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The antipsychotic aripiprazole is often used in the treatment of first-episode psychosis. Measuring aripiprazole blood levels provides an objective measure of treatment adherence, but this currently involves taking a venous blood sample and sending to a laboratory for analysis.
To detail the development, validation and utility of a new point of care (POC) test for finger-stick capillary blood concentrations of aripiprazole.
Analytical performance (sensitivity, precision, recovery and linearity) of the assay were established using spiked whole blood and control samples of varying aripiprazole concentration. Assay validation was performed over a 14-month period starting in July 2021. Eligible patients were asked to provide a finger-stick capillary sample in addition to their usual venous blood sample. Capillary blood samples were tested by the MyCare™ Insite POC analyser, which provided measurement of aripiprazole concentration in 6 min, and the venous blood sample was tested by the standard laboratory method.
A total of 101 patients agreed to measurements by the two methods. Venous blood aripiprazole concentrations as assessed by the laboratory method ranged from 17 to 909 ng/mL, and from 1 to 791 ng/mL using POC testing. The correlation coefficient between the two methods (r) was 0.96 and there was minimal bias (slope 0.91, intercept 4 ng/ml).
The MyCare Insite POC analyser is sufficiently accurate and reliable for clinical use. The availability of this technology will improve the assessment of adherence to aripiprazole and the optimising of aripiprazole dosing.
Ultrasound is the standard imaging technique for diagnosing lower limb deep venous thrombosis (DVT). The National Institute for Health and Care Excellence (NICE) guidance 158 recommendation 1.1.3 states that all patients with sufficient pretest probability for DVT should be offered a proximal leg vein ultrasound within four hours. However, due to high patient volumes, formal radiology department ultrasound wait times often exceed one week. Point-of-care ultrasound (POCUS) is used to bridge diagnostic delay in our emergency department (ED) .
This study aimed to quantify numbers offered POCUS for suspected proximal lower DVT in our ED and accuracy of such studies.
A retrospective review of electronic records was conducted for patients who underwent formal lower-limb ultrasound for suspected DVT at our hospital over a three-month period (August 1, 2022-October 12, 2022). Patient charts for all ED presentations were assessed to determine whether POCUS was offered and whether DVT was diagnosed.
Statistical analysis was conducted using PRISM v9.
80 formal ultrasound scans were performed at our hospital for lower limb DVT. 58 were requested for patients presenting to ED, of which 42 had complete records available meeting selection criteria.
POCUS was offered to 24 patients in ED (57.1%). Sensitivity was 66% (95% CI 12%- 98%), and specificity was 94.1% (95% CI 75%-99%). Overall accuracy was 90%, with only one false negative study identified at formal follow-up ultrasound.
Although sample size was small, our results suggest that POCUS is an accurate but underused tool to diagnose lower limb DVT. Developing a standardized protocol for performing and reporting POCUS DVT scans in ED should allow for earlier diagnosis and initiation of appropriate treatment where necessary.
In this research note, we document the extent to which negative beliefs about women's capacity to hold public office are widespread in Canada. Using a list experiment, our results demonstrate that many Canadians believe that men are “naturally better” leaders than are women and that women are “too emotional” and “too nice” for politics. While some groups are willing to explicitly own these views when asked directly about them (for example, older people, men, those who are more conservative and religious), others are unwilling to do so unless social desirability is mitigated (for example, younger people, left-leaning). By overcoming concerns with social desirability, we show that women still face explicit, often sexist, barriers in political work.
Impactful, transdisciplinary scientific discoveries are created by teams of researchers spanning multiple disciplines, but collaboration across disciplines can be challenging. We examined how team dynamics and collaboration are related to successes and barriers faced by teams of researchers from multiple disciplines.
A mixed-methods approach was used to examine 12 research teams granted multidisciplinary pilot awards. Team members were surveyed to assess their team dynamics and individual views about transdisciplinary research. Forty-seven researchers (59.5%) responded, including two to eight members from each funded team. Associations were examined between collaborative dynamics and scholarly product outcomes, including manuscripts, grant proposals, and awarded grants. One member from each team was selected for an in-depth interview to contextualize and extend information about collaborative processes, successes, and barriers to performing transdisciplinary research.
Quality of team interactions was positively associated with achievement of scholarly products (r = 0.64, p = 0.02). Satisfaction with team members (r = 0.38) and team collaboration scores (r = 0.43) also demonstrated positive associations with achievement of scholarly products, but these were not statistically significant. Qualitative results support these findings and add further insight into aspects of the collaborative process that were particularly important to foster success on multidisciplinary teams. Beyond scholarly metrics, additional successes from the multidisciplinary teams were identified through the qualitative portion of the study including career development and acceleration for early career researchers.
Both the quantitative and qualitative study results indicate that effective collaboration is critical to multidisciplinary research team success. Development and/or promotion of team science-based trainings for researchers would promote these collaborative skills.
Optimizing the effectiveness of a team-based approach to unite multiple disciplines in advancing specific translational areas of research is foundational to improving clinical practice. The current study was undertaken to examine investigators’ experiences of participation in transdisciplinary team science initiatives, with a focus on challenges and recommendations for improving effectiveness.
Qualitative interviews were conducted with investigators from twelve multidisciplinary teams awarded pilot research funding by the University of Kentucky College of Medicine to better understand the barriers and facilitators to effective team science within an academic medical center. An experienced qualitative researcher facilitated one-on-one interviews, which lasted about one hour. Structured consensus coding and thematic analysis were conducted.
The sample was balanced by gender, career stage (five were assistant professor at the time of the award, seven were senior faculty), and training (six were PhDs; six were MD physicians). Key themes at the team-level centered on the tension between clinical commitments and research pursuits and the limitations for effective team functioning. Access to tangible support from home departments and key university centers was identified as a critical organizational facilitator of successful project completion. Organizational barriers centered on operationalizing protected time for physicians, gaps in effective mentoring, and limitations in operational support.
Prioritizing tailored mentoring and career development support for early career faculty, and particularly physician faculty, emerged as a key recommendation for improving team science in academic medical centers. The findings contribute to establishing best practices and policies for team science in academic medical centers.
Nutrients can impact and regulate cellular metabolism and cell function which is particularly important for the activation and function of diverse immune subsets. Among the critical nutrients for immune cell function and fate, glutamine is possibly the most widely recognised immunonutrient, playing key roles in TCA cycle, heat shock protein responses and antioxidant systems. In addition, glutamine is also involved with inter-organ ammonia transport, and this is particularly important for not only immune cells, but also to the brain, especially in catabolic situations such as critical care and extenuating exercise. The well characterised fall in blood glutamine availability has been the main reason for studies to investigate the possible effects of glutamine replacement via supplementation but many of the results are in poor agreement. At the same time, a range of complex pathways involved in glutamine metabolism have been revealed via supplementation studies. This article will briefly review the function of glutamine in the immune system, with emphasis on metabolic mechanisms, and the emerging role of glutamine in the brain glutamate/gamma-amino butyric acid cycle. In addition, relevant aspects of glutamine supplementation are discussed.
Animal mass mortality events (MMEs) will increase with weather and climate extremes. MMEs can add significant stress to ecosystems through extraordinary nutrient pulses or contribute to potential disease transmission risks. Given their efficient removal of carrion biomass from landscapes, we argue here for the potential of scavenger guilds to be a key nature-based solution to mitigating MME effects. However, we caution that scavenger guilds alone will not be a silver bullet. It is critical for further research to identify how the composition of scavenger guilds and the magnitude of MMEs will determine when scavengers will buffer the impacts of such events on ecosystems and when intervention might be required. Some MMEs are too large for scavengers to remove efficiently, and there is a risk of MMEs subsidizing pest species, altering nutrient cycling or leading to disease spread. Prioritizing native scavenger taxa in conservation management policies may help to boost ecosystem resilience through preserving their key ecological services. This should be part of a multi-pronged approach to MME mitigation that combines scavenger conservation with practices such as carcass dispersal or removal when exceeding a threshold quantity. Policymakers are urged to identify such thresholds and to recognize both the insects and the vertebrate scavengers that could act as allies for mitigating the emerging problem of climate-driven MMEs.
Schizophrenia and bipolar disorder are complex mental illnesses that are associated with cognitive deficits. There is considerable cognitive heterogeneity that exists within both disorders. Studies that cluster schizophrenia and bipolar patients into subgroups based on their cognitive profile increasingly demonstrate that, relative to healthy controls, there is a severely compromised subgroup and a relatively intact subgroup. There is emerging evidence that telomere shortening, a marker of cellular senescence, may be associated with cognitive impairments. The aim of this study was to explore the relationship between cognitive subgroups in bipolar-schizophrenia spectrum disorders and telomere length against a healthy control sample.
Participants included a transdiagnostic group diagnosed with bipolar, schizophrenia or schizoaffective disorder (n = 73) and healthy controls (n = 113). Cognitive clusters within the transdiagnostic patient group, were determined using K-means cluster analysis based on current cognitive functioning (MATRICS Consensus Cognitive Battery scores). Telomere length was determined using quantitative PCRs genomic DNA extracted from whole blood. Emergent clusters were then compared to the healthy control group on telomere length.
Two clusters emerged within the patient group that were deemed to reflect a relatively intact cognitive group and a cognitively impaired subgroup. Telomere length was significantly shorter in the severely impaired cognitive subgroup compared to the healthy control group.
This study replicates previous findings of transdiagnostic cognitive subgroups and associates shorter telomere length with the severely impaired cognitive subgroup. These findings support emerging literature associating cognitive impairments in psychiatric disorders to accelerated cellular aging as indexed by telomere length.
Cognitive Bias Modification for paranoia (CBM-pa) is a novel, theory-driven psychological intervention targeting the biased interpretation of emotional ambiguity associated with paranoia. Study objectives were (i) test the intervention's feasibility, (ii) provide effect size estimates, (iii) assess dose–response and (iv) select primary outcomes for future trials.
In a double-blind randomised controlled trial, sixty-three outpatients with clinically significant paranoia were randomised to either CBM-pa or an active control (text reading) between April 2016 and September 2017. Patients received one 40 min session per week for 6 weeks. Assessments were given at baseline, after each interim session, post-treatment, and at 1- and 3-months post-treatment.
A total of 122 patients were screened and 63 were randomised. The recruitment rate was 51.2%, with few dropouts (four out of 63) and follow-up rates were 90.5% (1-month) and 93.7% (3-months). Each session took 30–40 min to complete. There was no statistical evidence of harmful effects of the intervention. Preliminary data were consistent with efficacy of CBM-pa over text-reading control: patients randomised to the intervention, compared to control patients, reported reduced interpretation bias (d = −0.48 to −0.76), improved symptoms of paranoia (d = −0.19 to −0.38), and lower depressed and anxious mood (d = −0.03 to −0.29). The intervention effect was evident after the third session.
CBM-pa is feasible for patients with paranoia. A fully powered randomised control trial is warranted.
It is the calling-card of experimental music that works (if they may be so termed) pose questions rather than provide answers. What is the experience? What happens if…? What set of possibilities might result from this set of constraints? Performers of experimental music hold such questions in the balance even whilst in any given performance asserting some kind of answer (response) at that moment in time. Doubt, multiplicity, and exploration are tropes of an experimental performance practice, and these are very often worked out in the act of performance itself. Indeterminate music, when certain musical aspects are left ‘open’ to performer interpretation, for example, problematises the nature of the work, allowing for multiple (sometimes even infinite) outcomes; other forms question the boundaries of experience, seeping into and absorbing the environmental sonicities within which it is situated. The focus of this chapter is music which experiments with temporal parameters and the consequent challenges to perception: how the whole is understood, and how the moment is experienced in relation to the whole. In this sense, the chapter offers a practice-based perspective of many of the more general philosophical puzzles already raised by Connor and Smith, Chapter 4, this volume.
Within the experimental tradition, how music works within and outside of time has been a defining feature, whether through disregarding time as a compositional constraint in indeterminate works such as Earle Brown's December 1952 or Christian Wolff's Edges (1968), or, quite the opposite, adopting clock-time as the primary formal feature, as in John Cage's 4’33” (1952) or 26’1.1499” for a string player (1955). Others have extended conventional boundaries of time in music through a focus upon perceptual change over long durations, in projects such as La Monte Young's The Tortoise, His Dreams and Journeys (1964), Pauline Oliveros's ‘Deep Listening’ practice, and Annea Lockwood's environmental installation pieces.
Music which questions and problematises the temporal experience presents issues no less for the performer than the listener. Traditionally, the goal of musical interpretation through performance has been to project an answer, to establish an interpretative model which serves to provide unity and coherence upon a musical work, even if that model may change from one performance to another.
Prisons are susceptible to outbreaks. Control measures focusing on isolation and cohorting negatively affect wellbeing. We present an outbreak of coronavirus disease 2019 (COVID-19) in a large male prison in Wales, UK, October 2020 to April 2021, and discuss control measures.
We gathered case-information, including demographics, staff-residence postcode, resident cell number, work areas/dates, test results, staff interview dates/notes and resident prison-transfer dates. Epidemiological curves were mapped by prison location. Control measures included isolation (exclusion from work or cell-isolation), cohorting (new admissions and work-area groups), asymptomatic testing (case-finding), removal of communal dining and movement restrictions. Facemask use and enhanced hygiene were already in place. Whole-genome sequencing (WGS) and interviews determined the genetic relationship between cases plausibility of transmission.
Of 453 cases, 53% (n = 242) were staff, most aged 25–34 years (11.5% females, 27.15% males) and symptomatic (64%). Crude attack-rate was higher in staff (29%, 95% CI 26–64%) than in residents (12%, 95% CI 9–15%).
Whole-genome sequencing can help differentiate multiple introductions from person-to-person transmission in prisons. It should be introduced alongside asymptomatic testing as soon as possible to control prison outbreaks. Timely epidemiological investigation, including data visualisation, allowed dynamic risk assessment and proportionate control measures, minimising the reduction in resident welfare.
Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
Although a growing number of healthcare facilities are implementing healthcare personnel (HCP) coronavirus disease 2019 (COVID-19) vaccination requirements, vaccine exemption request management as a part of such programs is not well described.
Infectious disease (ID) physician members of the Emerging Infections Network with infection prevention or hospital epidemiology responsibilities.
Eligible persons were sent a web-based survey focused on hospital plans and practices around exemption allowances from HCP COVID-19 vaccine requirements.
Of the 695 ID physicians surveyed, 263 (38%) responded. Overall, 160 respondent institutions (92%) allowed medical exemptions, whereas 132 (76%) allowed religious exemptions. In contrast, only 14% (n = 24) allowed deeply held personal belief exemptions. The types of medical exemptions allowed varied considerably across facilities, with allergic reactions to the vaccine or its components accepted by 145 facilities (84%). For selected scenarios commonly used as the basis for religious and deeply held personal belief exemption requests, 144 institutions (83%) would not approve exemptions focused on concerns regarding right of consent or violations of freedom of personal choice, and 140 institutions (81%) would not approve exemptions focused on introducing foreign substances into one’s body or the sanctity of the body. Most respondents noted plans for additional infection prevention interventions for HCP who received an exemption for COVID-19 vaccination.
Although many respondent institutions allowed exemptions from HCP COVID-19 vaccination requirements, the types of exemptions allowed and how the exemption programs were structured varied widely.
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
In view of the increasing complexity of both cardiovascular implantable electronic devices (CIEDs) and patients in the current era, practice guidelines, by necessity, have become increasingly specific. This document is an expert consensus statement that has been developed to update and further delineate indications and management of CIEDs in pediatric patients, defined as ≤21 years of age, and is intended to focus primarily on the indications for CIEDs in the setting of specific disease categories. The document also highlights variations between previously published adult and pediatric CIED recommendations and provides rationale for underlying important differences. The document addresses some of the deterrents to CIED access in low- and middle-income countries and strategies to circumvent them. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by class of recommendation and level of evidence. Several questions addressed in this document either do not lend themselves to clinical trials or are rare disease entities, and in these instances recommendations are based on consensus expert opinion. Furthermore, specific recommendations, even when supported by substantial data, do not replace the need for clinical judgment and patient-specific decision-making. The recommendations were opened for public comment to Pediatric and Congenital Electrophysiology Society (PACES) members and underwent external review by the scientific and clinical document committee of the Heart Rhythm Society (HRS), the science advisory and coordinating committee of the American Heart Association (AHA), the American College of Cardiology (ACC), and the Association for European Paediatric and Congenital Cardiology (AEPC). The document received endorsement by all the collaborators and the Asia Pacific Heart Rhythm Society (APHRS), the Indian Heart Rhythm Society (IHRS), and the Latin American Heart Rhythm Society (LAHRS). This document is expected to provide support for clinicians and patients to allow for appropriate CIED use, appropriate CIED management, and appropriate CIED follow-up in pediatric patients.
Violent criminal offenders with personality disorders (PD's) can cause immense harm, but are often deemed untreatable. This study aimed to conduct a randomized clinical trial to test the effectiveness of long-term psychotherapy for rehabilitating offenders with PDs.
We compared schema therapy (ST), an evidence-based psychotherapy for PDs, to treatment-as-usual (TAU) at eight high-security forensic hospitals in the Netherlands. Patients in both conditions received multiple treatment modalities and differed only in the individual, study-specific therapy they received. One-hundred-three male offenders with antisocial, narcissistic, borderline, or paranoid PDs, or Cluster B PD-not-otherwise-specified, were assigned to 3 years of ST or TAU and assessed every 6 months. Primary outcomes were rehabilitation, involving gradual reintegration into the community, and PD symptoms.
Patients in both conditions showed moderate to large improvements in outcomes. ST was superior to TAU on both primary outcomes – rehabilitation (i.e. attaining supervised and unsupervised leave) and PD symptoms – and six of nine secondary outcomes, with small to moderate advantages over TAU. ST patients moved more rapidly through rehabilitation (supervised leave, treatment*time: F(5308) = 9.40, p < 0.001; unsupervised leave, treatment*time: F(5472) = 3.45, p = 0.004), and showed faster improvements on PD scales (treatment*time: t(1387) = −2.85, p = 0.005).
These findings contradict pessimistic views on the treatability of violent offenders with PDs, and support the effectiveness of long-term psychotherapy for rehabilitating these patients, facilitating their re-entry into the community.