Once-Weekly Dulaglutide for the Treatment of Youths with Type 2 Diabetes.

BACKGROUND: The incidence of type 2 diabetes mellitus is increasing among youths. Once-weekly treatment with dulaglutide, a glucagon-like peptide-1 receptor agonist, may have efficacy with regard to glycemic control in youths with type 2 diabetes. METHODS: In a double-blind, placebo-controlled, 26-week trial, we randomly assigned participants (10 to <18 years of age; body-mass index [BMI], >85th percentile) being treated with lifestyle modifications alone or with metformin, with or without basal insulin, in a 1:1:1 ratio to receive once-weekly subcutaneous injections of placebo, dulaglutide at a dose of 0.75 mg, or dulaglutide at a dose of 1.5 mg. Participants were then included in a 26-week open-label extension study in which those who had received placebo began receiving dulaglutide at a weekly dose of 0.75 mg. The primary end point was the change from baseline in the glycated hemoglobin level at 26 weeks. Secondary end points included a glycated hemoglobin level of less than 7.0% and changes from baseline in the fasting glucose concentration and BMI. Safety was also assessed. RESULTS: A total of 154 participants underwent randomization. At 26 weeks, the mean glycated hemoglobin level had increased in the placebo group (0.6 percentage points) and had decreased in the dulaglutide groups (-0.6 percentage points in the 0.75-mg group and -0.9 percentage points in the 1.5-mg group, P<0.001 for both comparisons vs. placebo). At 26 weeks, a higher percentage of participants in the pooled dulaglutide groups than in the placebo group had a glycated hemoglobin level of less than 7.0% (51% vs. 14%, P<0.001). The fasting glucose concentration increased in the placebo group (17.1 mg per deciliter) and decreased in the pooled dulaglutide groups (-18.9 mg per deciliter, P<0.001), and there were no between-group differences in the change in BMI. The incidence of gastrointestinal adverse events was higher with dulaglutide therapy than with placebo. The safety profile of dulaglutide was consistent with that reported in adults. CONCLUSIONS: Treatment with dulaglutide at a once-weekly dose of 0.75 mg or 1.5 mg was superior to placebo in improving glycemic control through 26 weeks among youths with type 2 diabetes who were being treated with or without metformin or basal insulin, without an effect on BMI. (Funded by Eli Lilly; AWARD-PEDS ClinicalTrials.gov number, NCT02963766.).

Cas13b Is a Type VI-B CRISPR-Associated RNA-Guided RNase Differentially Regulated by Accessory Proteins Csx27 and Csx28.

CRISPR-Cas adaptive immune systems defend microbes against foreign nucleic acids via RNA-guided endonucleases. Using a computational sequence database mining approach, we identify two class 2 CRISPR-Cas systems (subtype VI-B) that lack Cas1 and Cas2 and encompass a single large effector protein, Cas13b, along with one of two previously uncharacterized associated proteins, Csx27 and Csx28. We establish that these CRISPR-Cas systems can achieve RNA interference when heterologously expressed. Through a combination of biochemical and genetic experiments, we show that Cas13b processes its own CRISPR array with short and long direct repeats, cleaves target RNA, and exhibits collateral RNase activity. Using an E. coli essential gene screen, we demonstrate that Cas13b has a double-sided protospacer-flanking sequence and elucidate RNA secondary structure requirements for targeting. We also find that Csx27 represses, whereas Csx28 enhances, Cas13b-mediated RNA interference. Characterization of these CRISPR systems creates opportunities to develop tools to manipulate and monitor cellular transcripts.

Myelography Using Energy-Integrating Detector CT Versus Photon-Counting Detector CT for Detection of CSF-Venous Fistulas in Patients With Spontaneous Intracranial Hypotension.

BACKGROUND. CSF-venous fistulas (CVFs), which are an increasingly recognized cause of spontaneous intracranial hypotension (SIH), are often diminutive in size and exceedingly difficult to detect by conventional imaging. OBJECTIVE. This purpose of this study was to compare energy-integrating detector (EID) CT myelography and photon-counting detector (PCD) CT myelography in terms of image quality and diagnostic performance for detecting CVFs in patients with SIH. METHODS. This retrospective study included 38 patients (15 men and 23 women; mean age, 55 ± 10 [SD] years) with SIH who underwent both clinically indicated EID CT myelography (slice thickness, 0.625 mm) and PCD CT myelography (slice thickness, 0.2 mm; performed in ultrahigh-resolution mode) to assess for CSF leak. Three blinded radiologists reviewed examinations in random order, assessing image noise, discernibility of spinal nerve root sleeves, and overall image quality (each assessed using a scale of 0-100, with 100 denoting highest quality) and recording locations of the CVFs. Definite CVFs were defined as CVFs described in CT myelography reports using unequivocal language and having an attenuation value greater than 70 HU. RESULTS. For all readers, PCD CT myelography, in comparison with EID CT myelography, showed higher mean image noise (reader 1: 69.9 ± 18.5 [SD] vs 37.6 ± 15.2; reader 2: 59.5 ± 8.7 vs 49.3 ± 12.7; and reader 3: 57.6 ± 13.2 vs 42.1 ± 16.6), higher mean nerve root sleeve discernibility (reader 1: 81.6 ± 21.7 [SD] vs 30.4 ± 13.6; reader 2: 83.6 ± 10 vs 70.1 ± 18.9; and reader 3: 59.6 ± 13.5 vs 50.5 ± 14.4), and higher mean overall image quality (reader 1: 83.2 ± 20.0 [SD] vs 38.1 ± 13.5; reader 2: 80.1 ± 10.1 vs 72.4 ± 19.8; and reader 3: 57.8 ± 11.2 vs 51.9 ± 13.6) (all p < .05). Eleven patients had a definite CVF. Sensitivity and specificity of EID CT myelography and PCD CT myelography for the detection of definite CVF were 45% and 96% versus 64% and 85%, respectively, for reader 1; 36% and 100% versus 55% and 96%, respectively, for reader 2; and 57% and 100% versus 55% and 93%, respectively, for reader 3. The sensitivity was significantly higher for PCD CT myelography than for EID CT myelography for reader 1 and reader 2 (both p < .05) and was not significantly different between the two techniques for reader 3 (p = .45); for all three readers, specificity was not significantly different between the two modalities (all p > .05). CONCLUSION. In comparison with EID CT myelography, PCD CT myelography yielded significantly improved image quality with significantly higher sensitivity for CVFs (for two of three readers), without significant loss of specificity. CLINICAL IMPACT. The findings support a potential role for PCD CT myelography in facilitating earlier diagnosis and targeted treatment of SIH, avoiding high morbidity during potentially prolonged diagnostic workups.

Evaluation of a long day care intervention targeting the mealtime environment and curriculum to increase children's vegetable intake: a cluster randomised controlled trial using the multiphase optimisation strategy framework.

OBJECTIVE: To determine the reach, adoption, implementation and effectiveness of an intervention to increase children's vegetable intake in long day care (LDC). DESIGN: A 12-week pragmatic cluster randomised controlled trial, informed by the multiphase optimisation strategy (MOST), targeting the mealtime environment and curriculum. Children's vegetable intake and variety was measured at follow-up using a modified Short Food Survey for early childhood education and care and analysed using a two-part mixed model for non-vegetable and vegetable consumers. Outcome measures were based on the RE-AIM framework. SETTING: Australian LDC centres. PARTICIPANTS: Thirty-nine centres, 120 educators and 719 children at follow-up. RESULTS: There was no difference between intervention and waitlist control groups in the likelihood of consuming any vegetables when compared with non-vegetable consumers for intake (OR = 0·70, (95 % CI 0·34-1·43), P = 0·32) or variety (OR = 0·73 (95 % CI 0·40-1·32), P = 0·29). Among vegetable consumers (n 652), there was no difference between groups in vegetable variety (exp(b): 1·07 (95 % CI:0·88-1·32, P = 0·49) or vegetable intake (exp(b): 1·06 (95 % CI: 0·78, 1·43)), P = 0·71) with an average of 1·51 (95 % CI 1·20-1·82) and 1·40 (95 % CI 1·08-1·72) serves of vegetables per day in the intervention and control group, respectively. Intervention educators reported higher skills for promoting vegetables at mealtimes, and knowledge and skills for teaching the curriculum, than control (all P < 0·001). Intervention fidelity was moderate (n 16/20 and n 15/16 centres used the Mealtime environment and Curriculum, respectively) with good acceptability among educators. The intervention reached 307/8556 centres nationally and was adopted by 22 % eligible centres. CONCLUSIONS: The pragmatic self-delivered online intervention positively impacted educator's knowledge and skills and was considered acceptable and feasible. Intervention adaptations, using the MOST cyclic approach, could improve intervention impact on children' vegetable intake.

Final analysis of the phase 3 randomized clinical trial comparing HD201 vs. referent trastuzumab in patients with ERBB2-positive breast cancer treated in the neoadjuvant setting.

BACKGROUND: The TROIKA trial established that HD201 and trastuzumab were equivalent in terms of primary endpoints (total pathological complete response) following neoadjuvant treatment. The objective of the present analysis was to compare survival outcomes and final safety. METHODS: In the TROIKA trial, patients with ERBB2-positive early breast cancer were randomized and treated with either HD201 or the referent trastuzumab. Eligible patients received 8 cycles of either HD201 or referent trastuzumab (loading dose, 8 mg/kg; maintenance dose, 6 mg/kg) every 3 weeks in combination with 8 cycles of chemotherapy (4 cycles of docetaxel, 75 mg/m2, followed by 4 cycles of epirubicin, 75 mg/m2, and cyclophosphamide, 500 mg/m2) in the neoadjuvant setting. The patients then underwent surgery followed by 10 cycles of adjuvant HD201 or referent trastuzumab according to their initial randomization to complete one year of trastuzumab-directed therapy. Event-free and overall survival rates were calculated using Kaplan-Meier analysis. The hazard ratio for event-free survival was estimated by Cox proportional hazards regression. RESULTS: The final analysis was performed after all patients completed the study at a median follow-up of 37.7 months (Q1-Q3, 37.3-38.1 months). A total of 502 randomized patients received either HD201 or the referent trastuzumab, and 474 (94.2%) were eligible for inclusion in the per-protocol set. In this population, the 3-year event-free survival rates were 85.6% (95% CI: 80.28-89.52) and 84.9% (95% CI: 79.54-88.88) in the HD201 and referent trastuzumab groups, respectively (log rank p = 0.938) (HR 1.02, 95% CI: 0.63-1.63; p = 0.945). The 3-year overall survival rates were comparable between the HD201 (95.6%; 95% CI: 91.90-97.59) and referent trastuzumab treatment groups (96.0%, 95% CI: 92.45-97.90) (log rank p = 0.606). During the posttreatment follow-up period, adverse events were reported for 64 (27.4%) and 72 (29.8%) patients in the HD201 and the reference trastuzumab groups, respectively. Serious adverse events were rare and none of which were related to the study treatment. CONCLUSIONS: This final analysis of the TROIKA trial further confirms the comparable efficacy and safety of HD201 and trastuzumab. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03013504.

RNA targeting with CRISPR-Cas13.

RNA has important and diverse roles in biology, but molecular tools to manipulate and measure it are limited. For example, RNA interference can efficiently knockdown RNAs, but it is prone to off-target effects, and visualizing RNAs typically relies on the introduction of exogenous tags. Here we demonstrate that the class 2 type VI RNA-guided RNA-targeting CRISPR-Cas effector Cas13a (previously known as C2c2) can be engineered for mammalian cell RNA knockdown and binding. After initial screening of 15 orthologues, we identified Cas13a from Leptotrichia wadei (LwaCas13a) as the most effective in an interference assay in Escherichia coli. LwaCas13a can be heterologously expressed in mammalian and plant cells for targeted knockdown of either reporter or endogenous transcripts with comparable levels of knockdown as RNA interference and improved specificity. Catalytically inactive LwaCas13a maintains targeted RNA binding activity, which we leveraged for programmable tracking of transcripts in live cells. Our results establish CRISPR-Cas13a as a flexible platform for studying RNA in mammalian cells and therapeutic development.

Disrupting future discounting: a commentary on an underutilised psychological approach for improving adherence to diet and physical activity interventions.

Non-communicable diseases (NCD) such as CVD and type 2 diabetes mellitus are major contributors to the burden of disease. NCD are largely driven by modifiable lifestyle factors including poor diet and insufficient physical activity, and consequently, prevention is a public health priority. Although diet and physical activity levels can be improved via lifestyle interventions, long-term adherence to such interventions remains low, which limits their effectiveness. Thus, it is critical to identify the underlying mechanisms that challenge uptake and adherence to such interventions. The current commentary discusses an important, but underexplored, psychological driver of poor adherence to lifestyle interventions, namely, future discounting, which describes the tendency to prefer smaller, short-term rewards over larger, long-term rewards. For example, in the nutrition domain, future discounting refers to valuing the immediate reward of excessive intake of energy-dense, nutrient-poor, discretionary foods high in salt, sugar, and saturated fat, and insufficient intake of low-energy, nutrient-dense, whole foods such as vegetables. Prominent theoretical models propose that excessive future discounting is a major contributor to the development of unhealthy lifestyle behaviours. Furthermore, a vast body of evidence suggests that future discounting plays a key role in risk of NCD. Thus, the evidence to date supports the idea that future discounting is an important multi-behaviour target for supporting lifestyle behaviour change; however, this approach has been largely neglected in preventive health efforts. Furthermore, this commentary discusses promising techniques (e.g. Episodic Future Thinking) for disrupting future discounting to promote improved adherence to lifestyle interventions aimed at reducing NCD risk.

Evaluation of a menu box delivery service for Australian long-day care services to improve food provision and child intake: a cluster randomised controlled trial.

OBJECTIVE: To evaluate the impact of a menu box delivery service tailored to the long-day care (LDC) setting on improving menu compliance with recommendations, children's diet quality and dietary intake while in care. DESIGN: A cluster randomised controlled trial in LDC centres randomly assigned to an intervention (menu box delivery) or comparison (menu planning training) group. The primary outcome was child food provision and dietary intake. Secondary outcomes include menu compliance and process evaluation, including acceptability, fidelity and menu cost (per child, per day). SETTING: South Australian LDC centres. PARTICIPANTS: Eight LDC centres (n 224 children) provided data. RESULTS: No differences were observed in serves/d between intervention and comparison centres, for provision (intervention, 0·9 inter-quartile range (IQR) 0·7-1·2; comparison, 0·8 IQR 0·5-1·3) or consumption (intervention, 0·5 IQR 0·2-0·8; comparison, 0·5 IQR 0·3-0·9) of vegetables. Child food provision and dietary intake were similar across both groups for all food groups (P < 0·05). At follow-up, all intervention centres met menu planning guidelines for vegetables, whereas only one comparison centre met guidelines. Intervention centre directors found the menu box delivery more acceptable than cooks. Cost of the intervention was AUD$2·34 greater than comparison centres (intervention, AUD$4·62 (95 % CI ($4·58, $4·67)); comparison, AUD$2·28 (95 % CI ($2·27, $2·30)) per child, per day). CONCLUSIONS: Menu compliance can be improved via a menu delivery service, delivering equivalent impacts on child food provision and dietary intake compared with an online training programme. Further exploration of cooks acceptability and cost is essential before scaling up to implementation.

Development of an initiatives package to increase children's vegetable intake in long day care centres using the Multiphase Optimisation Strategy (MOST) randomised factorial experiment.

OBJECTIVE: To inform a package of initiatives to increase children's vegetable intake while in long day care (LDC) by evaluating the independent and combined effects of three initiatives targeting food provision, the mealtime environment and the curriculum. DESIGN: Using the Multiphase Optimisation Strategy (MOST) framework, a 12-week, eight-condition (n 7 intervention, n 1 control) randomised factorial experiment was conducted. Children's dietary intake data were measured pre- and post-initiative implementation using the weighed plate waste method (1× meal and 2× between-meal snacks). Vegetable intake (g/d) was calculated from vegetable provision and waste. The optimal combination of initiatives was determined using a linear mixed-effects model comparing between-group vegetable intake at follow-up, while considering initiative fidelity and acceptability. SETTING: LDC centres in metropolitan Adelaide, South Australia. PARTICIPANTS: 32 centres, 276 staff and 1039 children aged 2-5 years. RESULTS: There were no statistically significant differences between any of the intervention groups and the control group for vegetable intake (all P > 0·05). The curriculum with mealtime environment group consumed 26·7 g more vegetables/child/day than control (ratio of geometric mean 3·29 (95 % CI 0·96, 11·27), P = 0·06). Completion rates for the curriculum (> 93 %) and mealtime environment (61 %) initiatives were high, and acceptability was good (4/5 would recommend), compared with the food provision initiative (0-50 % completed the menu assessment, 3/5 would recommend). CONCLUSION: A programme targeting the curriculum and mealtime environment in LDC may be useful to increase children's vegetable intake. Determining the effectiveness of this optimised package in a randomised controlled trial is required, as per the evaluation phase of the MOST framework.

Working together to increase Australian children's liking of vegetables: a position statement by the Vegetable Intake Strategic Alliance (VISA).

Children need to be repeatedly and consistently exposed to a variety of vegetables from an early age to achieve an increase in vegetable intake. A focus on enjoyment and learning to like eating vegetables at an early age is critical to forming favourable lifelong eating habits. Coordinated work is needed to ensure vegetables are available and promoted in a range of settings, using evidence-based initiatives, to create an environment that will support children's acceptance of vegetables. This will help to facilitate increased intake and ultimately realise the associated health benefits. The challenges and evidence base for a new approach are described.

Short-term risk prediction after major lower limb amputation: PERCEIVE study.

BACKGROUND: The accuracy with which healthcare professionals (HCPs) and risk prediction tools predict outcomes after major lower limb amputation (MLLA) is uncertain. The aim of this study was to evaluate the accuracy of predicting short-term (30 days after MLLA) mortality, morbidity, and revisional surgery. METHODS: The PERCEIVE (PrEdiction of Risk and Communication of outcomE following major lower limb amputation: a collaboratIVE) study was launched on 1 October 2020. It was an international multicentre study, including adults undergoing MLLA for complications of peripheral arterial disease and/or diabetes. Preoperative predictions of 30-day mortality, morbidity, and MLLA revision by surgeons and anaesthetists were recorded. Probabilities from relevant risk prediction tools were calculated. Evaluation of accuracy included measures of discrimination, calibration, and overall performance. RESULTS: Some 537 patients were included. HCPs had acceptable discrimination in predicting mortality (931 predictions; C-statistic 0.758) and MLLA revision (565 predictions; C-statistic 0.756), but were poor at predicting morbidity (980 predictions; C-statistic 0.616). They overpredicted the risk of all outcomes. All except three risk prediction tools had worse discrimination than HCPs for predicting mortality (C-statistics 0.789, 0.774, and 0.773); two of these significantly overestimated the risk compared with HCPs. SORT version 2 (the only tool incorporating HCP predictions) demonstrated better calibration and overall performance (Brier score 0.082) than HCPs. Tools predicting morbidity and MLLA revision had poor discrimination (C-statistics 0.520 and 0.679). CONCLUSION: Clinicians predicted mortality and MLLA revision well, but predicted morbidity poorly. They overestimated the risk of mortality, morbidity, and MLLA revision. Most short-term risk prediction tools had poorer discrimination or calibration than HCPs. The best method of predicting mortality was a statistical tool that incorporated HCP estimation.

Effect of expanded dulaglutide weekly doses (3.0 mg and 4.5 mg) on cardiovascular disease risk factors in participants with type 2 diabetes at increased cardiovascular disease risk: a post hoc analysis of the AWARD-11 study.

AIMS: This post hoc analysis investigated the effect of dulaglutide on cardiovascular disease (CVD) risk factors in subgroups of participants at increased CVD risk in the AWARD-11 study. METHODS: Participants who received once weekly dulaglutide 1.5, 3.0 or 4.5 mg for 52 weeks were categorized according to their baseline Framingham CVD risk category [low (N = 295), medium (N = 481) and high (N = 1054) risk], as well as their baseline CVD risk according to the REWIND study eligibility criteria (N = 953). Serum lipids and vital signs were assessed at baseline and at 52 weeks. Data were analysed as least squares mean percentage change from baseline for lipids and least squares mean change from baseline for vital signs. RESULTS: Demographic and baseline clinical characteristics were balanced across doses within the CVD risk groups. In the high Framingham CVD risk and REWIND-like groups, dulaglutide resulted in dose-related decreases in total cholesterol (≤6.0%), non-high-density lipoprotein cholesterol (≤8.8%), very-low-density lipoprotein cholesterol (≤19.4%) and triglycerides (≤21.5%), with little change in low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. Systolic and diastolic blood pressure decreased up to 5.6 mmHg and 1.6 mmHg, respectively, and heart rate increased up to 2 beats/min. CONCLUSIONS: This post hoc analysis suggests the magnitude of the favourable effects of dulaglutide 3.0 mg and 4.5 mg on several cardiometabolic CVD risk factors was similar to, if not greater than, those of dulaglutide 1.5 mg among participants with type 2 diabetes and increased CVD risk. CLINICALTRIALS: gov Identifier: NCT03495102.

Sensory swap: Modelling the impact of swapping discretionary choices for similar tasting core foods on the energy, nutrients and sensory properties of Australian diets.

Food choice is strongly driven by the sensory characteristics of foods with sweet, salty and fatty mouthfeel considered highly palatable and rewarding. Attempts to improve diet quality have not addressed sensory characteristics of diets before. This report describes a data modelling exercise that could underpin a dietary strategy to help support consumption of higher quality diets without compromising sensory preferences. This study used the Australian National Nutrition and Physical Activity Survey data (in 9341 adults) and the CSIRO sensory-diet database. A method was developed to find core food swaps which had a similar sensory profile as discretionary foods. This study investigated the impact of such swaps on energy and nutrient intake and the impact of the swaps on servings of food groups. The modelling resulted in a similar sensory profile of core foods to that of discretionary foods with hardness, sweetness and fatty mouthfeel all within 1-3% but the saltiness approached a 4% change. There was a small (3.6%) increase in energy intake. This swap strategy decreased the intake of risk nutrients such as saturated fat and added sugars, but not sodium, while increasing the intake of beneficial nutrients like calcium, zinc and vitamin C. Results also show that there was an increase in the intake of servings of core food groups such as fruits, grains, and dairy products but little change in vegetables. In conclusion, similar sensory swaps are possible and could underpin a diet strategy, that could be further refined through food appropriateness, to improve quality.

Differential impacts of economic and demographic variables on substance use patterns during the COVID-19 pandemic.

Background: The COVID-19 pandemic and subsequent economic crisis has provided a unique opportunity to investigate the effects of economic shifts on substance use. Existing literature on this relationship is limited and conflicting, warranting further exploration.Objective: This study aimed to identify relationships between socioeconomic status (SES), demographic variables, and substance use patterns before and after government-mandated business closures due to COVID-19.Methods: Participants were recruited based on self-reported substance use through Amazon's Mechanical Turk (MTurk). Qualifying participants (N = 315, 43% female, mean age = 35.35) reported their substance use and SES for two-week periods before and after pandemic-related business closures. Regression models analyzed relationships between substance use and study variables.Results: Regression models found that, during COVID-19 closures, greater financial strain predicted decreased benzodiazepine (ß = -1.12) and tobacco (ß = 1.59) use. Additionally, certain predictor variables (e.g., participants' age [ß = 1.22], race [ß = -4.43], psychiatric disorders including ADHD [ß = -2.73] and anxiety [ß = 1.53], and concomitant substance use [ß = 3.38]) predicted changes in substance use patterns; however, the directionality of these associations varied across substances.Conclusion: Specific substance use patterns were significantly and differentially impacted by economic strain, psychiatric diagnoses, and concomitant substance use. These results can help direct harm reduction efforts toward populations at greatest risk of harmful substance use following the pandemic.

Training Staff to Create Equivalence-Based Instruction Materials in Qualtrics.

Staff training is an important line of research to ensure that clinicians in the field of applied behavior analysis provide quality services. One approach to providing training involves the use of asynchronous training materials in which the trainer and trainee do not need to be physically present at the same time. This allows for training despite limited numbers of trainers or geographic restrictions. The purpose of this study was to train participants to create equivalence-based instruction (EBI) materials in Qualtrics, a commercial survey software package. In the first phase of the study, participants experienced a training package consisting of a video model and task analysis that described how to create EBI materials. Phase 2, evaluated whether the EBI materials created in Phase 1 led to equivalence-based responding. Results indicated that the training was effective for training staff and that staff found the training socially acceptable. Results also demonstrated that the EBI materials resulted in the learning of the trained and derived relations. Supplementary Information: The online version contains supplementary material available at 10.1007/s40732-021-00497-4.

Author Correction: High-speed volumetric imaging of neuronal activity in freely moving rodents.

In the version of this Brief Communication originally published online, ref. 21 included details for a conference paper (Pegard, N. C. et al. Paper presented at Novel Techniques in Microscopy: Optics in the Life Sciences, Vancouver, BC, Canada, 12-15 April 2015). The correct reference is the following: Pégard, N. C. et al. Optica 3, 517-524 (2016). This error has been corrected in the print, HTML and PDF versions of the paper.

High-speed volumetric imaging of neuronal activity in freely moving rodents.

Thus far, optical recording of neuronal activity in freely behaving animals has been limited to a thin axial range. We present a head-mounted miniaturized light-field microscope (MiniLFM) capable of capturing neuronal network activity within a volume of 700 × 600 × 360 µm3 at 16 Hz in the hippocampus of freely moving mice. We demonstrate that neurons separated by as little as ~15 µm and at depths up to 360 µm can be discriminated.

Learning Brain Dynamics With Coupled Low-Dimensional Nonlinear Oscillators and Deep Recurrent Networks.

Many natural systems, especially biological ones, exhibit complex multivariate nonlinear dynamical behaviors that can be hard to capture by linear autoregressive models. On the other hand, generic nonlinear models such as deep recurrent neural networks often require large amounts of training data, not always available in domains such as brain imaging; also, they often lack interpretability. Domain knowledge about the types of dynamics typically observed in such systems, such as a certain type of dynamical systems models, could complement purely data-driven techniques by providing a good prior. In this work, we consider a class of ordinary differential equation (ODE) models known as van der Pol (VDP) oscil lators and evaluate their ability to capture a low-dimensional representation of neural activity measured by different brain imaging modalities, such as calcium imaging (CaI) and fMRI, in different living organisms: larval zebrafish, rat, and human. We develop a novel and efficient approach to the nontrivial problem of parameters estimation for a network of coupled dynamical systems from multivariate data and demonstrate that the resulting VDP models are both accurate and interpretable, as VDP's coupling matrix reveals anatomically meaningful excitatory and inhibitory interactions across different brain subsystems. VDP outperforms linear autoregressive models (VAR) in terms of both the data fit accuracy and the quality of insight provided by the coupling matrices and often tends to generalize better to unseen data when predicting future brain activity, being comparable to and sometimes better than the recurrent neural networks (LSTMs). Finally, we demonstrate that our (generative) VDP model can also serve as a data-augmentation tool leading to marked improvements in predictive accuracy of recurrent neural networks. Thus, our work contributes to both basic and applied dimensions of neuroimaging: gaining scientific insights and improving brain-based predictive models, an area of potentially high practical importance in clinical diagnosis and neurotechnology.

Glycaemic efficacy of an expanded dose range of dulaglutide according to baseline glycated haemoglobin (HbA1c) subgroup: Post hoc analysis of AWARD-11.

The AWARD-11 trial demonstrated the safety and efficacy of dulaglutide 3.0 and 4.5 mg compared to dulaglutide 1.5 mg in patients with type 2 diabetes inadequately controlled with metformin. This post hoc analysis examined the change from baseline in glycated haemoglobin (HbA1c) and proportions of patients achieving HbA1c <7% at weeks 36 and 52 with dulaglutide 1.5 mg, 3.0 mg or 4.5 mg across clinically relevant baseline HbA1c subgroups (<8%; 8.0% to < 9.0%; 9.0% to < 10%; and ≥ 10%). Mean reductions in HbA1c were observed across all baseline HbA1c subgroups at 36 weeks (range of HbA1c change: 1.5 mg: -1.0% to -2.2%; 3.0 mg: -1.2% to -2.5%; and 4.5 mg: -1.2% to -3.2%). More patients randomized to 3.0 mg or 4.5 mg (vs. 1.5 mg) achieved HbA1c <7% at 36 weeks regardless of baseline HbA1c; the difference in proportions was greater at higher baseline HbA1c (P-interaction = 0.096). Similar patterns in glycaemic improvement and proportions achieving HbA1c <7% were observed at 52 weeks. Hypoglycaemia and gastrointestinal adverse events were similar among the HbA1c subgroups. Glycaemic control was improved with dulaglutide dose escalation from 1.5 mg to 3.0 mg or 4.5 mg across baseline HbA1c subgroups (<8%; 8.0% to < 9.0%; 9.0% to < 10%; and ≥ 10%).

Efficacy and safety of dulaglutide 3.0 and 4.5 mg in patients aged younger than 65 and 65 years or older: Post hoc analysis of the AWARD-11 trial.

AIM: To evaluate the efficacy and safety of dulaglutide 3.0 and 4.5 mg versus 1.5 mg when used as an add-on to metformin in subgroups defined by age (<65 and ≥65 years). MATERIALS AND METHODS: Of 1842 patients included in this post hoc analysis, 438 were aged 65 years or older and 1404 were younger than 65 years. The intent-to-treat (ITT) population, while on treatment without rescue medication, was used for all efficacy analyses; the ITT population without rescue medication was used for hypoglycaemia analyses; all other safety analyses used the ITT population. RESULTS: Patients aged 65 years or older and those younger than 65 years had a mean age of 69.5 and 53.2 years, respectively. In each age subgroup, the reduction from baseline in HbA1c and body weight (BW), and the proportion of patients achieving a composite endpoint of HbA1c of less than 7% (<53 mmol/mol) with no weight gain and no documented symptomatic or severe hypoglycaemia, were larger for dulaglutide 3.0 and 4.5 mg compared with dulaglutide 1.5 mg, but the treatment-by-age interactions were not significant. The safety profile for the additional dulaglutide doses was consistent with that of dulaglutide 1.5 mg and was similar between the age subgroups. CONCLUSION: Dulaglutide doses of 3.0 or 4.5 mg provided clinically relevant, dose-related improvements in HbA1c and BW with no significant treatment-by-age interactions, and with a similar safety profile across age subgroups.