We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.
To save content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about saving content to .
To save content items to your Kindle, first ensure no-reply@cambridge.org
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about saving to your Kindle.
Note you can select to save to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
Background: Epstein-Barr virus (EBV) infection is believed to be a critical prerequisite for the development of multiple sclerosis (MS). This study aims to investigate whether anti-EBV titres are elevated before the onset of MS symptoms in people with radiologically isolated syndrome (pwRIS) and to evaluate their association with markers of adverse clinical outcomes. Methods: Epstein-Barr nuclear antigen 1 (EBNA1) and viral capsid antigen (VCA) titres were quantified in a cohort of 47 pwRIS and 24 healthy controls using Enzyme-Linked Immuno-Sorbent Assay. Plasma glial fibrillary acidic protein (GFAP) and neurofilament light protein (NfL) were measured using single-molecule array. MRI lesion metrics and the development of MS symptoms over time were also evaluated. Results: EBNA1 titres were higher pwRIS compared to healthy controls (p=0.038), while VCA titres were not (p=0.237). A positive correlation was observed between EBNA1 titres and plasma GFAP in pwRIS (p=0.005). Neither EBNA1 nor VCA titres correlated with NfL. MRI lesion measures and the development of MS symptoms did not show any significant relationship with EBNA1 or VCA titres. Conclusions: Eelevated EBNA1 titres are detectable prior to MS symptom onset and correlate with GFAP, a biomarker associated with worse clinical outcomes. However, their role in disease progression and clinical outcomes requires further investigation.
Background: Radiologically isolated syndrome (RIS) is characterized by incidental MRI findings suggestive of multiple sclerosis in asymptomatic individuals. Emerging blood biomarkers, including neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and chitinase 3-like 1 protein (CHI3L1) are promising tools for evaluating neuroinflammation and neurodegeneration. Methods: This cross-sectional analysis included 47 individuals with RIS who underwent MRI and plasma biomarker assessments. Plasma levels of CHI3L1, NfL, and GFAP were measured using highly sensitive assays. Correlations between biomarkers and MRI markers, including T1-black holes (BHs), central vein sign (CVS) positive lesions, paramagnetic rim lesions (PRLs), choroid plexus volume (CPV), and thalamic and hippocampal volumes, were analyzed using linear regression. Results: Plasma CHI3L1 levels correlated with increased CPV (β = 0.347, p = 0.017) and reduced thalamic (β = -0.309, p = 0.035) and hippocampal (β = -0.535, p < 0.001) volumes. Plasma GFAP levels were associated with BHs, CVS, and PRLs, whereas plasma NfL showed no correlations with MRI measures. Conclusions: Plasma CHI3L1 correlates with subcortical grey matter atrophy and CPV increase in RIS, distinct from correlations observed with GFAP or NfL. This suggests that plasma CHI3L1 may reflect neurodegeneration and inflammation in RIS and provide insights into disease activity not captured by other biomarkers.
Background: In multiple sclerosis (MS), soluble mediators of neuroinflammation are released by activated lymphocytes and resident immune cells, leading to demyelination and neurodegeneration. Radiologically isolated syndrome (RIS) is an entity in which white matter lesions fulfilling criteria for MS occur in individuals without any suggestive symptoms. The exact nature of pro- and anti-inflammatory cytokines in blood, and their association with disease activity in RIS/MS requires further clarification. Methods: Plasma was collected and cryopreserved from healthy controls (HCs), people with RIS and relapsing-remitting MS (RRMS) at the Barlo MS Centre. All samples were analyzed with OLink Target 96 Inflammation Multiplex Immunoassay Panel. Results: Individuals with RIS (p=0.0001; p= 0.0007; p= 0.0012) and RRMS (p<0.0001; p= 0.0003; p= 0.00112) had significantly higher concentrations of hepatocyte growth factor (HGF), interleukin-6 (IL-6), and chemokine ligand 23 (CCL23) in plasma compared to HCs, and patients with RRMS (p=0.0087) had significantly higher concentrations of HGF compared to individuals with RIS. Conclusions: Our study demonstrates that HGF, IL-6 and CCL23 are significantly increased in the plasma of patients with RIS and RRMS compared to HCs. Our observations suggest that the biology of MS is present in those with RIS, and these neuroinflammatory mediators may serve as a biomarker of disease activity.
The COVID-19 pandemic presents a remarkable opportunity to put to work all of the research that has been undertaken in past decades on the elicitation and structural estimation of subjective belief distributions as well as preferences over atemporal risk, patience, and intertemporal risk. As contributors to elements of that research in laboratories and the field, we drew together those methods and applied them to an online, incentivized experiment in the United States. We have two major findings. First, the atemporal risk premium during the COVID-19 pandemic appeared to change significantly compared to before the pandemic, consistent with theoretical results of the effect of increased background risk on foreground risk attitudes. Second, subjective beliefs about the cumulative level of deaths evolved dramatically over the period between May and November 2020, a volatile one in terms of the background evolution of the pandemic.
We convey our experiences developing and implementing an online experiment to elicit subjective beliefs and economic preferences. The COVID-19 pandemic and associated closures of our laboratories required us to conduct an online experiment in order to collect beliefs and preferences associated with the pandemic in a timely manner. Since we had not previously conducted a similar multi-wave online experiment, we faced design and implementation considerations that are not present when running a typical laboratory experiment. By discussing these details more fully, we hope to contribute to the online experiment methodology literature at a time when many other researchers may be considering conducting an online experiment for the first time. We focus primarily on methodology; in a complementary study we focus on initial research findings.
Syncope is common among pediatric patients and is rarely pathologic. The mechanisms for symptoms during exercise are less well understood than the resting mechanisms. Additionally, inert gas rebreathing analysis, a non-invasive examination of haemodynamics including cardiac output, has not previously been studied in youth with neurocardiogenic syncope.
Methods:
This was a retrospective (2017–2023), single-center cohort study in pediatric patients ≤ 21 years with prior peri-exertional syncope evaluated with echocardiography and cardiopulmonary exercise testing with inert gas rebreathing analysis performed on the same day. Patients with and without symptoms during or immediately following exercise were noted.
Results:
Of the 101 patients (15.2 ± 2.3 years; 31% male), there were 22 patients with symptoms during exercise testing or recovery. Resting echocardiography stroke volume correlated with resting (r = 0.53, p < 0.0001) and peak stroke volume (r = 0.32, p = 0.009) by inert gas rebreathing and with peak oxygen pulse (r = 0.61, p < 0.0001). Patients with syncopal symptoms peri-exercise had lower left ventricular end-diastolic volume (Z-score –1.2 ± 1.3 vs. –0.36 ± 1.3, p = 0.01) and end-systolic volume (Z-score –1.0 ± 1.4 vs. −0.1 ± 1.1, p = 0.001) by echocardiography, lower percent predicted peak oxygen pulse during exercise (95.5 ± 14.0 vs. 104.6 ± 18.5%, p = 0.04), and slower post-exercise heart rate recovery (31.0 ± 12.7 vs. 37.8 ± 13.2 bpm, p = 0.03).
Discussion:
Among youth with a history of peri-exertional syncope, those who become syncopal with exercise testing have lower left ventricular volumes at rest, decreased peak oxygen pulse, and slower heart rate recovery after exercise than those who remain asymptomatic. Peak oxygen pulse and resting stroke volume on inert gas rebreathing are associated with stroke volume on echocardiogram.
To describe the use of cultures for acid-fast bacilli (AFB) and situations in which AFB cultures are unlikely to be of clinical benefit.
Design:
Retrospective descriptive study of AFB cultures submitted to Sentara Health microbiology laboratory from December 1, 2021, to December 1, 2023. Data were collected from the electronic medical record and included patient demographics, the service line that ordered the culture, specimen source, and culture results.
Setting:
Sentara Healthcare System.
Patients:
All patients who had specimens submitted to the microbiology laboratory during the study period were included.
Results:
A total of 13,944 AFB cultures from 8,243 patients were collected during the study period. Of these, 4.72% (n = 389) patients had a positive result, and 40 of 680 positive cultures were likely contaminants or non-mycobacterial. The average number of days between culture collection and positive results was 84.32 days (SD = 49.64) and 56.25 days (SD = 8.32) for negative results. Most cultures were ordered by medical subspecialties (44.06%, n = 6,144), followed by orthopedic providers (23.34%, n = 3,254) and surgical subspecialty providers (16.11%, n = 2,246). Most specimens were pulmonary (n = 6,620) with 619 (9.35%) positive cultures. Of 3,561 AFB cultures ordered from bone specimens, only 17 were positive (0.48%). The number of specimens processed by the microbiology laboratory required 2 full-time microbiology technicians to process specimens.
Conclusions:
Many AFB cultures were sent from patients who did not have clinical scenarios consistent with mycobacterial disease and cultures were not clinically indicated. Implementation of testing criteria could decrease AFB cultures and healthcare costs.
The identification of predictors of treatment response is crucial for improving treatment outcome for children with anxiety disorders. Machine learning methods provide opportunities to identify combinations of factors that contribute to risk prediction models.
Methods
A machine learning approach was applied to predict anxiety disorder remission in a large sample of 2114 anxious youth (5–18 years). Potential predictors included demographic, clinical, parental, and treatment variables with data obtained pre-treatment, post-treatment, and at least one follow-up.
Results
All machine learning models performed similarly for remission outcomes, with AUC between 0.67 and 0.69. There was significant alignment between the factors that contributed to the models predicting two target outcomes: remission of all anxiety disorders and the primary anxiety disorder. Children who were older, had multiple anxiety disorders, comorbid depression, comorbid externalising disorders, received group treatment and therapy delivered by a more experienced therapist, and who had a parent with higher anxiety and depression symptoms, were more likely than other children to still meet criteria for anxiety disorders at the completion of therapy. In both models, the absence of a social anxiety disorder and being treated by a therapist with less experience contributed to the model predicting a higher likelihood of remission.
Conclusions
These findings underscore the utility of prediction models that may indicate which children are more likely to remit or are more at risk of non-remission following CBT for childhood anxiety.
Research suggests that most mental health conditions have their onset in the critically social period of adolescence. Yet, we lack understanding of the potential social processes underlying early psychopathological development. We propose a conceptual model where daily-life social interactions and social skills form an intermediate link between known risk and protective factors (adverse childhood experiences, bullying, social support, maladaptive parenting) and psychopathology in adolescents – that is explored using cross-sectional data.
Methods
N = 1913 Flemish adolescent participants (Mean age = 13.8; 63% girls) were assessed as part of the SIGMA study, a large-scale, accelerated longitudinal study of adolescent mental health and development. Self-report questionnaires (on risk/protective factors, social skills, and psychopathology) were completed during class time; daily-life social interactions were measured during a subsequent six-day experience-sampling period.
Results
Registered uncorrected multilevel linear regression results revealed significant associations between all risk/protective factors and psychopathology, between all risk/protective factors and social processes, and between all social processes and psychopathology. Social processes (social skills, quantity/quality of daily social interactions) were uniquely predicted by each risk/protective factor and were uniquely associated with both general and specific types of psychopathology. For older participants, some relationships between social processes and psychopathology were stronger.
Conclusions
Unique associations between risk/protective factors and psychopathology signify the distinct relevance of these factors for youth mental health, whereas the broad associations with social processes support these processes as broad correlates. Results align with the idea of a social pathway toward early psychopathology, although follow-up longitudinal research is required to verify any mediation effect.
The modern marine megafauna is known to play important ecological roles and includes many charismatic species that have drawn the attention of both the scientific community and the public. However, the extinct marine megafauna has never been assessed as a whole, nor has it been defined in deep time. Here, we review the literature to define and list the species that constitute the extinct marine megafauna, and to explore biological and ecological patterns throughout the Phanerozoic. We propose a size cut-off of 1 m of length to define the extinct marine megafauna. Based on this definition, we list 706 taxa belonging to eight main groups. We found that the extinct marine megafauna was conspicuous over the Phanerozoic and ubiquitous across all geological eras and periods, with the Mesozoic, especially the Cretaceous, having the greatest number of taxa. Marine reptiles include the largest size recorded (21 m; Shonisaurus sikanniensis) and contain the highest number of extinct marine megafaunal taxa. This contrasts with today’s assemblage, where marine animals achieve sizes of >30 m. The extinct marine megafaunal taxa were found to be well-represented in the Paleobiology Database, but not better sampled than their smaller counterparts. Among the extinct marine megafauna, there appears to be an overall increase in body size through time. Most extinct megafaunal taxa were inferred to be macropredators preferentially living in coastal environments. Across the Phanerozoic, megafaunal species had similar extinction risks as smaller species, in stark contrast to modern oceans where the large species are most affected by human perturbations. Our work represents a first step towards a better understanding of the marine megafauna that lived in the geological past. However, more work is required to expand our list of taxa and their traits so that we can obtain a more complete picture of their ecology and evolution.
Laser plasma accelerators (LPAs) enable the generation of intense and short proton bunches on a micrometre scale, thus offering new experimental capabilities to research fields such as ultra-high dose rate radiobiology or material analysis. Being spectrally broadband, laser-accelerated proton bunches allow for tailored volumetric dose deposition in a sample via single bunches to excite or probe specific sample properties. The rising number of such experiments indicates a need for diagnostics providing spatially resolved characterization of dose distributions with volumes of approximately 1 cm${}^3$ for single proton bunches to allow for fast online feedback. Here we present the scintillator-based miniSCIDOM detector for online single-bunch tomographic reconstruction of dose distributions in volumes of up to approximately 1 cm${}^3$. The detector achieves a spatial resolution below 500 $\unicode{x3bc}$m and a sensitivity of 100 mGy. The detector performance is tested at a proton therapy cyclotron and an LPA proton source. The experiments’ primary focus is the characterization of the scintillator’s ionization quenching behaviour.
Unsupervised remote digital cognitive assessment makes frequent testing feasible and allows for measurement of learning across days on participants’ own devices. More rapid detection of diminished learning may provide a potentially valuable metric that is sensitive to cognitive change over short intervals. In this study we examine feasibility and predictive validity of a novel digital assessment that measures learning of the same material over 7 days in older adults.
Participants and Methods:
The Boston Remote Assessment for Neurocognitive Health (BRANCH) (Papp et al., 2021) is a web-based assessment administered over 7 consecutive days repeating the same stimuli each day to capture multi-day-learning slopes. The assessment includes Face-Name (verbal-visual associative memory), Groceries-Prices (numeric-visual associative memory), and Digits-Signs (speeded processing of numeric-visual associations). Our sample consisted of200 cognitively unimpaired older adults enrolled in ongoing observational studies (mean age=74.5, 63% female, 87% Caucasian, mean education=16.6) who completed the tasks daily, at home, on their own digital devices. Participants had previously completed in-clinic paper-and-pencil tests to compute a Preclinical Alzheimer’s Cognitive Composite (PACC-5). Mixed-effects models controlling for age, sex, and education were used to observe the associations between PACC-5 scores and both initial performance and multi-day learning on the three BRANCH measures.
Results:
Adherence was high with 96% of participants completing all seven days of consecutive assessment; demographic factors were not associated with differences in adherence. Younger participants had higher Day 1 scores all three measures, and learning slopes on Digit-Sign. Female participants performed better on Face-Name (T=3.35, p<.001) and Groceries-Prices (T=2.00, p=0.04) on Day 1 but no sex differences were seen in learning slopes; there were no sex differences on Digit-Sign. Black participants had lower Day 1 scores on Face-Name (T=-3.34, p=0.003) and Digit Sign (T=3.44, p=0.002), but no racial differences were seen on learning slopes for any measure. Education was not associated with any measure. First day performance on Face-Name (B=0.39, p<.001), but not learning slope B=0.008, p=0.302) was associated with the PACC5. For Groceries-Prices, both Day 1 (B=0.27, p<.001) and learning slope (B=0.02, p=0.03) were associated with PACC-5. The Digit-Sign scores at Day 1 (B=0.31, p<.001) and learning slope (B=0.06, p<.001) were also both associated with PACC-5.
Conclusions:
Seven days of remote, brief cognitive assessment was feasible in a sample of cognitively unimpaired older adults. Although various demographic factors were associated with initial performance on the tests, multi-day-learning slopes were largely unrelated to demographics, signaling the possibility of its utility in diverse samples. Both initial performance and learning scores on an associative memory and processing speed test were independently related to baseline cognition indicating that these tests’ initial performance and learning metrics are convergent but unique in their contributions. The findings signal the value of measuring differences in learning across days as a means towards sensitively identifying differences in cognitive function before signs of frank impairment are observed. Next steps will involve identifying the optimal way to model multi-day learning on these subtests to evaluate their potential associations with Alzheimer’s disease biomarkers.
The assortment of trillions of microorganisms resident along the human gastrointestinal tract, our gut microbiota, has co-evolved with us over thousands of years. It can influence a plethora of aspects of human physiology, including host metabolism, immunity and even brain function, cognition and behaviour across the lifespan. The gut microbiota and the brain can communicate with one another, directly and indirectly, through immune system modulation, tryptophan metabolism, vagus nerve activity, the enteric nervous system and bioactive microbial by-products, or metabolites produced by the gut microbiome. Indeed, the gut microbiota are responsible for a rich reservoir of novel metabolites and bioactive substances that can have pleiotropic functionalities for the host. Moreover, diet, an easily accessible and thus powerful interventional tool, can act as a modulator of gut-microbial composition and activity, impacting on host physiology. As such, nutrition is seen as one of the major modulators of the gut microbiota. Intriguingly, although psychiatric conditions often include a dietary aspect, much research investigating this link in clinical populations ignores this relationship, missing a key therapeutic avenue. This has led to the concept of nutritional psychiatry, where we can use food and supplements to support mental health and brain function. As a result, it is critical to consider emerging microbiome-targeted dietary approaches with the greatest potential to improve health outcomes in a psychiatric population.
We performed a preimplementation assessment of workflows, resources, needs, and antibiotic prescribing practices of trainees and practicing dentists to inform the development of an antibiotic-stewardship clinical decision-support tool (CDST) for dentists.
Methods:
We used a technology implementation framework to conduct the preimplementation assessment via surveys and focus groups of students, residents, and faculty members. Using Likert scales, the survey assessed baseline knowledge and confidence in dental providers’ antibiotic prescribing. The focus groups gathered information on existing workflows, resources, and needs for end users for our CDST.
Results:
Of 355 dental providers recruited to take the survey, 213 (60%) responded: 151 students, 27 residents, and 35 faculty. The average confidence in antibiotic prescribing decisions was 3.2 ± 1.0 on a scale of 1 to 5 (ie, moderate). Dental students were less confident about prescribing antibiotics than residents and faculty (P < .01). However, antibiotic prescribing knowledge was no different between dental students, residents, and faculty. The mean likelihood of prescribing an antibiotic when it was not needed was 2.7 ± 0.6 on a scale of 1 to 5 (unlikely to maybe) and was not meaningfully different across subgroups (P = .10). We had 10 participants across 3 focus groups: 7 students, 2 residents, and 1 faculty member. Four major themes emerged, which indicated that dentists: (1) make antibiotic prescribing decisions based on anecdotal experiences; (2) defer to physicians’ recommendations; (3) have limited access to evidence-based resources; and (4) want CDST for antibiotic prescribing.
Conclusions:
Dentists’ confidence in antibiotic prescribing increased by training level, but knowledge did not. Trainees and practicing dentists would benefit from a CDST to improve appropriateness of antibiotic prescribing.
Laser–plasma accelerated (LPA) proton bunches are now applied for research fields ranging from ultra-high-dose-rate radiobiology to material science. Yet, the capabilities to characterize the spectrally and angularly broad LPA bunches lag behind the rapidly evolving applications. The OCTOPOD translates the angularly resolved spectral characterization of LPA proton bunches into the spatially resolved detection of the volumetric dose distribution deposited in a liquid scintillator. Up to 24 multi-pinhole arrays record projections of the scintillation light distribution and allow for tomographic reconstruction of the volumetric dose deposition pattern, from which proton spectra may be retrieved. Applying the OCTOPOD at a cyclotron, we show the reliable retrieval of various spatial dose deposition patterns and detector sensitivity over a broad dose range. Moreover, the OCTOPOD was installed at an LPA proton source, providing real-time data on proton acceleration performance and attesting the system optimal performance in the harsh laser–plasma environment.
This study evaluated whether COVID-19-specific risk factors (e.g., feeling guilty for not being present with the deceased at the time of the loss and feeling emotionally distant from the deceased prior to the loss) were associated with prolonged grief disorder (PGD) symptomatology or diagnosis among young adults bereaved due to any cause (e.g., illness and violent loss).
Methods
We surveyed 196 young adults who had a family member/close friend die during the COVID-19 pandemic. Participants completed the PGD-12 Questionnaire and the 10-item Pandemic Grief Risk Factors (PGRF) Questionnaire.
Results
More time spent with the deceased before the loss and greater endorsement of pandemic grief risk factors were associated with increased PGD symptoms and a greater likelihood of meeting the diagnostic criteria for PGD.
Significance of results
The COVID-19 pandemic created unique risk factors that affected the grieving process for bereaved individuals, regardless of whether the death was related to COVID-19 infection. These findings add to a growing body of literature examining grief and loss within the unique context of the COVID-19 pandemic and suggest that there may be detrimental long-term psychological outcomes for these bereaved individuals, regardless of the cause of death. Routine screening for these unique risk factors in medical and psychological clinics is warranted to help identify those individuals who could benefit from early intervention. Also, it will be important to understand and possibly modify evidence-based interventions and prevention programs to directly address the identified unique PGRF.
Large-scale societal issues such as public health crises highlight the need to communicate scientific information, which is often uncertain, accurately to the public and policy makers. The challenge is to communicate the inherent scientific uncertainty — especially about the underlying quality of the evidence — whilst supporting informed decision making. Little is known about the effects that such scientific uncertainty has on people’s judgments of the information. In three experimental studies (total N=6,489), we investigate the influence of scientific uncertainty about the quality of the evidence on people’s perceived trustworthiness of the information and decision making. We compare the provision of high, low, and ambiguous quality-of-evidence indicators against providing no such cues. Results show an asymmetric relationship: people react more strongly to cues of low quality of evidence than they do to high quality of evidence compared to no cue. While responses to a cue of high quality of evidence are not significantly different from no cue; a cue of low or uncertain quality of evidence is accompanied by lower perceived trustworthiness and lower use of the information in decision making. Cues of uncertain quality of evidence have a similar effect to those of low quality. These effects do not change with the addition of a reason for the indicated quality level. Our findings shed light on the effects of the communication of scientific uncertainty on judgment and decision making, and provide insights for evidence-based communications and informed decision making for policy makers and the public.
Borderline personality disorder (BPD) is a mental health condition characterized by emotion dysregulation, interpersonal impairment, and high suicidality. Dialectical behaviour therapy (DBT) is the most widely studied psychotherapeutic treatment for BPD. To date, the vast majority of DBT research has focused on cisgender women, with a notable lack of systematic investigation of sex and/or gender differences in treatment response. In order to encourage effective, equitable treatment of BPD, further investigation into treatment targets in this population is critical. Here, we employed a systematic strategy to delineate gaps in the DBT literature pertaining to sex and gender differences and propose directions for future research. Findings demonstrate a significant discrepancy in measurement of sex and gender, particularly among gender-diverse individuals. Exploring DBT treatment response across the full spectrum of genders will facilitate the provision of more tailored, impactful care to all individuals who suffer from BPD.
Key learning aims
(1) To date, DBT treatment literature has focused almost exclusively on cisgender women, with only two of 253 DBT studies in current literature accounting for transgender and gender diverse (TGD) individuals.
(2) Recognize how gender minority stress may impact the prevalence of BPD among TGD individuals.
(3) Learn how future research initiatives can be employed to rectify this gap in the DBT literature.
By transforming from a manufacturer into a PSS provider, the business model of a company changes. In particular with service-oriented business models, the importance of tangible products alters. Instead of selling products, PSS providers need product fleets that enable the provision of services. If the manufacturer of the product and the provider of the PSS fleet are identical, the products can be designed specifically for the PSS. This paper introduces a framework that supports the design of modular PSS fleets so that the product architecture is optimised for the requirements of the fleet.