Gold-catalysed Heck reaction: Fact or fiction? Correspondence on “Unlocking the Chain Walking Process in Gold Catalysis”

Two recent high-profile publications reported the formation of Heck-type arylated alkenes catalysed by MeDalPhosAuCl / AgOTf (J. Am. Chem. Soc. 2023, 145, 8810) and their cyclisation to tetralines (Angew. Chem. Int. Ed. 2023, e202312786). It was claimed that these were the first demonstrations in gold catalysis of alkene insertion into Au-aryl bonds, β-H elimination and chain-walking by Au-H dications. We show here that in fact this chemistry is a two-stage process. Only the first step, the production of an alkyl triflate ester as the primary organic product by the well-known alkene heteroarylation sequence, involves gold. The subsequent formation of Heck-type olefins and their cyclisation to tetralines represent classical H+-triggered carbocationic chemistry. These steps proceed in the absence of gold with identical results. Literature claims of new gold reactivity such as chain walking by the putative [LAuH]2+ dication have no basis in fact

An exact solution to the inverse problem of steady free-surface flow over topography

A simple exact solution is presented to the inverse problem in steady, two-dimensional idealised flow over topography that seeks the bottom profile given knowledge of the free-surface data. Attention is focused on the case when a uniform stream flows over a localised obstacle, although the solution is not restricted to this case. The inverse problem is formulated as a Stieltjes integral equation which is solved exactly using a Fourier transform. The solution requires the analytic continuation of two real functions representing the surface speed and the angle between the surface velocity vector and the horizontal. Some example surface profiles and their corresponding bottom topographies are discussed. Although the solution requires the prescription of the surface as a function of the velocity potential, it is shown to closely resemble the corresponding profile in physical space, even for quite large surface displacements, while significant discrepancy occurs at the bottom. Inference of the bottom profile from discrete surface data is accomplished by way of polynomial interpolation and rational approximation in the complex plane for the sample case of a hydraulic fall

Automated closed-loop insulin delivery for the management of type 1 diabetes during pregnancy: the AiDAPT RCT

Background There are over 2000 pregnancies annually in women with type 1 diabetes in the UK. Despite recent improvements in diabetes technology, most women cannot achieve and maintain the recommended pregnancy glucose targets. Thus, one in two babies experience complications requiring neonatal care unit admission. Recent studies demonstrate that hybrid closed-loop therapy, in which algorithms adjust insulin delivery according to continuous glucose measurements, is effective for managing type 1 diabetes outside of pregnancy, but efficacy during pregnancy is unclear. Objective To examine the clinical efficacy of hybrid closed-loop compared to standard insulin therapy in pregnant women with type 1 diabetes. Design A multicentre, parallel-group, open-label, randomised, controlled trial in pregnant women with type 1 diabetes. Setting Nine antenatal diabetes clinics in England, Scotland and Northern Ireland. Participants Pregnant women with type 1 diabetes and above-target glucose levels, defined as glycated haemoglobin A1c of ≥ 48 mmol/mol (6.5%) in early pregnancy. Interventions A hybrid closed-loop system compared to standard insulin delivery (via insulin pump or multiple daily injections) with continuous glucose monitoring. Outcome measures The primary outcome is the difference between the intervention and control groups in percentage time spent in the pregnancy glucose target range (3.5–7.8 mmol/l) as measured by continuous glucose monitoring from 16 weeks’ gestation until delivery. Secondary outcomes include overnight time in range, time above range (> 7.8 mmol/l), glycated haemoglobin A1c, safety outcomes (diabetic ketoacidosis, severe hypoglycaemia, adverse device events), psychosocial functioning obstetric and neonatal outcomes. Results The percentage of time that maternal glucose levels were within target range was higher with closed-loop than standard insulin therapy: 68.2 ± 10.5 in closed-loop and 55.6 ± 12.5 in the control group (mean‑adjusted difference 10.5 percentage points, 95% confidence interval 7.0 to 14.0; p < 0.001). Results were consistent in secondary outcomes, with less time above range (−10.2%, 95% confidence interval −13.8 to −6.6%; p < 0.001), higher overnight time in range (12.3%, 95% confidence interval 8.3 to 16.2%; p < 0.001) and lower glycated haemoglobin A1c (−0.31%, 95% confidence interval −0.50 to −0.12%; p < 0.002) all favouring closed-loop. The treatment effect was apparent from early pregnancy and consistent across clinical sites, maternal glycated haemoglobin A1c categories and previous insulin regimen. Maternal glucose improvements were achieved with 3.7 kg less gestational weight gain and without additional hypoglycaemia or total daily insulin dose. There were no unanticipated safety problems (six vs. five severe hypoglycaemia cases, one diabetic ketoacidosis per group) and seven device-related adverse events associated with closed-loop. There were no between-group differences in patient-reported outcomes. There was one shoulder dystocia in the closed-loop group and four serious birth injuries, including one neonatal death in the standard care group. Limitations Our results cannot be extrapolated to closed-loop systems with higher glucose targets, and our sample size did not provide definitive data on maternal and neonatal outcomes. Conclusions Hybrid closed-loop therapy significantly improved maternal glycaemia during type 1 diabetes pregnancy. Our results support National Institute for Health and Care Excellence guideline recommendations that hybrid closed-loop therapy should be offered to all pregnant women with type 1 diabetes. Future work Future trials should examine the effectiveness of hybrid closed-loop started before pregnancy, or as soon as possible after pregnancy confirmation

Efficacy and moderators of efficacy of cognitive behavioural therapies with a trauma focus in children and adolescents: an individual participant data meta-analysis of randomised trials

Background: Existing clinical trials of cognitive behavioural therapies with a trauma focus (CBTs-TF) are underpowered to examine key variables that might moderate treatment effects. We aimed to determine the efficacy of CBTs-TF for young people, relative to passive and active control conditions, and elucidate putative individual-level and treatment-level moderators.   Methods: This was an individual participant data meta-analysis of published and unpublished randomised studies in young people aged 6−18 years exposed to trauma. We included studies identified by the latest UK National Institute of Health and Care Excellence guidelines (completed on Jan 29, 2018) and updated their search. The search strategy included database searches restricted to publications between Jan 1, 2018, and Nov 12, 2019; grey literature search of trial registries ClinicalTrials.gov and ISRCTN; preprint archives PsyArXiv and bioRxiv; and use of social media and emails to key authors to identify any unpublished datasets. The primary outcome was post-traumatic stress symptoms after treatment (<1 month after the final session). Predominantly, one-stage random-effects models were fitted. This study is registered with PROSPERO, CRD42019151954.   Findings: We identified 38 studies; 25 studies provided individual participant data, comprising 1686 young people (mean age 13·65 years [SD 3·01]), with 802 receiving CBTs-TF and 884 a control condition. The risk-of-bias assessment indicated five studies as low risk and 20 studies with some concerns. Participants who received CBTs-TF had lower mean post-traumatic stress symptoms after treatment than those who received the control conditions, after adjusting for post-traumatic stress symptoms before treatment (b=−13·17, 95% CI −17·84 to −8·50, p<0·001, τ2=103·72). Moderation analysis indicated that this effect of CBTs-TF on post-traumatic stress symptoms post-treatment increased by 0·15 units (b=−0·15, 95% CI −0·29 to −0·01, p=0·041, τ2=0·03) for each unit increase in pre-treatment post-traumatic stress symptoms.   Interpretation: This is the first individual participant data meta-analysis of young people exposed to trauma. Our findings support CBTs-TF as the first-line treatment, irrespective of age, gender, trauma characteristics, or carer involvement in treatment, with particular benefits for those with higher initial distress

Effectiveness of technology-assisted vs face-to-face cognitive behavioural therapy for anxiety and depression in children and young people: A systematic review and meta-analysis

Background: Cognitive Behavioural Therapy (CBT) has been proven to be effective for anxiety and depression in children and young people (CYP). Over the past 20 years there have been several attempts at delivering CBT through apps, online software, videogames, but also with a therapist via phone or videoconferencing platforms, with promising results for the “technology-assisted” versions. However, most research, have compared online CBT to waiting lists, and not many studies looked at the effectiveness of face-to-face (f2f) CBT versus technology-assisted CBT. Methods: Adopting the PRISMA guidelines, we evaluated 1849 citations and identified 10 eligible studies. Studies were identified through the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, PubMed/MEDLINE, Web of Science, and Scopus. Results: Ten studies met our inclusion criteria. The studies included a variety of technology-assisted forms of CBT, including videoconferencing and online CBT. Of these, seven looked at the effectiveness of technology-assisted CBT for anxiety in CYP, and seven looked at depression. The meta-analyses had low heterogeneity and showed that technology-assisted CBT was non-inferior to f2f CBT for anxiety and depression in CYP (d = 0.06 and 0.12 respectively). Conclusions: Technology-assisted CBT may be a valid alternative for the treatment of anxiety and depression in CYP. Future studies should consider what specific delivery modalities are most cost-effective

Global topology of human connectome is insensitive to early life environments – A prospective longitudinal study of the general population

The widely acknowledged detrimental impact of early adversity on child development has driven efforts to understand the underlying mechanisms that may mediate these effects within the developing brain. Recent efforts have begun to move beyond associating adversity with the morphology of individual brain regions towards determining if and how adversity might shape their interconnectivity. However, whether adversity effects a global shift in the organisation of whole-brain networks remains unclear. In this study, we assessed this possibility using parental questionnaire and diffusion imaging data from The Avon Longitudinal Study of Parents and Children (ALSPAC, N = 913), a prospective longitudinal study spanning more than 20 years. We tested whether a wide range of adversities—including experiences of abuse, domestic violence, physical and emotional cruelty, poverty, neglect, and parental separation—measured by questionnaire within the first seven years of life were significantly associated with the tractography-derived connectome in young adulthood. We tested this across multiple measures of organisation and using a computational model that simulated the wiring economy of the brain. We found no significant relationships between early exposure to any form of adversity and the global organisation of the structural connectome in young adulthood. We did detect local differences in the medial prefrontal cortex, as well as an association between weaker brain wiring constraints and greater externalising behaviour in adolescence. Our results indicate that further efforts are necessary to delimit the magnitude and functional implications of adversity-related differences in connectomic organization. Research Highlights: Diverse prospective measures of the early-life environment do not predict the organisation of the DTI tractography-derived connectome in young adulthood Wiring economy of the connectome is weakly associated with externalising in adolescence, but not internalising or cognitive ability Further work is needed to establish the scope and significance of global adversity-related differences in the structural connectome

Reasoning with Polysemes: When Default Inferences Beat Contextual Information.

How, and how strongly, do default comprehension inferences shape verbal reasoning? When do they lead to fallacies? We address these questions for reasoning with polysemous verbs (verbs with distinct, but related senses) and ask when their use leads to fallacies of equivocation. The ‘linguistic salience bias hypothesis’ specifies conditions where subordinate uses of unbalanced polysemes trigger defeasible default inferences that are supported only by the dominant sense but influence further cognition, regardless. But does this happen even where the verb is preceded by disambiguating context that invites subordinate interpretations from the start? We present three experimental-philosophy studies that address this question: We use the psycholinguistic cancellation paradigm and fixation time measurements to examine inferences from polysemous appearance verbs. We find that default inferences can beat even preceding contextual information. Beyond their psycho-linguistic interest, findings have important philosophical consequences

Saltmarsh blue carbon accumulation rates and their relationship with sea-level rise on a multi-decadal timescale in northern England

Saltmarshes are widely thought to sequester carbon at rates significantly exceeding those found in terrestrial environments. This ability arises from the in-situ production of plant biomass and the effective trapping and storage of both autochthonous and allochthonous organic carbon. The role saltmarshes play in climate change mitigation, through accumulating ‘blue’ carbon, depends on both the rate at which carbon accumulates within sediments and the rapidity with which carbon is remineralised. It has been hypothesised that carbon accumulation rates, in turn, depend on the local rate of relative sea-level rise, with faster sea-level rise providing more accommodation space for carbon storage. This relationship has been investigated over long (millennial) and short (decadal) timescales but without accounting for the impact of higher quantities of labile carbon in more recently deposited sediment. This study addresses these three key aspects in a saltmarsh sediment study from Lindisfarne National Nature Reserve (NNR), northern England, where there is a comparatively pristine marsh. We quantify rates of carbon accumulation by combining a Bayesian age-depth model based on 210Pb and 137Cs activities with centimetre-resolution organic carbon density measurements. We also use thermogravimetric analyses to determine the relative proportions of labile and recalcitrant organic matter and calculate the net recalcitrant organic matter accumulation rate. Results indicate that during the 20th century more carbon accumulated at the Lindisfarne NNR saltmarsh during decades with relatively high rates of sea-level rise. The post-depositional loss of labile carbon down the core results in a weaker though still significant relationship between recalcitrant organic matter accumulation and sea-level change. Thus, that increasing saltmarsh carbon accumulation is driven by higher rates of sea-level rise is demonstrated over recent multi-decadal timescales

A redox switch allows binding of ferrous and ferric ions in the cyanobacterial iron binding protein FutA from Prochlorococcus

The marine cyanobacterium Prochlorococcus is a main contributor to global photosynthesis, whilst being limited by iron availability. Cyanobacterial genomes typically encode two different types of FutA iron binding proteins: periplasmic FutA2 ABC transporter subunits bind ferric (Fe3+), while cytosolic FutA1 binds ferrous (Fe2+). Owing to their small size and their economized genome Prochlorococcus ecotypes typically possess a single futA gene. How the encoded FutA protein might bind different Fe oxidation states was previously unknown. Here we use structural biology techniques at room temperature to probe the dynamic behavior of FutA. Neutron diffraction confirmed four negatively charged tyrosinates, that together with a solvent molecule coordinate iron in trigonal bipyramidal geometry. Positioning of the positively charged Arg103 side chain in the second coordination shell was consistent with an overall charge-neutral ferric binding state in structures determined by neutron diffraction and serial femtosecond crystallography. Conventional rotation X-ray crystallography using a home source revealed X-ray induced photoreduction of the iron center with observation of the ferrous binding state; here, an additional positioning of the Arg203 side chain in the second coordination shell maintained an overall charge neutral ferrous binding site. Room temperature dose series using serial synchrotron crystallography and an XFEL X-ray pump-probe approach capture the transition between ferric and ferrous states, revealing how Arg203 operates as a switch to accommodate the different iron oxidation states. This switching ability of the Prochlorococcus FutA protein may reflect ecological adaptation by genome streamlining and loss of specialized FutA proteins

Out of the way, human! Understanding post-adoption of last-mile delivery robots

The pace of technological development is exceeding expectations and transforming the landscape of last-mile delivery. This study investigates how users' post-adoption behavior in using delivery robots is formed. Based on the task-technology fit (TTF) model, we present a research model that includes both direct and indirect factors that have been previously overlooked in the literature. We collected data from 550 users of delivery robots. Our structural equation modelling results show that two hedonic- (i.e., gratification and anthropomorphism) and three utilitarian- (i.e., service quality experience, delivery task requirements, and user-facing technology performance) driven factors predict perceived TTF in using delivery robots. Value-in-use and trust have sequential mediating effects that connect perceived TTF and service reuse likelihood and word-of-mouth recommendation. Our findings suggest ways to improve last-mile delivery robot strategies and provide practical implications for the industry