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Using the dual-pathway framework (Beach et al., 2022a), we tested a Neuro-immune Network (NIN) hypothesis: i.e., that chronically elevated inflammatory processes may have delayed (i.e., incubation) effects on young adult substance use, leading to negative health outcomes. In a sample of 449 participants in the Family and Community Health Study who were followed from age 10 to age 29, we examined a non-self-report index of young adult elevated alcohol consumption (EAC). By controlling self-reported substance use at the transition to adulthood, we were able to isolate a significant delayed (incubation) effect from childhood exposure to danger to EAC (β = −.157, p = .006), which contributed to significantly worse aging outomes. Indirect effects from danger to aging outcomes via EAC were: GrimAge (IE = .010, [.002, .024]), Cardiac Risk (IE = −.004, [−.011, −.001]), DunedinPACE (IE = .002, [.000, .008]). In exploratory analyses we examined potential sex differences in effects, showing slightly stronger incubation effects for men and slightly stronger effects of EAC on aging outcomes for women. Results support the NIN hypothesis that incubation of immune pathway effects contributes to elevated alcohol consumption in young adulthood, resulting in accelerated aging and elevated cardiac risk outcomes via health behavior.
Clozapine-induced gastrointestinal hypomotility (CIGH) can cause constipation, which may progress to ileus, intestinal perforation and other life-threatening conditions. There were at least 527 unique cases of harmful CIGH (172 deaths) assessed by strict criteria in the UK, 1992–2017.
Aims
To assess the impact of strengthened warnings about the risks of CIGH, such as those issued by the UK Medicines and Healthcare products Regulatory Agency (MHRA) (2017) and the US Food and Drug Administration (2020), on reports of harmful CIGH in the UK.
Method
We audited UK MHRA Yellow Card reports recorded as clozapine-related gastrointestinal disorders, 2018–end 2022.
Results
Of 335 unique reports (36 fatal, 26 male) that met initial CIGH criteria, there were 129 (22 fatal, 18 male) that met the final CIGH inclusion criteria. Reports of non-fatal CIGH (final criteria) averaged 26 per year (15 in 2022). Deaths averaged four per year (two in 2022). Where data were available the greatest proportion of deaths occurred after 10–14 years of clozapine treatment.
Conclusions
Publicity aimed at raising awareness of the problem posed by CIGH has been associated with a reduction in harmful CIGH as reported to the UK MHRA since 2017. Continued vigilance is needed to reduce risk. Stopping smoking may pose a particular risk and should be monitored carefully.
While dialectal variation is often investigated from a geographical angle, there exists substantial variation both within the community and individual. The aim of the present article is to investigate the extent to which spatial, occupational, and age-related factors are associated with the diversity of linguistic variants reported per informant at a given locality. Drawing on colloquial language data from the Atlas zur deutschen Alltagssprache ‘Atlas of Colloquial German,’ we found that informants from southeastern Germany and Austria reported familiarity with more variants. Moreover, we multifactorially operationalize occupational complexity, a variable that can capture the effects of different communicative, technical, and physical skills required in a job (via the Dictionary of Occupational Titles). Bayesian multilevel modeling revealed that informants in occupations involving physical precision work and communicative complexity reported less familiarity with variants, and that younger informants were familiar with a wider range of variants.
We present a re-discovery of G278.94+1.35a as possibly one of the largest known Galactic supernova remnants (SNRs) – that we name Diprotodon. While previously established as a Galactic SNR, Diprotodon is visible in our new Evolutionary Map of the Universe (EMU) and GaLactic and Extragalactic All-sky MWA (GLEAM) radio continuum images at an angular size of $3{{{{.\!^\circ}}}}33\times3{{{{.\!^\circ}}}}23$, much larger than previously measured. At the previously suggested distance of 2.7 kpc, this implies a diameter of 157$\times$152 pc. This size would qualify Diprotodon as the largest known SNR and pushes our estimates of SNR sizes to the upper limits. We investigate the environment in which the SNR is located and examine various scenarios that might explain such a large and relatively bright SNR appearance. We find that Diprotodon is most likely at a much closer distance of $\sim$1 kpc, implying its diameter is 58$\times$56 pc and it is in the radiative evolutionary phase. We also present a new Fermi-LAT data analysis that confirms the angular extent of the SNR in gamma rays. The origin of the high-energy emission remains somewhat puzzling, and the scenarios we explore reveal new puzzles, given this unexpected and unique observation of a seemingly evolved SNR having a hard GeV spectrum with no breaks. We explore both leptonic and hadronic scenarios, as well as the possibility that the high-energy emission arises from the leftover particle population of a historic pulsar wind nebula.
Disease-modifying therapies (DMTs) for Alzheimer’s disease (AD) are emerging following successful clinical trials of therapies targeting amyloid beta (Aβ) protofibrils or plaques. Determining patient eligibility and monitoring treatment efficacy and adverse events, such as Aβ-related imaging abnormalities, necessitates imaging with MRI and PET. The Canadian Consortium on Neurodegeneration in Aging (CCNA) Imaging Workgroup aimed to synthesize evidence and provide recommendations on implementing imaging protocols for AD DMTs in Canada.
Methods:
The workgroup employed a Delphi process to develop these recommendations. Experts from radiology, neurology, biomedical engineering, nuclear medicine, MRI and medical physics were recruited. Surveys and meetings were conducted to achieve consensus on key issues, including protocol standardization, scanner strength, monitoring protocols based on risk profiles and optimal protocol lengths. Draft recommendations were refined through multiple iterations and expert discussions.
Results:
The recommendations emphasize standardized acquisition imaging protocols across manufacturers and scanner strengths to ensure consistency and reliability of clinical treatment decisions, tailored monitoring protocols based on DMTs’ safety and efficacy profiles, consistent monitoring regardless of perceived treatment efficacy and MRI screening on 1.5T or 3T scanners with adapted protocols. An optimal protocol length of 20–30 minutes was deemed feasible; specific sequences are suggested.
Conclusion:
The guidelines aim to enhance imaging data quality and consistency, facilitating better clinical decision-making and improving patient outcomes. Further research is needed to refine these protocols and address evolving challenges with new DMTs. It is recognized that administrative, financial and logistical capacity to deliver additional MRI and positron emission tomography scans require careful planning.
The physical health comorbidities and premature mortality experienced by people with mental illness has led to an increase in exercise services embedded as part of standard care in hospital-based mental health services. Despite the increase in access to exercise services for people experiencing mental illness, there is currently a lack of guidelines on the assessment and triage of patients into exercise therapy.
Aims
To develop guidelines for the pre-exercise screening and health assessment of patients engaged with exercise services in hospital-based mental healthcare and to establish an exercise therapy triage framework for use in hospital-based mental healthcare.
Method
A Delphi technique consisting of two online surveys and two rounds of focus group discussions was used to gain consensus from a multidisciplinary panel of experts.
Results
Consensus was reached on aspects of pre-exercise health screening, health domain assessment, assessment tools representing high-value clinical assessment, and the creation and proposed utilisation of an exercise therapy triage framework within exercise therapy.
Conclusions
This study is the first of its kind to provide guidance on the implementation of exercise therapy within Australian hospital-based mental healthcare. The results provide recommendations for appropriate health assessment and screening of patients in exercise therapy, and provide guidance on the implementation and triage of patients into exercise therapy via a stepped framework to determine (a) the timeliness of exercise therapy required and (b) the level of support required in the delivery of their exercise therapy.
Researchers increasingly rely on aggregations of radiocarbon dates from archaeological sites as proxies for past human populations. This approach has been critiqued on several grounds, including the assumptions that material is deposited, preserved, and sampled in proportion to past population size. However, various attempts to quantitatively assess the approach suggest there may be some validity in assuming date counts reflect relative population size. To add to this conversation, here we conduct a preliminary analysis coupling estimates of ethnographic population density with late Holocene radiocarbon dates across all counties in California. Results show that counts of late Holocene radiocarbon-dated archaeological sites increase significantly as a function of ethnographic population density. This trend is robust across varying sampling windows over the last 5000 BP. Though the majority of variation in dated-site counts remains unexplained by population density. Outliers reveal how departures from the central trend may be influenced by regional differences in research traditions, development-driven contract work, organic preservation, and landscape taphonomy. Overall, this exercise provides some support for the “dates-as-data” approach and offers insights into the conditions where the underlying assumptions may or may not hold.
The dynamics of our species’ dispersal into the Pacific remains intensely debated. The authors present archaeological investigations in the Raja Ampat Islands, north-west of New Guinea, that provide the earliest known evidence for humans arriving in the Pacific more than 55 000–50 000 years ago. Seafaring simulations demonstrate that a northern equatorial route into New Guinea via the Raja Ampat Islands was a viable dispersal corridor to Sahul at this time. Analysis of faunal remains and a resin artefact further indicates that exploitation of both rainforest and marine resources, rather than a purely maritime specialisation, was important for the adaptive success of Pacific peoples.
The foliicolous lichen Gallaicolichen pacificus exhibits unique goniocystangia-like structures named peltidiangia and peltidia. Its taxonomic classification within the Ascomycota has been unclear due to the absence of ascomata and lack of molecular data. Here we clarify the phylogenetic affinities of Gallaicolichen pacificus by analyzing mitochondrial small subunit ribosomal RNA (mtSSU) sequences obtained from specimens collected in New Caledonia. Ascomata and ascospores of G. pacificus, previously unknown, are described and illustrated for the first time. The results from the molecular and morphological analyses clearly indicate that Gallaicolichen pacificus belongs to the Porinaceae and is closely related to Porina guianensis. This is a remarkable extension of the already known, wide morphological diversity of thalli and diaspores produced within this family.
The concept of a forest transition – a regional shift from deforestation to forest recovery – tends to equate forest area expansion with sustainability, assuming that more forest is good for people and the environment. To promote debate and more just and ecologically sustainable outcomes during this period of intense focus on forests (such as the United Nations’ Decade on Ecological Restoration, the Trillion Trees initiative and at the United Nations’ Climate Change Conferences), we synthesize recent nuanced and integrated research to inform forest management and restoration in the future. Our results reveal nine pitfalls to assuming forest transitions and sustainability are automatically linked. The pitfalls are as follows: (1) fixating on forest quantity instead of quality; (2) masking local diversity with large-scale trends; (3) expecting U-shaped temporal trends of forest change; (4) failing to account for irreversibility; (5) framing categories and concepts as universal/neutral; (6) diverting attention from the simplification of forestlands into single-purpose conservation forests or intensive production lands; (7) neglecting social power transitions and dispossessions; (8) neglecting productivism as the hidden driving force; and (9) ignoring local agency and sentiments. We develop and illustrate these pitfalls with local- and national-level evidence from Southeast Asia and outline forward-looking recommendations for research and policy to address them. Forest transition research that neglects these pitfalls risks legitimizing unsustainable and unjust policies and programmes of forest restoration or tree planting.
OBJECTIVES/GOALS: Our objective is to characterize excitatory, inhibitory, and neuromodulatory components of the voluntary motor command at the level of the spinal motoneuron in people with multiple sclerosis (MS). This information will provide insight into neural mechanisms of motor dysfunction and their heterogeneity among patients with MS. METHODS/STUDY POPULATION: Due to advances in high-density surface EMG (HDsEMG) decomposition and the recent development of a paradigm for reverse engineering of motor unit population discharge, we can feasibly estimate aspects of excitatory, inhibitory, and neuromodulatory components of the voluntary motor command in humans on a person-specific basis. We tested 11 ambulatory patients with MS and mild-moderate disability. We recorded HDsEMG from tibialis anterior (TA) and soleus (SOL) during isometric plantarflexion and dorsiflexion, performed as slow triangle contractions. EMG was decomposed into motor unit spike trains using blind source separation. We calculated a number of motor unit variables, most notably delta-F, which estimates motoneuron excitability and the balance of neuromodulatory and inhibitory inputs. RESULTS/ANTICIPATED RESULTS: There were consistent differences in MS patients vs. controls. For TA, values were decreased for delta-F (3.9 vs. 5.9 pps), initial firing rate acceleration (5.8 vs. 7.1 pps), firing rate range (9.3 vs. 11.9 pps), and max firing rate (12.3 vs. 15.0 pps). SOL had more modest decreases in delta-F (3.0 vs. 3.8 pps) and firing rate range (4.8 vs. 5.6 pps). Self-sustained firing was longer for MS patients. Within a patient, abnormalities in motor unit variables were not consistent across muscles and legs. Interestingly, there were several abnormalities in the patients with a normal clinical motor exam, indicating that perhaps our measures are sensitive to subclinical changes in processing of voluntary motor commands. DISCUSSION/SIGNIFICANCE: Excitatory, inhibitory, and neuromodulatory components of the voluntary motor command must be appropriately balanced for skilled motor output. This study is the first to characterize how they are disrupted in MS, providing foundational information to inform the development of mechanistically-based rehabilitation interventions.
In the 1980s, heart transplantation was the first successful treatment for infants born with hypoplastic left heart syndrome. Infants who have required heart transplantation benefit from immunologic “advantages,” including long-term survival free from cardiac allograft vasculopathy. Currently ∼ 90% of children undergoing a heart transplant are reaching their first-year anniversary and the clinical practices of paediatric heart transplantation have dramatically improved. These successes are largely attributed to research sponsored by the Pediatric Heart Transplant Study Group, the International Society of Heart and Lung Transplantation and, more recently, the Non-profits Enduring Hearts and Additional Ventures. Despite these successes, the field is challenged to increase progress to achieve long-term survival into adulthood. The wait-list mortality, especially among infants, is unacceptably high often leading to palliative measures that can increase post-transplant mortality. Cardiac allograft vasculopathy remains a major cause for progressive graft loss of function and sudden death. The relative tolerance seen in immature recipients has not been translated to modifying older recipients’ post-transplant outcomes. The modifiable cause(s) for the increased risks of transplantation in children of different ethnicities and races require definition. Addressing these challenges faces the reality that for-profit research favours funding adult recipients, with ∼ 10-fold greater numbers, and their more modest longevity goals. Advocacy for funding “incentives” such as the Orphan Drug rules in the United States and upholding principles of equity and inclusion are critical to addressing the challenges of paediatric heart transplant recipients worldwide.
Economic games provide models of real-world contexts in which researchers can probe dispositional and structural determinants of intergroup relations. Most intergroup games focus on determinants of aggression between groups and constrain the possibilities for peace. However, paradigms such as the intergroup parochial and universal cooperation game allow for peaceful intergroup relations and can be adapted for the study of peace.
Neither the hype exemplified in some exaggerated claims about deep neural networks (DNNs), nor the gloom expressed by Bowers et al. do DNNs as models in vision science justice: DNNs rapidly evolve, and today's limitations are often tomorrow's successes. In addition, providing explanations as well as prediction and image-computability are model desiderata; one should not be favoured at the expense of the other.
In 2003, Bohman, Frieze, and Martin initiated the study of randomly perturbed graphs and digraphs. For digraphs, they showed that for every $\alpha \gt 0$, there exists a constant $C$ such that for every $n$-vertex digraph of minimum semi-degree at least $\alpha n$, if one adds $Cn$ random edges then asymptotically almost surely the resulting digraph contains a consistently oriented Hamilton cycle. We generalize their result, showing that the hypothesis of this theorem actually asymptotically almost surely ensures the existence of every orientation of a cycle of every possible length, simultaneously. Moreover, we prove that we can relax the minimum semi-degree condition to a minimum total degree condition when considering orientations of a cycle that do not contain a large number of vertices of indegree $1$. Our proofs make use of a variant of an absorbing method of Montgomery.
We recently reported on the radio-frequency attenuation length of cold polar ice at Summit Station, Greenland, based on bi-static radar measurements of radio-frequency bedrock echo strengths taken during the summer of 2021. Those data also allow studies of (a) the relative contributions of coherent (such as discrete internal conducting layers with sub-centimeter transverse scale) vs incoherent (e.g. bulk volumetric) scattering, (b) the magnitude of internal layer reflection coefficients, (c) limits on signal propagation velocity asymmetries (‘birefringence’) and (d) limits on signal dispersion in-ice over a bandwidth of ~100 MHz. We find that (1) attenuation lengths approach 1 km in our band, (2) after averaging 10 000 echo triggers, reflected signals observable over the thermal floor (to depths of ~1500 m) are consistent with being entirely coherent, (3) internal layer reflectivities are ≈–60$\to$–70 dB, (4) birefringent effects for vertically propagating signals are smaller by an order of magnitude relative to South Pole and (5) within our experimental limits, glacial ice is non-dispersive over the frequency band relevant for neutrino detection experiments.
Controversies continue as to how many pharyngeal arches, with their contained arteries, are to be found in the developing human. Resolving these controversies is of significance to paediatric cardiologists since many investigating abnormalities of the extrapericardial arterial pathways interpret their findings on the basis of persistence of a fifth set of such arteries within an overall complement of six sets. The evidence supporting such an interpretation is open to question. In this review, we present the history of the existence of six such arteries, emphasising that the initial accounts of human development had provided evidence for the existence of only five sets. We summarise the current evidence that substantiates these initial findings. We then show that the lesions interpreted on the basis of persistence of the non-existing fifth arch arteries are well described on the basis of the persistence of collateral channels, known to exist during normal development, or alternatively due to remodelling of the aortic sac.
Women and gender-diverse people with early psychosis are at risk for suboptimal sexual health outcomes, yet little research has explored their sexual health experiences.
Aims
This study explored sexual health experiences and related priorities among women and gender-diverse people with early psychosis, to identify opportunities for improvements in sexual health and well-being.
Method
Semi-structured individual qualitative interviews explored how patient participants (n = 19, aged 18–31 years, cisgender and transgender women and non-binary individuals) receiving clinical care from early psychosis programmes in Ontario, Canada, experienced their sexual health, including sexual function and behaviour. Thematic analysis was conducted, with triangulation from interviews/focus groups with clinicians (n = 36) who provide sexual and mental healthcare for this population.
Results
Three key themes were identified based on patient interviews: theme 1 was the impact of psychotic illness and its treatments on sexual function and activity, including variable changes in sex drive, attitudes and behaviours during acute psychosis, vulnerability to trauma and medications; theme 2 related to intimacy and sexual relationships in the context of psychosis, with bidirectional effects between relationships and mental health; and theme 3 comprised autonomy, identity and intersectional considerations, including gender, sexuality, culture and religion, which interplay with psychosis and sexual health. Clinicians raised each of these priority areas, but emphasised risk prevention relative to patients’ more holistic view of their sexual health and well-being.
Conclusions
Women and non-binary people with early psychosis have wide-ranging sexual health priorities, affecting many facets of their lives. Clinical care should incorporate this knowledge to optimise sexual health and well-being in this population.
In this study we provide the first comprehensive camera-trap assessment of terrestrial mammals in the Yangambi landscape, comprising the Yangambi Biosphere Reserve and a logging concession in the Democratic Republic of the Congo. The terrestrial mammal community in this area exhibits lower occupancy and species richness compared to other conservation areas in the Congo Basin. The community is dominated by four species: Emin's pouched rat Cricetomys emini (1.3 kg), African brush-tailed porcupine Atherurus africanus (2.8 kg), blue duiker Philantomba monticola (5 kg) and bay duiker Cephalophus dorsalis (12 kg), which are known to be highly resilient. Large ungulates and medium-sized carnivores have particularly low abundances. Our study also confirmed the presence of four species categorized as threatened on the IUCN Red List: the chimpanzee Pan troglodytes, giant ground pangolin Smutsia gigantea, black-bellied pangolin Phataginus tetradactyla and white-bellied pangolin Phataginus tricuspis. Our findings highlight the need to consider wildlife conservation at the landscape level, including the logging concession, where species showed higher occupancy levels compared to the Biosphere Reserve, and highlighting the need for planning infrastructure construction and developing mitigation schemes, reducing forest degradation from logging and developing permanent cash crop agriculture. Landscape-level conservation will only be possible if a collaborative management model steered by local communities is developed with the participation of all constituencies.
The history of Welsh newspapers over the twentieth century encompasses a wider shift in which a consciously politicised national identity began to emerge. This chapter intends to examine the evolution of that form of identity politics throughout the century: to use it as a prism through which to view wider developments in Welsh journalism and an opportunity to engage in a meaningful comparison between the English and Welsh language press in Wales. To that end, the chapter will take five pivotal events relating to the evolution of Welsh nationalist politics, distributed broadly equally throughout the century. It will use archival material to assess the reception of those events in newspapers from each region of Denis Balsom's ‘Three Wales Model’ (1985), a much-cited attempt to encapsulate the cultural and political fragmentation of Wales. Those five events are: the General Election of 1900, the foundation of Plaid Cymru 1925, the arson attack on the Penyberth ‘bombing school’ 1936, the election of Plaid Cymru MP Gwynfor Evans 1966, and the devolution referendum 1997.
Towards the end of the nineteenth century, Wales underwent a period of profound cultural change in which a nascent identity politics developed, arguably for the first time. The consciousness of nationhood was deeply rooted, but the notion that political structures might give expression to that consciousness began to emerge in political debate (Davies 1994). The role of newspapers in forging, interpreting and critiquing this politicised version of national identity forms the basis of this chapter.
Applying Anderson's (1983) theories on the role of newspapers in creating and sustaining a sense of nation is rendered problematic in Wales, partly because of the highly contested nature of the ‘project’, and partly because it is always underpinned by the changing nature of the relationship with ‘Britishness’. However, to echo Bingham and Conboy's (2015) findings in the wider British context, though the way this was done changed over time, there was continuity in the fact that the same issues were returned to continually by the popular press. The five events analysed in this chapter therefore provide some kind of temporal (as well as thematic) framework with which to underpin what would otherwise be an unwieldy and unhelpfully broad topic.