framework. RESULTS: Thirty-five studies were included. There was a range of underlying medical conditions including mild cognitive impairment and dementia (n=5), cardiac (n=4), stroke (n=3), falls (n=3), hip fracture (n=2), diabetes (n=2), breast cancer (n=1), Parkinson's disease (n=1), depression (n=1), chronic health problems (n=1), osteoarthritis (n=1), leg ulcer (n=1), neck pain (n=1) and foot problems (n=1). The intervention types being developed included multicomponent, support based, cognitive, physical activities, nursing led, falls prevention and occupational therapy led. Twelve studies (34%) did not report using a framework. Five frameworks were reported with the Medical Research Council (MRC) framework for developing and evaluating complex interventions being the most frequently cited (77%, n=17). CONCLUSION: At present, the MRC framework is the most popular for developing rehabilitation interventions for older adults. Many studies do not report using a framework. Further, specific guidance to assist this complex field of rehabilitation research is required.

Motivation as a mechanism underpinning exercise-based falls prevention programmes for older adults with cognitive impairment: a realist review.

OBJECTIVES: This review aimed to identify mechanisms underlying participation in falls prevention interventions, in older adults with cognitive impairment. In particular we studied the role of motivation. DESIGN: A realist review of the literature. DATA SOURCES: EMBASE, MEDLINE, CINAHL, the Cochrane Library, PsycINFO and PEDRO. ELIGIBILITY CRITERIA: Publications reporting exercise-based interventions for people with cognitive impairment, including dementia, living in the community. DATA EXTRACTION AND SYNTHESIS: A 'rough programme theory' (a preliminary model of how an intervention works) was developed, tested against findings from the published literature and refined. Data were collected according to elements of the programme theory and not isolated to outcomes. Motivation emerged as a key element, and was prioritised for further study. RESULTS: An individual will access mechanisms to support participation when they think that exercise will be beneficial to them. Supportive mechanisms include having a 'gate-keeper', such as a carer or therapist, who shares responsibility for the perception of exercise as beneficial. Lack of access to support decreases adherence and participation in exercise. Motivational mechanisms were particularly relevant for older adults with mild-to-moderate dementia, where the exercise intervention was multicomponent, in a preferred setting, at the correct intensity and level of progression, correctly supported and considered, and flexibly delivered. CONCLUSION: Motivation is a key element enabling participation in exercise-based interventions for people with cognitive impairment. Many of the mechanisms identified in this review have parallels in motivational theory. Clinically relevant recommendations were derived and will be used to further develop and test a motivationally considered exercise-based falls intervention for people with mild dementia. PROSPERO REGISTRATION NUMBER: CRD42015030169.