Denaturing purifications demonstrate that PRC2 and other widely reported chromatin proteins do not appear to bind directly to RNA in vivo.

Polycomb repressive complex 2 (PRC2) is reported to bind to many RNAs and has become a central player in reports of how long non-coding RNAs (lncRNAs) regulate gene expression. Yet, there is a growing discrepancy between the biochemical evidence supporting specific lncRNA-PRC2 interactions and functional evidence demonstrating that PRC2 is often dispensable for lncRNA function. Here, we revisit the evidence supporting RNA binding by PRC2 and show that many reported interactions may not occur in vivo. Using denaturing purification of in vivo crosslinked RNA-protein complexes in human and mouse cell lines, we observe a loss of detectable RNA binding to PRC2 and chromatin-associated proteins previously reported to bind RNA (CTCF, YY1, and others), despite accurately mapping bona fide RNA-binding sites across others (SPEN, TET2, and others). Taken together, these results argue for a critical re-evaluation of the broad role of RNA binding to orchestrate various chromatin regulatory mechanisms.

Views and experiences of healthcare practitioners supporting people with COPD who have used activity monitors: "More than just steps".

INTRODUCTION: Activity monitors (apps and wearables) are increasingly used by the general population, including people with Chronic Obstructive Pulmonary Disease (COPD). There is potential for activity monitors to support increases in physical activity for people with COPD and healthcare practitioners (HCPs) are likely to be key in supporting their use, but little is currently known about HCPs' views or experiences. This qualitative research aimed to explore HCPs' views and experiences of supporting people with COPD who have used activity monitors. METHODS: Seventeen semi-structured telephone or online interviews were conducted with HCPs between September 2020 and May 2021. HCPs included two nurses, an occupational therapist, a physician, and 13 physiotherapists. Participants were recruited via social media advertisements. They all had experience of supporting people with COPD who had used activity monitors. Interviews were analysed using reflexive thematic analysis. FINDINGS: Four themes were developed highlighting the challenges and benefits of HCPs supporting patients with using activity monitors and utilising patient-collected activity data; 1) Skills and experience are needed to increase accessibility and engagement, 2) Objectively monitored physical activity can support exercise prescription, 3) Applications of activity monitors vary across different settings, and 4) Support is needed for future use of activity monitors. DISCUSSION: HCPs recognised the potential for activity monitors to impact patients' ability to self-manage their COPD. However, there is a lack of guidance and information to support integration within practice. Future research is needed to co-develop information and guidelines for people with COPD and HCPs.

A Systematic Review of Inequalities in the Mental Health Experiences of Black African, Black Caribbean and Black-mixed UK Populations: Implications for Action.

BACKGROUND: Measurable differences in the experience and treatment of mental health conditions have been found to exist between different racial categories of community groups. The objective of this research was to review the reported mental health of Black African-Caribbean communities in the UK, determinants of mental health, and interventions to enhance their experiences of mental health services. METHOD: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement was applied. To be included, papers must be published in a peer reviewed journal; report on adult populations (over 18) from any of Black African, Black Caribbean or Black mixed people in the UK; and assess (quantitative), or discuss (qualitative) mental health experiences, determinants of mental health, or interventions intended to enhance experiences of mental health services among the target population. The aims, inclusion criteria, data extraction, and data quality evaluation were specified in advance. Searches were conducted using EBSCO (PsychInfo; MEDLINE; CINAHL Plus; psychology and behavioural sciences collection). The search strategy included search terms relating to the aim. Risk of bias was assessed using a standard tool, records were organised using Endnote, and data were extracted and synthesised using Microsoft Excel. RESULTS: Thirty-six studies were included, of which 26 were quantitative and six reported exclusively on Black participants. Black populations were less likely to access mental health support via traditional pathways due to stigma and mistrust of mental health services. Black Africans especially, sought alternative help from community leaders, which increased the likelihood of accessing treatment at the point of crisis or breakdown, which in turn increased risk of being detained under the Mental Health Act and via the criminal justice system. DISCUSSION: Findings suggest a cycle of poor mental health, coercive treatment, stigma, and mistrust of services as experienced by Black communities. Evidence was limited by poorly defined ethnic categories, especially where Black populations were subsumed into one category. It is recommended that mental health services work collaboratively with cultural and faith communities in supporting Black people to cope with mental illness, navigate mental health pathways, and provide culturally appropriate advice. Protocol Registration Number PROSPERO CRD42021261510.

De novo mapping of α-helix recognition sites on protein surfaces using unbiased libraries.

The α-helix is one of the most common protein surface recognition motifs found in nature, and its unique amide-cloaking properties also enable α-helical polypeptide motifs to exist in membranes. Together, these properties have inspired the development of α-helically constrained (Helicon) therapeutics that can enter cells and bind targets that have been considered "undruggable", such as protein-protein interactions. To date, no general method for discovering α-helical binders to proteins has been reported, limiting Helicon drug discovery to only those proteins with previously characterized α-helix recognition sites, and restricting the starting chemical matter to those known α-helical binders. Here, we report a general and rapid screening method to empirically map the α-helix binding sites on a broad range of target proteins in parallel using large, unbiased Helicon phage display libraries and next-generation sequencing. We apply this method to screen six structurally diverse protein domains, only one of which had been previously reported to bind isolated α-helical peptides, discovering 20 families that collectively comprise several hundred individual Helicons. Analysis of 14 X-ray cocrystal structures reveals at least nine distinct α-helix recognition sites across these six proteins, and biochemical and biophysical studies show that these Helicons can block protein-protein interactions, inhibit enzymatic activity, induce conformational rearrangements, and cause protein dimerization. We anticipate that this method will prove broadly useful for the study of protein recognition and for the development of both biochemical tools and therapeutics for traditionally challenging protein targets.

What Are the Experiences of People with COPD Using Activity Monitors?: A Qualitative Scoping Review.

Physical activity monitoring technology (e.g. smartphone apps or wearables) can objectively record physical activity levels, potentially support interventions to increase activity levels, and support the self-management of Chronic Obstructive Pulmonary Disease (COPD). Insight into patients' experiences of monitoring physical activity is needed to inform future healthcare practice and policy utilizing this technology to support long-term positive health behavior change. This scoping review aimed to explore the experiences of using technology for monitoring physical activity among people with COPD. The Joanna Briggs Institute scoping review methodological framework was used. Relevant scientific databases (CINAHL Complete, MEDLINE, PsycINFO, SPORTDiscus, Cochrane Library and Scopus) were searched from 1st January 2016 to 16th March 2021. Thematic synthesis was used to analyze the data. Twelve studies exploring the experiences of people with COPD using technology for monitoring physical activity were included in the synthesis. Seven themes were developed and summarize experiences: 1) Monitoring and keeping track of their activity and health, 2) Supporting motivation to be active, 3) Acceptability of the device, 4) Experiencing technical issues with the device, 5) Setting appropriate and achievable goals for their health condition, 6) Integrating the device into their life and daily routine, and 7) Perceived physical and psychological benefits of using the device. Further high-quality research is needed to understand the experiences of people with COPD using technology to monitor physical activity in everyday life and better self-manage their health condition. Supporting people with COPD to monitor their physical activity could enable them to better self-manage their health condition.

GABARAP sequesters the FLCN-FNIP tumor suppressor complex to couple autophagy with lysosomal biogenesis.

Adaptive changes in lysosomal capacity are driven by the transcription factors TFEB and TFE3 in response to increased autophagic flux and endolysosomal stress, yet the molecular details of their activation are unclear. LC3 and GABARAP members of the ATG8 protein family are required for selective autophagy and sensing perturbation within the endolysosomal system. Here, we show that during the conjugation of ATG8 to single membranes (CASM), Parkin-dependent mitophagy, and Salmonella-induced xenophagy, the membrane conjugation of GABARAP, but not LC3, is required for activation of TFEB/TFE3 to control lysosomal capacity. GABARAP directly binds to a previously unidentified LC3-interacting motif (LIR) in the FLCN/FNIP tumor suppressor complex and mediates sequestration to GABARAP-conjugated membrane compartments. This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. Thus, the GABARAP-FLCN/FNIP-TFEB axis serves as a molecular sensor that coordinates lysosomal homeostasis with perturbations and cargo flux within the autophagy-lysosomal network.

Seeded droplet microfluidic system for small molecule crystallization.

A microfluidic approach to seeded crystallization has been demonstrated using abacavir hemisulfate, a nucleoside analog reverse transcriptase inhibitor, in droplet reactors to control polymorphism and produce particles with a low particle size distribution. Two techniques are introduced: (1) the first technique involves an emulsion system consisting of a dispersed phase solvent and a continuous phase, which holds slight solubility of the dispersed phase solvent. The dispersed phase contains both a dissolved active pharmaceutical ingredient (API) and seeds of the desired polymorph. While the continuous phase enables solvent extraction, the negligible solubility of the API allows for growth of seeds inside droplets via extraction and subsequent API saturation. This technique demonstrates the ability to crystallize the API in spherical agglomerates via slow extraction of droplets. (2) The second technique utilizes a combined dispersed phase by joining in-flow a seed suspension stream with a supersaturated active pharmaceutical ingredient (API) stream. The combined dispersed phase is emulsified in a continuous phase for which the dispersed phase solvent and the API are both insoluble - droplets are incubated at temperatures below their saturation limit to induce crystal growth. Decreasing the concentration of seeds in its input stream resulted in a decreased number of crystals per droplet, increase in crystal size, and decrease in PSD. Temperature cycling was utilized as a proof of concept to demonstrate the ability to reduce the number of seeds per droplet where the optimal goal is to obtain a single seed per droplet for all droplets. Utilizing this approach in conjunction with the ability to produce monodispersed droplet reactors allows for enhanced control of particle size distribution (PSD) by precisely controlling the available mass for each individual seed crystal. The development of this technique as a proof-of-concept for crystallization can be expanded to manufacturing scales in a continuous manner using parallelized droplet generators and flow reactors to precisely control the temperature and crystal growth kinetics of individual droplets.

Metabolic modeling using statistical and spreadsheet software: Application to the glucose minimal model.

Kinetic non-linear metabolic models are used extensively in medical research and increasingly for clinical diagnostic purposes. An example of such a model is the Glucose Minimal Model by Bergman and colleagues [1]. This model is similar to pharmacokinetic/pharmacodynamic models in that like pharmacokinetic/pharmacodynamic models, it is based on a small number of fairly simple ordinary differential equations and it aims to determine how the changing concentration of one blood constituent influences the concentration of another constituent. Although such models may appear prima facie, to be relatively simple, they have gained a reputation of being difficult to fit to data, especially in a consistent and repeatable fashion. Consequently, researchers and clinicians have generally relied on dedicated software packages to do this type of modeling. This article describes the use of statistical and spreadsheet software for fitting the Glucose Minimal Model to data from an insulin modified intravenous glucose tolerance test (IM-IVGTT). A novel aspect of the modeling is that the differential equations that are normally used to describe insulin action and the disposition of plasma glucose are first solved and expressed in their explicit forms so as to facilitate the estimation of Glucose Minimal Model parameters using the nonlinear (nl) optimization procedure within statistical and spreadsheet software. The most important clinical parameter obtained from the Glucose Minimal Model is insulin sensitivity (SI). Using IM-IVGTT data from 42 horses in one experiment and 48 horses in a second experiment, we demonstrate that estimates of SI derived from the Glucose Minimal Model fitted to data using STATA and Excel, are highly concordant with SI estimates obtained using the industry standard software, MinMod Millennium. This work demonstrates that there is potential for statistical and spreadsheet software to be applied to a wide range of kinetic non-linear modeling problems.

Impact of type 2 diabetes on hospitalization and mortality in people with malignancy.

AIM: To compare the characteristics of and outcomes for people with malignancies with and without a co-diagnosis of diabetes. METHODS: Emergency department and hospital discharge data from a single centre for the period between 1 January 2015 and 31 December 2017 were used to identify people with a diagnosis of a malignancy and diabetes. Multivariate Cox regression models were used to estimate the effect of diabetes on all-cause mortality. A truncated negative binomial regression model was used to assess the impact of diabetes on length of hospital inpatient stay. Prentice-Williams-Peterson total time models were used to assess the effect of diabetes on number of emergency department re-presentations and inpatient re-admissions. RESULTS: Of 7004 people identified with malignancies, 1195 (17.1%) were also diagnosed with diabetes. A diagnosis of diabetes was associated with a greater number of inpatient re-admissions [adjusted hazard ratio 1.13 (95% CI 1.03, 1.24)], a greater number of emergency department re-presentations [adjusted hazard ratio 1.13 (95% CI 1.05, 1.22)] and longer length of stay [adjusted incidence rate ratio 1.14 (95% CI 1.04, 1.25)]. A co-diagnosis of diabetes was also associated with a 48% increased risk of all-cause mortality [adjusted hazard ratio 1.48 (95% CI 1.22-1.76)]. CONCLUSIONS: People with malignancies and diabetes had significantly more emergency department presentations, more inpatient admissions, longer length of hospital stay and higher rates of all-cause mortality compared to people with a malignancy without diabetes.

Automated vehicles and older drivers in Canada.

INTRODUCTION: As seniors represent a growing proportion of the driving population, research about how automated vehicles can help improve older driver safety and mobility is highly relevant. This paper examines the knowledge, attitudes and perceptions of older drivers towards limited self-driving vehicles (LSDVs), and how these variables can influence the likelihood that they will rely on this technology. METHOD: The study includes data from a previous national survey (N = 2662) about automated vehicle technology, with new analyses to test hypothetical models using structural equation modeling. Results of the first model were confirmed and built upon with a second more complex model that incorporated the construct "behavioral adaptation." Focus groups with older drivers were also conducted (N = 38) to help reveal nuances in older drivers' knowledge, attitudes, perceptions, and behaviors regarding this technology. RESULTS: Survey results demonstrated that feelings of safety and knowledge about LSDVs are positively related to perceived ease of use and adoption of the technology. The positive association between safety and perceived ease of use was further highlighted when comparing responses of older drivers to those of younger age groups, as older drivers were significantly less likely to agree that LSDVs were easy to use and were significantly less agreeable about feeling safe using them. Focus groups results confirmed that safety and knowledge of LSDVs are essential to the likelihood of adopting this technology, and revealed a high receptivity among older drivers to educational strategies and tools to increase their knowledge of LSDVs. Implications for educational strategies and safety benefits for older drivers are discussed. Practical applications: Results provide insight into strategies to encourage the early adoption of automated vehicles by older drivers and facilitate a safer transition towards automated vehicles that is lead by a cohort of safety-conscious drivers.

Exosomes derived from induced vascular progenitor cells promote angiogenesis in vitro and in an in vivo rat hindlimb ischemia model.

Induced vascular progenitor cells (iVPCs) were created as an ideal cell type for regenerative medicine and have been reported to positively promote collateral blood flow and improve cardiac function in a rat model of myocardial ischemia. Exosomes have emerged as a novel biomedicine that mimics the function of the donor cells. We investigated the angiogenic activity of exosomes from iPVCs (iVPC-Exo) as a cell-free therapeutic approach for ischemia. Exosomes from iVPCs and rat aortic endothelial cells (RAECs) were isolated using a combination of ultrafiltration and size-exclusion chromatography. Nanoparticle tracking analysis revealed that exosome isolates fell within the exosomal diameter (<150 nm). These exosomes contained known markers Alix and TSG101, and their morphology was validated using transmission electron microscopy. When compared with RAECs, iVPCs significantly increased the secretion of exosomes. Cardiac microvascular endothelial cells and aortic ring explants were pretreated with RAEC-Exo or iVPC-Exo, and basal medium was used as a control. iVPC-Exo exerted an in vitro angiogenic effect on the proliferation, tube formation, and migration of endothelial cells and stimulated microvessel sprouting in an ex vivo aortic ring assay. Additionally, iVPC-Exo increased blood perfusion in a hindlimb ischemia model. Proangiogenic proteins (pentraxin-3 and insulin-like growth factor-binding protein-3) and microRNAs (-143-3p, -291b, and -20b-5p) were found to be enriched in iVPC-Exo, which may mediate iVPC-Exo induced vascular growth. Our findings demonstrate that treatment with iVPC-Exo promotes angiogenesis in vitro, ex vivo, and in vivo. Collectively, these findings indicate a novel cell-free approach for therapeutic angiogenesis.NEW & NOTEWORTHY The results of this work demonstrate exosomes as a novel physiological mechanism by which induced vascular progenitor cells exert their angiogenic effect. Moreover, angiogenic cargo of proteins and microRNAs may define the biological contributors in activating endothelial cells to form a new capillary plexus for ischemic vascular diseases.

The waveguiding of sound using lines of resonant holes.

The dispersion of an acoustic surface wave supported by a line of regularly spaced, open ended holes in an acrylic plate, is characterised by precise measurement of its localised acoustic fields. We illustrate the robust character of this surface wave and show its potential for control of sound by the acoustic waveguiding provided by a ring of regularly spaced holes. A single line of open-ended holes is shown to act as simple acoustic waveguide that can be readily manipulated to control the flow of sound.

Canadian wildlife-vehicle collisions: An examination of knowledge and behavior for collision prevention.

OBJECTIVES: This study examines drivers' responses to wildlife on Canadian roads. The objective of this paper is to demonstrate that knowledge of what to do when encountering wildlife on the road does not always translate into the appropriate behavior to avoid a collision. METHODS: Data from the Traffic Injury Research Foundation's (TIRF) 2016 Road Safety Monitor (RSM) and data from TIRF's National Fatality Database from 2000 to 2014 were analyzed to test hypotheses based on the theory of planned behavior. Logistic regression and piecewise linear regression were used. RESULTS: Analyses of the data showed that the prevalence of fatal WVCs has remained relatively consistent, and that the majority of persons killed in WVCs died in crashes that involved large mammals. The majority of fatalities occurred in the summer (182 or 38.4%) and fall (163 or 34.4%). The RSM data revealed that 60.9% [50.5, 70.4] of respondents who previously hit an animal indicated that drivers should slow down and steer straight when confronted with wildlife, while 47.3% [37.1, 57.6] of respondents indicated this was the action they took when they hit wildlife. Comparatively, 59.5% [56.6, 62.4] of respondent who have not hit an animal indicated this was an appropriate response. Additionally, 33.2% [24, 44] of respondents who previously hit an animal indicated that drivers should swerve to avoid a collision with wildlife, while 37.5% [28.2, 47.8] of respondents indicated this was the action they took when they hit wildlife. CONCLUSIONS: Many drivers are unaware of what the safest method of WVC prevention is. Further, while a subgroup of drivers may have the knowledge and intention to slow down and steer straight even if the animal is directly in the path, i.e., the safest possible behavior, they are not necessarily adopting this behavior. Practical applications: Recommendations are formulated to address this discrepancy, as well as practical applications.

Phosphorylation of synaptic GTPase-activating protein (synGAP) by polo-like kinase (Plk2) alters the ratio of its GAP activity toward HRas, Rap1 and Rap2 GTPases.

SynGAP is a Ras and Rap GTPase-activating protein (GAP) found in high concentration in the postsynaptic density (PSD) fraction from mammalian forebrain where it binds to PDZ domains of PSD-95. Phosphorylation of pure recombinant synGAP by Ca2+/calmodulin-dependent protein kinase II (CaMKII) shifts the balance of synGAP's GAP activity toward inactivation of Rap1; whereas phosphorylation by cyclin-dependent kinase 5 (CDK5) has the opposite effect, shifting the balance toward inactivation of HRas. These shifts in balance contribute to regulation of the numbers of surface AMPA receptors, which rise during synaptic potentiation (CaMKII) and fall during synaptic scaling (CDK5). Polo-like kinase 2 (Plk2/SNK), like CDK5, contributes to synaptic scaling. These two kinases act in concert to reduce the number of surface AMPA receptors following elevated neuronal activity by tagging spine-associated RapGAP protein (SPAR) for degradation, thus raising the level of activated Rap. Here we show that Plk2 also phosphorylates and regulates synGAP. Phosphorylation of synGAP by Plk2 stimulates its GAP activity toward HRas by 65%, and toward Rap1 by 16%. Simultaneous phosphorylation of synGAP by Plk2 and CDK5 at distinct sites produces an additive increase in GAP activity toward HRas (∼230%) and a smaller, non-additive increase in activity toward Rap1 (∼15%). Dual phosphorylation also produces an increase in GAP activity toward Rap2 (∼40-50%), an effect not produced by either kinase alone. As we previously observed for CDK5, addition of Ca2+/CaM causes a substrate-directed doubling of the rate and stoichiometry of phosphorylation of synGAP by Plk2, targeting residues also phosphorylated by CaMKII. In summary, phosphorylation by Plk2, like CDK5, shifts the ratio of GAP activity of synGAP to produce a greater decrease in active Ras than in active Rap, which would produce a shift toward a decrease in the number of surface AMPA receptors in neuronal dendrites.

Marteilia refringens and Marteilia pararefringens sp. nov. are distinct parasites of bivalves and have different European distributions.

Marteilia refringens causes marteiliosis in oysters, mussels and other bivalve molluscs. This parasite previously comprised two species, M. refringens and Marteilia maurini, which were synonymized in 2007 and subsequently referred to as M. refringens 'O-type' and 'M-type'. O-type has caused mass mortalities of the flat oyster Ostrea edulis. We used high throughput sequencing and histology to intensively screen flat oysters and mussels (Mytilus edulis) from the UK, Sweden and Norway for infection by both types and to generate multi-gene datasets to clarify their genetic distinctiveness. Mussels from the UK, Norway and Sweden were more frequently polymerase chain reaction (PCR)-positive for M-type (75/849) than oysters (11/542). We did not detect O-type in any northern European samples, and no histology-confirmed Marteilia-infected oysters were found in the UK, Norway and Sweden, even where co-habiting mussels were infected by the M-type. The two genetic lineages within 'M. refringens' are robustly distinguishable at species level. We therefore formally define them as separate species: M. refringens (previously O-type) and Marteilia pararefringens sp. nov. (M-type). We designed and tested new Marteilia-specific PCR primers amplifying from the 3' end of the 18S rRNA gene through to the 5.8S gene, which specifically amplified the target region from both tissue and environmental samples.

Impact of egg handling and conditions during extended storage on egg quality.

The international trade of shell eggs has become more important in recent years in order to feed a growing worldwide population, meet food manufacturing demands, and address supply issues during disease outbreaks or product recalls. The primary barriers for the export and import of shell eggs are: whether to wash eggs and egg storage temperature. The current study was undertaken to compare egg quality factors as influenced by egg washing and storage temperature. Three lots of nest run white shell eggs were collected on consecutive d from a commercial in-line egg production facility. The treatment and storage conditions were selected to encompass the primary egg handling and storage conditions utilized throughout the world: washed; washed, oiled; and unwashed stored at 4°C; and unwashed stored at 22°C. Eggs were assessed weekly from 0 to 15 wk. Percent egg weight loss was greatest for the unwashed 22°C eggs (15.72%) and least for washed, oiled 4°C (0.33%, P < 0.0001). Less than 24 h at 22°C had a greater impact on yolk shape measurements decline than 15 wk at 4°C (P < 0.05). After 15 wk, average Haugh unit scores for all refrigerated treatments were still Grade A, and unwashed 22°C dropped from Grade AA to almost Grade B in one week. Room temperature storage of eggs rapidly declines egg quality. Egg treatment did not impact egg quality factors when stored at 4°C. Washing and oiling eggs before refrigerated storage did suppress the rate of egg weight loss.

Asymmetric changes in circulating insulin levels after an increase compared with a reduction in insulin pump basal rate in people with Type 1 diabetes.

AIMS: To investigate circulating insulin profiles after a clinically relevant insulin pump basal rate increase vs a reduction, and the associated glucose responses. METHODS: A cohort of 12 adults with Type 1 diabetes undertook this two-stage university hospital study using Accu-Chek pumps (Roche Diagnostics, Mannheim, Germany) and insulin aspart. An insulin basal rate change of 0.2 unit/h (increase in first stage, reduction in second stage) was implemented at ~09:30 h, after a single overnight basal rate (without bolus insulin), while fasting participants rested. Frequent venous samples for the assessment of plasma free insulin, glucose and cortisol were collected from 60 min before until 300 min after rate change. The primary outcome was time to steady-state insulin. RESULTS: The 0.2-unit/h rate change represented a mean ± sd alteration of 23 ± 6%. After the rate increase, the median (interquartile range) times to 80% and 90% steady-state insulin were 170 (45) min and 197 (87) min, respectively. By contrast, after rate reduction, 80% steady-state insulin was not achieved. After the rate increase, mean ± se insulin levels increased by 4.3 ± 3.1%, 12.0 ± 2.9% and 25.6 ± 2.6% at 60, 120 and 300 min, respectively (with no significant difference until 180 min). After the rate reduction, insulin decreased by 8.3 ± 3.0% at 300 min (with no significant difference until 300 min). After rate reduction, glucose levels paradoxically declined by 17.4 ± 3.7% after 300 min; cortisol levels also fell during observation (P = 0.0003). CONCLUSIONS: The time to circulating insulin change after a 0.2-unit/h basal rate change was substantial, and was greater after a reduction than after an increase. Counter-regulatory hormone circadian variation may affect glycaemia when implementing minor changes at low basal rates. Both direction of basal rate change, and time of day, warrant consideration when anticipating the clinical effects of basal rate changes.

An evaluation of Nova Scotia's alcohol ignition interlock program.

Alcohol ignition interlock programs for offenders aim to reduce recidivism among convicted drink drivers. This study presents an evaluation of Nova Scotia's interlock program implemented in 2008 in order to assess its effectiveness to reduce impaired driving and to help identify areas for improvement. Data used include conviction and crash records of individual participants; provincial monthly counts of alcohol-related charges, convictions and fatal and serious crashes; and interlock logged events. Methods used include descriptive statistics, survival analysis, time series and logistic regression analysis. With respect to specific deterrence (i.e., preventing recidivism) there was a 90% reduction in recidivism among voluntary participants since participation in the interlock program and a 79% reduction after these participants exited from the program. With respect to general deterrence (i.e., referring to a preventative effect on the entire population of drivers in Nova Scotia) there were temporary decreases in the numbers of alcohol-related charges (13.32%) and convictions (9.93%) and a small significant decrease in the number of fatal and serious injury alcohol-related crashes, following the implementation of the program. The evidence suggests the interlock program was better at preventing harm due to alcohol-impaired driving than the alternative of not using the interlock program. Recommendations were formulated supporting the continuation of the interlock program in Nova Scotia.