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Negative symptoms are a key feature of several psychiatric disorders. Difficulty identifying common neurobiological mechanisms that cut across diagnostic boundaries might result from equifinality (i.e., multiple mechanistic pathways to the same clinical profile), both within and across disorders. This study used a data-driven approach to identify unique subgroups of participants with distinct reward processing profiles to determine which profiles predicted negative symptoms.
Methods
Participants were a transdiagnostic sample of youth from a multisite study of psychosis risk, including 110 individuals at clinical high-risk for psychosis (CHR; meeting psychosis-risk syndrome criteria), 88 help-seeking participants who failed to meet CHR criteria and/or who presented with other psychiatric diagnoses, and a reference group of 66 healthy controls. Participants completed clinical interviews and behavioral tasks assessing four reward processing constructs indexed by the RDoC Positive Valence Systems: hedonic reactivity, reinforcement learning, value representation, and effort–cost computation.
Results
k-means cluster analysis of clinical participants identified three subgroups with distinct reward processing profiles, primarily characterized by: a value representation deficit (54%), a generalized reward processing deficit (17%), and a hedonic reactivity deficit (29%). Clusters did not differ in rates of clinical group membership or psychiatric diagnoses. Elevated negative symptoms were only present in the generalized deficit cluster, which also displayed greater functional impairment and higher psychosis conversion probability scores.
Conclusions
Contrary to the equifinality hypothesis, results suggested one global reward processing deficit pathway to negative symptoms independent of diagnostic classification. Assessment of reward processing profiles may have utility for individualized clinical prediction and treatment.
The clinical high-risk (CHR) state for psychosis demonstrates considerable clinical heterogeneity, presenting challenges for clinicians and researchers alike. Basic symptoms, to date, have largely been ignored in explorations of clinical profiles.
Aims
We examined clinical profiles by using a broader spectrum of CHR symptoms, including not only (attenuated) psychotic, but also basic symptoms.
Method
Patients (N = 875) of specialised early intervention centres for psychosis in Germany and Switzerland were assessed with the Schizophrenia Proneness Instruments and the Structured Interview for Psychosis-Risk Syndromes. Latent class analysis was applied to CHR symptoms to identify clinical profiles. Additionally, demographics, other symptoms, current non-psychotic DSM-IV axis I disorders and neurocognitive variables were assessed to further describe and compare the profiles.
Results
A three-class model was best fitting the data, whereby basic symptoms best differentiated between the profiles (η2 = 0.08–0.52). Class 1 had a low probability of CHR symptoms, the highest functioning and lowest other psychopathology, neurocognitive deficits and transition-to-psychosis rate. Class 2 had the highest probability of basic and (attenuated) positive symptoms (excluding hallucinations), lowest functioning, highest symptom load, most neurocognitive deficits and highest transition rate (55.1%). Class 3 was mostly characterised by attenuated hallucination, and was otherwise intermediate between the other two classes. Comorbidity rates were comparable across classes, with some class differences in diagnostic categories.
Conclusions
Our profiles based on basic and (attenuated) psychotic symptoms provide clinically useful entities by parsing out heterogeneity in clinical presentation. In future, they could guide class-specific intervention.
The field of misinformation studies has experienced a boom of scholarship in recent years. Buoyed by the emergence of information operations surrounding the 2016 election and the rise of so-called “fake news,” researchers hailing from fields ranging from philosophy to computer science have taken up the challenge of detecting, analyzing, and theorizing false and misleading information online. In an attempt to understand the spread of misinformation online, researchers have adapted concepts from different disciplines. Concepts from epidemiology, for example, have opened doors to thinking about spread, contagion, and resistance. The life sciences offer concepts and theories to further extend what we know about how misinformation adapts; by viewing information as an organism within a complex ecosystem, we can better understand why some narratives succeed and others fail. Collaborations between misinformation researchers and life scientists to develop responsible adaptations of fitness models can bolster misinformation research.
Community-acquired pneumonia (CAP) is a leading cause of hospitalizations and mortality in the US. Overuse of extended spectrum antibiotics (ESA) for CAP contributes to antimicrobial resistance. The 2019 Infectious Diseases Society of America/American Thoracic Society CAP guidelines emphasize de-escalation of ESA following negative cultures, early switch to oral (PO) antibiotics, and limited duration of therapy (DOT). This study describes clinicians’ acceptance of an infectious diseases-trained (ID) pharmacist-led stewardship recommendations in hospitalized patients with CAP.
Methods:
This prospective, single-arm, cohort study included adults admitted with a diagnosis of pneumonia to six Cleveland Clinic hospitals receiving ID pharmacist-led stewardship recommendations. The ID pharmacist provided recommendations for ESA de-escalation, DOT, intravenous (IV) to PO transition, and antimicrobial discontinuation. Descriptive statistics were used to describe clinician acceptance rates.
Results:
From November 1, 2022, to January 31, 2024, the ID pharmacist made recommendations for 685 patient encounters to 327 clinicians. Of these patients, 52% received an ESA and 15% had severe CAP. There were 959 recommendations: ESA de-escalation (19%), DOT (46%), IV to PO transition (19%), antimicrobial discontinuation (13%), and other (3%). Clinicians accepted 693 recommendations (72%): IV to PO transition (148/184, 80%), ESA de-escalation (141/181 78%), antimicrobial discontinuation (94/128, 73%), DOT (286/437, 65%), and other (24/29, 83%).
Conclusion:
Clinicians were generally receptive to ID pharmacist-led CAP recommendations with an overall acceptance rate of 72%. Prescribers were most receptive to recommendations for IV to PO conversion and least receptive to limiting DOT.
OBJECTIVES/GOALS: Fluid boluses are administered to hypotensive, critically ill children but may not reverse hypotension, leading to delay of vasoactive infusion, end-organ damage, and mortality. We hypothesize that a machine learning-based model will predict which children will have sustained response to fluid bolus. METHODS/STUDY POPULATION: We will conduct a single-center retrospective observational cohort study of hypotensive critically ill children who received intravenous isotonic fluid of at least 10 ml/kg within 72 hours of pediatric intensive care unit admission between 2013 and 2023. We will extract physiologic variables from stored bedside monitors data and clinical variables from the EHR. Fluid responsive (FR) will be defined as a MAP increase by 310%. We will construct elastic net, random forest, and a long short-term memory models to predict FR. We will compare complicated course (multiple organ dysfunction on day 7 or death by day 28) between: 1) FRs and non-FRs, 2) predicted FRs and non-FRs, 3), FRs and non-FRs stratified by race/ethnicity, and 4) FRs and non-FRs stratified by sex as a biologic variable. RESULTS/ANTICIPATED RESULTS: We anticipate approximately 800 critically ill children will receive 2,000 intravenous isotonic fluid boluses, with a 60% rate of FR. We anticipate being able to complete all three models. We hypothesize that the model with the best performance will be the long short-term memory model and the easiest to interpret will be the tree-based random forest model. We hypothesize non-FRs will have a higher complicated course than FRs and that predicted non-FRs will have a higher rate of complicated course than FRs. Based on previous adult studies, we hypothesize that there will be a higher rate of complicated course in patients of black race and/or Hispanic ethnicity when compared to non-Hispanic white patients. We also hypothesize that there will be no difference in complicated course when comparing sex as a biologic variable. DISCUSSION/SIGNIFICANCE: We have a critical need for easily-deployed, real-time prediction of fluid response to personalize and improve resuscitation for children in shock. We anticipate the clinical application of such a model will decrease time with hypotension for critically ill children, leading to decreased morbidity and mortality.
Biodesign is a relatively new interdisciplinary field, which has grown rapidly over the last decade (as evidenced for example by the growth in student teams entering the Biodesign Challenge from 9 in 2016 to 52 in 2024).
Early exposure to neighborhood social fragmentation has been shown to be associated with schizophrenia. The impact of social fragmentation and friendships on distressing psychotic-like experiences (PLE) remains unknown. We investigate the relationships between neighborhood social fragmentation, number of friends, and distressing PLE among early adolescents.
Methods
Data were collected from the Adolescent Brain Cognitive Development Study. Generalized linear mixed models tested associations between social fragmentation and distressing PLE, as well as the moderating role of the number of total and close friends.
Results
Participants included 11 133 adolescents aged 9 to 10, with 52.3% being males. Greater neighborhood social fragmentation was associated with higher levels of distressing PLE (adjusted β = 0.05; 95% CI: 0.01–0.09). The number of close but not total friends significantly interacted with social fragmentation to predict distressing PLE (adjusted β = −0.02; 95% CI: −0.04 to <−0.01). Among those with fewer close friends, the association between neighborhood social fragmentation and distressing PLE was significant (adjusted β = 0.07; 95% CI: 0.03–0.11). However, among those with more close friends, the association was non-significant (adjusted β = 0.03; 95% CI: −0.01 to 0.07).
Conclusions
Greater neighborhood social fragmentation is associated with higher levels of distressing PLE, particularly among those with fewer close friends. Further research is needed to disentangle aspects of the interaction between neighborhood characteristics and the quality of social interactions that may contribute to psychosis, which would have implications for developing effective interventions at the individual and community levels.
This study builds on the work by Rehman et al (2022) who argued that transcranial magnetic stimulation (TMS) treatment not only helps treat depression but also decreases sleep problems such as difficulty falling asleep,staying asleep, and waking too early. The present study further explores differences in sleep onset latency, meaning the time it takes to fall asleep, and duration of sleep per night in the pre and post treatment phases of rTMS. The information regarding major attributes of sleep is critical because recent research shows that about 90% of patients with major depressive disorder (MDD) also struggle with sleep disorders (Li et al., 2022), and sleeping for less than seven hours may eventually lead to sleep deprivation (Hirshkowitz et al., 2015), with increased risk of physical and mental health problems (Sheehan et al, 2019). Sleep onset latency estimates vary from individual to individual but typical sleep latency is considered between 10 to 20 minutes (Jung et al, 2013). As it has been shown that overall sleep problems improve with rTMS, we hypothesized that self-reported sleep onset latency will decrease, and sleep duration will increase.
Participants and Methods:
All participants met inclusion criteria for MDD diagnosis and completed a full course of TMS treatment (N=470; Mean age=53.45, SD=13.73). The sample was mostly male (81%) and ethnically diverse: 77.7% non-Hispanic White, 13.3% Black Americans, 1.9% Asian, 0.2 % Asian Indian, and 1.9% other ethnicities. Sleep problems were assessed using the following questions at the pre and post treatment stages: the number of minutes it takes to fall asleep and duration of sleep each night.
Results:
A Wilcoxon matched-pairs signed-rank test was conducted to determine whether there was a difference in sleep onset latency and hours of sleep per night between pre and post intervention. The results indicated a significant difference in time to fall asleep between pre and post treatment (pre-treatment M = 1.19, SD = 0.99, post-treatment M = 0.93, SD = 0.91; z = -5.01, p < .001. In addition, there was a significant increase in the minutes of sleep per night in pre (M = 6.11, SD = 2.07) compared to the post treatment (M = 6.32, SD = 1.77), z = -2.56, p = .010.
Conclusions:
Reduced sleep is known to negatively impact mood, cognitive ability, work performance, and immune function (Besedovsky et al., 2012; Killgore, 2010; Massar et al, 2019; Vandekerckhove & Wang, 2018). Similarly, longer sleep onset latency can cause an individual to enter the first sleep stage later than expected and complete fewer sleep cycles. The results of the present study show the effectiveness of rTMS in decreasing sleep onset latency and increasing the duration of sleep. Given the comorbidity and bidirectionality between sleep disturbances and mood disorders (Fang et al., 2019; Palagini et al., 2019), further researching treatments such as rTMS to improve sleep as a means to also improve mood is crucial. We propose acquiring knowledge about sleep attributes as an essential part of clinicians’ work early on in the rTMS treatment in order to monitor an individual’s global functioning level in light of improved sleep.
It was a pleasure to review these two books by renowned authorities on the importance of bird remains, both for interpreting archaeological sites and for understanding how human interaction with wild birds has evolved in Western Europe. Wild birds are very important in helping to interpret many archaeological sites and, when I am directing excavations, I always keep to hand Alan Cohen and Dale Serjeantson's manual for identifying bird bones (Cohen & Serjeantson 1996) and I recommend it to the students who participate. For over 60 years Anne Eastham's tireless dedication to Quaternary avifauna and her assiduous preparation, by meticulously dissecting birds to build a comprehensive skeletal reference collection, have furthered the archaeological interpretation of many Western European Palaeolithic sites.
OBJECTIVES/GOALS: Selinexor is a novel XPO1 inhibitor that blocks nuclear export, thus impairing DNA repair and causing apoptosis. Our goal was to conduct preclinical and clinical studies to test our hypothesis that selinexor’s efficacy is boosted by priming with temozolomide and is associated with a tissue biomarker. METHODS/STUDY POPULATION: We leveraged a team science approach through the NCI Cancer Therapy Evaluation Program (CTEP) to design preclinical experiments, develop a novel RNAseq analysis pipeline, and use pre-existing clinical experience to open an early phase clinical trial for recurrent glioblastoma. Team members included a CTEP medical officer, cancer biologist, pharmacist, industry scientist, translational scientist, and early career clinician scientist mentored by an expert clinician scientist. Based on preclinical results, participants in the clinical trial experimental arm will receive sequential temozolomide 150mg/m2 on days 1-5 and a starting dose of selinexor 60mg on days 8 and 15 of a 28-day cycle. Participants in the control arm will receive monotherapy temozolomide. RESULTS/ANTICIPATED RESULTS: Sequential treatment of U87 cells and intracranial xenografts had superior DNA damage (É£H2A.X, cleaved PARP) and overall survival compared to combination or single-agent (HR 0.25 [95% CI, 0.07-0.84]; p=0.01, log-rank). We used the top-scoring gene pair method to identify an RNAseq signature associated with response to selinexor. We then designed a trial for first recurrent MGMT methylated glioblastoma. Primary objectives are safety and preliminary efficacy. Secondary objectives are overall response rate, efficacy, and validation of a molecular signature. Phase 1 dose finding (n=12) will be followed by a randomized phase 2 (n=72); using proportional hazards regression, RHR 0.5 with p DISCUSSION/SIGNIFICANCE: The NCI CTEP Project Team employs team science as a framework to successfully develop multidisciplinary collaborations, build investigator trial experience, and lead the way to future research opportunities. Our trial addresses a significant unmet need to offer novel therapies and molecular biomarkers in glioblastoma.
There is currently little consensus as to how burnout is best defined and measured, and whether the syndrome should be afforded clinical status. The latter issue would be advanced by determining whether burnout is a singular dimensional construct varying only by severity (and with some level of severity perhaps indicating clinical status), or whether a categorical model is superior, presumably reflecting differing ‘sub-clinical’ versus ‘clinical’ or ‘burning out’ vs ‘burnt out’ sub-groups. This study sought to determine whether self-diagnosed burnout was best modelled dimensionally or categorically.
Methods:
We recently developed a new measure of burnout which includes symptoms of exhaustion, cognitive impairment, social withdrawal, insularity, and other psychological symptoms. Mixture modelling was utilised to determine if scores from 622 participants on the measure were best modelled dimensionally or categorically.
Results:
A categorical model was supported, with the suggestion of a sub-syndromal class and, after excluding such putative members of that class, two other classes. Analyses indicated that the latter bimodal pattern was not likely related to current working status or differences in depression symptomatology between participants, but reflected subsets of participants with and without a previous diagnosis of a mental health condition.
Conclusion:
Findings indicated that sub-categories of self-identified burnout experienced by the lay population may exist. A previous diagnosis of a mental illness from a mental health professional, and therefore potentially a psychological vulnerability factor, was the most likely determinant of the bimodal data, a finding which has theoretical implications relating to how best to model burnout.
The Welfare We Want? presents a detailed and unique comparison of welfare policies in Britain and America. A team of international experts outlines, compares and contrasts the reform strategies pursued in each country and summarises the results to date.
This study aimed to explore effects of adjunctive minocycline treatment on inflammatory and neurogenesis markers in major depressive disorder (MDD). Serum samples were collected from a randomised, placebo-controlled 12-week clinical trial of minocycline (200 mg/day, added to treatment as usual) for adults (n = 71) experiencing MDD to determine changes in interleukin-6 (IL-6), lipopolysaccharide binding protein (LBP) and brain derived neurotrophic factor (BDNF). General Estimate Equation modelling explored moderation effects of baseline markers and exploratory analyses investigated associations between markers and clinical outcomes. There was no difference between adjunctive minocycline or placebo groups at baseline or week 12 in the levels of IL-6 (week 12; placebo 2.06 ± 1.35 pg/ml; minocycline 1.77 ± 0.79 pg/ml; p = 0.317), LBP (week 12; placebo 3.74 ± 0.95 µg/ml; minocycline 3.93 ± 1.33 µg/ml; p = 0.525) or BDNF (week 12; placebo 24.28 ± 6.69 ng/ml; minocycline 26.56 ± 5.45 ng/ml; p = 0.161). Higher IL-6 levels at baseline were a predictor of greater clinical improvement. Exploratory analyses suggested that the change in IL-6 levels were significantly associated with anxiety symptoms (HAMA; p = 0.021) and quality of life (Q-LES-Q-SF; p = 0.023) scale scores. No other clinical outcomes were shown to have this mediation effect, nor did the other markers (LBP or BDNF) moderate clinical outcomes. There were no overall changes in IL-6, LBP or BDNF following adjunctive minocycline treatment. Exploratory analyses suggest a potential role of IL-6 on mediating anxiety symptoms with MDD. Future trials may consider enrichment of recruitment by identifying several markers or a panel of factors to better represent an inflammatory phenotype in MDD with larger sample size.
The aim of this review is to provide an overview of the complex interactions between dietary fibre and the resident microbial community in the human gut. The microbiota influences both health maintenance and disease development. In the large intestine, the microbiota plays a crucial role in the degradation of dietary carbohydrates that remain undigested in the upper gut (non-digestible carbohydrates or fibre). Dietary fibre contains a variety of different types of carbohydrates, and its breakdown is facilitated by many different microbial enzymes. Some microbes, termed generalists, are able to degrade a range of different carbohydrates, whereas others are more specialised. Furthermore, the physicochemical characteristics of dietary fibre, such as whether it enters the gut in soluble or insoluble form, also likely influence which microbes can degrade it. A complex nutritional network therefore exists comprising primary degraders able to attack complex fibre and cross feeders that benefit from fibre breakdown intermediates or fermentation products. This leads predominately to the generation of the short-chain fatty acids (SCFA) acetate, propionate and butyrate, which exert various effects on host physiology, including the supply of energy, influencing glucose and lipid metabolism and anti-carcinogenic and anti-inflammatory actions. In order to effectively modulate the gut microbiota through diet, there is a need to better understand the complex competitive and cooperative interactions between gut microbes in dietary fibre breakdown, as well as how gut environmental factors and the physicochemical state of fibre originating from different types of diets influence microbial metabolism and ecology in the gut.
In the UK, central government implemented public sector funding cuts following the global economic crash in 2008. These cuts were applied from 2010 and local authorities are at the forefront of central government's austerity measures. This chapter describes Gateshead Council's approach to place-based working during austerity and an initiative it developed. Austerity measures meant that existing levels of service provision were impossible to maintain, and within the council, there was increasing awareness that many residents were also feeling the effects of austerity and were in precarious financial and socio-economic circumstances. Gateshead's response endeavours to coordinate stretched resources, working in collaboration with colleagues from other organisations to influence partnership working in order to achieve better outcomes for residents.
The approach, ‘Thriving for All – Tackling Poverty in Gateshead’ (originating from Gateshead Council's ‘Making Gateshead a place where everyone thrives’ (Gateshead Council, no date) strategy and referred to as Thrive in this chapter), was launched at a conference in February 2018 and brought people together from diverse organisations to tackle key social justice issues around poverty and inequality. The chapter begins by outlining local authority austerity and its effects, and considering the development of partnership and place-based working and the role of the local authority. The development of the Thrive approach is described, reflecting how it might contribute to social renewal and social justice, and the challenges of implementing the approach.
Local authority austerity
To reduce the public deficit caused by the global financial crash in 2008 and the additional debt that was incurred through the British government's rescue of UK banks, austerity measures were introduced that resulted in public sector spending cuts (Blyth, 2013). Between the financial years of 2010/11 to 2017/18, the amount of central government funding to local authorities almost halved (a 49.1 per cent reduction) (Comptroller and Auditor General, 2018: 7). Local government's response to the cuts has increasingly been to limit, begin charging for or reconfigure non-statutory services (Hastings et al, 2015a, 2015b), as well as cutting levels of staff (Lowndes and McCaughie, 2013). In Gateshead, from 2010 to the 2019/20 financial year, the core grant from central government fell by 52 per cent (higher than the national average), meaning a loss of £400 per person and £900 per property (Ramsey, 2018: 11).
Alfred Hitchcock’s films are renowned the world over, and a mountain of literature has detailed seemingly every facet of them. Yet remarkably few studies have solely focused on the recurring motifs in Hitchcock’s films. Michael Walker remedies this surprising gap in Hitchcock literature with an innovative and in-depth study of the sustained motifs and themes threaded through Hitchcock’s entire body of work. Combing through all fifty-two extant feature films and representative episodes from Hitchcock’s television series, Walker traces over forty motifs that emerge in recurring objects, settings, character-types, and events. Whether the loaded meaning of staircases, the symbolic status of keys and handbags, homoeroticism, guilt and confession, or the role of art, Walker analyzes such elements to reveal a complex web of cross-references in Hitchcock’s art. He also gives full attention to the broader social contexts in which the motifs and themes are played out, arguing that these interwoven elements add new and richer depths to Hitchcock’s oeuvre. An invaluable, encyclopedic resource for the scholar and fan, Hitchcock’s Motifs is a fascinating study of one of the best-known and most admired film directors in history.