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Despite custodial grandchildren's (CG) traumatic histories and risk for psychological difficulties, knowledge is scant regarding the frequencies, types, and consequences es of adverse childhood experiences (ACEs) they have encountered. We examined self-reported ACEs via online surveys with 342 CG (ages 12 to 18) who were recruited to participate in an RCT of a social intelligence training program. ACEs were assessed by 14 widely used items, and risk for internalizing (ID) and externalizing (ED) difficulties were measured using 80 th percentile cut-offs on the Strengths and Difficulties Questionnaire. Classification and regression tree analyses included all 14 ACEs (along with CG gender and age) as predictors of ID and ED risk separately. Given possible comorbidity, analyses were run with and without the other risk type as a predictor. Less than 9% of CG self-reported no ACEs, 48.6% reported two to five ACEs, and 30.5 % reported ≥ 6. Irrespective of ED risk, bullying from peers strongly predicted ID risk. ED risk was peak among CG who also had risk for ID. Without ID risk as a predictor, ED risk was highest among CG who were emotionally abused, not lived with a substance abuser, and encountered neighborhood violence. The frequency and types of ACEs observed were alarmingly higher than those among the general population, suggesting that many CG have histories of trauma and household dysfunction. That a small number of ACEs among the 14 studied here were significant predictors of ID and ED risk challenges the widespread belief of a cumulative dose ACE effect., Competing Interests: Competing Interests The authors have no relevant financial or non-financial interests to disclose.

High frequency oscillations are a promising biomarker of outcome in intractable epilepsy. Prior high frequency oscillation work focused on counting high frequency oscillations on individual channels, and it is still unclear how to translate those results into clinical care. We show that high frequency oscillations arise as network discharges that have valuable properties as predictive biomarkers. Here, we develop a tool to predict patient outcome before surgical resection is performed, based on only prospective information. In addition to determining high frequency oscillation rate on every channel, we performed a correlational analysis to evaluate the functional connectivity of high frequency oscillations in 28 patients with intracranial electrodes. We found that high frequency oscillations were often not solitary events on a single channel, but part of a local network discharge. Eigenvector and outcloseness centrality were used to rank channel importance within the connectivity network, then used to compare patient outcome by comparison with the seizure onset zone or a proportion within the proposed resected channels (critical resection percentage). Combining the knowledge of each patient's seizure onset zone resection plan along with our computed high frequency oscillation network centralities and high frequency oscillation rate, we develop a Naïve Bayes model that predicts outcome (positive predictive value: 100%) better than predicting based upon fully resecting the seizure onset zone (positive predictive value: 71%). Surgical margins had a large effect on outcomes: non-palliative patients in whom most of the seizure onset zone was resected ('definitive surgery', ≥ 80% resected) had predictable outcomes, whereas palliative surgeries (<80% resected) were not predictable. These results suggest that the addition of network properties of high frequency oscillations is more accurate in predicting patient outcome than seizure onset zone alone in patients with most of the seizure onset zone removed and offer great promise for informing clinical decisions in surgery for refractory epilepsy., Competing Interests: S.V.G. and W.C.S. have a licensing agreement with Natus Medical, Inc., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: Intranasal medications have been proposed as adjuncts to out-of-hospital cardiac arrest (OHCA) care. We sought to quantify the effects of intranasal medication administration (INMA) in OHCA workflows., Methods: We conducted separate randomized OHCA simulation trials with lay rescuers (LRs) and first responders (FRs). Participants were randomized to groups performing hands-only cardiopulmonary resuscitation (CPR)/automated external defibrillator with or without INMA during the second analysis phase. Time to compression following the second shock (CPR2) was the primary outcome and compression quality (chest compression rate (CCR) and fraction (CCF)) was the secondary outcome. We fit linear regression models adjusted for CPR training in the LR group and service years in the FR group., Results: Among LRs, INMA was associated with a significant increase in CPR2 (mean diff. 44.1 s, 95% CI: 14.9, 73.3), which persisted after adjustment ( p  = 0.005). We observed a significant decrease in CCR (INMA 95.1 compressions per min (cpm) vs control 104.2 cpm, mean diff. -9.1 cpm, 95% CI -16.6, -1.6) and CCF (INMA 62.4% vs control 69.8%, mean diff. -7.5%, 95% CI -12.0, -2.9). Among FRs, we found no significant CPR2 delays (mean diff. -2.1 s, 95% CI -15.9, 11.7), which persisted after adjustment ( p  = 0.704), or difference in quality (CCR INMA 115.5 cpm vs control 120.8 cpm, mean diff. -5.3 cpm, 95% CI -12.6, 2.0; CCF INMA 79.6% vs control 81.2% mean diff. -1.6%, 95% CI -7.4, 4.3%)., Conclusions: INMA in LR resuscitation was associated with diminished resuscitation performance. INMA by FR did not impede key times or quality., Competing Interests: Mr. Dowker reports grant‐funding from the National Institutes of Health (grant R01‐HL137964), travel support from National Association of EMS Physicians (NAEMSP)/GMR Foundation, and concurrent employment as a firefighter/EMT with the Green Oak Charter Township Fire Department a licensed nontransporting Basic Life Support (BLS) agency in Michigan. Ms. Majhail and Ms. Scott report employment, during one or more phases of the study, with Emergent Health Partners, a licensed transporting Advanced Life Support (ALS) agency that serves as a regional provider of BLS/ALS medical transport and 911 dispatched emergency response in southern Michigan. Dr. Brent reports a leadership position for the Washtenaw/Livingston Medical Control Authority, she is an Air Medical Physician Association Board Member, NAEMSP Air Medical Committee Vice Chair, NAEMSP Council of EMS Fellowship Directors Vice Chair, and grant funding CMB Toyota Grant on Prehospital Medical Drones, and travel support from Air Medical Physician Association. Dr. Smith reports effort as associate medical director for the Washtenaw/Livingston Medical Control Authority, a regional EMS oversight body. Dr. Berger reports grant funding from AHRQ R01 HS025411‐02BCBSM Foundation, Dr. Neumar reports the following grant support National Institutes of Health: K12HL133304, R01HL133129, R34HL130738 ‐ Institution; Laerdal Foundation‐Institution, and he is SaveMiHeart President and Board Chair, ILCOR cochair. All other authors report no relevant interests., (© 2024 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Alzheimer's Disease and related dementias (ADRD) are an increasing threat to global health initiatives. Efforts to prevent the development of ADRD require understanding behaviors that increase and decrease risk of neurodegeneration and cognitive decline, in addition to uncovering the underlying biological mechanisms behind these effects. Stress exposure and alcohol consumption have both been associated with increased risk for ADRD in human populations. However, our ability to understand causal mechanisms of ADRD requires substantial preclinical research. In this review, we summarize existing human and animal research investigating the connections between lifetime stress and alcohol exposures and ADRD., Competing Interests: None., (© 2024 The Authors. Published by Elsevier Inc.)

Metabolic disorders such as type 2 diabetes, fatty liver disease, hyperlipidemia, and obesity commonly co-occur but clinical treatment options do not effectively target all disorders. Calorie restriction, semaglutide, rosiglitazone, and mitochondrial uncouplers have all demonstrated efficacy against one or more obesity-related metabolic disorders, but it currently remains unclear which therapeutic strategy best targets the combination of hyperglycaemia, liver fat, hypertriglyceridemia, and adiposity. Herein we performed a head-to-head comparison of 5 treatment interventions in the female db/db mouse model of severe metabolic disease. Treatments included ∼60 % calorie restriction (CR), semaglutide, rosiglitazone, BAM15, and niclosamide ethanolamine (NEN). Results showed that BAM15 and CR improved body weight and liver steatosis to levels superior to semaglutide, NEN, and rosiglitazone, while BAM15, semaglutide, and rosiglitazone improved glucose tolerance better than CR and NEN. BAM15, CR, semaglutide, and rosiglitazone all had efficacy against hypertriglyceridaemia. These data provide a comprehensive head-to-head comparison of several key treatment strategies for metabolic disease and highlight the efficacy of mitochondrial uncoupling to correct multiple facets of the metabolic disease milieu in female db/db mice., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kyle Hoehn reports financial support was provided by National Institutes of Health and National Health and Medical Research Council. Kyle Hoehn reports a relationship with Uncoupler Therapeutics, Inc. that includes: board membership and equity or stocks. Kyle Hoehn reports a relationship with Life Biosciences, Inc. that includes: equity or stocks. Kyle Hoehn has a patent via University of Virginia. Webster Santos reports financial support was provided by National Institutes of Health. Webster Santos reports a relationship with Uncoupler Therapeutics, Inc. that includes: board membership and equity or stocks. Webster Santos reports a relationship with Life Biosciences, Inc. that includes: equity or stocks., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

In a 2016 screen of natural product extracts, a new family of natural products, the cahuitamycins, was discovered and found to inhibit biofilm formation in the human pathogen Acinetobacter baumannii . The proposed molecular structures contained an unusual piperazic acid residue, which piqued interest related to their structure/function and biosynthesis. Herein we disclose the first total synthesis of the proposed structure of cahuitamycin A in a 12-step longest linear sequence and 18% overall yield. Comparison of spectral and biological data of the authentic natural product and synthetic compound revealed inconsistentancies with the isolated metabolite. We therefore executed the diverted total synthesis of three isomeric compounds, which were also found to be disparate from the isolated natural product. This work sets the stage for future synthetic and biochemical investigations of an important class of natural products.

The present study aimed to identify intergenerational patterns of attachment insecurity among grandmothers, adolescent grandchildren, and birth mothers in custodial grandfamilies and to test the relations among triadic attachment patterns and grandchild socioemotional outcomes. Prior research with custodial grandfamilies has found distinct "profiles" reflecting patterns of closeness between grandmothers, grandchildren, and birth mothers. However, no studies have tested patterns of attachment insecurity among members of the triad, despite the likelihood of attachment disruption in grandfamilies. Moreover, previous studies have only examined links between profile and grandmother outcomes or rudimentary grandchild outcomes. In a sample of 230 grandmother-grandchild dyads from a larger randomized controlled trial testing the efficacy of an online social intelligence training program for grandfamilies, latent profile analysis (LPA) was conducted to identify profiles of intergenerational attachment insecurity, using grandmother and grandchild reports. Profile differences in grandchild internalizing and externalizing problems, social skills, self-esteem, and prosocial behavior were examined. We identified three profiles: isolated mother, grandchild-linked, and disconnected. Overall, grandchildren in disconnected families (in which attachment insecurity between all three members of the triad was high) fared worst. Grandchildren in isolated mother families (in which only grandmother-grandchild attachment insecurity was low) fared best. A secure attachment relationship between grandmother and adolescent grandchild may buffer effects of attachment insecurity between the grandchild and birth mother. These findings inform intervention efforts and highlight the utility of family- and attachment-focused research for building understanding of custodial grandfamilies. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

1. Significant advances in computational ethology have allowed the quantification of behaviour in unprecedented detail. Tracking animals in social groups, however, remains challenging as most existing methods can either capture pose or robustly retain individual identity over time but not both. 2. To capture finely resolved behaviours while maintaining individual identity, we built NAPS (NAPS is ArUco Plus SLEAP), a hybrid tracking framework that combines state-of-the-art, deep learning-based methods for pose estimation (SLEAP) with unique markers for identity persistence (ArUco). We show that this framework allows the exploration of the social dynamics of the common eastern bumblebee ( Bombus impatiens ). 3. We provide a stand-alone Python package for implementing this framework along with detailed documentation to allow for easy utilization and expansion. We show that NAPS can scale to long timescale experiments at a high frame rate and that it enables the investigation of detailed behavioural variation within individuals in a group. 4. Expanding the toolkit for capturing the constituent behaviours of social groups is essential for understanding the structure and dynamics of social networks. NAPS provides a key tool for capturing these behaviours and can provide critical data for understanding how individual variation influences collective dynamics., Competing Interests: CONFLIC T OF INTEREST STATEMENT The authors have no conflict of interest to declare.

The nicotinamide adenine dinucleotide (NAD + ) precursor nicotinamide mononucleotide (NMN) is a proposed therapy for age-related disease, whereby it is assumed that NMN is incorporated into NAD + through the canonical recycling pathway. During oral delivery, NMN is exposed to the gut microbiome, which could modify the NAD + metabolome through enzyme activities not present in the mammalian host. We show that orally delivered NMN can undergo deamidation and incorporation in mammalian tissue via the de novo pathway, which is reduced in animals treated with antibiotics to ablate the gut microbiome. Antibiotics increased the availability of NAD + metabolites, suggesting the microbiome could be in competition with the host for dietary NAD + precursors. These findings highlight new interactions between NMN and the gut microbiome., (© 2023 Federation of European Biochemical Societies.)

We sought to characterize the unique role of somatostatin (SST) in the prelimbic (PL) cortex in mice. We performed slice electrophysiology in pyramidal and GABAergic neurons to characterize the pharmacological mechanism of SST signaling and fiber photometry of GCaMP6f fluorescent calcium signals from SST neurons to characterize the activity profile of SST neurons during exploration of an elevated plus maze (EPM) and open field test (OFT). We used local delivery of a broad SST receptor (SSTR) agonist and antagonist to test causal effects of SST signaling. SSTR activation hyperpolarizes layer 2/3 pyramidal neurons, an effect that is recapitulated with optogenetic stimulation of SST neurons. SST neurons in PL are activated during EPM and OFT exploration, and SSTR agonist administration directly into the PL enhances open arm exploration in the EPM. This work describes a broad ability for SST peptide signaling to modulate microcircuits within the prefrontal cortex and related exploratory behaviors., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Adolescent drug consumption has increased risks to the individual compared to consumption in adulthood, due to the likelihood of long-term and permanent behavioral and neurological adaptations. However, little is known about how adolescent alcohol consumption influences the maturation and trajectory of cortical circuit development. Here, we explore the consequences of adolescent binge drinking on somatostatin (SST) neuronal function in superficial layers of the prelimbic (PL) cortex in male and female SST-Ai9 mice. We find that adolescent drinking-in-the-dark (DID) produces sex-dependent increases in intrinsic excitability of SST neurons, with no change in overall SST cell number, persisting well into adulthood. While we did not find evidence of altered GABA release from SST neurons onto other neurons within the circuit, we found a complementary reduction in layer II/III pyramidal neuron excitability immediately after binge drinking; however, this hypoexcitability rebounded towards increased pyramidal neuron activity in adulthood in females, suggesting long-term homeostatic adaptations in this circuit. Together, this suggests that binge drinking during key developmental timepoints leads to permanent changes in PL microcircuitry function, which may have broad behavioral implications., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A new visible-light-driven method for the carboxylation of (hetero)aryl/vinyl bromides has been developed using catalytic 4CzIPN, nickel, phenyl triflimide, and sodium formate as a carboxylation agent. Interestingly, we found catalytic phenyl triflimide plays an essential role in promoting the reaction. While many C(sp 2 ) carboxylation reactions require harsh reagents or gaseous carbon dioxide, we demonstrate the mild and facile construction of carboxylic acids from readily available starting materials.

Given the scarce past research on custodial grandparents' early life circumstances, we investigated frequencies, patterns, and predictors of 14 adverse childhood experiences (ACEs) reported by 355 custodial grandmothers (CGMs). Predominant ACEs were bullying (54.6%), verbal abuse (51.5%), physical abuse (45.4%), and living with a substance abuser (41.1%). Only 11% of CGMs reported 0 ACEs, whereas 52.4% reported >4. Latent class analyses yielded three classes of ACE exposure: minimal (54.1%), physical/emotional abuse (25.9%), and complex (20.0%). Age was the only demographic factor related to ACE class, with the complex class being younger than the other two. MANCOVAs with age as a covariate revealed that different ACE profiles have unique impacts on CGMs' physical and psychological well-being. We conclude that ACEs are highly prevalent among CGMs and a serious public health concern. Future research addressing ACEs among CGMs is critical in order to support these caregivers and promote resilience in custodial grandfamilies.

Aims and Objectives: To explore the value of using Karl Jaspers' lived experience concept of 'grasping' in remediating the reported dauntingness of formulation., Conclusions: Formulation can be construed as both the process and explication of understanding why a patient is presenting in a particular way. In an automatic process of abduction, 'feeling into' the mind of the other, hypotheses are posted to consciousness with little mental effort as meaningful connections are grasped. Subsequent more deliberative reasoning is synthesised continuously and with surprisingly little mental effort into the best explanation(s). Karl Jaspers' introduction to Psychiatry of the concepts involved, empathy and understanding, and his aim of making their use more scientific established the ongoing, often fierce debate about the ontology of Psychiatry; empirical versus interpretive. Trainees must resolve this for themselves in explicating a formulation, risking exposure of their prejudices. Jaspers' emphasis on the lived experience of empathic understanding that psychiatrists bring to their work found him often using the term 'grasp' rather than 'empathise'. 'Grasping' seems to convey more vividly and meaningfully the role that empathy plays in the initial ascertainment of mood and the subsequent hypothesis discovery, testing and synthesis.

Objective: In the United States, police are often important co-responders to 911 calls with emergency medical services for medical emergencies. To date, there remains a lack of a comprehensive understanding of the mechanisms by which police response modifies time to in-hospital medical care for traumatically injured patients. Further, it remains unclear if differentials exist within or between communities. A scoping review was performed to identify studies evaluating prehospital transport of traumatically injured patients and the role or impact of police involvement., Methods: PubMed, SCOPUS, and Criminal Justice Abstracts databases were utilized to identify articles. English-language, US-based, peer-reviewed articles published on or prior to March 30, 2022 were eligible for inclusion., Results: Of 19,437 articles initially identified, 70 articles were selected for full review and 17 for final inclusion. Key findings included (1) current law enforcement practices involving scene clearance introduce the potential for delayed patient transport but to date there is little research quantifying delays; (2) police transport protocols may decrease transport times; and (3) there are no studies examining the potential impact of scene clearance practices at the patient or community level., Conclusions: Our results highlight that police are often the first on scene when responding to traumatic injuries and have an active role via scene clearance or, in some systems, patient transport. Despite the significant potential for impact on patient well-being, there remains a paucity of data examining and driving current practices., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

We conducted this first ever study comparing reports of custodial grandchildren's (CG) psychological difficulties obtained jointly from 163 custodial grandmothers (CGM) and their CG between ages 6-12. Internalizing and externalizing difficulties were indicated by whether any of the corresponding scales on the Strengths and Difficulties Questionnaire (SDQ, reported by CGM) or Dominic Interactive (DI, reported by CG) reached the 90th percentile. Internalizing and externalizing difficulties were reported by informant types at rates higher than those typically observed in the general population, with externalizing difficulties being more prevalent among male CG. At the dichotomous level of (dis)agreement, nearly two-thirds of informant pairs showed concordance regarding whether or not they reported the CG at the 90th percentile on either externalizing and internalizing difficulties. When (dis)agreement was further broken into four specific categories (i.e., "neither report", "both report", "CGM only", and "CG only", CGM's use of mental health services, race, depressive and anxiety symptoms, harsh/punitive discipline, and warmth impacted such concordance as did CG's gender, age, and use of mental health services. The overall findings were remarkably similar regardless of which specific SDQ and DI scales were used in the analyses. The present study unearths new ground regarding the extent to which grandchildren's distress is similarly perceived by CG themselves versus their CGMs. Such findings are important to the extent that accurate estimates exist regarding the emotional difficulties CG face and lay the groundwork for timely and efficacious interventions designed to alleviate their distress., Competing Interests: We have no conflicts of interest of any type to report here.

With modelling becoming increasingly important in helping to inform decisions about animal diseases, it is essential that the process be optimised to gain the maximum benefit for the decision-maker. Here, the authors set out ten steps that can improve this process for all concerned. Four steps describe initialisation to ensure that the question, answer and timescale are defined; two steps describe the modelling process and quality assurance; and four steps describe the reporting stage. The authors believe that this greater emphasis at the beginning and end of a modelling project will increase the relevance of the work and understanding of the results, and thus contribute towards better decision-making.

Objective: Guided by a life-course perspective, we examine the nature of daily life among custodial grandmothers (CGM) through documenting daily positive and negative affect, reporting daily negative and positive events, and emotional reactivity/responsiveness to daily negative and positive events. We also examine whether CGM age, adverse childhood experiences (ACEs), and social relationship quality with grandchild are associated with each indicator., Methods: We applied multilevel models to 200 CGM (Mage = 61, SD = 5.66) who were recruited from across the United States and completed a daily survey for 14 consecutive days prior to commencing a randomized clinical trial., Results: Older age and reporting fewer ACEs were associated with better overall and less variability in daily well-being. Positive events were reported on 83% of days and negative events were reported on 56% of days. Daily well-being was lower when a negative event was reported and higher when a positive event was reported. Reporting more ACEs was associated with greater exposure to daily negative events and stronger gains in daily well-being when a daily positive event was reported. Older age was associated with lesser declines in daily well-being on days when a negative event was reported., Discussion: In accordance with the life-course perspective, our findings illustrate how the timing of being a CGM (age) and the cumulative nature of development (ACEs) affect daily well-being and negative and positive events for CGM. Our discussion focuses on resources to consider when building resilience-focused interventions for promoting the health and well-being of CGM., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Hemoglobin (Hb) is a modifiable risk factor for adverse pregnancy outcomes. Studies have reported conflicting associations between maternal Hb levels and adverse pregnancy outcomes, including preterm birth (PTB), low birth weight (LBW), and perinatal mortality., Objective: In this study, we aimed to estimate the shape and magnitude of associations between maternal Hb levels in early (7-12 wk gestation) and late pregnancy (27-32 wk gestation) and pregnancy outcomes in a high-income setting., Methods: We used data from 2 UK population-based pregnancy cohorts: the Avon Longitudinal Study of Parents and Children (ALSPAC) and Pregnancy Outcome Prediction Study (POPS). We used multivariable logistic regression models to examine the relationship between Hb and pregnancy outcomes, adjusting for maternal age, ethnicity, BMI, smoking status, and parity. Main outcome measures were PTB, LBW, small for gestational age (SGA), pre-eclampsia (PET), and gestational diabetes mellitus (GDM)., Results: Mean Hb in ALSPAC were 12.5 g/dL (SD = 0.90) and 11.2 g/dL (SD = 0.92) in early and late pregnancy, respectively, and 12.7 g/dL (SD = 0.82) and 11.4 g/dL (SD = 0.82) in POPS. In the pooled analysis, there was no evidence of associations between a higher Hb in early pregnancy (7-12 wk gestation) and PTB (OR per 1 g/dL of Hb: 1.09; 95% CI: 0.97, 1.22), LBW (1.12: 0.99, 1.26), and SGA (1.06; 0.97, 1.15). Higher Hb in late pregnancy (27-32 wk gestation) was associated with PTB (1.45: 1.30, 1.62), LBW (1.77: 1.57, 2.01), and SGA (1.45: 1.33, 1.58). Higher Hb in early and late pregnancy was associated with PET in ALSPAC (1.36: 1.12, 1.64) and (1.53: 1.29, 1.82), respectively, but not in POPS (1.17:0.99, 1.37) and (1.03: 0.86, 1.23). There was an association with a higher Hb and GDM in ALSPAC in both early and late pregnancy [(1.51: 1.08, 2.11) and (1.35: 1.01, 1.79), respectively], but not in POPS [(0.98: 0.81, 1.19) and (0.83: 0.68, 1.02)]., Conclusions: Higher maternal Hb may identify the risk of adverse pregnancy outcomes. Further research is required to investigate if this association is causal and to identify the underlying mechanisms., (Copyright © 2022. Published by Elsevier Inc.)

Objective: Calorie restriction is a first-line treatment for overweight individuals with metabolic impairments. However, few patients can adhere to long-term calorie restriction. An alternative approach to calorie restriction that also causes negative energy balance is mitochondrial uncoupling, which decreases the amount of energy that can be extracted from food. Herein we compare the metabolic effects of calorie restriction with the mitochondrial uncoupler BAM15 in the db/db mouse model of severe hyperglycemia, obesity, hypertriglyceridemia, and fatty liver., Methods: Male db/db mice were treated with ∼50% calorie restriction, BAM15 at two doses of 0.1% and 0.2% (w/w) admixed in diet, or 0.2% BAM15 with time-restricted feeding from 5 weeks of age. Mice were metabolically phenotyped over 4 weeks with assessment of key readouts including body weight, glucose tolerance, and liver steatosis. At termination, liver tissues were analysed by metabolomics and qPCR., Results: Calorie restriction and high-dose 0.2% BAM15 decreased body weight to a similar extent, but mice treated with BAM15 had far better improvement in glucose control. High-dose BAM15 treatment completely normalized fasting glucose and glucose tolerance to levels similar to lean db/+ control mice. Low-dose 0.1% BAM15 did not affect body mass but partially improved glucose tolerance to a similar degree as 50% calorie restriction. Both calorie restriction and high-dose BAM15 significantly improved hyperglucagonemia and liver and serum triglyceride levels. Combining high-dose BAM15 with time-restricted feeding to match the time that calorie restricted mice were fed resulted in the best metabolic phenotype most similar to lean db/+ controls. BAM15-mediated improvements in glucose control were associated with decreased glucagon levels and decreased expression of enzymes involved in hepatic gluconeogenesis., Conclusions: BAM15 and calorie restriction treatments improved most metabolic disease phenotypes in db/db mice. However, mice fed BAM15 had superior effects on glucose control compared to the calorie restricted group that consumed half as much food. Submaximal dosing with BAM15 demonstrated that its beneficial effects on glucose control are independent of weight loss. These data highlight the potential for mitochondrial uncoupler pharmacotherapies in the treatment of metabolic disease., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

The ε4 variant of apolipoprotein E (APOE) is the strongest and most common genetic risk factor for Alzheimer's disease (AD). While the mechanism of conveyed risk is incompletely understood, promotion of inflammation, dysregulated metabolism, and protein misfolding and aggregation are contributors to accelerating disease. Here we determined the concurrent effects of systemic metabolic changes and brain inflammation in young (3-month-old) and aged (18-month-old) male and female mice carrying the APOE4 gene. Using functional metabolic assays alongside multivariate modeling of hippocampal cytokine levels, we found that brain cytokine signatures are predictive of systemic metabolic outcomes, independent of AD proteinopathies. Male and female mice each produce different cytokine signatures as they age and as their systemic metabolic phenotype declines, and these signatures are APOE genotype dependent. Ours is the first study to identify a quantitative and predictive link between systemic metabolism and specific pathological cytokine signatures in the brain. Our results highlight the effects of APOE4 beyond the brain and suggest the potential for bi-directional influence of risk factors in the brain and periphery., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In wildlife disease management there are few diseases for which vaccination is a viable option. The human vaccine BCG has been used for the control of bovine tuberculosis in badgers since 2010 and is expected to increase. Understanding the long-term effects of repeated vaccination campaigns on disease prevalence is vital, but modelling thus far has generally assumed that a vaccine provides perfect protection to a proportion of the population, and that animals exposed to a repeated vaccination have a second independent chance of becoming protected. We held a workshop with experts in the field to obtain consensus over the main pathways for partial protection in the badger, and then simulated these using an established model. The available data supported the possibility that some individuals receive no benefit from the BCG vaccine, others may result in a delayed disease progression and in the remaining animals, vaccine protected the individual from any onward transmission. Simulating these pathways using different levels of overall efficacy demonstrated that partial protection leads to a reduced effect of vaccination, but in all of the identified scenarios it was still possible to eradicate disease in an isolated population with no disease introduction. We also identify those potential vaccination failures that require further investigation to determine which of our proposed pathways is the more likely., (Crown Copyright © 2022. Published by Elsevier B.V. All rights reserved.)

The incidence of bovine tuberculosis (TB, caused by Mycobacterium bovis) in cattle has been associated with TB in badgers (Meles meles) in parts of England. The aim was to identify badger-associated M. bovis reservoirs in the Edge Area, between the High- and Low-Risk Areas for cattle TB. Data from badger TB surveys were sparse. Therefore, a definition for a local M. bovis reservoir potentially shared by cattle and badgers was developed using cattle TB surveillance data. The performance of the definition was estimated through Latent Class Analysis using badger TB survey data. Spatial units (25 km 2 ) in the Edge Area were classified as having a reservoir if they had (i) at least one TB incident in at least three of the previous 7 years, (ii) at least one TB incident in a cattle herd confirmed by post-mortem tests as due to M. bovis infection and not attributable to cattle movements in the previous 2 years and (iii) more confirmed TB incidents than un-confirmed in the previous 2 years. Approximately 20% of the Edge Area was classified as having a local M. bovis reservoir using the cattle-based definition. Assuming 15% TB prevalence in Edge Area badgers, sensitivity for the local M. bovis reservoir definition varied from 25.7% [95% credible interval (CrI): 10.7%-85.1%] to 64.8% (95% CrI: 48.1%-88.0%). Specificity was 91.9% (CrI: 83.6%-97.4%). Over 90% of the local reservoir was in stable endemic TB areas identified through previous work and its spatial distribution was largely consistent with local veterinary knowledge. Uncertainty in the reservoir spatial distribution was explored through its recalculation in spatial units shifted in different directions. We recommend that the definition is re-evaluated as further data on badger infection with M. bovis become available., (© 2021 Crown copyright. Transboundary and Emerging Diseases published by Wiley-VCH GmbH. This article is published with the permission of the Controller of HMSO and the Queen's Printer for Scotland.)

Social isolation, particularly in early life, leads to deleterious physiological and behavioral outcomes. Here, we leverage new high-throughput tools to comprehensively investigate the impact of isolation in the bumblebee, Bombus impatiens, from behavioral, molecular, and neuroanatomical perspectives. We reared newly emerged bumblebees in complete isolation, in small groups, or in their natal colony, and then analyzed their behaviors while alone or paired with another bee. We find that when alone, individuals of each rearing condition show distinct behavioral signatures. When paired with a conspecific, bees reared in small groups or in the natal colony express similar behavioral profiles. Isolated bees, however, showed increased social interactions. To identify the neurobiological correlates of these differences, we quantified brain gene expression and measured the volumes of key brain regions for a subset of individuals from each rearing condition. Overall, we find that isolation increases social interactions and disrupts gene expression and brain development. Limited social experience in small groups is sufficient to preserve typical patterns of brain development and social behavior., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Advances in the study of neurological conditions have been possible because of pluripotent stem cell technologies and organoids. Studies have described the generation of neural ectoderm-derived retinal and brain structures from pluripotent stem cells. However, the field is still troubled by technical challenges, including high culture costs and variability. Here, we describe a simple and economical protocol that reproducibly gives rise to the neural retina and cortical brain regions from confluent cultures of stem cells. The spontaneously generated cortical organoids are transcriptionally comparable with organoids generated by other methods. Furthermore, these organoids showed spontaneous functional network activity and proteomic analysis confirmed organoids maturity. The generation of retinal and brain organoids in close proximity enabled their mutual isolation. Suspension culture of this complex organoid system demonstrated the formation of nerve-like structures connecting retinal and brain organoids, which might facilitate the investigation of neurological diseases of the eye and brain., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The 21st century has seen an enormous growth in emergency medical services (EMS) information technology systems, with corresponding accumulation of large volumes of data. Despite this growth, integration efforts between EMS-based systems and electronic health records, and public-sector databases have been limited due to inconsistent data structure, data missingness, and policy and regulatory obstacles. Efforts to integrate EMS systems have benefited from the evolving science of entity resolution and record linkage. In this chapter, we present the history and fundamentals of record linkage techniques, an overview of past uses of this technology in EMS, and a look into the future of record linkage techniques for integrating EMS data systems including the use of machine learning-based techniques.

Objective: The minor allele (A) of the rs373863828 variant (p.Arg457Gln) in CREBRF is restricted to indigenous peoples of the Pacific islands (including New Zealand Māori and peoples of Polynesia), with a frequency of up to 25% in these populations. This allele associates with a large increase in body mass index (BMI) but with significantly lower risk of type-2 diabetes (T2D). It remains unclear whether the increased BMI is driven by increased adiposity or by increased lean mass., Methods: We undertook body composition analysis using DXA in 189 young men of Māori and Pacific descent living in Aotearoa New Zealand. Further investigation was carried out in two orthologous Arg458Gln knockin mouse models on FVB/NJ and C57BL/6j backgrounds., Results: The rs373863828 A allele was associated with lower fat mass when adjusted for BMI (p < 0.05) and was associated with significantly lower circulating levels of the muscle inhibitory hormone myostatin (p < 0.05). Supporting the human data, significant reductions in adipose tissue mass were observed in the knockin mice. This was more significant in older mice in both backgrounds and appeared to be the result of reduced age-associated increases in fat mass. The older male knockin mice on C57BL/6j background also had increased grip strength (p < 0.01) and lower levels of myostatin (p < 0.05)., Conclusion: Overall, these results prove that the rs373863828 A-allele is associated with a reduction of myostatin levels which likely contribute to an age-dependent lowering of fat mass, at least in males., (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

While negative impacts of COVID-19-related remote instruction on children continue to emerge, it appears that vulnerable students will disproportionately bear the burden. One such vulnerable population is children being raised by grandparents. The purpose of this mixed methods study was to gain insight into custodial grandmothers' (CGMs) experiences of their grandchildren's remote instruction, as well as individual and contextual factors associated with these experiences. A national sample of 315 CGMs, drawn from two randomized clinical trials, completed an online survey in Spring of 2020. Results of a thematic analysis and supplemental quantitative analyses revealed three themes. First, access to technology and instructional supports were critical to the success of remote instruction, with barriers being difficulties using technology and poor-quality remote instruction. Next, grandchild socioemotional difficulties, and fit with remote instruction, were central to their engagement and success with remote instruction. Finally, CGMs experienced multiple stressors related to managing the demands of remote instruction, work, and family. Challenges associated with remote instruction were related to pre-pandemic difficulties such as grandchild problems and CGM depressive symptoms. Collectively, the results highlight how multiple adversities may have amplified grandchildren's existing vulnerability to negative outcomes. Implications are addressed, including strategies for supporting children raised by grandparents beyond the COVID-19 pandemic., Competing Interests: The authors declare no conflicts of interest., (© 2022 Wiley Periodicals LLC.)

A low-cost, scalable and reproducible approach for the mass production of screen-printed electrode (SPE) platforms that have varying percentage mass incorporations of 2D hexagonal boron nitride (2D-hBN) (2D-hBN/SPEs) is demonstrated herein. These novel 2D-hBN/SPEs are explored as a potential metal-free electrocatalysts towards oxygen reduction reactions (ORRs) within acidic media where their performance is evaluated. A 5% mass incorporation of 2D-hBN into the SPEs resulted in the most beneficial ORR catalysis, reducing the ORR onset potential by ca. 200 mV in comparison to bare/unmodified SPEs. Furthermore, an increase in the achievable current of 83% is also exhibited upon the utilisation of a 2D-hBN/SPE in comparison to its unmodified equivalent. The screen-printed fabrication approach replaces the less-reproducible and time-consuming drop-casting technique of 2D-hBN and provides an alternative approach for the large-scale manufacture of novel electrode platforms that can be utilised in a variety of applications.

Objective: To explore the theme identified by Bagster et al. 1 in their selective psychiatric literature review that formulation can appear daunting., Conclusion: Formulation is understandably daunting, even though it occurs in all human encounters. The plural nature of mental symptoms is such that anxiety-provoking intuitive judgement is required at all points in both the process and explication of formulation, a type of instinctive guessing. There are no rules for this, because the laws of vertical integration of systems are not established. Guidelines are more appropriate than 'instructions'. Much of the wider mental health and clinical reasoning literature addresses intuitive judgement, but the current psychiatric literature tends to focus on pattern recognition as a deliberative cognitive act of Type 2 processes. Arguably this reductionism adds to the dauntingness. Anxiety detected about the intuitive judgement involved can be addressed in supervision, taking into account the psychological mindedness of the trainee.

The desire to understand how the brain generates and patterns behavior has driven rapid methodological innovation in tools to quantify natural animal behavior. While advances in deep learning and computer vision have enabled markerless pose estimation in individual animals, extending these to multiple animals presents unique challenges for studies of social behaviors or animals in their natural environments. Here we present Social LEAP Estimates Animal Poses (SLEAP), a machine learning system for multi-animal pose tracking. This system enables versatile workflows for data labeling, model training and inference on previously unseen data. SLEAP features an accessible graphical user interface, a standardized data model, a reproducible configuration system, over 30 model architectures, two approaches to part grouping and two approaches to identity tracking. We applied SLEAP to seven datasets across flies, bees, mice and gerbils to systematically evaluate each approach and architecture, and we compare it with other existing approaches. SLEAP achieves greater accuracy and speeds of more than 800 frames per second, with latencies of less than 3.5 ms at full 1,024 × 1,024 image resolution. This makes SLEAP usable for real-time applications, which we demonstrate by controlling the behavior of one animal on the basis of the tracking and detection of social interactions with another animal., (© 2022. The Author(s).)

Background: Patients at high risk of severe preeclampsia and fetal growth restriction have low circulating levels of placental growth factor and features of maternal vascular malperfusion placental pathology at delivery. Multimodal screening and commencement of aspirin prophylaxis at 11 to 13 weeks' gestation markedly reduces the risk of preterm delivery with preeclampsia. However, the additional role of low-molecular-weight heparin and mechanisms of action remain uncertain. Because low-molecular-weight heparin augments the production and release of placental growth factor in vitro by both placental villi and vascular endothelium, it may be effective to suppress the risk of severe preeclampsia in a niche group of high-risk patients with low circulating placental growth factor in the early second trimester., Objective: This study aimed to define a gestational age-specific reference range for placental growth factor and to test the hypothesis that prophylactic low-molecular-weight heparin administered in the early second trimester may restore deficient circulating placental growth factor levels and thereby prolong pregnancy., Study Design: Centile curves for circulating placental growth factor levels from 12 to 36 weeks' gestation were derived using quantile regression of combined data from a published cohort of 4207 unselected nulliparous patients in Cambridge, United Kingdom, at 4 sampling time points (12, 20, 28, and 36 weeks' gestation) and the White majority (n=531) of a healthy nulliparous cohort in Toronto, Canada, at 16 weeks' gestation using the same test platform. Within a specialty high-risk clinic in Toronto, a niche group of 7 patients with a circulating placental growth factor at the <10th centile in the early second trimester received daily prophylactic low-molecular-weight heparin (enoxaparin; 40 mg subcutaneously) and were followed up until delivery (group 1). Their baseline characteristics, delivery details, and placental pathologies were compared with 5 similar patients who did not receive low-molecular-weight heparin during the observation period (group 2) and further with 21 patients who delivered with severe preeclampsia (group 3) in the same institution., Results: A gestational age-specific reference range for placental growth factor levels at weekly intervals between 12 and 36 weeks was established for White women with singleton pregnancies. Within group 1, 5 of 7 patients demonstrated a sustained increase in circulating placental growth factor levels, whereas placental growth factor levels did not increase in group 2 or group 3 patients who did not receive low-molecular-weight heparin. Group 1 patients receiving low-molecular-weight heparin therapy exhibited a later gestation at delivery, relative to groups 2 and 3 (36 weeks [33-37] vs 23 weeks [22-26] and 28 weeks [27-31], respectively), and consequently had higher birthweights (1.93 kg [1.1-2.7] vs 0.32 kg [0.19-0.39] and 0.73 kg [0.52-1.03], respectively). The incidence of stillbirth was lowest in group 1 (14% [1 of 7]), relative to groups 2 and 3 (80% [4 of 5] and 29% [6 of 21], respectively). Maternal vascular malperfusion was the most common placental pathology found in association with abnormal uterine artery Doppler., Conclusion: In patients at high risk of a serious adverse pregnancy outcome owing to placental disease, the addition of low-molecular-weight heparin to aspirin prophylaxis in the early second trimester may restore deficient circulating placental growth factor to mediate an improved perinatal outcome. These data support the implementation of a multicenter pilot randomized control trial where patients are recruited primarily based on the assessment of placental function in the early second trimester., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: The objective of this study was to compare the biomechanics of using a double layered human dermal allograft to a single layered human dermal allograft in superior capsular reconstruction., Methods: Five cadaveric shoulders were tested. The superior translation of the humerus and the subacromial contact pressure were measured at 0°, 30° and 60° of glenohumeral abduction in the following six conditions: (1) intact rotator cuff, (2) irreparable supraspinatus tear, (3) superior capsular reconstruction using a double layered human dermal allograft with and (4) without posterior suturing, (5) superior capsular reconstruction using a single human dermal allograft with and (6) without posterior suturing., Results: There was a significant increase in superior translation of the humerus and subacromial contact pressure when comparing torn supraspinatus to intact shoulder. All superior capsular reconstruction repairs lead to a reduction in superior translation and subacromial contact pressures compared to after the supraspinatus tear except for single layered superior capsular reconstruction repair without posterior suturing. There was no difference in superior translation and subacromial contact pressures comparing the intact shoulder to any of the superior capsular reconstruction constructs., Conclusion: Superior capsular reconstruction using a single or double layered human dermal allograft improves superior translation after supraspinatus repair. There is some biomechanical benefit of a double layered human dermal allograft technique over a single layered graft technique in superior capsular reconstruction., Level of Evidence: IV., (© 2020 The British Elbow & Shoulder Society.)

Objectives: This study sought to identify patients with repaired tetralogy of Fallot (rTOF) at high risk of death and malignant ventricular arrhythmia (VA)., Background: To date there is no robust risk stratification scheme to predict outcomes in adults with rTOF., Methods: Consecutive patients were prospectively recruited for late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) to define right and left ventricular (RV, LV) fibrosis in addition to proven risk markers., Results: The primary endpoint was all-cause mortality. Of the 550 patients (median age 32 years, 56% male), 27 died (mean follow-up 6.4 ± 5.8; total 3,512 years). Mortality was independently predicted by RVLGE extent, presence of LVLGE, RV ejection fraction ≤47%, LV ejection fraction ≤55%, B-type natriuretic peptide ≥127 ng/L, peak exercise oxygen uptake (V0 2 ) ≤17 mL/kg/min, prior sustained atrial arrhythmia, and age ≥50 years. The weighted scores for each of the preceding independent predictors differentiated a high-risk subgroup of patients with a 4.4%, annual risk of mortality (area under the curve [AUC]: 0.87; P < 0.001). The secondary endpoint (VA), a composite of life-threatening sustained ventricular tachycardia/resuscitated ventricular fibrillation/sudden cardiac death occurred in 29. Weighted scores that included several predictors of mortality and RV outflow tract akinetic length ≥55 mm and RV systolic pressure ≥47 mm Hg identified high-risk patients with a 3.7% annual risk of VA (AUC: 0.79; P < 0.001) RVLGE was heavily weighted in both risk scores caused by its strong relative prognostic value., Conclusions: We present a score integrating multiple appropriately weighted risk factors to identify the subgroup of patients with rTOF who are at high annual risk of death who may benefit from targeted therapy., Competing Interests: Funding Support and Author Disclosures This work was supported by the British Heart Foundation (FS/11/38/28864), Drs Babu-Narayan and Heng were funded by the British Heart Foundation. Prof Dudley Pennell is a consultant to Siemens. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

It is increasingly recommended that hypothesis-generating studies be conducted after initial RCTs in order to identify moderators of differential treatment efficacy on individual outcomes. Such analyses are important because they help clarify the best inclusion and exclusion criteria or choice of stratification for maximizing power in subsequent RCTs, reduce the chances of discarding interventions that may appear to lack efficacy when only average treatment effects are taken into consideration, and facilitate the matching of individual clients to treatment alternatives. We identified predictors and moderators of treatment-related change in psychological distress among custodial grandmothers ( n  = 343) assigned within a prior RCT to behavior parent training (BPT), cognitive behavior therapy (CBT), or information only control (IOC) conditions. Latent change scores in psychological distress were estimated for each grandmother across pre-test to post-test and pre-test to six months, as indicated by self-reported and clinical ratings of depression and anxiety symptoms. These estimates served as outcomes in classification and regression tree analyses conducted separately within the CBT and BPT conditions to identify predictors of treatment efficacy. Matched groups based upon identified predictors were then formed across all RCT conditions, and Predictor × RCT Condition interactions were computed to test for moderation of differential treatment efficacy. Grandmother age was the only predictor and moderator of BPT efficacy at both measurement points, whereas multifaceted predictors and moderators emerged for CBT which varied by time since treatment.

The Arg457Gln missense variant in the CREBRF gene has previously been identified as driving excess body weight in Pacific/Oceanic populations. Intriguingly, Arg457Gln variant carriers also demonstrate paradoxical reductions in diabetes risk, indicating that the gene has a critical role in whole-body metabolism. To study the function of this variant in more detail, we generated mice on an FVB/N background with the Crebrf Arg458Gln variant knocked in to replace the endogenous Crebrf . The whole-body metabolic phenotype was characterized for male and female mice on a regular chow diet or an 8-week high-fat challenge. Regular assessment of body composition found that the Crebrf variant had no influence on total body weight or fat mass at any time point. Glucose tolerance tests demonstrated no obvious genotype effect on glucose homeostasis, with indirect calorimetry measures of whole-body energy expenditure likewise unaffected. Male chow-fed variant carriers displayed a trend towards increased lean mass and significantly reduced sensitivity to insulin administration. Overall, this novel mouse model showed only limited phenotypic effects associated with the Crebrf missense variant. The inability to recapitulate results of human association studies may invite reconsideration of the precise mechanistic link between CREBRF function and the risks of obesity and diabetes in variant allele carriers.

Social services, including the child welfare system, are often heavily involved in situations where children are returned to the care of their parents, after being raised in kinship care by their grandparents. While previous research has highlighted custodial grandparents' service needs and the challenges they experience when accessing services and working with social service professionals, few studies have examined social services in the context of reunifying grandfamilies. Informed by bioecological theory, the aim of this qualitative study was to examine custodial grandmothers' perceptions of the role of social services in the process of their grandchildren being reunified with a biological parent. Semi-structured, in-depth interviews were conducted with a purposeful sample of 16 custodial grandmothers whose grandchildren had experienced reunification. Findings from a grounded theory analysis revealed grandmothers' perceptions that having a strong connection with a responsive caseworker facilitated successful reunification, as did ongoing efforts to address the parental issues that had resulted in the grandmother assuming a custodial role. Unfortunately, grandmothers also perceived barriers to successful reunification. These included having their perspectives dismissed by caseworkers and judges as well as the child welfare system prioritizing reunification, often to the perceived detriment of their grandchildren. Implications for policy and practice with reunifying grandfamilies are addressed., 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.

DNA replication timing and three-dimensional (3D) genome organization are associated with distinct epigenome patterns across large domains. However, whether alterations in the epigenome, in particular cancer-related DNA hypomethylation, affects higher-order levels of genome architecture is still unclear. Here, using Repli-Seq, single-cell Repli-Seq, and Hi-C, we show that genome-wide methylation loss is associated with both concordant loss of replication timing precision and deregulation of 3D genome organization. Notably, we find distinct disruption in 3D genome compartmentalization, striking gains in cell-to-cell replication timing heterogeneity and loss of allelic replication timing in cancer hypomethylation models, potentially through the gene deregulation of DNA replication and genome organization pathways. Finally, we identify ectopic H3K4me3-H3K9me3 domains from across large hypomethylated domains, where late replication is maintained, which we purport serves to protect against catastrophic genome reorganization and aberrant gene transcription. Our results highlight a potential role for the methylome in the maintenance of 3D genome regulation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Assess the feasibility and impact of nanopore-based 16S rRNA gene sequencing (Np16S) service on antibiotic treatment for acute severe pneumonia on the intensive care unit (ICU)., Methods: Speciation and sequencing accuracy of Np16S on isolates with bioinformatics pipeline optimisation, followed by technical evaluation including quality checks and clinical-reporting criteria analysing stored respiratory samples using single-sample flow cells. Pilot service comparing Np16S results with all routine respiratory tests and impact on same-day antimicrobial prescribing., Results: Np16S correctly identified 140/167 (84%) isolates after 1h sequencing and passed quality control criteria including reproducibility and limit-of-detection. Sequencing of 108 stored respiratory samples showed concordance with routine culture in 80.5% of cases and established technical and clinical reporting criteria. A 10-week same-day pilot Np16S service analysed 45 samples from 37 patients with suspected community (n=15) or hospital acquired (n=30) pneumonia. Np16S showed concordance compared with all routine culture or molecular tests for 27 (82%) of 33 positive samples. It identified the causative pathogen in 32/33 (97%) samples and contributed to antimicrobial treatment changes for 30 patients (67%)., Conclusions: This study demonstrates feasibility of providing a routine same-day nanopore sequencing service that makes a significant contribution to early antibiotic prescribing for bacterial pneumonia in the ICU., Competing Interests: Declaration of Competing Interest All authors completed the ICMJE COI Disclosure form and declared no conflict of interest., (Copyright © 2021 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

We developed an effective method for reductive radical formation that utilizes the radical anion of carbon dioxide (CO 2 •- ) as a powerful single electron reductant. Through a polarity matched hydrogen atom transfer (HAT) between an electrophilic radical and a formate salt, CO 2 •- formation occurs as a key element in a new radical chain reaction. Here, radical chain initiation can be performed through photochemical or thermal means, and we illustrate the ability of this approach to accomplish reductive activation of a range of substrate classes. Specifically, we employed this strategy in the intermolecular hydroarylation of unactivated alkenes with (hetero)aryl chlorides/bromides, radical deamination of arylammonium salts, aliphatic ketyl radical formation, and sulfonamide cleavage. We show that the reactivity of CO 2 •- with electron-poor olefins results in either single electron reduction or alkene hydrocarboxylation, where substrate reduction potentials can be utilized to predict reaction outcome.

Three-dimensional eukaryotic genome organization provides the structural basis for gene regulation. In Drosophila melanogaster , genome folding is characterized by somatic homolog pairing, where homologous chromosomes are intimately paired from end to end; however, how homologs identify one another and pair has remained mysterious. Recently, this process has been proposed to be driven by specifically interacting 'buttons' encoded along chromosomes. Here, we turned this hypothesis into a quantitative biophysical model to demonstrate that a button-based mechanism can lead to chromosome-wide pairing. We tested our model using live-imaging measurements of chromosomal loci tagged with the MS2 and PP7 nascent RNA labeling systems. We show solid agreement between model predictions and experiments in the pairing dynamics of individual homologous loci. Our results strongly support a button-based mechanism of somatic homolog pairing in Drosophila and provide a theoretical framework for revealing the molecular identity and regulation of buttons., Competing Interests: MC, JB, AJ, AR, NL, NS, DV, GM, JJ, DJ, HG No competing interests declared, (© 2021, Child et al.)

Background: The critical shoulder angle (CSA) is a radiographic measurement that provides an assessment of both glenoid inclination and acromial length. Higher values may correlate with the presence of rotator cuff tears. However, it is difficult to obtain a high-quality true anteroposterior (AP) radiograph of the shoulder, with any excess scapular version or flexion/extension resulting in deviation from the true CSA value. Three-dimensional (3D) bony reconstructions of computed tomography (CT) shoulder scans may be able to be rotated to obtain a similar view to that of true AP radiographs., Aim: To compare CSA measurements performed on 3D bony CT reconstructions, with those on corresponding true AP radiographs., Methods: CT shoulder scans were matched with true AP radiographs that were classified as either Suter-Henninger type A or C quality. 3D bony reconstructions were segmented from the CT scans, and rotated to replicate an ideal true AP view. Two observers performed CSA measurements using both CT and radiographic images. Measurements were repeated after a one week interval. Reliability was assessed using intraclass correlation coefficients (ICCs) and Bland-Altman plots [bias, limits of agreement (LOA)]., Results: Twenty CT shoulder scans were matched. The mean CSA values were 32.55° (± 4.26°) with radiographs and 29.82° (± 3.49°) with the CT-based method [mean difference 2.73° (± 2.86°); P < 0.001; bias +2.73°; LOA -2.17° to +7.63°]. There was a strong correlation between the two methods ( r = 0.748; P < 0.001). Intra-observer reliability was similar, but the best intra-observer values were achieved by the most experienced observer using the CT-based method [ICC: 0.983 (0.958-0.993); bias +0.03°, LOA -1.28° to +1.34°]. Inter-observer reliability was better with the CT-based method [ICC: 0.897 (0.758-0.958), bias +0.24°, LOA -2.93° to +3.41°]., Conclusion: The described CT-based method may be a suitable alternative for critical shoulder angle measurement, as it overcomes the difficulty in obtaining a true AP radiographic view., Competing Interests: Conflict-of-interest statement: We have no financial relationships to disclose., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

The dearomative cyclization of linear amides to complex spirocyclic butyrolactams has been enabled by photoredox catalysis through a reductive radical-polar crossover mechanism. This mechanism operates with precision on unactivated aromatic substrates to give a wide range of 1,4-hydroalkylation products. This method utilizes a simple organic catalyst/reductant pair to deliver products in a highly flexible manner with respect to substitution, and the products can be further functionalized under simple conditions to afford a collection of motifs. The mechanistic analysis performed here outlines the salient features of this strategy, which were applied to prepare a collection of complex scaffolds including the anticonvulsive agent gabapentin., Competing Interests: The authors declare no competing financial interest.

The objective of this study was to investigate the accuracy of universal third trimester umbilical artery (UA) Doppler to predict adverse pregnancy outcome at term. We searched Medline, EMBASE, the Cochrane library and ClinicalTrials.gov from inception to October 2020 and we also analyzed previously unpublished data from a prospective cohort study of nulliparous women, the Pregnancy Outcome Prediction (POP) study. We included studies that performed a third-trimester ultrasound scan in unselected, low or mixed risk populations, excluding studies which only included high risk pregnancies. Meta-analysis was performed using the hierarchal summary receiver operating characteristic curve (HSROC) analysis and bivariate logit-normal models. We identified 13 studies (including the POP study) involving 67,764 pregnancies which met our inclusion criteria. The overall quality was variable and only six studies (N = 5777 patients) blinded clinicians to the UA Doppler result. The summary sensitivity and positive likelihood ratio (LR) for small for gestational age (SGA; birthweight <10th centile) were 21.7% (95% CI 13.2-33.6%) and 2.65 (95% CI 1.89-3.72) respectively. The summary positive LR for NICU admission and metabolic acidosis were 1.35 (95% CI 0.93-1.97) and 1.34 (95% CI 0.86-2.08) respectively. The results were similar in the POP study: associations with SGA (positive LR 2.66 [95% CI 2.11-3.36]) and severe SGA (birthweight <3rd centile; positive LR 3.27 [95% CI 2.29-4.68]) but no statistically significant association with neonatal morbidity. We conclude that third trimester UA Doppler has moderate predictive accuracy for small for gestational age but not for indicators of neonatal morbidity in unselected and low risk pregnancies., (Copyright © 2021. Published by Elsevier Ltd.)

The novel coronavirus SARS-CoV-2 likely emerged from a wildlife source with transmission to humans followed by rapid geographic spread throughout the globe and severe impacts on both human health and the global economy. Since the onset of the pandemic, there have been many instances of human-to-animal transmission involving companion, farmed and zoo animals, and limited evidence for spread into free-living wildlife. The establishment of reservoirs of infection in wild animals would create significant challenges to infection control in humans and could pose a threat to the welfare and conservation status of wildlife. We discuss the potential for exposure, onward transmission and persistence of SARS-CoV-2 in an initial selection of wild mammals (bats, canids, felids, mustelids, great apes, rodents and cervids). Dynamic risk assessment and targeted surveillance are important tools for the early detection of infection in wildlife, and here we describe a framework for collating and synthesising emerging information to inform targeted surveillance for SARS-CoV-2 in wildlife. Surveillance efforts should be integrated with information from public and veterinary health initiatives to provide insights into the potential role of wild mammals in the epidemiology of SARS-CoV-2., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2021.)