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    In vitro cannabinoid activity profiling of generic ban-evading brominated synthetic cannabinoid receptor agonists and their analogs

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    Following the enactment of a generic ban in China in 2021, the synthetic cannabinoid market has been evolving, now encompassing even wider structural diversity. Compounds carrying a brominated core such as ADB-5'Br-BUTINACA (ADMB-B-5Br-INACA) and tail-less analogs, such as ADB-5'Br-INACA (ADMB-5Br-INACA), MDMB-5'Br-INACA, and ADB-INACA (ADMB-INACA), have been detected since late 2021. This study investigated the cannabinoid receptor (CB) activation potential of synthesized (S)-enantiomers of these substances, as well as of two predicted analogs MDMB-5'Br-BUTINACA (MDMB-B-5Br-INACA) and ADB-5'F-BUTINACA (ADMB-B-5F-INACA), using CB1 and CB2 β-arrestin 2 recruitment assays and a CB1 intracellular calcium release assay. Surprisingly, the tail-less (S)-ADB-5'Br-INACA and (S)-MDMB-5'Br-INACA retained CB activity, albeit with a decreased potency compared to their tailed counterparts (S)-ADB-5'Br-BUTINACA and (S)-MDMB-5'Br-BUTINACA, respectively, which were potent and efficacious CB1 agonists. Also, at CB2 , tail-less analogs showed a lower potency but increased efficacy. Removing the bromine substitution ((S)-ADB-INACA) resulted in a reduced activity at CB1 ; however, this effect was less prominent at CB2 . Looking at tailed analogs, replacing the bromine with a fluorine substitution ((S)-ADB-5'F-BUTINACA) resulted in an increased potency and efficacy at both receptors. Furthermore, as ADB-5'Br-INACA and MDMB-5'Br-INACA have been frequently detected together in Scottish prisons, this study also evaluated the CB1 receptor activation potential of different mixtures of their respective reference standards, showing no unexpected cannabimimetic effect of combining both substances. Lastly, two powders seized by Belgian Customs and confirmed to contain ADB-5'Br-INACA and MDMB-5'Br-INACA, respectively, were assessed for CB activity. Based on the comparison with their reference standards, varying degrees of purity were suspected.</p

    Non-surgical adjunctive interventions for accelerating tooth movement in patients undergoing orthodontic treatment

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    Background: Deviation from a normal bite can be defined as malocclusion. Orthodontic treatment takes 20 months on average to correct malocclusion. Accelerating the rate of tooth movement may help to reduce the duration of orthodontic treatment and associated unwanted effects including orthodontically induced inflammatory root resorption (OIIRR), demineralisation and reduced patient motivation and compliance. Several non-surgical adjuncts have been advocated with the aim of accelerating the rate of orthodontic tooth movement (OTM). Objectives: To assess the effect of non-surgical adjunctive interventions on the rate of orthodontic tooth movement and the overall duration of treatment.Search methods: An information specialist searched five bibliographic databases up to 6 September 2022 and used additional search methods to identify published, unpublished and ongoing studies.Selection criteria: We included randomised controlled trials (RCTs) of people receiving orthodontic treatment using fixed or removable appliances along with non-surgical adjunctive interventions to accelerate tooth movement. We excluded split-mouth studies and studies that involved people who were treated with orthognathic surgery, or who had cleft lip or palate, or other craniofacial syndromes or deformities.Data collection and analysis: Two review authors were responsible for study selection, risk of bias assessment and data extraction; they carried out these tasks independently. Disagreements were resolved by discussion amongst the review team to reach consensus. Main results: We included 23 studies, none of which were rated as low risk of bias overall. We categorised the included studies as testing light vibrational forces or photobiomodulation, the latter including low level laser therapy and light emitting diode. The studies assessed non-surgical interventions added to fixed or removable orthodontic appliances compared to treatment without the adjunct. A total of 1027 participants (children and adults) were recruited with loss to follow-up ranging from 0% to 27% of the original samples. Certainty of the evidence For all comparisons and outcomes presented below, the certainty of the evidence is low to very low. Light vibrational forces Eleven studies assessed how applying light vibrational forces (LVF) affected orthodontic tooth movement (OTM). There was no evidence of a difference between the intervention and control groups for duration of orthodontic treatment (MD -0.61 months, 95% confidence interval (CI) -2.44 to 1.22; 2 studies, 77 participants); total number of orthodontic appliance adjustment visits (MD -0.32 visits, 95% CI -1.69 to 1.05; 2 studies, 77 participants); orthodontic tooth movement during the early alignment stage (reduction of lower incisor irregularity (LII)) at 4-6 weeks (MD 0.12 mm, 95% CI -1.77 to 2.01; 3 studies, 144 participants), or 10-16 weeks (MD -0.18 mm, 95% CI -1.20 to 0.83; 4 studies, 175 participants); rate of canine distalisation (MD -0.01 mm/month, 95% CI -0.20 to 0.18; 2 studies, 40 participants); or rate of OTM during en masse space closure (MD 0.10 mm per month, 95% CI -0.08 to 0.29; 2 studies, 81 participants). No evidence of a difference was found between LVF and control groups in rate of OTM when using removable orthodontic aligners. Nor did the studies show evidence of a difference between groups for our secondary outcomes, including patient perception of pain, patient-reported need for analgesics at different stages of treatment and harms or side effects. Photobiomodulation Ten studies assessed the effect of applying low level laser therapy (LLLT) on rate of OTM. We found that participants in the LLLT group had a statistically significantly shorter length of time for the teeth to align in the early stages of treatment (MD -50 days, 95% CI -58 to -42; 2 studies, 62 participants) and required fewer appointments (-2.3, 95% CI -2.5 to -2.0; 2 studies, 125 participants). There was no evidence of a difference between the LLLT and control groups in OTM when assessed as percentage reduction in LII in the first month of alignment (1.63%, 95% CI -2.60 to 5.86; 2 studies, 56 participants) or in the second month (percentage reduction MD 3.75%, 95% CI -1.74 to 9.24; 2 studies, 56 participants). However, LLLT resulted in an increase in OTM during the space closure stage in the maxillary arch (MD 0.18 mm/month, 95% CI 0.05 to 0.33; 1 study; 65 participants; very low level of certainty) and the mandibular arch (right side MD 0.16 mm/month, 95% CI 0.12 to 0.19; 1 study; 65 participants). In addition, LLLT resulted in an increased rate of OTM during maxillary canine retraction (MD 0.01 mm/month, 95% CI 0 to 0.02; 1 study, 37 participants). These findings were not clinically significant. The studies showed no evidence of a difference between groups for our secondary outcomes, including OIIRR, periodontal health and patient perception of pain at early stages of treatment. Two studies assessed the influence of applying light-emitting diode (LED) on OTM. Participants in the LED group required a significantly shorter time to align the mandibular arch compared to the control group (MD -24.50 days, 95% CI -42.45 to -6.55, 1 study, 34 participants). There is no evidence that LED application increased the rate of OTM during maxillary canine retraction (MD 0.01 mm/month, 95% CI 0 to 0.02; P = 0.28; 1 study, 39 participants ). In terms of secondary outcomes, one study assessed patient perception of pain and found no evidence of a difference between groups. Authors' conclusions: The evidence from randomised controlled trials concerning the effectiveness of non-surgical interventions to accelerate orthodontic treatment is of low to very low certainty. It suggests that there is no additional benefit of light vibrational forces or photobiomodulation for reducing the duration of orthodontic treatment. Although there may be a limited benefit from photobiomodulation application for accelerating discrete treatment phases, these results have to be interpreted with caution due to their questionable clinical significance. Further well-designed, rigorous RCTs with longer follow-up periods spanning from start to completion of orthodontic treatment are required to determine whether non-surgical interventions may reduce the duration of orthodontic treatment by a clinically significant amount, with minimal adverse effects.</p

    The evolving centres of gravity in China's oil and gas industry:Evidence from infrared radiation imaging gas flaring data

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    Traditional macro data distort information on oil and gas exploitation and processing capacities and cannot track the movement of gas combustion. This study proposes a new way to retrieve those capacities and to explore changes in the trajectory of China's oil and gas exploitation and processing centres via gas flaring based on a combination of kernel clustering-kernel principal component analysis (KPCA) and spatial methods. We use data from the Visible Infrared Imaging Radiometer Suite (VIIRS) between 2012 and 2016. Results show that the upstream centre of gravity of oil and gas exploitation and processing in China moved to the southwest and the downstream centre of gravity moved to the southeast. Results of Kernel clustering-KPCA show that production, processing and transportation of oil and gas production moved from inland areas to coastal ports. Results from spatial analysis show existence of the influence of inter-regional externalities on the development of oil and gas exploitation and processing. The new economic geography theory provides a theoretical framework to explain the spatial evolution of oil and gas exploration and processing. Empirical findings of the changing path of the oil and gas exploitation and processing centres of gravity and the kernel clustering-KPCA analysis provide a scientific basis for tracking the effectiveness of government environmental policy and for policymaking on mitigation of combustion gases. This novel application extends the utilisation of the VIIRS and can be applied globally for tracking dynamic changes in the centre of gravity of oil and gas exploration and processing

    HiBiT Cellular Thermal Shift Assay (HiBiT CETSA)

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    Cellular thermal shift assay (CETSA) is based on the thermal stabilization of the protein target by a compound binding. Thus, CETSA can be used to measure a compound's cellular target engagement and permeability. HiBiT CETSA method is quantitative and has higher throughput compared to the traditional Western-based CETSA. Here, we describe the protocol for a HiBiT CETSA, which utilizes a HiBiT tag derived from the NanoLuciferase (NanoLuc) that upon complementation by LgBiT NanoLuc tag produces a bright signal enabling tracking of the effects of increasing temperature on the stability of a protein-of-interest in the presence/absence of various compounds. Exposure of a HiBiT-tagged protein to increasing temperatures induces protein denaturation and thus decreased LgBiT complementation and NanoLuc signal. As the stability of proteins at higher temperatures can be influenced by the compound binding, this method enables screening for target engagement in living or permeabilized cells.</p

    Prolonged continuous theta burst stimulation increases motor corticospinal excitability and intracortical inhibition in patients with neuropathic pain:An exploratory, single-blinded, randomized controlled trial

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    Objectives: A new paradigm for Transcranial Magnetic Stimulation (TMS), referred to as prolonged continuous theta burst stimulation (pcTBS), has recently received attention in the literature because of its advantages over high frequency repetitive TMS (HF-rTMS). Clinical advantages include less time per intervention session and the effects appear to be more robust and reproducible than HF-rTMS to modulate cortical excitability. HF-rTMS targeted at the primary motor cortex (M1) has demonstrated analgesic effects in patients with neuropathic pain but their mechanisms of action are unclear and pcTBS has been studied in healthy subjects only. This study examined the neural mechanisms that have been proposed to play a role in explaining the effects of pcTBS targeted at the M1 and DLPFC brain regions in neuropathic pain (NP) patients with Type 2 diabetes.Methods: Forty-two patients with painful diabetic neuropathy were randomized to receive a single session of pcTBS targeted at the left M1 or left DLPFC. pcTBS stimulation consisted of 1,200 pulses delivered in 1 min and 44 s with a 35-45 min gap between sham and active pcTBS stimulation. Both the activity of the descending pain system which was examined using conditioned pain modulation and the activity of the ascending pain system which was assessed using temporal summation of pain were recorded using a handheld pressure algometer by measuring pressure pain thresholds. The amplitude of the motor evoked potential (MEP) was used to measure motor corticospinal excitability and GABA activity was assessed using short (SICI) and long intracortical inhibition (LICI). All these measurements were performed at baseline and post-pcTBS stimulation.Results: Following a single session of pcTBS targeted at M1 and DLPFC, there was no change in BPI-DN scores and on the activity of the descending (measured using conditioned pain modulation) and ascending pain systems (measured using temporal summation of pain) compared to baseline but there was a significant improvement of &gt;13% in perception of acute pain intensity, increased motor corticospinal excitability (measured using MEP amplitude) and intracortical inhibition (measured using SICI and LICI).Conclusion: In patients with NP, a single session of pcTBS targeted at the M1 and DLPFC modulated the neurophysiological mechanisms related to motor corticospinal excitability and neurochemical mechanisms linked to GABA activity, but it did not modulate the activity of the ascending and descending endogenous modulatory systems. In addition, although BPI-DN scores did not change, there was a 13% improvement in self-reported perception of acute pain intensity.</p

    Effectiveness of out-patient based acute heart failure care:A pilot randomised controlled trial

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    Objectives: Acute heart failure (AHF) hospitalisation is associated with 10% mortality. Outpatient based management (OPM) of AHF appeared effective in observational studies. We conducted a pilot randomised controlled trial (RCT) comparing OPM with standard inpatient care (IPM).Methods: We randomised patients with AHF, considered to need IV diuretic treatment for &gt;2 days, to IPM or OPM. We recorded all-cause mortality, and the number of days alive and out-of-hospital (DAOH). Quality of life, mental well-being and Hope scores were assessed. Mean NHS cost savings and 95% central range (CR) were calculated from bootstrap analysis. Follow-up: 60 days.Results: Eleven patients were randomised to IPM and thirteen to OPM. There was no statistically significant difference in all-cause mortality during the index episode (1/11vs 0/13) and up to 60 days follow-up (2/11 vs 2/13) [p=0.86]. The OPM group accrued more DAOH {47 [36,51] vs 59 [41,60], p=0.13}. Two patients randomised to IPM (vs 6OPM) were readmitted [p=0.31]. Hope scores increased more with OPM within 30 days but dropped to lower levels than IPM by 60 days. More out-patients had increased total well-being scores by 60 days (p=0.04). OPM was associated with mean cost savings of£2,658 (95% CR 460 - 4,857) per patient.Conclusions: Patients with acute HF randomised to OPM accrued more days alive out of hospital (albeit not statistically significantly in this small pilot study). OPM is favoured by patients and carers and is associated with improved mental well-being and cost savings

    Final reflections and next steps for policy, programming and research

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    The concluding chapter reflects upon the key themes that have emerged across the case studies and contributions of this edited collection, which collective illustrate the importance of a relational, contextualised and intersectional lens on adolescents and young people’s citizenship. Key conceptual and empirical contributions to understanding adolescent and young people’s civic and political voice and agency are identified, as well as the implications for research, policy and programming with adolescents and young people in the Global South. Finally, the chapter asks ‘where next?' for work in this field.</p

    A Ground Truth Data Set of Gas Chromatography mass spectrometry (GCMS) Analysed Synthesised Methylamphetamine

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    An open source data set of methylamphetamine data. These data are made available via a creative commons attribution license 4.0 international https://creativecommons.org/licenses/by/4.0

    Associations of offspring birthweight and placental weight with subsequent parental coronary heart disease:survival regression using the walker cohort

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    Low birth weight (BW) is consistently correlated with increased parental risk of subsequent cardiovascular disease, but the links with offspring placental weight (PW) are mostly unexplored. We have investigated the associations between parental coronary heart disease (CHD) and offspring BW and PW using the Walker cohort, a collection of 48,000 birth records from Dundee, Scotland, from the 1950s and 1960s. We linked the medical history of 13,866 mothers and 8,092 fathers to their offspring's records and performed Cox survival analyses modelling maternal and paternal CHD risk by their offspring's BW, PW, and the ratio between both measurements. We identified negative associations between offspring BW and both maternal (hazard ratio [HR]: 0.91, 95% confidence interval [CI]: 0.88-0.95) and paternal (HR: 0.96, 95% CI: 0.93-1.00) CHD risk, the stronger maternal correlation being consistent with previous reports. Offspring PW to BW ratio was positively associated with maternal CHD risk (HR: 1.14, 95% CI: 1.08-1.21), but the associations with paternal CHD were not significant. These analyses provide additional evidence for intergenerational associations between early growth and parental disease, identifying directionally opposed correlations of maternal CHD with offspring BW and PW, and highlight the importance of the placenta as a determinant of early development and adult disease.</p

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