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"In Their Own Words": A Qualitative Exploration of Lived Experience and Healthcare Professional Perspectives on Evaluating a Digital Intervention for Binge Eating.
OBJECTIVE: Eating disorders characterized by binge eating are prevalent yet under-recognized, limiting access to effective care. The digital, programme-led (self-help) version of Enhanced Cognitive Behavior Therapy (CBT-E) offers a potentially scalable treatment. This study gathered insights from individuals with lived experience of binge eating (LE) and healthcare professionals (HCPs) to inform the design of a randomized controlled trial evaluating the intervention's effectiveness and to support early-stage implementation planning. METHOD: Four focus groups were conducted with 20 participants (8 with LE, 12 HCPs). Discussions explored recruitment strategies, participant engagement, meaningful outcome measures, and barriers to implementation. Data were analyzed using thematic analysis. RESULTS: Two overarching themes were identified: (1) Reach People in Accessible and Supportive Ways, and (2) Be Open to Different Experiences of Progress. Participants emphasized inclusive recruitment and compassionate, hopeful messaging. Stigma and limited recognition of binge eating were cited as recruitment barriers in healthcare settings. Both groups recommended community and online platforms to enhance reach. Participants stressed the importance of outcomes beyond symptom reduction (e.g., emotional well-being) and qualitative methods to capture recovery narratives. Findings also highlighted implementation-relevant factors, including how interventions are framed and delivered, and how engagement can be optimized. DISCUSSION: Perspectives from individuals with LE and HCPs support a person-centred trial aligned with the needs of those experiencing binge eating and those providing care, while considering both evaluative and implementation priorities. Findings inform strategies to enhance reach and understanding of digital intervention outcomes, contributing to trial designs that are consistent with real-world care and meaningful to participants.
Dual-site beta transcranial alternating current stimulation during a bimanual coordination task modulates functional connectivity between motor areas.
BACKGROUND: Communication within brain networks depends on functional connectivity. One promising approach to modulate such connectivity between cortical areas is dual-site transcranial alternating current stimulation (tACS), which non-invasively applies weak alternating currents to two brain areas. OBJECTIVES: /Hypotheses: In the current study, we aimed to modulate inter-regional functional connectivity with dual-site tACS to bilateral primary motor cortices (M1s) during bimanual coordination and, in turn, alter behaviour. METHODS: Using functional magnetic resonance imaging (fMRI), we recorded participants' brain responses during a bimanual coordination task in a concurrent tACS-fMRI design. While performing a slow and fast version of the task, participants received one of three types of beta (20 Hz) dual-site tACS over both M1s: zero-phase, jittered-phase or sham, in a within-participant, repeated measures design. RESULTS: While we did not observe any significant tACS effects on behaviour, the study revealed an attenuation effect of zero-phase tACS on interhemispheric connectivity. Additionally, the two active types of tACS (zero-phase and jittered-phase) differed in the task-related M1 connectivity with other motor cortical regions, such as premotor cortex and supplementary motor area. Furthermore, individual E-field strengths were related to functional connectivity in the zero-phase condition. CONCLUSIONS: Dual-site beta tACS over both M1s altered functional connectivity between motor areas. However, this effect did not translate significantly to the behavioural level in the presence of a restricted sample size. Future studies may thus integrate mechanistic measures, such as measures of interhemispheric inhibition, to strengthen causal interpretations.
Personalizing transcranial electrical stimulation.
Transcranial electrical stimulation (tES) encompasses non-invasive neuromodulation techniques, such as transcranial direct and alternating current stimulation, which modulate the central nervous system to probe causal links between the brain and behavior and treat disorders. Unfortunately, fixed stimulation paradigms induce variable effects due to intra- and interindividual factors. Consequently, personalized approaches to tES are increasingly used. In this review, we highlight this emerging domain of human brain stimulation, examining strategies for the personalization of stimulation parameters and their underlying rationales. Multiparameter personalization and the identification of markers indicating tES efficacy represent promising directions. Personalization is not a panacea for all the challenges of tES, but marks an essential step toward reducing the variability of this technique.
Detection of neutralising antibodies to SARS-CoV-2 to determine population exposure in Scottish blood donors between March and May 2020.
BackgroundThe progression and geographical distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United Kingdom (UK) and elsewhere is unknown because typically only symptomatic individuals are diagnosed. We performed a serological study of blood donors in Scotland in the spring of 2020 to detect neutralising antibodies to SARS-CoV-2 as a marker of past infection and epidemic progression.AimOur objective was to determine if sera from blood bank donors can be used to track the emergence and progression of the SARS-CoV-2 epidemic.MethodsA pseudotyped SARS-CoV-2 virus microneutralisation assay was used to detect neutralising antibodies to SARS-CoV-2. The study comprised samples from 3,500 blood donors collected in Scotland between 17 March and 18 May 2020. Controls were collected from 100 donors in Scotland during 2019.ResultsAll samples collected on 17 March 2020 (n = 500) were negative in the pseudotyped SARS-CoV-2 virus microneutralisation assay. Neutralising antibodies were detected in six of 500 donors from 23 to 26 March. The number of samples containing neutralising antibodies did not significantly rise after 5-6 April until the end of the study on 18 May. We found that infections were concentrated in certain postcodes, indicating that outbreaks of infection were extremely localised. In contrast, other areas remained comparatively untouched by the epidemic.ConclusionAlthough blood donors are not representative of the overall population, we demonstrated that serosurveys of blood banks can serve as a useful tool for tracking the emergence and progression of an epidemic such as the SARS-CoV-2 outbreak.
Ancient genomes reveal insights into ritual life at Chichén Itzá.
The ancient city of Chichén Itzá in Yucatán, Mexico, was one of the largest and most influential Maya settlements during the Late and Terminal Classic periods (AD 600-1000) and it remains one of the most intensively studied archaeological sites in Mesoamerica1-4. However, many questions about the social and cultural use of its ceremonial spaces, as well as its population's genetic ties to other Mesoamerican groups, remain unanswered2. Here we present genome-wide data obtained from 64 subadult individuals dating to around AD 500-900 that were found in a subterranean mass burial near the Sacred Cenote (sinkhole) in the ceremonial centre of Chichén Itzá. Genetic analyses showed that all analysed individuals were male and several individuals were closely related, including two pairs of monozygotic twins. Twins feature prominently in Mayan and broader Mesoamerican mythology, where they embody qualities of duality among deities and heroes5, but until now they had not been identified in ancient Mayan mortuary contexts. Genetic comparison to present-day people in the region shows genetic continuity with the ancient inhabitants of Chichén Itzá, except at certain genetic loci related to human immunity, including the human leukocyte antigen complex, suggesting signals of adaptation due to infectious diseases introduced to the region during the colonial period.
The impact of school reopening on the spread of COVID-19 in England.
By mid-May 2020, cases of COVID-19 in the UK had been declining for over a month; a multi-phase emergence from lockdown was planned, including a scheduled partial reopening of schools on 1 June 2020. Although evidence suggests that children generally display mild symptoms, the size of the school-age population means the total impact of reopening schools is unclear. Here, we present work from mid-May 2020 that focused on the imminent opening of schools and consider what these results imply for future policy. We compared eight strategies for reopening primary and secondary schools in England. Modifying a transmission model fitted to UK SARS-CoV-2 data, we assessed how reopening schools affects contact patterns, anticipated secondary infections and the relative change in the reproduction number, R. We determined the associated public health impact and its sensitivity to changes in social distancing within the wider community. We predicted that reopening schools with half-sized classes or focused on younger children was unlikely to push R above one. Older children generally have more social contacts, so reopening secondary schools results in more cases than reopening primary schools, while reopening both could have pushed R above one in some regions. Reductions in community social distancing were found to outweigh and exacerbate any impacts of reopening. In particular, opening schools when the reproduction number R is already above one generates the largest increase in cases. Our work indicates that while any school reopening will result in increased mixing and infection amongst children and the wider population, reopening schools alone in June 2020 was unlikely to push R above one. Ultimately, reopening decisions are a difficult trade-off between epidemiological consequences and the emotional, educational and developmental needs of children. Into the future, there are difficult questions about what controls can be instigated such that schools can remain open if cases increase. This article is part of the theme issue 'Modelling that shaped the early COVID-19 pandemic response in the UK'.
Diversity of HLA Class I and Class II blocks and conserved extended haplotypes in Lacandon Mayans.
Here we studied HLA blocks and haplotypes in a group of 218 Lacandon Maya Native American using a high-resolution next generation sequencing (NGS) method. We assessed the genetic diversity of HLA class I and class II in this population, and determined the most probable ancestry of Lacandon Maya HLA class I and class II haplotypes. Importantly, this Native American group showed a high degree of both HLA homozygosity and linkage disequilibrium across the HLA region and also lower class II HLA allelic diversity than most previously reported populations (including other Native American groups). Distinctive alleles present in the Lacandon population include HLA-A*24:14 and HLA-B*40:08. Furthermore, in Lacandons we observed a high frequency of haplotypes containing the allele HLA-DRB1*04:11, a relatively frequent allele in comparison with other neighboring indigenous groups. The specific demographic history of the Lacandon population including inbreeding, as well as pathogen selection, may have elevated the frequencies of a small number of HLA class II alleles and DNA blocks. To assess the possible role of different selective pressures in determining Native American HLA diversity, we evaluated the relationship between genetic diversity at HLA-A, HLA-B and HLA-DRB1 and pathogen richness for a global dataset and for Native American populations alone. In keeping with previous studies of such relationships we included distance from Africa as a covariate. After correction for multiple comparisons we did not find any significant relationship between pathogen diversity and HLA genetic diversity (as measured by polymorphism information content) in either our global dataset or the Native American subset of the dataset. We found the expected negative relationship between genetic diversity and distance from Africa in the global dataset, but no relationship between HLA genetic diversity and distance from Africa when Native American populations were considered alone.
Disentangling frontal-striatal contributions to exploration
In this issue of Neuron, Treuting et al.1 present a dissociation between the way anterior cingulate cortex (ACC) and striatum use prediction errors to shape exploration in complementary ways, with ACC tracking prediction errors to reduce uncertainty regarding available choices and striatum using prediction errors to amplify value estimates.
Like a Punch in the Gut: A Novel Perspective On Annual Recurrences of Ulcerative Colitis.
BACKGROUND: Ulcerative colitis (UC), a chronic inflammatory bowel disease, causes stomach pain, diarrhea, and rectal bleeding. The exact cause is unknown, but it is thought to involve genetic, environmental, and psychological factors. Some people experience annual flare-ups without obvious reason. This article adopts a theory-driven approach to consider how and why past traumatic events may contribute to annual flare-ups. METHODS: We applied learning theory, which explains the development of re-experiencing phenomena in post-traumatic stress disorder (PTSD), to better understand the occurrence of annual flares in patients living with UC. RESULTS: Two possibilities emerged in which associative learning may contribute to annual UC flares. First, flare-ups could be a physical response to sensory cues in the present that overlap with trauma experienced at the first onset of UC. Annual episodes may strengthen the UC flare as a learned physiological response to trauma reminders. Second, flare-ups may result from elevated stress due to trauma re-experiencing at anniversaries. Sensory features of the initial UC trauma may be associated with strong reactions, which generalize to similar stimuli, triggering re-experiencing symptoms and increasing psychological stress. Elevated stress raises glucocorticoid levels, promoting UC-specific inflammation. Stimulus discrimination from cognitive therapy for PTSD may help to over-ride the associations that have formed between sensory features of past trauma, linked reactions, and similar cues in the present. CONCLUSIONS: Research is needed to understand how traumatic events influence the onset and recurrence of ulcerative colitis, as well as the potential benefits of stimulus discrimination for reducing the frequency of annual flares.
m6A and the NEXT complex direct Xist RNA turnover and X inactivation dynamics
X chromosome inactivation (XCI) in mammals is orchestrated by the non-coding RNA Xist which, together with specific interacting proteins, functions in cis to silence an entire X chromosome. Defined sites on Xist RNA carry the N6-methyladenosine (m6A) modification and perturbation of the m6A writer complex has been found to abrogate Xist-mediated gene-silencing. However, the relative contribution of m6A and its mechanism of action remain unclear. Here, we investigate the role of m6A in XCI by applying rapid degron-mediated depletion of METTL3, the catalytic subunit of the m6A writer complex, an approach that minimises indirect effects due to transcriptome-wide depletion of m6A. We find that acute loss of METTL3/m6A accelerates Xist-mediated gene silencing, and that this correlates with increased levels and stability of Xist transcripts. We show that Xist RNA turnover is mediated by the nuclear exosome targeting (NEXT) complex but is independent of the principal nuclear m6A reader protein YTHDC1. Our findings demonstrate that the primary function of m6A on Xist RNA is to promote Xist RNA turnover which in turn regulates XCI dynamics.
Best Oculomotor Endpoints for Clinical Trials in Hereditary Ataxias: A Systematic Review and Consensus by the Ataxia Global Initiative Working Group on Digital‑Motor Biomarkers.
Oculomotor deficits are common in hereditary cerebellar ataxias (HCAs) and their quantitative assessment offers a sensitive and reliable manner to capture disease-severity and progression. As a group of experts of the Ataxia Global Initiative to support trial readiness, we previously established harmonized methodology for quantitative oculomotor assessments in HCAs. Here, we aimed to identify to most promising oculomotor/vestibular outcomes as endpoints for future trials. Through a systematic MEDLINE search we identified 130 articles reporting oculomotor/vestibular recordings in patients with HCAs. A total of 2,018 subjects were included: 1,776 with genetically-confirmed and 242 with clinically-defined HCAs. Studied diseases included spinocerebellar ataxias (SCA) 1/2/3/6/7/27B, episodic ataxia type 2, Friedreich ataxia, RFC1-related ataxia, fragile X-associated tremor/ataxia syndrome, cerebrotendinous xanthomatosis, ataxia-telangiectasia, ataxia with oculomotor apraxia types 1&2, and Niemann-Pick disease type C. We identified up to four oculomotor/vestibular outcomes per diagnostic entity, based on their ability to robustly discriminate patients from controls, correlate with disease-severity, detect longitudinal change, and represent different disease stages. For each parameter we provide recommendations for recordings. While the implementation of quantitative assessments into clinical trials offers a unique opportunity to track dysfunction of oculomotor/vestibular networks and to assess the impact of interventions, in some HCAs, endpoint qualification of available outcomes requires further validation to characterize their reliability, sensitivity to change, and minimally important change to patients. For all HCAs for which quantitative data are scarce or lacking, there is an urgent need for prospective studies covering a broader range of oculomotor/vestibular domains as approaching new treatments require harmonized and reliable endpoints.
Almost there: learning to navigate approximately with a grid map.
Grid map navigation, in which animals use intersecting environmental gradients to judge the spatial relationship between their location and their goal, has been proposed to account for impressive navigational abilities across various taxa. However, the precise mechanisms by which animals navigate using environmental gradients are obscure: first, how do animals extrapolate the spatial distribution of gradients, and second, how do they combine spatial information from multiple gradients? Various models of the extrapolation and combination of spatial gradients have been proposed, but the ontogeny of these mechanisms is little considered. Animals might be predisposed to utilise particular navigational strategies, with these fixed through development; alternatively, mechanisms might arise and change through learning. To investigate this, we trained artificial neural networks, as simple computational learning models, to navigate in virtual bicoordinate grid environments, and tested their outputs against previously proposed models. We found neural networks initially adopted 'the approximate model': determining their displacement in each gradient independently and summing these to approximate goalward directions. This supports the suggestion that this model represents a relatively simple mechanism to adopt in complex environments. However, by the end of training, neural networks no longer conformed to the model predictions, hence adopting this mechanism for a limited period only. Thus, the predictions of these models might be met only in certain developmental stages as animals learn. Conversely, the neural networks extrapolated gradients differently depending on the environment. These results facilitate more nuanced predictions of how animal navigation might develop through learning. These predictions should be tested as large tracking datasets of animal movements accumulate.
Pre-laying sex differences in reproductive roles can constrain foraging behaviour in a monomorphic seabird
Sex differences in foraging behaviour can arise in monomorphic species when reproductive roles differ. How these differences shape foraging behaviour during the pre-laying period—an understudied reproductive stage in seabirds—remains unclear. In a monomorphic procellariform seabird, the Manx shearwater (Puffinus puffinus), we compare foraging behaviour between sexes during pre- and post-laying periods. Prior to laying, sex roles differ, with females synthesizing the egg, while males are thought to primarily engage in nest defence. We found that pre-laying females take longer at-sea trips that are more distant from the colony, whilst males visit the colony more frequently, and undertake more dives. For males, pre-laying dives are shallower than those during the post-laying period. Sex differences largely diminish post-laying, as reproductive roles become more equivalent between sexes. We suggest that increased colony visitation during pre-laying may constrain males to closer foraging sites and these may be of poorer quality than those reached by females. We found that colony visitation appears to restrict evening foraging opportunities for males, as birds must commute to the breeding site for nocturnal visits. Our results show that significant differences in reproductive roles before egg-laying can constrain at-sea foraging behaviour. Understanding these differences can facilitate understanding of how sex-specific foraging behaviour may interact with human-induced changes in marine environments.
Eradication of Helicobacter pylori for prevention of aspirin-associated peptic ulcer bleeding in adults over 65 years: the HEAT RCT.
BACKGROUND: Peptic ulcers in patients on aspirin are associated with Helicobacter pylori infection. We investigated whether H. pylori eradication would protect against aspirin-associated ulcer bleeding. METHODS: The Helicobacter Eradication Aspirin Trial was a randomised placebo-controlled trial (European Union Drug Regulating Authorities Clinical Trials 2011-003425-96), conducted in United Kingdom primary care using routinely collected clinical data. Consenting participants aged ≥ 60 years prescribed aspirin ≤ 325 mg but not ulcerogenic or gastroprotective medication underwent C13 urea breath testing for H. pylori. Those with a positive test were randomised to receive either a combination of clarithromycin 500 mg, metronidazole 400 mg and lansoprazole 30 mg, or placebos twice daily for 7 days. The primary outcome, time to death or hospitalisation due to peptic ulcer bleeding, was analysed using a Cox proportional hazards model. FINDINGS: Between 14 September 2012 and 22 November 2017, 30,166 participants underwent H. pylori breath testing, 5367 had a positive result, 5352 were randomised to an intention-to-treat population of 2677 (eradication) and 2675 (placebo) and followed up for a median of 5.0 years (interquartile range 3.9-6.4). Statistical analysis of the primary outcome showed an overall hazard ratio of 0.69 [95% confidence interval 0.38 to 1.25; p = 0.22], but there was a significant departure from the proportional hazards assumption (p = 0.0068), requiring analysis split at the median time to event: 2.5 years. There was a significant reduction in the primary outcome in the eradication treatment group in the first 2.5 years (hazard ratio 0.35, 95% confidence interval 0.14 to 0.89; p = 0.028) but not the second period (hazard ratio 1.31, 95% confidence interval 0.55 to 3.11). The number needed to treat (first period) was 238 (95% confidence interval 184 to 1661). Results in the first 2.5 years remained significant when accounting for the competing risk of death (p = 0.028). During the study period, 657 participants died (306 in the eradication group and 351 in the controls group; hazard ratio 0.86, 95% confidence interval 0.74 to 1.01; p = 0.058). Malignancy was the most common cause of death and largely accounted for the numerical difference between the treatment groups. A health economic analysis found proactive screening not cost-effective, since the monetised benefits of the intervention in preventing a peptic ulcer bleed failed to outweigh the costs. INTERPRETATION: Helicobacter pylori eradication protects against aspirin-associated peptic ulcer bleeding, but this may not be sustained or cost-effective when applied non-selectively to our study population. The possibility that H. pylori eradication, on a background of aspirin use, might affect death from malignancies warrants further evaluation. LIMITATIONS AND FUTURE WORK: Studying subjects already established on aspirin probably contributed to the low event rate. A future study should investigate subjects starting on aspirin when the event rate is higher. TRIAL REGISTRATION: This trial is registered as ISRCTN10134725; ClinicalTrials.gov number NCT01506986. FUNDING: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 09/55/52) and is published in full in Health Technology Assessment; Vol. 29, No. 42. See the NIHR Funding and Awards website for further award information.
Recent-onset atrial fibrillation: challenges and opportunities.
Atrial fibrillation (AF) is increasingly diagnosed early, close to its first occurrence due to: (i) increased public awareness with self-screening; (ii) health care initiatives including population screening and opportunistic case finding; and (iii) increased use and surveillance of implantable cardiac devices. At its onset, AF is often low burden, and cardiovascular co-morbidities may be absent or at an early stage. Thus, the management of recent-onset AF has become an issue of growing importance. Professional guidelines have traditionally focused on anticoagulant thromboprophylaxis, generally recommending a cautious approach to rhythm control, and priority has been given to rate control to alleviate symptoms. In recent guidelines, the importance of managing lifestyle and co-morbidities has increased. The AF-SCREEN collaboration proposes that a vigorous approach to active management of recent-onset AF may be warranted. This includes addressing co-morbidities and promoting healthy lifestyles to prevent the emergence or progression of AF and associated cardiovascular disease, as well as the initiation of active rhythm control ± anticoagulation to prevent AF-related morbidity and mortality, including stroke and heart failure (HF). Intuitively, intervention early after AF onset would be beneficial since lifestyle and co-morbidity management, plus rhythm control and anticoagulation, are important contributors to improved outcomes in patients with established AF, but robust evidence is lacking for recent-onset AF. There is a delicate balance between achieving favourable outcomes such as preventing strokes, HF and AF progression vs the complications and potential adverse effects of interventions. Given the serious long-term consequences, innovative approaches are necessary to determine the value and risks of initiating active therapy very early in the course of AF. More data are needed to guide the best management of recent-onset AF, bearing AF burden in mind. Long-term studies using large national databases linked to electronic medical records and rhythm monitoring devices offer excellent opportunities. Shorter-term studies focusing on reducing AF burden to slow AF progression and studies focusing on outcomes such as HF could be used in both randomized clinical trials and observational cohort studies.