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Background: Neurointerventional radiology (NIR) is a growing field, offering minimally invasive treatments for cerebrovascular conditions like ischemic stroke. However, no comprehensive analysis of the current NIR landscape in Canada exists. This study aims to evaluate the NIR landscape through analysis of hospital-based services and training programs. Methods: Publicly available hospital data, fellowship programs, and national workforce statistics were analyzed to assess the expansion of NIR centers, practitioners, and services in Canada. The analysis focused on temporal trends in geographic distributions, specialists, and training programs. Results: From 2022 to 2024, the number of NIR centers increased by 20% (from 25 to 30), with new sites established in British Columbia, Quebec, and Newfoundland. Seven accredited RCPSC NIR training programs were identified, with 2 new programs expected to begin training fellows by 2030. Annual trainee enrollment also increased by about 10% per year, with over 50% being from radiology backgrounds. Endovascular thrombectomy, the most common NIR procedure, has seen an annual volume increase of approximately 13% since 2019. Conclusions: NIR is experiencing substantial growth in Canada across centers and training sites, aligning with public health goals. However, continued investment in infrastructure and workforce development is required to ensure equitable access to life-saving neurointerventional therapies nationally.
Objectives/Goals: Transmission-blocking vaccines hold promise for malaria elimination by reducing community transmission. But a major challenge that limits the development of efficacious vaccines is the vast parasite’s genetic diversity. This work aims to assess the genetic diversity of the Pfs25 vaccine candidate in complex infections across African countries. Methods/Study Population: We employed next-generation amplicon deep sequencing to identify nonsynonymous single nucleotide polymorphisms (SNPs) in 194 Plasmodium falciparum samples from four endemic African countries: Senegal, Tanzania, Ghana, and Burkina Faso. The individuals aged between 1 and 74 years, but most of them ranged from 1 to 19 years, and all presented symptomatic P. falciparum infection. The genome amplicon sequencing was analyzed using Geneious software and P. falciparum 3D7 as a reference. The SPNs were called with a minimum coverage of 500bp, and for this work, we used a very sensitive threshold of 1% variant frequency to determine the frequency of SNPs. The identified SNPs were threaded to the crystal structure of the Pfs25 protein, which allowed us to predict the impact of the novel SNP in the protein or antibody binding. Results/Anticipated Results: We identified 26 SNPs including 24 novel variants, and assessed their population prevalence and variant frequency in complex infections. Notably, five variants were detected in multiple samples (L63V, V143I, S39G, L63P, and E59G), while the remaining 21 were rare variants found in individual samples. Analysis of country-specific prevalence showed varying proportions of mutant alleles, with Ghana exhibiting the highest prevalence (44.6%), followed by Tanzania (12%), Senegal (11.8%), and Burkina Faso (2.7%). Moreover, we categorized SNPs based on their frequency, identifying dominant variants (>25%), and rare variants (Discussion/Significance of Impact: We identified additional SNPs in the Pfs25 gene beyond those previously reported. However, the majority of these newly discovered display low variant frequency and population prevalence. Further research exploring the functional implications of these variations will be important to elucidate their role in malaria transmission.
Objectives/Goals: People with insulin-treated diabetes face hypoglycemia risk due to imperfect insulin replacement and impaired counterregulation. We identified the dopamine antagonist, metoclopramide, as a potential treatment. Hypothesis: Treatment with metoclopramide will prevent the development of impaired counterregulatory response to hypoglycemia. Methods/Study Population: In a pre-clinical model, diabetes was induced in 10-week-old Sprague-Dawley rats with streptozotocin (STZ, 65 mg/kg IP). Rats were divided into three groups: 1) diabetic controls (STZ+RS, n = 6), 2) recurrent hypoglycemia (STZ+RH, n = 7), and 3) recurrent hypoglycemia + metoclopramide (STZ+RH+MET, 3 mg/kg IP, n = 7). After 3 days, all rats underwent a hyperinsulinemic (50 mU/kg/min) and hypoglycemic (~45 mg/dl) clamp. In the clinical trial, adults with Type 1 diabetes (age 20–60, ≥5 years duration) were enrolled in a phase II, double-blinded, placebo-controlled trial. Awareness status was assessed via Gold score, and subjects maintained drug regimens and underwent two hyperinsulinemic-hypoglycemic clamps (where blood glucose was lowered to 100, 65, 55, and 45 mg/dl) to assess counterregulation. Results/Anticipated Results: In the pre-clinical model, glucose infusion rates (GIR) to maintain hypoglycemia were higher in STZ+RH (27±0.9 mg/kg/min) than STZ+RS (19±0.8 mg/kg/min, p Discussion/Significance of Impact: Metoclopramide improves glucoregulatory, sympathoadrenal, and counterregulatory responses to hypoglycemia in pre-clinical models, suggesting dopaminergic regulation. While clinical data are still blinded, increased epinephrine and growth hormone responses suggest treatment may preserve or restore counterregulation.
This study investigates the seasonal and regional distribution of paediatric laryngomalacia admissions in the United States, hypothesizing higher admission rates in winter and colder regions due to reduced sunlight exposure affecting vitamin D levels.
Methods
We analyzed data from the 2016 Kids’ Inpatient Database (KID), focusing on children under three years old. Laryngomalacia cases were identified using International Classification of Diseases and Related Health Problems 10th Revision (ICD-10) code Q31.5. Seasonal and regional differences in admission rates were assessed using Pearson’s chi-squared test, with a significance level of p less than 0.05.
Results
Of 4,512,196 estimated national admissions, 11,638 were due to laryngomalacia. Admissions increased by 10.0 per cent in winter and decreased by 10.9 per cent in summer (p < 0.005). Regionally, admissions were higher in the Midwest/Central (18.6 per cent) and Northeast (9.3 per cent) and lower in the South (7.4 per cent) and West (11.1 per cent) (p < 0.005).
Conclusion
Laryngomalacia admissions are significantly influenced by seasonal and regional factors, likely related to environmental conditions affecting vitamin D synthesis.
Glacier and snow melt are the primary sources of water for streams, and rivers in upper Indus region of the western Himalaya. However, the magnitude of runoff from this glacierized basin is expected to vary with the available energy in the catchment. Here, we used a physically based energy balance model to estimate the surface energy and surface mass balance (SMB) of the upper Chandra Basin glaciers for 7 hydrological years from 2015 to 2022. A strong seasonality is observed, with net radiation being the dominant energy flux in the summer, while latent and sensible heat flux dominated in the winter. The estimated mean annual SMB of the upper Chandra Basin glaciers is −0.51 ± 0.28 m w.e. a−1, with a cumulative SMB of −3.54 m w.e during 7 years from 2015 to 2022. We find that the geographical factors like aspect, slope, size and elevation of the glacier contribute towards the spatial variability of SMB within the study region. The findings reveal that a 42% increase in precipitation is necessary to counteract the additional mass loss resulting from a 1°C increase in air temperature for the upper Chandra Basin glaciers.
In response to the COVID-19 pandemic, we rapidly implemented a plasma coordination center, within two months, to support transfusion for two outpatient randomized controlled trials. The center design was based on an investigational drug services model and a Food and Drug Administration-compliant database to manage blood product inventory and trial safety.
Methods:
A core investigational team adapted a cloud-based platform to randomize patient assignments and track inventory distribution of control plasma and high-titer COVID-19 convalescent plasma of different blood groups from 29 donor collection centers directly to blood banks serving 26 transfusion sites.
Results:
We performed 1,351 transfusions in 16 months. The transparency of the digital inventory at each site was critical to facilitate qualification, randomization, and overnight shipments of blood group-compatible plasma for transfusions into trial participants. While inventory challenges were heightened with COVID-19 convalescent plasma, the cloud-based system, and the flexible approach of the plasma coordination center staff across the blood bank network enabled decentralized procurement and distribution of investigational products to maintain inventory thresholds and overcome local supply chain restraints at the sites.
Conclusion:
The rapid creation of a plasma coordination center for outpatient transfusions is infrequent in the academic setting. Distributing more than 3,100 plasma units to blood banks charged with managing investigational inventory across the U.S. in a decentralized manner posed operational and regulatory challenges while providing opportunities for the plasma coordination center to contribute to research of global importance. This program can serve as a template in subsequent public health emergencies.
Behaviour Change Communication (BCC) intervention programmes often lack documentation of successful processes. This manuscript aims to describe the development of Program Impact Pathway (PIP) using Theory of Change (ToC) approach for a mHealth BCC intervention titled ‘Mobile Solutions Aiding Knowledge for Health Improvement (M-SAKHI)’ aimed at reducing stunting in infants at 18 months of age.
Design:
The PIP was developed using ToC to design the intervention and plan its implementation. Literature review and data from previous pilots helped to identify health service gaps that needed to be addressed by the PIP of this intervention.
Setting:
M-SAKHI was implemented in 244 villages under governance of forty primary health centres of Nagpur and Bhandara districts of eastern Maharashtra in central India.
Participants:
The study investigators and the public health stakeholders participated in developing the PIP. M-SAKHI evaluation study recruited 2501 pregnant women who were followed up through delivery until their infants were 18 months old.
Results:
The PIP was developed, and it identified the following pathways for the final impact: (1) improving maternal and infant nutrition, (2) early recognition of maternal and infant danger signs, (3) improving access and utilisation to healthcare services, (4) improving hygiene, sanitation and immunisation practices, and (5) improving implementation and service delivery of community health workers through their training, monitoring and supervision in real time.
Conclusion:
This paper will illustrate the significance of development of PIP for M-SAKHI. It can aid other community-based programmes to design their PIP for nutrition-based BCC interventions.
Chronic pain patients often contend with insomnia symptoms, creating a reciprocal relationship that adds complexity to their condition. Evaluating interventions targeting insomnia in this population becomes paramount, given the intertwined nature of pain and sleep disturbances.
Objectives
This retrospective pretest design aimed to assess the efficacy of an Internet-delivered sound healing intervention in reducing insomnia severity and addressing sleep- and pain-related parameters among individuals with chronic pain.
Methods
Conducted as a community-based project, Tuning for Health provided support to individuals grappling with long-term illnesses. The intervention involved the virtual delivery of a specially crafted sound track using tuning forks over a 6-week period, supervised by an experienced therapist and administered weekly for an hour. Participants were instructed to play the track daily at a time convenient for them. A total of 68 participants (mean age 59.3 years) completed the intervention. Outcome measures, including the Insomnia Severity Index (ISI), a sleep diary, and assessments for anxiety, depression, and pain-related parameters, were collected at the end of the 6-week intervention and repeated after a 6-month follow-up. Negative effects were monitored and reported.
Results
Significant immediate interaction effects (time by treatment) were observed for the pain severity, ISI and various sleep parameters, such as sleep efficiency, sleep onset latency, early morning awakenings, and wake time after sleep onset. A time effect for anxiety and depression was noted at the 6-month follow-up. The group exhibited highly significant improvements in pain-related parameters. At the 6-month follow-up, sustained enhancements in sleep parameters and mental health were reported, with no reported side effects.
Conclusions
These unique results suggest the potential efficacy of sound healing in alleviating chronic pain and associated insomnia. Further research with a larger sample size is warranted to validate these findings. Combining sound healing with other treatments may offer enhanced outcomes for individuals dealing with both chronic pain and comorbid insomnia. This study lays the groundwork for future investigations into the promising intersection of sound healing, chronic pain management, and sleep improvement.
Background: Shared decision-making (SDM) is a dynamic, patient-engaged approach to collaborative medical care. Limited SDM tools exist in pregnancy. We aimed to examine the need and usability of a novel SDM tool for pharmaco-therapeutic treatment of neurological conditions in pregnancy. Methods: This is an exploratory mixed-methods study. Non-pregnant women of any age were recruited using convenience, purposive sampling from an academic neurology clinic in Toronto. Participants reported the user friendliness of the SDM by completing the systems usability (SUS) questionnaire and participated in a focus group to further elaborate on their experience. Results: Eleven participants completed the survey 45% each between age 31-40, and 51-60. Median time spent on the tool was 17.2 minutes, and median SUS score 70 (<68 being not usable). Thematic data analysis from 2 focus groups, identified technical and content improvements: use of inclusive language, simplified design, and importance of patient engagement in SDM. Conclusions: Based on our preliminary results, a SDM web-tool for medication-related concerns of pregnant patients with neurological conditions is needed and usable. With integration of patients’ lived experiences, this novel tool may serve as an anchor point for future work in this field.
PTEN hamartoma tumour syndrome (PHTS) comprises a group of genetic disorders with varied clinical presentations, including macrocephaly, developmental delay, and increased cancer susceptibility. Recent reports have highlighted the occurrence of tonsil-related issues in PHTS.
Methods
Clinical data focusing on tonsil-related pathology and tonsillectomy details (indications, histology and post-operative complications) were collected from 53 patients with PHTS.
Results
Tonsil issues affected 58 per cent of the cohort, with 43 per cent requiring tonsillectomy. Primary indications for tonsillectomy included obstructive sleep apnoea (43 per cent), recurrent tonsillitis (17 per cent) and other causes (17 per cent). Tonsil-related problems were observed both before (45 per cent) and after (55 per cent) PHTS. Tonsillectomy with adenoidectomy was the predominant surgical intervention performed (87 per cent), spanning a broad age range (1–27 years old).
Discussion
Our findings highlight the complex nature of PHTS and its association with tonsil-related pathology, demonstrating its relevance for ENT surgeons. Early recognition and intervention are pivotal for managing sleep apnoea and the associated health problems.
To compare how clinical researchers generate data-driven hypotheses with a visual interactive analytic tool (VIADS, a visual interactive analysis tool for filtering and summarizing large datasets coded with hierarchical terminologies) or other tools.
Methods:
We recruited clinical researchers and separated them into “experienced” and “inexperienced” groups. Participants were randomly assigned to a VIADS or control group within the groups. Each participant conducted a remote 2-hour study session for hypothesis generation with the same study facilitator on the same datasets by following a think-aloud protocol. Screen activities and audio were recorded, transcribed, coded, and analyzed. Hypotheses were evaluated by seven experts on their validity, significance, and feasibility. We conducted multilevel random effect modeling for statistical tests.
Results:
Eighteen participants generated 227 hypotheses, of which 147 (65%) were valid. The VIADS and control groups generated a similar number of hypotheses. The VIADS group took a significantly shorter time to generate one hypothesis (e.g., among inexperienced clinical researchers, 258 s versus 379 s, p = 0.046, power = 0.437, ICC = 0.15). The VIADS group received significantly lower ratings than the control group on feasibility and the combination rating of validity, significance, and feasibility.
Conclusion:
The role of VIADS in hypothesis generation seems inconclusive. The VIADS group took a significantly shorter time to generate each hypothesis. However, the combined validity, significance, and feasibility ratings of their hypotheses were significantly lower. Further characterization of hypotheses, including specifics on how they might be improved, could guide future tool development.
Depression is common in persons with MS (PwMS), substantially contributing to morbidity and mortality. Depression can dually impact PwMS as both a psychosocial reaction to living with the disease and a neurological effect of it. Cardinal features of depression include reduced ability to seek and experience pleasure, often attributed to dysregulation of the brain's reward system. People with depression exhibit atypical reward processing, as do fatigued PwMS. However, it is unclear whether MS itself affects reward processing, and whether it interacts with depression. The current study explored the associations of depression, MS, and their interaction on reward responsiveness. We hypothesized that depression and MS would independently be associated with poorer reward responsiveness and that they would interact synergistically to impair reward responsiveness.
Participants and Methods:
Forty PwMS and 40 healthy age- and education-matched healthy controls (HC) participated in a computerized switching task with high- and low-reward manipulations. The Chicago Multiscale Depression Inventory (CMDI) Mood subscale measured depressive symptoms. The Behavioral Inhibition/Activation Scales (BIS/BAS) measured self-reported reward responsiveness and behavioral inhibition. Switching task performance was measured as response time (RT) and accuracy. Performance differences between the high- and low-reward conditions represented performance-based reward responsiveness. Linear mixed effects models were used to estimate the associations of MS and depression with reward responsiveness, behavioral inhibition, and task performance.
Results:
Depression, but not MS, was associated with higher BIS scores (p=.007). Neither depression nor MS was associated with BAS subscales. On the switching task, participants who reported lower depression responded to reward such that they were slightly faster in the high-reward condition compared to the low-reward condition (p=.07). By contrast, in participants who reported higher depression, there was no effect of reward on response time. Additionally, MS (p=.009) and depression (p=.018) were each associated with slower response times. Regarding accuracy, no effects of reward were observed; however, there was an interaction between MS and depression. Among HC participants, depression was not related to accuracy. In comparison, PwMS who reported higher depression were more accurate than PwMS who reported less depression (p=.043).
Conclusions:
Consistent with hypotheses, higher depressive symptoms were associated with increased behavioral inhibition. Depression was not associated with self-reported reward responsiveness, but it was associated with reduced reward responsiveness on a cognitive task. Contrary to hypotheses, MS was not associated with reduced reward responsiveness. Additionally, higher depression and an MS diagnosis were related to slower response time, consistent with prior findings that psychomotor slowing is a hallmark feature of both disorders. Interestingly, we observed a unique behavioral trend in PwMS, such that PwMS with higher depressive symptoms were more accurate than PwMS with lower depressive symptoms, whereas this relationship was not present among HCs. Altogether, depression in both PwMS and cognitively healthy individuals may be associated with blunted reward responsiveness, but MS does not exacerbate this relationship. In fact, PwMS with depression may be more conscientious in their functioning and therefore perform better on cognitive task accuracy. Continued work should examine how reward processing and its underlying mechanisms may differ in depressed PwMS.
Investigate and mitigate a cluster of Candida auris cases among incarcerated patients in a maximum-security prison hospital utilizing contact tracing, screening, whole genome sequencing, and environmental sampling and decontamination.
Design:
Outbreak investigation.
Setting:
Inpatient prison hospital affiliated with an academic tertiary referral center.
Patients:
Inmates of the Texas Department of Criminal Justice.
Methods:
Epidemiologic and environmental investigations were conducted including contact tracing, point prevalence surveys, and environmental sampling. Whole genome sequencing was performed on positive patient isolates.
Results:
Following a clinical case of C. auris fungemia, 344 patients underwent C. auris surveillance screening. Eight (2.3%) patients were identified with C. auris colonization. All patients were male. Our index patient was the only clinical case and death. Whole genome sequencing was performed on the nine patient isolates. All isolates were clade III (Africa) and clustered together with the largest SNP difference being 21. Environmental cultures from 7 of 61 rooms (11.5%) were positive following terminal disinfection with bleach. Sites nearest to the patient were most often positive including the hospital bed rails and bedside table. The transmission cluster was successfully mitigated within 60 days of identification.
Conclusions:
Implementation of an aggressive surveillance and decontamination program resulted in mitigation of a C. auris transmission cluster among our incarcerated patients. This investigation provides valuable insight into C. auris transmission in the incarcerated population, which is not considered a classic high-risk population as well as the challenges faced to stop transmission in a facility that requires the use of shared patient environments.
We investigate the effects of fluid elasticity on the flow forces and the wake structure when a rigid cylinder is placed in a viscoelastic flow and is forced to oscillate sinusoidally in the transverse direction. We consider a two-dimensional, uniform, incompressible flow of viscoelastic fluid at $Re=100$, and use the FENE-P model to represent the viscoelastic fluid. We study how the flow forces and the wake patterns change as the amplitude of oscillations, $A^*$, the frequency of oscillations (inversely proportional to a reduced velocity, $U^*$), the Weissenberg number, $Wi$, the square of maximum polymer extensibility, $L^2$, and the viscosity ratio, $\beta$, change individually. We calculate the lift coefficient in phase with cylinder velocity to determine the range of different system parameters where self-excited oscillations might occur if the cylinder is allowed to oscillate freely. We also study the effect of fluid elasticity on the added mass coefficient as these parameters change. The maximum elastic stress of the fluid occurs in between the vortices that are observed in the wake. We observe a new mode of shedding in the wake of the cylinder: in addition to the primary vortices that are also observed in the Newtonian flows, secondary vortices that are caused entirely by the viscoelasticity of the fluid are observed in between the primary vortices. We also show that, for a constant $Wi$, the strength of the polymeric stresses increases with increasing reduced velocity or with decreasing amplitude of oscillations.
Since the initial publication of A Compendium of Strategies to Prevent Healthcare-Associated Infections in Acute Care Hospitals in 2008, the prevention of healthcare-associated infections (HAIs) has continued to be a national priority. Progress in healthcare epidemiology, infection prevention, antimicrobial stewardship, and implementation science research has led to improvements in our understanding of effective strategies for HAI prevention. Despite these advances, HAIs continue to affect ∼1 of every 31 hospitalized patients,1 leading to substantial morbidity, mortality, and excess healthcare expenditures,1 and persistent gaps remain between what is recommended and what is practiced.
The widespread impact of the coronavirus disease 2019 (COVID-19) pandemic on HAI outcomes2 in acute-care hospitals has further highlighted the essential role of infection prevention programs and the critical importance of prioritizing efforts that can be sustained even in the face of resource requirements from COVID-19 and future infectious diseases crises.3
The Compendium: 2022 Updates document provides acute-care hospitals with up-to-date, practical expert guidance to assist in prioritizing and implementing HAI prevention efforts. It is the product of a highly collaborative effort led by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Disease Society of America (IDSA), the Association for Professionals in Infection Control and Epidemiology (APIC), the American Hospital Association (AHA), and The Joint Commission, with major contributions from representatives of organizations and societies with content expertise, including the Centers for Disease Control and Prevention (CDC), the Pediatric Infectious Disease Society (PIDS), the Society for Critical Care Medicine (SCCM), the Society for Hospital Medicine (SHM), the Surgical Infection Society (SIS), and others.
We sought to evaluate the impact of antibiotic selection and duration of therapy on treatment failure in older adults with catheter-associated urinary tract infection (CA-UTI).
Methods:
We conducted a population-based cohort study comparing antibiotic treatment options and duration of therapy for non-hospitalized adults aged 66 and older with presumed CA-UTI (defined as an antibiotic prescription and an organism identified in urine culture in a patient with urinary catheterization documented within the prior 90 d). The primary outcome was treatment failure, a composite of repeat urinary antibiotic prescribing, positive blood culture with the same organism, all-cause hospitalization or mortality, within 60 days. We determined the risk of treatment failure accounting for age, sex, comorbidities, and healthcare exposure using log-binomial regression.
Results:
Of 4,436 CA-UTI patients, 2,709 (61.1%) experienced treatment failure. Compared to a reference of TMP-SMX (61.9% failure), of those treated with fluoroquinolones, 56.3% experienced failure (RR 0.91, 95% CI: 0.85–0.98) and 60.9% of patients treated with nitrofurantoin experienced failure (RR 1.02, 95% CI: 0.94–1.10). Compared to 5–7 days of therapy (treatment failure: 59.4%), 1–4 days was associated with 69.5% failure (RR 1.15, 95% CI: 1.05–1.27), and 8–14 days was associated with a 62.0% failure (RR 1.05, 95% CI: 0.99–1.11).
Conclusions:
Although most treatment options for CA-UTI have a similar risk of treatment failure, fluoroquinolones, and treatment durations ≥ 5 days in duration appear to be associated with modestly improved clinical outcomes. From a duration of therapy perspective, this study provides reassurance that relatively short courses of 5–7 days may be reasonable for CA-UTI.
Preventing psychiatric admissions holds benefits for patients as well as healthcare systems. The Clinical Global Impression-Severity (CGI-S) scale is a 7-point measurement of symptom severity, independent of diagnosis, which has shown capability of predicting risk of hospitalisation in schizophrenia. Due to its routine use in clinical practice and ease of administration, it may have potential as a transdiagnostic predictor of hospitalisation.
Objectives
To investigate whether early trajectories of CGI-S scores predict risk of hospitalisation over a 6 month-follow-up period.
Methods
A retrospective cohort study was conducted, analysing Electronic Health Record (EHR) data from the NeuroBlu Database (Patel et al. BMJ Open 2022;12:e057227). Patients were included if they had a psychiatric diagnosis and at least 5 recorded CGI-S scores within a 2-month period, defined as the ‘index’ period. The relationship between early CGI-S trajectories and risk of hospitalisation was investigated using Cox regression. The analysis was adjusted for age, gender, race, number of years in education, and psychiatric diagnosis. Early CGI-S trajectories were estimated as clinical severity (defined as the mean CGI-S score during the index period) and clinical instability (defined as a generalised Root Mean Squared Subsequent Differences of all CGI-S scores recorded during the index period). The primary outcome was time to psychiatric hospitalisation up to 6 months following the index period. Patients who had been hospitalised before or within the index period were excluded.
Results
A total of 36,914 patients were included (mean [SD] age: 29.7 [17.5] years; 57.3% female). Clinical instability (hazard ratio: 1.09, 95% CI 1.07-1.10, p<0.001) and severity (hazard ratio: 1.11, 95% CI 1.09-1.12, p<0.001) independently predicted risk of hospitalisation. These associations were consistent across all psychiatric diagnoses. Patients in the top 50% of severity and/or instability were at a 45% increased risk of hospitalisation compared to those in the bottom 50% (Figure 1).
Image:
Conclusions
Early CGI-S trajectories reflecting clinical severity and instability independently predict risk of hospitalisation across diagnoses. This risk was compounded when instability and severity were present together. These results have translation potential in predicting individuals who are at high risk of hospitalisation and could benefit from preventative strategies to mitigate this risk.
Disclosure of Interest
E. Palmer Employee of: Holmusk, M. Taquet Consultant of: Holmusk, K. Griffiths Employee of: Holmusk, S. Ker Employee of: Holmusk, C. Liman Employee of: Holmusk, S. N. Wee Employee of: Holmusk, S. Kollins Employee of: Holmusk, R. Patel Grant / Research support from: National Institute of Health Research (NIHR301690); Medical Research Council (MR/S003118/1); Academy of Medical Sciences (SGL015/1020); Janssen, Employee of: Holmusk
Bribery for access to public goods and services remains a widespread and seemingly innocuous practice which disproportionately targets the poor and helps keep them poor. Furthermore, its aggregate effects erode the legitimacy of government institutions and their capacity to fairly administer public goods and services as well as protection under the law. Drawing on original evidence using social norms methodology, this research tests underlying beliefs and expectations which sustain persistent forms of bribery and draws attention to the presence of pluralistic ignorance and consequent collective action problems. With examples focused on bribery in traffic law enforcement, healthcare, and education—three critical areas where bribery is often identified as an entrenched practice—this article contributes new evidence of: (a) the presence of pluralistic ignorance, a common social comparison error, surrounding bribery behavior; (b) differing social evaluations of bribe-solicitation; and finally, (c) how this context might exacerbate collective action problems. This empirical case study of Nigeria shows that even though more people are likely to be directly affected by bribery during routine interactions with public officials and institutions and many believe this practice is wrong, most people incorrectly believe that others in their community tolerate or even accept bribery behavior.
OBJECTIVES/GOALS: Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). In this study, we perform an epigenetic-focused functional genomics screen in GBM organoids and identify WDR5 as an essential epigenetic regulator in the SOX2-enriched, therapy resistant cancer stem cell niche. METHODS/STUDY POPULATION: Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche. Our niche-specific screens identified WDR5, an H3K4 histone methyltransferase responsible for activating specific gene expression, as indispensable for GBM CSC growth and survival. RESULTS/ANTICIPATED RESULTS: In GBM CSC models, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, required for stem cell maintenance and including the POU5F1(OCT4)::SOX2 motif. We incorporated a SOX2/OCT4 motif driven GFP reporter system into our CSC cell models and found that WDR5 inhibitor treatment resulted in dose-dependent silencing of stem cell reporter activity. Further, WDR5 inhibitor treatment altered the stem cell state, disrupting CSC in vitro growth and self-renewal as well as in vivo tumor growth. DISCUSSION/SIGNIFICANCE: Our results unveiled the role of WDR5 in maintaining the CSC state in GBM and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers. This conceptual and experimental framework can be applied to many cancers, and can unmask unique microenvironmental biology and rationally designed combination therapies.