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Background: Physical activity can support smoking cessation for smokers wanting to quit, but there have been no studies on supporting smokers wanting only to reduce. More broadly, the effect of motivational support for such smokers is unclear. Objectives The objectives were to determine if motivational support to increase physical activity and reduce smoking for smokers not wanting to immediately quit helps reduce smoking and increase abstinence and physical activity, and to determine if this intervention is cost-effective. Design This was a multicentred, two-arm, parallel-group, randomised (1 : 1) controlled superiority trial with accompanying trial-based and model-based economic evaluations, and a process evaluation. Setting and participants Participants from health and other community settings in four English cities received either the intervention (n = 457) or usual support (n = 458). Intervention The intervention consisted of up to eight face-to-face or telephone behavioural support sessions to reduce smoking and increase physical activity. Main outcome measures The main outcome measures were carbon monoxide-verified 6- and 12-month floating prolonged abstinence (primary outcome), self-reported number of cigarettes smoked per day, number of quit attempts and carbon monoxide-verified abstinence at 3 and 9 months. Furthermore, self-reported (3 and 9 months) and accelerometer-recorded (3 months) physical activity data were gathered. Process items, intervention costs and cost-effectiveness were also assessed. Results The average age of the sample was 49.8 years, and participants were predominantly from areas with socioeconomic deprivation and were moderately heavy smokers. The intervention was delivered with good fidelity. Few participants achieved carbon monoxide-verified 6-month prolonged abstinence [nine (2.0%) in the intervention group and four (0.9%) in the control group; adjusted odds ratio 2.30 (95% confidence interval 0.70 to 7.56)] or 12-month prolonged abstinence [six (1.3%) in the intervention group and one (0.2%) in the control group; adjusted odds ratio 6.33 (95% confidence interval 0.76 to 53.10)]. At 3 months, the intervention participants smoked fewer cigarettes than the control participants (21.1 vs. 26.8 per day). Intervention participants were more likely to reduce cigarettes by ≥ 50% by 3 months [18.9% vs. 10.5%; adjusted odds ratio 1.98 (95% confidence interval 1.35 to 2.90] and 9 months [14.4% vs. 10.0%; adjusted odds ratio 1.52 (95% confidence interval 1.01 to 2.29)], and reported more moderate-to-vigorous physical activity at 3 months [adjusted weekly mean difference of 81.61 minutes (95% confidence interval 28.75 to 134.47 minutes)], but not at 9 months. Increased physical activity did not mediate intervention effects on smoking. The intervention positively influenced most smoking and physical activity beliefs, with some intervention effects mediating changes in smoking and physical activity outcomes. The average intervention cost was estimated to be £239.18 per person, with an overall additional cost of £173.50 (95% confidence interval −£353.82 to £513.77) when considering intervention and health-care costs. The 1.1% absolute between-group difference in carbon monoxide-verified 6-month prolonged abstinence provided a small gain in lifetime quality-adjusted life-years (0.006), and a minimal saving in lifetime health-care costs (net saving £236). Conclusions There was no evidence that behavioural support for smoking reduction and increased physical activity led to meaningful increases in prolonged abstinence among smokers with no immediate plans to quit smoking. The intervention is not cost-effective. Limitations Prolonged abstinence rates were much lower than expected, meaning that the trial was underpowered to provide confidence that the intervention doubled prolonged abstinence. Future work Further research should explore the effects of the present intervention to support smokers who want to reduce prior to quitting, and/or extend the support available for prolonged reduction and abstinence. Trial registration This trial is registered as ISRCTN47776579. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 4. See the NIHR Journals Library website for further project information. Plain language summary: NHS pharmacological and behavioural support helps smokers wanting to quit, and physical activity may also help. It is unclear if behavioural support for those not ready to quit may lead to more quit attempts and abstinence from smoking. A total of 915 smokers who wanted to reduce their smoking, but who had not yet quit, were recruited and randomised to receive an intervention or brief support as usual (brief advice to quit), in Plymouth, London, Oxford and Nottingham. The intervention involved up to eight sessions (by telephone or in person) of motivational support to reduce smoking and increase physical activity (and more sessions to support a quit attempt). Participants self-reported smoking and physical activity information at the start of the trial and after 3 and 9 months. Self-reported quitters confirmed their abstinence with a biochemical test of expired air or saliva. Our main interest was in whether or not the groups differed in the proportion who remained abstinent for at least 6 months. Overall, only 1–2% remained abstinent for 6 months. Although it appeared that a greater proportion did so after receiving the intervention, because few participants were abstinent, the results are not conclusive. However, the intervention had beneficial effects on less rigorous outcomes, including a reduction in the self-reported number of cigarettes smoked, and a greater proportion of intervention than control participants with self-reported and biochemically verified abstinence at 3 months. The intervention also helped participants to reduce, by at least half, the number of cigarettes they smoked at 3 and 9 months, and to report more physical activity, but only at 3 months. Despite reasonable intervention engagement and some short-term changes in smoking and physical activity, the trial does not provide evidence that this intervention would help smokers to quit for at least 6 months nor would it be cost-effective, with an average cost of £239 per smoker. Scientific summary: Background Behavioural support to aid smoking cessation is an effective and cost-effective intervention for smokers wanting to quit. Motivational support can reduce smoking, with greater reductions leading to successful quitting, but the evidence is fairly weak for those not wanting to immediately quit. Smoking reduction studies may involve two types of smokers: (1) those who want to quit and are willing to reduce first rather than quit abruptly and (2) those who do not want to quit (immediately) but are interested in smoking reduction or harm reduction. At least four studies have investigated the effects of behavioural support for smokers wanting to reduce but not quit, and provide imprecise or no evidence of effects on smoking reduction, quitting and sustained abstinence. Exercise has been shown to aid smoking cessation for those wanting to quit, but there is only exploratory evidence that promoting physical activity (PA) and supporting smoking reduction can facilitate smoking reduction and quitting. A definitive study is needed to determine the effectiveness and cost-effectiveness of behavioural support for smoking reduction and increasing PA, on smoking outcomes, especially prolonged, carbon monoxide-verified smoking abstinence. Objectives The overall aim of the Trial of physical Activity-assisted Reduction of Smoking (TARS) was to determine if adding a motivational intervention to reduce smoking and increase PA to usual support was more effective and cost-effective in facilitating carbon monoxide-verified 6-month floating prolonged abstinence. The specific research questions were as follows. Compared with usual support, did the TARS intervention: increase the proportion of participants achieving carbon monoxide-verified 6-month floating prolonged abstinence at 9 months post baseline? increase the proportion of participants reporting a ≥ 50% reduction in the number of cigarettes smoked (between baseline and 3 months, and baseline and 9 months)? increase the proportion of participants achieving carbon monoxide-verified 12-month floating prolonged abstinence at 15 months post baseline? increase the proportion of participants achieving self-reported and carbon monoxide-verified point prevalence abstinence at 3 and 9 months post baseline? increase self-reported PA at 3 and 9 months post baseline, and accelerometer-assessed PA at 3 months post baseline? improve body mass index, quality of life, sleep, cigarette cravings and other beliefs about smoking and PA at 3 and 9 months post baseline? What were the intervention, health-care and social care costs, compared with support as usual, at 9 months post baseline? Was the intervention cost-effective, compared with usual support, (1) at 9 months, and (2) over a longer-term/lifetime horizon? Were the trial methods and intervention acceptable and feasible, based on an embedded internal pilot phase? Did the intervention demonstrate good fidelity (design, training, delivery, receipt and enactment) and acceptability and what were the mechanisms of action of the intervention? Methods The study involved a multicentred, parallel, two-group, individually randomised controlled, superiority trial with a mixed-methods embedded process evaluation and economic evaluations. Recruitment took place over 16 months from January 2018, with follow-up assessments ending in October 2020 (with only minimal overlap with COVID-19 restrictions) around four English cities: Plymouth, Nottingham, London and Oxford. Intervention participants were offered up to eight face-to-face or telephone behavioural support sessions to reduce smoking and increase PA, with up to six additional sessions if a participant wanted support with cessation. Substantial patient and public involvement supported both the development and evaluation of a pilot trial of the intervention, and adaptations for the present intervention. An intervention manual underpinned the training and remote supervision of eight health trainers (HTs) across four sites, and all aspects of intervention fidelity (design, training, receipt, delivery and enactment) were assessed. The client-centred intervention was informed by motivational interviewing and linked to self-determination theory. It aimed to empower participants to decide what support they required, and where, when and for how long, and, if the participant became ready to quit, to provide appropriate support. Control participants received brief advice on smoking cessation. Participants were recruited from primary and secondary care and community settings. Participants were adult smokers (≥ 18 years) who smoked ≥ 10 cigarettes per day (for at least 1 year), who wanted to reduce smoking but not quit immediately. Smokers were ineligible if they were unable to engage in at least 15 minutes of moderate-intensity PA, had any illness or injury that might be exacerbated by exercise, or were unable to engage in the trial and/or the intervention because of a language barrier or for other reasons. Following screening and consent, participants completed baseline assessments face to face or via telephone. At 3 and 9 months post baseline, participants were posted a questionnaire (and an accelerometer at 3 months for a random sample). Participants reporting having made a quit attempt and not having smoked at follow-up were invited to complete a biochemical verification of abstinence. Most did this with a carbon monoxide expired air test, but a few were posted a saliva cotinine test kit late in the trial as a result of COVID-19 restrictions. Those with carbon monoxide-verified abstinence at 9 months were also followed up at 15 months. The primary outcome was carbon monoxide-verified 6-month floating prolonged (i.e. with no fixed quit date) abstinence between 3 and 9 months. Other smoking measures were carbon monoxide-verified 12-month floating prolonged abstinence, point prevalence self-reported abstinence and number of cigarettes smoked per day, and carbon monoxide-verified abstinence and number of quit attempts at both 3 and 9 months. Analyses of smoking abstinence outcomes were in line with the Russell Standard, with non-responders assumed to be still smoking. Self-reported (3 and 9 months) and accelerometer-recorded (3 months) PA, body mass index, sleep and quality of life were also assessed at 3 and 9 months. The embedded mixed-methods process evaluation was split into two phases: (1) an initial evaluation linked to the internal pilot phase and (2) the subsequent main trial phase, with four workstreams as follows – (1) data related to levels of intervention engagement; (2) assessment of intervention delivery, receipt and enactment fidelity, using survey items related to the intervention logic model and recorded intervention sessions; (3) mediation analyses of changes in PA and process measures on outcomes; and (4) an embedded qualitative study with HT and intervention participant interviews. The health economic evaluation included an estimation of the cost of delivering the intervention from data collected during the trial, supplemented by investigator estimates. A trial-based economic evaluation was conducted using patient-reported resource use and health-related quality of life (EuroQol-5 Dimensions, five-level version), collected in questionnaire booklets at baseline and at 3 and 9 months post randomisation. Aggregate costs and quality-adjusted life-years (QALYs) over a 9-month time horizon were estimated and regression methods were used to adjust for potential confounders. A decision-analytic model was developed following a review of the existing literature. Smoking cessation rates were assumed to affect rates of coronary obstructive pulmonary disease, coronary heart disease, stroke and lung cancer, as well as quality of life and other smoking-related causes of mortality. Lifetime costs and QALYs were estimated. Results The sample (n = 915) had a mean age of 49.8 [standard deviation (SD) 13.9] years; 55% were female and 85% identified as white. Sixty per cent lived within one of the four highest-ranked deciles for social deprivation. They initially smoked an average of 18.0 cigarettes daily, with 77.68% smoking within 30 minutes of waking, and reported doing a median of 337 minutes of moderate to vigorous physical activity (MVPA) weekly. Primary analysis Using the Russell Standard, assuming missing participant data at follow-up implied continued smoking, 0.9% (n = 4) of control and 2.0% (n = 9) of intervention participants achieved carbon monoxide-verified 6-month floating prolonged abstinence between 3 and 9 months. This difference was not statistically significant [fully adjusted estimated odds ratio 2.30, 95% confidence interval (CI) 0.70 to 7.56; p = 0.169]. Including participants who achieved the outcome between 9 and 15 months increased this to 2.2% (n = 10) and 3.1% (n = 14) in the control and intervention groups, respectively, which was also not statistically significantly different (fully adjusted estimated odds ratio 1.43, 95% CI 0.62 to 3.26; p = 0.398). For the 19 and 20 participants followed up at 15 months, 0.2% (n = 1) and 1.3% (n = 6) of the overall control and intervention groups, respectively, achieved carbon monoxide-verified 12-month floating prolonged abstinence, which was also not statistically significantly different (fully adjusted estimated odds ratio 6.3, 95% CI 0.8 to 53.1; p = 0.089). Secondary outcomes The intervention had weak effects on self-reported 7-day point prevalence abstinence at 3 months (5.5% vs. 2.9%, adjusted odds ratio 1.99, 95% CI 1.00 to 3.94; p = 0.049), but there was no evidence of a statistically significant effect on carbon monoxide-verified point prevalence abstinence at 3 months (3.7% vs. 1.8%, adjusted odds ratio 2.19, 95% CI 0.93 to 5.14; p = 0.071). Nor was there an intervention effect at 9 or 15 months, compared with control, for either of these outcomes. The intervention group reported smoking fewer cigarettes daily than the control group at 3 months (adjusted mean difference –5.62, 95% CI –9.80 to –1.44; p = 0.009), but not at 9 months (adjusted mean difference 0.95, 95% CI –5.37 to 3.46; p = 0.671). A greater proportion of intervention participants reported having reduced their daily number of cigarettes smoked by at least 50%, up to 3 months (18.9% vs. 10.5%, adjusted odds ratio 1.98, 95% CI 1.35 to 2.90; p

Photonic engineered materials have benefitted in recent years from exciting developments in computational electromagnetics and inverse-design tools. However, a commonly encountered issue is that highly performant and structurally complex functional materials found through inverse-design can lose significant performance upon being fabricated. This work introduces a method using deep learning (DL) to exhaustively analyze how structural issues affect the robustness of metasurface supercells, and we show how systems can be designed to guarantee significantly better performance. Moreover, we show that an exhaustive study of structural error is required to make strong guarantees about the performance of engineered materials. The introduction of DL into the inverse-design process makes this problem tractable, enabling optimization runtimes to be measurable in days rather than months and allowing designers to establish exhaustive metasurface robustness guarantees.

Optical metasurfaces, planar subwavelength nanoantenna arrays with the singular ability to sculpt wavefront in almost arbitrary manners, are poised to become a powerful tool enabling compact and high-performance optics with novel functionalities. A particularly intriguing research direction within this field is active metasurfaces, whose optical response can be dynamically tuned postfabrication, thus allowing a plurality of applications unattainable with traditional bulk optics. Designing reconfigurable optics based on active metasurfaces is, however, presented with a unique challenge, since the optical quality of the devices must be optimized at multiple optical states. In this article, we provide a critical review on the active meta-optics design principles and algorithms that are applied across structural hierarchies ranging from single meta-atoms to full meta-optical devices. The discussed approaches are illustrated by specific examples of reconfigurable metasurfaces based on optical phase-change materials.

The PHENIX experiment at RHIC has measured the dielectron continuum and the ω and ϕ light vector mesons using hadronic and dielectron decay channels in √sNN = 200 GeV p+p, d+Au, Cu+Cu and Au+Au collisions. The ω and ϕ mesons experience no strong cold nuclear matter effects but in central heavy ion collisions their yields are suppressed at high pT, extending to intermediate pT for the ϕ. The comparison of the ω and ϕ suppression to the suppression of other hadrons suggests parton energy loss for high pT mesons and favors a recombination production mechanism for intermediate pT ϕ mesons. The dielectron continuum shows a low mass excess in central Au+Au and Cu+Cu collisions while the p+p and d+Au spectra agree with their respective cocktails. The low mass excess consists of a high pT thermal virtual photon component and a much larger low pT component.

Abstract The concept of the Knowledge Translation Platform (KTP) provides cohesion and leadership for national–level knowledge translation efforts. In this review, we discuss nine key lessons documenting the experience of the Zambia Forum for Health Research, primarily to inform and exchange experience with the growing community of African KTPs. Lessons from ZAMFOHR’s organizational development include the necessity of selecting a multi-stakeholder and -sectoral Board of Directors; performing comprehensive situation analyses to understand not only the prevailing research-and-policy dynamics but a precise operational niche; and selecting a leader that bridges the worlds of research and policy. Programmatic lessons include focusing on building the capacity of both policy-makers and researchers; building a database of local evidence and national-level actors involved in research and policy; and catalyzing work in particular issue areas by identifying leaders from the research community, creating policy-maker demand for research evidence, and fostering the next generation by mentoring both up-and-coming researchers and policy–makers. Ultimately, ZAMFOHR’s experience shows that an African KTP must pay significant attention to its organizational details. A KTP must also invest in the skill base of the wider community and, more importantly, of its own staff. Given the very real deficit of research-support skills in most low-income countries – in synthesis, in communications, in brokering, in training – a KTP must spend significant time and resources in building these types of in-house expertise. And lastly, the role of networking cannot be underestimated. As a fully-networked KTP, ZAMFOHR has benefited from the innovations of other KTPs, from funding opportunities and partnerships, and from invaluable technical support from both African and northern colleagues.

Abstract For many sub-Saharan African countries, a National Health Research System (NHRS) exists more in theory than in reality, with the health system itself receiving the majority of investments. However, this lack of attention to NHRS development can, in fact, frustrate health systems in achieving their desired goals. In this case study, we discuss the ongoing development of Zambia’s NHRS. We reflect on our experience in the ongoing consultative development of Zambia’s NHRS and offer this reflection and process documentation to those engaged in similar initiatives in other settings. We argue that three streams of concurrent activity are critical in developing an NHRS in a resource-constrained setting: developing a legislative framework to determine and define the system’s boundaries and the roles all actors will play within it; creating or strengthening an institution capable of providing coordination, management and guidance to the system; and focusing on networking among institutions and individuals to harmonize, unify and strengthen the overall capacities of the research community.

Abstract Background Blood pressure (BP) lowering in people who have had a stroke or transient ischaemic attack (TIA) leads to reduced risk of further stroke. However, it is not clear what the target BP should be, since intensification of therapy may lead to additional adverse effects. PAST BP will determine whether more intensive BP targets can be achieved in a primary care setting, and whether more intensive therapy is associated with adverse effects on quality of life. Methods/Design This is a randomised controlled trial (RCT) in patients with a past history of stroke or TIA. Patients will be randomised to two groups and will either have their blood pressure (BP) lowered intensively to a target of 130 mmHg systolic, (or by 10 mmHg if the baseline systolic pressure is between 125 and 140 mmHg) compared to a standard group where the BP will be reduced to a target of 140 mmHg systolic. Patients will be managed by their practice at 1-3 month intervals depending on level of BP and followed-up by the research team at six monthly intervals for 12 months. 610 patients will be recruited from approximately 50 general practices. The following exclusion criteria will be applied: systolic BP The primary outcome will be change in systolic BP over twelve months. Secondary outcomes include quality of life, adverse events and cardiovascular events. In-depth interviews with 30 patients and 20 health care practitioners will be undertaken to investigate patient and healthcare professionals understanding and views of BP management. Discussion The results of this trial will inform whether intensive blood pressure targets can be achieved in people who have had a stroke or TIA in primary care, and help determine whether or not further research is required before recommending such targets for this population. Trial Registration ISRCTN29062286

Antenatal depression and maternal nutrition can influence infant temperament. Although broad-spectrum-micronutrients (BSM: vitamins and minerals) given above Recommended Dietary Allowances during pregnancy can mitigate symptoms of antenatal depression, their associated effects on infant temperament are unknown. One hundred and fourteen New Zealand mother-infant dyads (45 infants exposed to BSM during pregnancy (range of exposure during pregnancy: 12-182 days) to treat antenatal depressive symptoms (measured by Edinburgh Postnatal Depression Scale) and 69 non-exposed infants) were followed antenatally and for 12 months postpartum to determine the influence of in utero BSM exposure on infant temperament. The Infant Behavior Questionnaire-Revised: Very Short-Form assessed temperament at 4 (T1), 6 (T2) and 12 (T3) months postpartum via online questionnaire. Latent growth curve modeling showed BSM exposure, antenatal depression and infant sex did not statistically significantly predict initial levels or longitudinal changes in orienting/regulatory capacity (ORC), positive affectivity/surgency (PAS) or negative affectivity (NEG). Higher gestational age was positively associated with initial PAS, and smaller increases between T1 and T3. Breastfeeding occurrence was positively associated with initial NEG. Although not significant, BSM exposure exerted small, positive effects on initial NEG ( β  = -0.116) and longitudinal changes in ORC ( β  = 0.266) and NEG ( β  = -0.235). While BSM exposure did not significantly predict infant temperament, it may mitigate risks associated with antenatal depression. BSM-exposed infants displayed temperamental characteristics on par with typical pregnancies, supporting the safety of BSM treatment for antenatal depression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Campbell, Dys, Henderson, Bradley and Rucklidge.)

Background: Antenatal depression is a risk factor for poor infant outcomes. Broad-spectrum-micronutrients (vitamins and minerals) have shown efficacy in treating psychiatric symptoms in non-pregnant populations and are associated with reduced incidence of adverse birth outcomes, and improvements in neonatal development. We investigated the effects of treatment of antenatal depression with micronutrients above the Recommended Dietary Allowance on infant development compared to treatment with antidepressant medications and controls., Method: One-hundred-and-three infants were assessed using the Brazelton Neonatal Behavioral Assessment Scale (NBAS) within 28 days of birth: 37 exposed to micronutrients in-utero (50-182 days exposure), 18 to antidepressants in-utero (exposure for full gestation), and 48 controls whose mothers received neither treatment nor experienced depressive symptoms., Results: Controlling for gestational age and parity, there were significant group differences on habituation, orientation, motor, state regulation, autonomic stability and reflexes (p < .05). Micronutrient-exposed performed better than antidepressant-exposed and controls on habituation, motor and autonomic stability (p < .05), effect sizes ranged 1.0-1.7 and 0.5-1.0, respectively. Antidepressant-exposed performed significantly worse on orientation and reflexes compared to micronutrient-exposed and controls. Micronutrient-exposed had significantly better state regulation compared to antidepressant-exposed. There was an association between micronutrient exposure length and better habituation (r = 0.41, p = .028). Micronutrient exposure was generally identified as a stronger predictor of neonatal performance over maternal depression, social adversity, gestational age and infant sex., Conclusion: In-utero micronutrient exposure appears to mitigate risks of depression on infant outcomes showing positive effects on infant behavior, on par with or better than typical pregnancies and superior to antidepressants. Limitations include differential exposure to micronutrients/antidepressants and lack of group blinding., Competing Interests: Declaration of competing interest None of the authors have any conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Although the mechanisms underlying dystonia are largely unknown, dystonia is often associated with abnormal dopamine neurotransmission. DOPA-responsive dystonia (DRD) is a prototype disorder for understanding dopamine dysfunction in dystonia because it is caused by mutations in genes necessary for the synthesis of dopamine and alleviated by the indirect-acting dopamine agonist l-DOPA. Although adaptations in striatal dopamine receptor-mediated intracellular signaling have been studied extensively in models of Parkinson's disease, another movement disorders associated with dopamine deficiency, little is known about dopaminergic adaptations in dystonia. To identify the dopamine receptor-mediated intracellular signaling associated with dystonia, we used immunohistochemistry to quantify striatal protein kinase A activity and extracellular signal-related kinase (ERK) phosphorylation after dopaminergic challenges in a knockin mouse model of DRD. l-DOPA treatment induced the phosphorylation of both protein kinase A substrates and ERK largely in D1 dopamine receptor-expressing striatal neurons. As expected, this response was blocked by pretreatment with the D1 dopamine receptor antagonist SCH23390. The D2 dopamine receptor antagonist raclopride also significantly reduced the phosphorylation of ERK; this contrasts with models of parkinsonism in which l-DOPA-induced ERK phosphorylation is not mediated by D2 dopamine receptors. Further, the dysregulated signaling was dependent on striatal subdomains whereby ERK phosphorylation was largely confined to dorsomedial (associative) striatum while the dorsolateral (sensorimotor) striatum was unresponsive. This complex interaction between striatal functional domains and dysregulated dopamine-receptor mediated responses has not been observed in other models of dopamine deficiency, such as parkinsonism, suggesting that regional variation in dopamine-mediated neurotransmission may be a hallmark of dystonia., (Copyright © 2023 IBRO. Published by Elsevier Ltd. All rights reserved.)

Networks of spiking neurons with adaption have been shown to be able to reproduce a wide range of neural activities, including the emergent population bursting and spike synchrony that underpin brain disorders and normal function. Exact mean-field models derived from spiking neural networks are extremely valuable, as such models can be used to determine how individual neurons and the network they reside within interact to produce macroscopic network behaviours. In the paper, we derive and analyze a set of exact mean-field equations for the neural network with spike frequency adaptation. Specifically, our model is a network of Izhikevich neurons, where each neuron is modeled by a two dimensional system consisting of a quadratic integrate and fire equation plus an equation which implements spike frequency adaptation. Previous work deriving a mean-field model for this type of network, relied on the assumption of sufficiently slow dynamics of the adaptation variable. However, this approximation did not succeed in establishing an exact correspondence between the macroscopic description and the realistic neural network, especially when the adaptation time constant was not large. The challenge lies in how to achieve a closed set of mean-field equations with the inclusion of the mean-field dynamics of the adaptation variable. We address this problem by using a Lorentzian ansatz combined with the moment closure approach to arrive at a mean-field system in the thermodynamic limit. The resulting macroscopic description is capable of qualitatively and quantitatively describing the collective dynamics of the neural network, including transition between states where the individual neurons exhibit asynchronous tonic firing and synchronous bursting. We extend the approach to a network of two populations of neurons and discuss the accuracy and efficacy of our mean-field approximations by examining all assumptions that are imposed during the derivation. Numerical bifurcation analysis of our mean-field models reveals bifurcations not previously observed in the models, including a novel mechanism for emergence of bursting in the network. We anticipate our results will provide a tractable and reliable tool to investigate the underlying mechanism of brain function and dysfunction from the perspective of computational neuroscience., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neural firing in many inhibitory networks displays synchronous assembly or clustered firing, in which subsets of neurons fire synchronously, and these subsets may vary with different inputs to, or states of, the network. Most prior analytical and computational modeling of such networks has focused on 1D networks or 2D networks with symmetry (often circular symmetry). Here, we consider a 2D discrete network model on a general torus, where neurons are coupled to two or more nearest neighbors in three directions (horizontal, vertical, and diagonal), and allow different coupling strengths in all directions. Using phase model analysis, we establish conditions for the stability of different patterns of clustered firing behavior in the network. We then apply our results to study how variation of network connectivity and the presence of heterogeneous coupling strengths influence which patterns are stable. We confirm and supplement our results with numerical simulations of biophysical inhibitory neural network models. Our work shows that 2D networks may exhibit clustered firing behavior that cannot be predicted as a simple generalization of a 1D network, and that heterogeneity of coupling can be an important factor in determining which patterns are stable., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Miller, Ryu, Wang, Booth and Campbell.)

Fatty acid (FA) signaling contributes to β-cell mass expansion in response to nutrient excess, but the underlying mechanisms are poorly understood. In the presence of elevated glucose, FA metabolism is shifted toward synthesis of complex lipids, including sphingolipids. Here, we tested the hypothesis that sphingolipids are involved in the β-cell proliferative response to FA. Isolated rat islets were exposed to FA and 16.7 mmol/L glucose for 48-72 h, and the contribution of the de novo sphingolipid synthesis pathway was tested using the serine palmitoyltransferase inhibitor myriocin, the sphingosine kinase (SphK) inhibitor SKI II, or knockdown of SphK, fatty acid elongase 1 (ELOVL1) and acyl-CoA-binding protein (ACBP). Rats were infused with glucose and the lipid emulsion ClinOleic and received SKI II by gavage. β-Cell proliferation was assessed by immunochemistry or flow cytometry. Sphingolipids were analyzed by liquid chromatography-tandem mass spectrometry. Among the FAs tested, only oleate increased β-cell proliferation. Myriocin, SKI II, and SphK knockdown all decreased oleate-induced β-cell proliferation. Oleate exposure did not increase the total amount of sphingolipids but led to a specific rise in 24:1 species. Knockdown of ACBP or ELOVL1 inhibited oleate-induced β-cell proliferation. We conclude that unsaturated very-long-chain sphingolipids produced from the available C24:1 acyl-CoA pool mediate oleate-induced β-cell proliferation in rats., (© 2022 by the American Diabetes Association.)

While critical for neurotransmitter synthesis, 14-3-3 proteins are often assumed to have redundant functions due to their ubiquitous expression, but despite this assumption, various 14-3-3 isoforms have been implicated in regulating metabolism. We previously reported contributions of 14-3-3ζ in β cell function, but these studies were performed in tumor-derived MIN6 cells and systemic KO mice. To further characterize the regulatory roles of 14-3-3ζ in β cell function, we generated β cell-specific 14-3-3ζ-KO mice. Although no effects on β cell mass were detected, potentiated glucose-stimulated insulin secretion (GSIS), mitochondrial function, and ATP synthesis were observed. Deletion of 14-3-3ζ also altered the β cell transcriptome, as genes associated with mitochondrial respiration and oxidative phosphorylation were upregulated. Acute 14-3-3 protein inhibition in mouse and human islets recapitulated the enhancements in GSIS and mitochondrial function, suggesting that 14-3-3ζ is the critical isoform in β cells. In dysfunctional db/db islets and human islets from type 2 diabetic donors, expression of Ywhaz/YWHAZ, the gene encoding 14-3-3ζ, was inversely associated with insulin secretion, and pan-14-3-3 protein inhibition led to enhanced GSIS and mitochondrial function. Taken together, this study demonstrates important regulatory functions of 14-3-3ζ in the regulation of β cell function and provides a deeper understanding of how insulin secretion is controlled in β cells.

In February 2020, burn prevention experts from a variety of professional backgrounds gathered for a national Burn Prevention Summit. Through lively discussion and debate, this group came to a consensus on several core burn prevention concepts in order to create a framework for burn prevention program planning. The resulting document includes components of a successful program, a five-step process for program planning, best practices in messaging, and general advice from the summit attendees. This framework is designed for both novice professionals who are new to burn prevention programming development and experienced professionals who would like to strengthen existing programming., (© American Burn Association 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Human papillomavirus (HPV) testing is the cornerstone of cervical cancer screening, with outstanding sensitivity but only moderate specificity. We evaluated whether reflex testing for cancer biomarkers improves the sensitivity/specificity balance of screening., Methods: Cervical samples from women in Cape Town, South Africa, ages 30-65 years, were collected and tested with Xpert HPV and with real-time PCR to detect mRNA for cyclin-dependent kinase inhibitor 2A (CDKN2A), topoisomerase 2 alpha (TOP2A), and Ki67 (MKi67). Women with histologically confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+; 85 women without and 166 with HIV) and women with no cervical disease (331 without and 257 with HIV) were included., Results: When used as reflex tests after a positive HPV result, biomarkers discriminated well between women with and without CIN2+. The inclusion of both CDKN2A and MKi67 had the best performance, with area under the curve (AUC) of 0.9171 and 0.8734 in women without and with HIV, respectively. Although excellent, these performance parameters did not improve on an approach utilizing only HPV testing with more stringent cycle threshold cutoffs and HPV genotype selection, which achieved AUC of 0.9059 and 0.8705 in women without and with HIV, respectively., Conclusions: Biomarkers can be used as triage after positive HPV results but do not outperform an approach utilizing higher viral load cutoffs on selected high-risk genotypes., Impact: A screening approach using HPV testing alone can be more easily implemented at the point of care., (©2022 American Association for Cancer Research.)

Objective: Social Pediatrics focuses on targeting and mitigating the effects of the social determinants of health on a child's well-being and development. Negative health outcomes have been seen in children who have faced poverty, food insecurity, inadequate housing, and traumatic events. In particular, children who come from socioeconomically disadvantaged households are more likely to develop behavioural problems. The purpose of this study is to explore the experiences of caregivers for children with a behaviour-related disorder. This includes children affected by attention, academic, and social issues (e.g. attention-deficit hyperactivity disorder, autism spectrum disorder). This study will aim to understand the strengths, barriers, and social limitations to accessing and receiving care for children with behavioural disorders.  Methods: A qualitative descriptive design was used to conduct three focus groups. Of the 64 caregivers contacted, a total of 13 participants agreed to be in the study. All focus groups were analyzed using inductive thematic analysis.  Results: Preliminary findings suggest that caregivers value pediatricians who spend time, communicate, and make a human connection with their patients. Barriers included physician turnover, long wait times for referrals, and a lack of knowledge regarding services and programs available in their area. Three major themes emerged from this study including (1) timeliness to care, (2) advocacy, and (3) relationship building., Conclusion: Findings suggested that caregivers valued pediatricians who spend time to make a human connection with their patients. Barriers included physician turnover, long wait times for referrals, and a lack of knowledge of available services. Caregivers who were young mothers felt an added layer of judgement when accessing the necessary care for their children. This study is important as it contributes to our knowledge on the role Social Pediatrics can play in the care of children with behaviour-related disorders., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Thevathasan et al.)

Controllable genetic manipulation is an indispensable tool in research, greatly advancing our understanding of cell biology and physiology. However in β-cells, transgene silencing, low inducibility, ectopic expression, and off-targets effects are persistent challenges. In this study, we investigated whether an inducible Tetracycline (Tet)-Off system with β-cell-specific mouse insulin promoter (MIP)-itTA-driven expression of tetracycline operon (TetO)-Cre Jaw/J could circumvent previous issues of specificity and efficacy. Following assessment of tissue-specific gene recombination, β-cell architecture, in vitro and in vivo glucose-stimulated insulin secretion, and whole-body glucose homeostasis, we discovered that expression of any tetracycline-controlled transactivator (e.g., improved itTA, reverse rtTA, or tTA) in β-cells significantly reduced Insulin gene expression and decreased insulin content. This translated into lower pancreatic insulin levels and reduced insulin secretion in mice carrying any tTA transgene, independent of Cre recombinase expression or doxycycline exposure. Our study echoes ongoing challenges faced by fundamental researchers working with β-cells and highlights the need for consistent and comprehensive controls when using the tetracycline-controlled transactivator systems (Tet-On or Tet-Off) for genome editing., (© 2021 by the American Diabetes Association.)

During pancreas development, endocrine progenitors differentiate into the islet cell subtypes, which undergo further functional maturation in postnatal islet development. In islet β-cells, genes involved in glucose-stimulated insulin secretion are activated, and glucose exposure increases the insulin response as β-cells mature. We investigated the role of H3K4 trimethylation in endocrine cell differentiation and functional maturation by disrupting TrxG complex histone methyltransferase activity in mouse endocrine progenitors. In the embryo, genetic inactivation of TrxG component Dpy30 in NEUROG3 + cells did not affect the number of endocrine progenitors or endocrine cell differentiation. H3K4 trimethylation was progressively lost in postnatal islets, and the mice displayed elevated nonfasting and fasting glycemia as well as impaired glucose tolerance by postnatal day 24. Although postnatal endocrine cell proportions were equivalent to controls, islet RNA sequencing revealed a downregulation of genes involved in glucose-stimulated insulin secretion and an upregulation of immature β-cell genes. Comparison of histone modification enrichment profiles in NEUROG3 + endocrine progenitors and mature islets suggested that genes downregulated by loss of H3K4 trimethylation more frequently acquire active histone modifications during maturation. Taken together, these findings suggest that H3K4 trimethylation is required for the activation of genes involved in the functional maturation of pancreatic islet endocrine cells., (© 2021 by the American Diabetes Association.)

Liver development is controlled by key signals and transcription factors that drive cell proliferation, migration, differentiation and functional maturation. In the adult liver, cell maturity can be perturbed by genetic and environmental factors that disrupt hepatic identity and function. Developmental signals and fetal genetic programmes are often dysregulated or reactivated, leading to dedifferentiation and disease. Here, we highlight signalling pathways and transcriptional regulators that drive liver cell development and primary liver cancers. We also discuss emerging models derived from pluripotent stem cells, 3D organoids and bioengineering for improved studies of signalling pathways in liver cancer and regenerative medicine., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

The human brain constitutes one of the most advanced networks produced by nature, consisting of billions of neurons communicating with each other. However, this communication is not in real-time, with different communication or time-delays occurring between neurons in different brain areas. Here, we investigate the impacts of these delays by modeling large interacting neural circuits as neural-field systems which model the bulk activity of populations of neurons. By using a Master Stability Function analysis combined with numerical simulations, we find that delays (1) may actually stabilize brain dynamics by temporarily preventing the onset to oscillatory and pathologically synchronized dynamics and (2) may enhance or diminish synchronization depending on the underlying eigenvalue spectrum of the connectivity matrix. Real eigenvalues with large magnitudes result in increased synchronizability while complex eigenvalues with large magnitudes and positive real parts yield a decrease in synchronizability in the delay vs. instantaneously coupled case. This result applies to networks with fixed, constant delays, and was robust to networks with heterogeneous delays. In the case of real brain networks, where the eigenvalues are predominantly real, owing to the nearly symmetric nature of these weight matrices, biologically plausible, small delays, are likely to increase synchronization, rather than decreasing it., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Al-Darabsah, Chen, Nicola and Campbell.)

Neurons in the inhibitory network of the striatum display cell assembly firing patterns which recent results suggest may consist of spatially compact neural clusters. Previous computational modeling of striatal neural networks has indicated that non-monotonic, distance-dependent coupling may promote spatially localized cluster firing. Here, we identify conditions for the existence and stability of cluster firing solutions in which clusters consist of spatially adjacent neurons in inhibitory neural networks. We consider simple non-monotonic, distance-dependent connectivity schemes in weakly coupled 1-D networks where cells make stronger connections with their kth nearest neighbors on each side and weaker connections with closer neighbors. Using the phase model reduction of the network system, we prove the existence of cluster solutions where neurons that are spatially close together are also synchronized in the same cluster, and find stability conditions for these solutions. Our analysis predicts the long-term behavior for networks of neurons, and we confirm our results by numerical simulations of biophysical neuron network models. Our results demonstrate that an inhibitory network with non-monotonic, distance-dependent connectivity can exhibit cluster solutions where adjacent cells fire together., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Black arsenic phosphorus single crystals were grown using a short-way transport technique resulting in crystals up to 12 × 110μmand ranging from 200 nm to 2μmthick. The reaction conditions require tin, tin (IV) iodide, gray arsenic, and red phosphorus placed in an evacuated quartz ampule and ramped up to a maximum temperature of 630 °C. The crystal structure and elemental composition were characterized using Raman spectroscopy, x-ray diffraction, and x-ray photoelectron spectroscopy, cross-sectional transmission microscopy, and electron backscatter diffraction. The data provides valuable insight into the growth mechanism. A previously developed b-P thin film growth technique can be adapted to b-AsP film growth with slight modifications to the reaction duration and reactant mass ratios. Devices fabricated from exfoliated bulk-b-AsP grown in the same reaction condition as the thin film growth process are characterized, showing an on-off current ratio of 10 2 , a threshold voltage of -60 V, and a peak field-effect hole mobility of 23 cm 2 V -1 s -1 at V d = -0.9 V and V g = -60 V., (© 2021 IOP Publishing Ltd.)

Glucagon-Like Peptide-1 (GLP-1) is an important peptide hormone secreted by L-cells in the gastrointestinal tract in response to nutrients. It is produced by the differential cleavage of the proglucagon peptide. GLP-1 elicits a wide variety of physiological responses in many tissues that contribute to metabolic homeostasis. For these reasons, therapies designed to either increase endogenous GLP-1 levels or introduce exogenous peptide mimetics are now widely used in the management of diabetes. In addition to GLP-1 production from L-cells, recent reports suggest that pancreatic islet alpha cells may also synthesize and secrete GLP-1. Intra-islet GLP-1 may therefore play an unappreciated role in islet health and glucose regulation, suggesting a potential functional paracrine role for islet-derived GLP-1. In this review, we assess the current literature from an islet-centric point-of-view to better understand the production, degradation, and actions of GLP-1 within the endocrine pancreas in rodents and humans. The relevance of intra-islet GLP-1 in human physiology is discussed regarding the potential role of intra-islet GLP-1 in islet health and dysfunction.

Objective: Maintenance of glucose homeostasis requires the precise regulation of hormone secretion from the endocrine pancreas. Free fatty acid receptor 4 (FFAR4/GPR120) is a G protein-coupled receptor whose activation in islets of Langerhans promotes insulin and glucagon secretion and inhibits somatostatin secretion. However, the contribution of individual islet cell types (α, β, and δ cells) to the insulinotropic and glucagonotropic effects of GPR120 remains unclear. As gpr120 mRNA is enriched in somatostatin-secreting δ cells, we hypothesized that GPR120 activation stimulates insulin and glucagon secretion via inhibition of somatostatin release., Methods: Glucose tolerance tests were performed in mice after administration of selective GPR120 agonist Compound A. Insulin, glucagon, and somatostatin secretion were measured in static incubations of isolated mouse islets in response to endogenous (ω-3 polyunsaturated fatty acids) and/or pharmacological (Compound A and AZ-13581837) GPR120 agonists. The effect of Compound A on hormone secretion was tested further in islets isolated from mice with global or somatostatin cell-specific knock-out of gpr120. Gpr120 expression was assessed in pancreatic sections by RNA in situ hybridization. Cyclic AMP (cAMP) and calcium dynamics in response to pharmacological GPR120 agonists were measured specifically in α, β, and δ cells in intact islets using cAMPER and GCaMP6 reporter mice, respectively., Results: Acute exposure to Compound A increased glucose tolerance, circulating insulin, and glucagon levels in vivo. Endogenous and/or pharmacological GPR120 agonists reduced somatostatin secretion in isolated islets and concomitantly demonstrated dose-dependent potentiation of glucose-stimulated insulin secretion and arginine-stimulated glucagon secretion. Gpr120 was enriched in δ cells. Pharmacological GPR120 agonists reduced cAMP and calcium levels in δ cells but increased these signals in α and β cells. Compound A-mediated inhibition of somatostatin secretion was insensitive to pertussis toxin. The effect of Compound A on hormone secretion was completely absent in islets from mice with either global or somatostatin cell-specific deletion of gpr120 and partially reduced upon blockade of somatostatin receptor signaling by cyclosomatostatin., Conclusions: Inhibitory GPR120 signaling in δ cells contributes to both insulin and glucagon secretion in part by mitigating somatostatin release., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

The free fatty-acid receptors FFAR1 (GPR40) and FFAR4 (GPR120) are implicated in the regulation of insulin secretion and insulin sensitivity, respectively. Although GPR120 and GPR40 share similar ligands, few studies have addressed possible interactions between these 2 receptors in the control of glucose homeostasis. Here we generated mice deficient in gpr120 (Gpr120KO) or gpr40 (Gpr40KO), alone or in combination (Gpr120/40KO), and metabolically phenotyped male and female mice fed a normal chow or high-fat diet. We assessed insulin secretion in isolated mouse islets exposed to selective GPR120 and GPR40 agonists singly or in combination. Following normal chow feeding, body weight and energy intake were unaffected by deletion of either receptor, although fat mass increased in Gpr120KO females. Fasting blood glucose levels were mildly increased in Gpr120/40KO mice and in a sex-dependent manner in Gpr120KO and Gpr40KO animals. Oral glucose tolerance was slightly reduced in male Gpr120/40KO mice and in Gpr120KO females, whereas insulin secretion and insulin sensitivity were unaffected. In hyperglycemic clamps, the glucose infusion rate was lower in male Gpr120/40KO mice, but insulin and c-peptide levels were unaffected. No changes in glucose tolerance were observed in either single or double knock-out animals under high-fat feeding. In isolated islets from wild-type mice, the combination of selective GPR120 and GPR40 agonists additively increased insulin secretion. We conclude that while simultaneous activation of GPR120 and GPR40 enhances insulin secretion ex vivo, combined deletion of these 2 receptors only minimally affects glucose homeostasis in vivo in mice., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In this work, we consider a general conductance-based neuron model with the inclusion of the acetycholine sensitive, M-current. We study bifurcations in the parameter space consisting of the applied current [Formula: see text], the maximal conductance of the M-current [Formula: see text] and the conductance of the leak current [Formula: see text]. We give precise conditions for the model that ensure the existence of a Bogdanov-Takens (BT) point and show that such a point can occur by varying [Formula: see text] and [Formula: see text]. We discuss the case when the BT point becomes a Bogdanov-Takens-cusp (BTC) point and show that such a point can occur in the three-dimensional parameter space. The results of the bifurcation analysis are applied to different neuronal models and are verified and supplemented by numerical bifurcation diagrams generated using the package MATCONT. We conclude that there is a transition in the neuronal excitability type organised by the BT point and the neuron switches from Class-I to Class-II as conductance of the M-current increases.

Background: In patients with haematuria, a fast, noninvasive test with high sensitivity (SN) and negative predictive value (NPV), which is able to detect or exclude bladder cancer (BC), is needed. A newly developed urine assay, Xpert Bladder Cancer Detection (Xpert), measures five mRNA targets (ABL1, CRH, IGF2, UPK1B, and ANXA10) that are frequently overexpressed in BC., Objective: To validate the performance of Xpert in patients with haematuria., Design, Setting, and Participants: Voided precystoscopy urine specimens were prospectively collected at 22 sites from patients without prior BC undergoing cystoscopy for haematuria. Xpert, cytology, and UroVysion procedures were performed. Technical validation was performed and specificity (SP) was determined in patients without BC., Outcome Measurements and Statistical Analysis: Test characteristics were calculated based on cystoscopy and histology results, and compared between Xpert, cytology, and UroVysion., Results and Limitations: We included 828 patients (mean age 64.5 yr, 467 males, 401 never smoked). Xpert had an SN of 78% (95% confidence interval [CI]: 66-87) overall and 90% (95% CI: 76-96) for high-grade (HG) tumours. The NPV was 98% (95% CI: 97-99) overall. The SP was 84% (95% CI: 81-86). In patients with microhaematuria, only one HG patient was missed (NPV 99%). Xpert had higher SN and NPV than cytology and UroVysion. Cytology had the highest SP (97%). In a separate SP study, Xpert had an SP of 89% in patients with benign prostate hypertrophy and 92% in prostate cancer patients., Conclusions: Xpert is an easy-to-use, noninvasive test with improved SN and NPV compared with cytology and UroVysion, representing a promising tool for identifying haematuric patients with a low likelihood of BC who might not need to undergo cystoscopy., Patient Summary: Xpert is an easy-to-perform urine test with good performance compared with standard urine tests. It should help identify (micro)haematuria patients with a very low likelihood to have bladder cancer., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

We study a model for a network of synaptically coupled, excitable neurons to identify the role of coupling delays in generating different network behaviors. The network consists of two distinct populations, each of which contains one excitatory-inhibitory neuron pair. The two pairs are coupled via delayed synaptic coupling between the excitatory neurons, while each inhibitory neuron is connected only to the corresponding excitatory neuron in the same population. We show that multiple equilibria can exist depending on the strength of the excitatory coupling between the populations. We conduct linear stability analysis of the equilibria and derive necessary conditions for delay-induced Hopf bifurcation. We show that these can induce two qualitatively different phase-locked behaviors, with the type of behavior determined by the sizes of the coupling delays. Numerical bifurcation analysis and simulations supplement and confirm our analytical results. Our work shows that the resting equilibrium point is unaffected by the coupling, thus the network exhibits bistability between a rest state and an oscillatory state. This may help understand how rhythms spontaneously arise in neuronal networks.

Aim: To examine whether early addition of sitagliptin to metformin is associated with a delay in type 2 diabetes progression., Methods: Administrative health records from Alberta, Canada, for the period April 2008 to March 2015, were used to conduct a retrospective cohort study in new metformin users. People who started sitagliptin on the same day they initiated metformin therapy were compared with those who added sitagliptin later. Insulin initiation served as a surrogate marker for diabetes progression, and multivariable logistic regression models were used to evaluate the association with sitagliptin addition (costart vs later use). A mixed-effects linear regression model was used to examine the effect of timing of sitagliptin addition on HbA 1c change over 1 year., Results: The mean (sd) age of the 8764 people who used sitagliptin was 52.1 (11.1) years, 5665 (64.6%) were men, and 1153 (13.2%) started sitagliptin on the same day as metformin. Insulin was added to the therapy of 173 (15.0%) costarters and 1453 (19.1%) later sitagliptin users. The adjusted odds ratio for adding insulin was 0.76 (95% CI 0.64 to 0.90) in favour of costarting sitagliptin. HbA 1c levels decreased in both groups 1 year after starting sitagliptin, with costarters having a significantly greater reduction [absolute between-group difference of 0.5% (95% CI 0.3 to 0.7)] compared with later sitagliptin users., Conclusion: Costarting drug therapy with sitagliptin and metformin was associated with a lower likelihood of disease progression in people with type 2 diabetes compared with adding sitagliptin later., (© 2019 Diabetes UK.)

Key Points: 25-Hydroxyvitamin D (25OHD) is a partial agonist of TRPV1 whereby 25OHD can weakly activate TRPV1 yet antagonize the stimulatory effects of the full TRPV1 agonists capsaicin and oleoyl dopamine. 25OHD binds to TRPV1 within the same vanilloid binding pocket as capsaicin. 25OHD inhibits the potentiating effects of PKC-mediated TRPV1 activity. 25OHD reduces T-cell activation and trigeminal neuron calcium signalling mediated by TRPV1 activity. These results provide evidence that TRPV1 is a novel receptor for the biological actions of vitamin D in addition to the well-documented effects of vitamin D upon the nuclear vitamin D receptor. The results may have important implications for our current understanding of certain diseases where TRPV1 and vitamin D deficiency have been implicated, such as chronic pain and autoimmune diseases, such as type 1 diabetes., Abstract: The capsaicin receptor TRPV1 plays an important role in nociception, inflammation and immunity and its activity is regulated by exogenous and endogenous lipophilic ligands. As vitamin D is lipophilic and involved in similar biological processes as TRPV1, we hypothesized that it directly regulates TRPV1 activity and function. Our calcium imaging and electrophysiological data demonstrate that vitamin D (25-hydroxyvitamin D (25OHD) and 1,25-hydroxyvitamin D (1,25OHD)) can weakly activate TRPV1 at physiologically relevant concentrations (100 nM). Furthermore, both 25OHD and 1,25OHD can inhibit capsaicin-induced TRPV1 activity (IC 50  = 34.3 ± 0.2 and 11.5 ± 0.9 nM, respectively), but not pH-induced TRPV1 activity, suggesting that vitamin D interacts with TRPV1 in the same region as the TRPV1 agonist capsaicin. This hypothesis is supported by our in silico TRPV1 structural modelling studies, which place 25OHD in the same binding region as capsaicin. 25OHD also attenuates PKC-dependent TRPV1 potentiation via interactions with a known PKC phospho-acceptor residue in TRPV1. To provide evidence for a physiological role for the interaction of vitamin D with TRPV1, we employed two different cellular models known to express TRPV1: mouse CD4 + T-cells and trigeminal neurons. Our results indicate that 25OHD reduces TRPV1-induced cytokine release from T-cells and capsaicin-induced calcium activity in trigeminal neurons. In summary, we provide evidence that vitamin D is a novel endogenous regulator of TRPV1 channel activity that may play an important physiological role in addition to its known effects through the canonical nuclear vitamin D receptor pathway., (© 2020 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Objectives: Our study shows that glucagon-like peptide-1 (GLP-1) is secreted within human islets and may play an unexpectedly important paracrine role in islet physiology and pathophysiology. It is known that α cells within rodent and human pancreatic islets are capable of secreting GLP-1, but little is known about the functional role that islet-derived GLP-1 plays in human islets., Methods: We used flow cytometry, immunohistochemistry, perifusions, and calcium imaging techniques to analyse GLP-1 expression and function in islets isolated from cadaveric human donors with or without type 2 diabetes. We also used immunohistochemistry to analyse GLP-1 expression within islets from pancreatic biopsies obtained from living donors., Results: We have demonstrated that human islets secrete ∼50-fold more GLP-1 than murine islets and that ∼40% of the total human α cells contain GLP-1. Our results also confirm that dipeptidyl peptidase-4 (DPP4) is expressed in α cells. Sitagliptin increased GLP-1 secretion from cultured human islets but did not enhance glucose-stimulated insulin secretion (GSIS) in islets from non-diabetic (ND) or type 2 diabetic (T2D) donors, suggesting that β cell GLP-1 receptors (GLP-1R) may already be maximally activated. Therefore, we tested the effects of exendin-9, a GLP-1R antagonist. Exendin-9 was shown to reduce GSIS by 39% and 61% in ND islets and T2D islets, respectively. We also observed significantly more GLP-1+ α cells in T2D islets compared with ND islets obtained from cadaveric donors. Furthermore, GLP-1+ α cells were also identified in pancreatic islet sections obtained from living donors undergoing surgery., Conclusions: In summary, we demonstrated that human islets secrete robust amounts of GLP-1 from an α cell subpopulation and that GLP-1R signalling may support GSIS to a greater extent in T2D islets., (Copyright © 2020 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Background: Untreated antenatal depression and anxiety can be associated with short and long term health impacts on the pregnant woman, her infant and the rest of the family. Alternative interventions to those currently available are needed. This clinical trial aims to investigate the efficacy and safety of a broad-spectrum multinutrient formula as a treatment for symptoms of depression and anxiety in pregnant women and to determine the impact supplementation has on the general health and development of the infant., Methods: This randomised, controlled trial will be conducted in Canterbury, New Zealand between April 2017 and June 2022. One hundred and twenty women aged over 16 years, between 12 and 24 weeks gestation and who score ≥ 13 on the Edinburgh Postnatal Depression Scale (EPDS) will be randomly assigned to take the intervention (n = 60) or an active control formula containing iodine and riboflavin (n = 60) for 12 weeks. After 12 weeks, participants can enter an open-label phase until the birth of their infant and naturalistically followed for the first 12 months postpartum. Infants will be followed until 12 months of age. Randomisation will be computer-generated, with allocation concealment by opaque sequentially numbered envelopes. Participants and the research team including data analysts will be blinded to group assignment. The EPDS and the Clinical Global Impressions Scale of Improvement (CGI-I) will be the maternal primary outcome measures of this study and will assess the incidence of depression and anxiety and the improvement of symptomatology respectively. Generalized linear mixed effects regression models will analyse statistical differences between the multinutrient and active control group on an intent-to-treat basis. A minimum of a three-point difference in EPDS scores between the groups will identify clinical significance. Pregnancy outcomes, adverse events and side effects will also be monitored and reported., Discussion: Should the multinutrient formula be shown to be beneficial for both the mother and the infant, then an alternative treatment option that may also improve the biopsychosocial development of their infants can be provided for pregnant women experiencing symptoms of depression and anxiety., Trial Registration: Trial ID: ACTRN12617000354381 ; prospectively registered at Australian New Zealand Clinical Trials Registry on 08/03/2017.

Tranistion metal dichalcogenides are a promising family of materials for electronics and optoelectronics, in part due to their range of bandgaps that can be modulated by layer number. Here, we show that WSe 2 can be selectively grown with one, two, or three layers, as regulated by a one-step hydrogen-controlled chemical vapor deposition (H-CVD) process involving cyclical pulses of H 2 flow. The physical and vibrational properties of the resulting mono-, bi-, and tri-layer WSe 2 films are characterized by atomic force microscopy and Raman spectroscopy. Modifying the H-CVD process to include more than three H 2 pulses results in thicker WSe 2 films, however the thickness of these films is not well controlled and feature small, bulk-like pyramidal islands. Transmission electron microscopy analysis reveals that most of these islands exhibit a spiral structure and appear to be grown via screw-dislocation-driven growth, similar to other works. Therefore, the H-CVD process is demonstrated to be a powerful tool for controlling the layer thickness of WSe 2 , but its practicality is limited to the few-layer regime.

Metabolic syndrome is defined by hyperlipidemia and cardiovascular complications. We have examined whether inhibition of glycosphingolipid synthesis can interfere with metabolic syndrome in a male mouse model of type II diabetes (db/db). The db/db and control mice (C57/BL6) (n = 6) fed chow for 30 weeks received vehicle (5% Tween-80 in PBS; 100 μl), or a biopolymer-encapsulated D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (BPD) glycosphingolipid synthesis inhibitor daily via oral gavage for 6 weeks. Echocardiography revealed increased Ao-IMT in db/db mice compared to control. However, BPD decreased Ao-IMT, monohexosylceramide and dihexosylceramide, LDL, triglycerides, glucose, and raised HDL levels in db/db mice. This was due to increased gene expression of HMG-CoA reductase, LDLr, SREBP2, and bile acids: Cy7-a hydroxylase, LXR and FXR, lipoprotein lipase, VLDL receptor and PPAR. Treatment also increased the expression of superoxide dismutase-II to reduce the pro-oxidant status in these mice. We observed that decreased cholesterol levels correlated with decreased cholesterol sensing proteins e.g. NPC1 gene/protein expression and mammalian target of rapamycin (mTORC-1) and reduced body weight. Thus, glycosphingolipid synthesis inhibition is a novel approach to manage metabolic syndrome and reduce body weight in diabetic mice and with potential applications in humans., Competing Interests: Declaration of competing interest None., (Copyright © 2020. Published by Elsevier Inc.)

Dystonia is a movement disorder characterized by involuntary muscle contractions, twisting movements, and abnormal postures that may affect one or multiple body regions. Dystonia is the third most common movement disorder after Parkinson's disease and essential tremor. Despite its relative frequency, small molecule therapeutics for dystonia are limited. Development of new therapeutics is further hampered by the heterogeneity of both clinical symptoms and etiologies in dystonia. Recent advances in both animal and cell-based models have helped clarify divergent etiologies in dystonia and have facilitated the identification of new therapeutic targets. Advances in medicinal chemistry have also made available novel compounds for testing in biochemical, physiological, and behavioral models of dystonia. Here, we briefly review motor circuit anatomy and the anatomical and functional abnormalities in dystonia. We then discuss recently identified therapeutic targets in dystonia based on recent preclinical animal studies and clinical trials investigating novel therapeutics., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We study synaptically coupled neuronal networks to identify the role of coupling delays in network synchronized behaviour. We consider a network of excitable, relaxation oscillator neurons where two distinct populations, one excitatory and one inhibitory, are coupled with time-delayed synapses. The excitatory population is uncoupled, while the inhibitory population is tightly coupled without time delay. A geometric singular perturbation analysis yields existence and stability conditions for periodic solutions where the excitatory cells are synchronized and different phase relationships between the excitatory and inhibitory populations can occur, along with formulae for the periods of such solutions. In particular, we show that if there are no delays in the coupling, oscillations where the excitatory population is synchronized cannot occur. Numerical simulations are conducted to supplement and validate the analytical results. The analysis helps to explain how coupling delays in either excitatory or inhibitory synapses contribute to producing synchronized rhythms. This article is part of the theme issue 'Nonlinear dynamics of delay systems'.

Appropriate regulation of genes that coordinate pancreas progenitor proliferation and differentiation is required for pancreas development. Here, we explore the role of H3K4 methylation and the Trithorax group (TrxG) complexes in mediating gene expression during pancreas development. Disruption of TrxG complex assembly, but not catalytic activity, prevented endocrine cell differentiation in pancreas progenitor spheroids. In vivo loss of TrxG catalytic activity in PDX1 + cells increased apoptosis and the fraction of progenitors in the G1 phase of the cell cycle. Pancreas progenitors were reallocated to the acinar lineage, primarily at the expense of NEUROG3 + endocrine progenitors. Later in development, acinar and endocrine cell numbers were decreased, and increased gene expression variance and reduced terminal marker activation in acinar cells led to their incomplete differentiation. These findings demonstrate that TrxG co-activator activity is required for gene induction, whereas TrxG catalytic activity and H3K4 methylation help maintain transcriptional stability., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

A single-step, direct silicon-substrate growth of black phosphorus (BP) crystals is achieved in a self-contained short-way transport technique under low-pressure conditions (<1.5 MPa). A 115 nm-thick BP hero single crystal is formed with lateral dimensions of 10 × 85 μm. The synthesis proceeds with Sn, SnI 4 , and red phosphorus and has a well-defined phosphorus phase dependency on the SnI 4 concentration. Furthermore, in situ Sn passivation of BP occurs. This allows long-term stability with no sign of any degradation after 4 months of exposure to ambient conditions. Single-crystal BP flakes and multigrain flakes with high- and low-angle grain boundaries are achieved. Electron backscatter diffraction determined crystal growth to be independent of the substrate, which is further supported by successful growth on various substrates, including sapphire, silicon nitride, silicon, and silicon oxide. Cross-sectional transmission electron microscopy of a single crystal flake provides valuable insight into the growth mechanism. Elemental Sn encapsulates BP crystals, and crystalline SnI x inclusions are found to be scattered throughout the BP crystal. It is suggested that SnI x inclusions may provide the dominant mechanism for seeding vertical growth. IR absorption measurements for thin and bulk BP recipes show an equal response below E g dominated by free carrier absorption. FET devices fabricated from thin-film and bulk BP recipes show improved device performance compared to unpassivated BP films of equal thickness with an on/off current ratio >10 2 .

In recent years, there has been a substantial increase in the diagnosis of attention deficit hyperactivity disorder (ADHD) in children. Without appropriate management of symptoms and care, ADHD has been associated with a variety of negative child and adult outcomes. Environmental and familial factors that may contribute to three different pediatric referral types (academic, behavioural, and attentional) associated with ADHD were examined in the current study. In total, data from 477 families who were interviewed as a part of the intake process to a pediatric clinic were included in this study. Data for the current study was extracted from the intake questionnaires and included information on family history of mental health issues, socioeconomic status, and family relationships. The sample included children between the ages of three and 17 and mostly comprised males ( n = 340). A frequency analysis of the data demonstrated relatively high rates of mental health issues within families (61.4%); almost half of the mothers reported some post-secondary education (46.1%) and most reported having normal relationships with their children (mothers, 78%; fathers, 62.9%). Finally, three stepwise regression analyses were conducted to predict referral type. All three regressions yielded significant models. Fifteen percent of the variability of the academic referral type was predicted by being male, age at the time of referral, mother's education level, and mother's learning. The behavioural referral types were predicted by a family history of depression, being male, mother-child relationship, and age at the time of referral; these accounted for 23% of the variance. Attentional referral type was predicted only by mother-child relationship that captured 6% of the variance. Overall, this study describes a population of parents of children with academic, behavioural, and attention-related referrals to pediatrics. Results indicate that mothers have a profound influence on their child's referral types, something that may transfer into later diagnosis and perhaps prognosis. Clinicians and researchers alike should focus their efforts toward developing integrative service assessment and treatment approaches that include important people in the child's life. The implementation of Community Social Pediatrics (a streamlined, inclusive approach to care) should be considered in urban centres like this one, where referrals like this are prevalent., Competing Interests: The authors have declared that no competing interests exist.

Background: A fast, noninvasive test with high sensitivity (SN) and a negative predictive value (NPV), which is able to detect recurrences in bladder cancer (BC) patients, is needed. A newly developed urine assay, Xpert Bladder Cancer Monitor (Xpert), measures five mRNA targets (ABL1, CRH, IGF2, UPK1B, and ANXA10) that are frequently overexpressed in BC., Objective: To validate Xpert characteristics in patients previously diagnosed with non-muscle-invasive BC., Design, Setting, and Participants: Voided precystoscopy urine samples were prospectively collected at 22 sites. Xpert, cytology, and UroVysion were performed. If cystoscopy was suspicious for BC, a histologic examination was performed. Additionally, technical validation was performed and specificity was determined in patients without a history or clinical evidence of BC., Outcome Measurements and Statistical Analysis: Test characteristics were calculated based on cystoscopy and histology results, and compared between Xpert, cytology, and UroVysion., Results and Limitations: Of the eligible patients, 239 with a history of BC had results for all assays. The mean age was 71 yr; 190 patients were male, 53 never smoked, and 64% had previous intravesical immunotherapy (35%) or chemotherapy (29%). Forty-three cases of recurrences occurred. Xpert had overall SN of 74% (95% confidence interval [CI]: 60-85) and 83% (95% CI: 64-93) for high-grade (HG) tumors. The NPV was 93% (95% CI: 89-96) overall and 98% (95% CI: 94-99) for HG tumors. Specificity was 80% (95% CI: 73-85). Xpert SN and NPV were superior to those of cytology and UroVysion. Specificity in non-BC individuals (n=508) was 95% (95% CI: 93-97)., Conclusions: Xpert has an improved NPV compared with UroVysion and cytology in patients under follow-up for BC. It represents a promising tool for excluding BC in these patients, reducing the need for cystoscopy., Patient Summary: Xpert is an easy-to-perform urine test with good performance compared with standard urine tests. It should help optimize the follow-up of recurrent bladder cancer patients., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

We formulate a conductance-based model for a 3-neuron motif associated with Childhood Absence Epilepsy (CAE). The motif consists of neurons from the thalamic relay (TC) and reticular nuclei (RT) and the cortex (CT). We focus on a genetic defect common to the mouse homolog of CAE which is associated with loss of GABA A receptors on the TC neuron, and the fact that myelination of axons as children age can increase the conduction velocity between neurons. We show the combination of low GABA A mediated inhibition of TC neurons and the long corticothalamic loop delay gives rise to a variety of complex dynamics in the motif, including bistability. This bistability disappears as the corticothalamic conduction delay shortens even though GABA A activity remains impaired. Thus the combination of deficient GABA A activity and changing axonal myelination in the corticothalamic loop may be sufficient to account for the clinical course of CAE.

Obese individuals are often at risk for nonalcoholic fatty liver disease (NAFLD), insulin resistance, type 2 diabetes (T2D), and cardiovascular diseases such as angina, thereby requiring combination therapies for their comorbidities. Ranolazine is a second-line antianginal agent that also improves glycemia, and our aim was to determine whether ranolazine modifies the progression of obesity-induced NAFLD. Twelve-week-old C57BL/6J male mice were fed a low-fat or high-fat diet for 10 weeks and then treated for 30 days with either vehicle control or ranolazine (50 mg/kg via daily s.c. injection). Glycemia was monitored via glucose/pyruvate/insulin tolerance testing, whereas in vivo metabolism was assessed via indirect calorimetry. Hepatic triacylglycerol content was quantified via the Bligh and Dyer method. Consistent with previous reports, ranolazine treatment reversed obesity-induced glucose intolerance, which was associated with reduced body weight and hepatic steatosis, as well as increased hepatic pyruvate dehydrogenase (PDH) activity. Ranolazine's actions on hepatic PDH activity may be directly mediated, as ranolazine treatment reduced PDH phosphorylation (indicative of increased PDH activity) in HepG2 cells. Therefore, in addition to mitigating angina, ranolazine also reverses NAFLD, which may contribute to its documented glucose-lowering actions, situating ranolazine as an ideal antianginal therapy for obese patients comorbid for NAFLD and T2D.