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Treatment-resistant depression (TRD) poses a significant clinical challenge, with limited evidence guiding long-term pharmacological strategies. Esketamine, a glutamatergic modulator, has demonstrated short-term efficacy in TRD, but data on its extended use in real-world settings remains scarce.
Aims
This study aimed to evaluate the long-term effectiveness and side-effects of intranasal esketamine in adults with TRD over more than 100 treatment sessions.
Method
We conducted a retrospective, single-arm, pre–post study of 20 patients with TRD at a psychiatric out-patient clinic in the United Arab Emirates. All participants received ≥100 sessions of intranasal esketamine alongside oral antidepressants. Depression and anxiety symptoms were assessed with the Patient Health Questionnaire-9 (PHQ-9) and Generalised Anxiety Disorder-7 (GAD-7) scales. Side-effects were monitored through blood pressure, sedation, dissociation, urinary symptoms and psychiatric symptoms.
Results
After an average of 129 esketamine sessions (mean duration 2.5 years), PHQ-9 and GAD-7 scores significantly decreased (P < 0.001). A total of 85% of patients improved in depressive severity, with 25% achieving remission; 65% improved in anxiety severity, and 20% reached remission. Esketamine was generally well tolerated; side-effects were mild and transient, with no serious adverse events. However, urinary symptoms suggestive of cystitis occurred in 20% of patients, highlighting the need for ongoing monitoring in long-term treatment.
Conclusions
Intranasal esketamine demonstrated sustained effectiveness and an acceptable side-effect profile in a real-world TRD cohort with extensive psychiatric comorbidity. These findings support its long-term use in complex clinical populations, and underscore the need for further prospective, multi-site studies.
The bidirectional Glenn surgery is an important staging procedure for patients with single ventricle physiology. Approximately 1000 children are born each year in the United States with this subset of CHD. There is limited data regarding optimal post-operative management for these children. We surveyed paediatric cardiac intensive care providers surrounding their management strategies after the bidirectional Glenn surgery.
Design:
An anonymous survey was distributed via email to paediatric cardiac intensive care providers. The survey included anonymised demographic data and focused on post-operative physiologic targets for patients recovering after the bidirectional Glenn surgery.
Subjects:
Thirty-five paediatric cardiac intensive care providers responded to an anonymous 12-question survey. Subjects were mostly comprised of paediatric cardiac intensive care attendings (80%), with an average of 7.86 years of training. The respondents primarily practised in settings with medical trainees, and all practised in settings with extracorporeal membrane oxygenation capabilities.
Intervention:
Respondents were asked to complete a web-based survey. Five of the survey questions were devoted to background demographic data, and seven questions were aimed at identifying physiologic targets. Two of the seven questions were in relation to a provided clinical vignette.
Measurements and main results:
This survey demonstrated that there is a lack of consensus in the management of patients after the bidirectional Glenn surgery. Specifically, granular SpO2, mean arterial pressure, and pH Goals were all less than 75% consensus. This survey highlights the variable practice patterns in providers taking care of patients after the bidirectional Glenn surgery, and further demonstrates the need for physiologic and outcome-driven targets to optimise the post-operative care.
Efforts to curb online hate speech depend on our ability to reliably detect it at scale. Previous studies have highlighted the strong zero-shot classification performance of large language models (LLMs), offering a potential tool to efficiently identify harmful content. Yet for complex and ambivalent tasks like hate speech detection, pre-trained LLMs can be insufficient and carry systemic biases. Domain-specific models fine-tuned for the given task and empirical context could help address these issues, but, as we demonstrate, the quality of data used for fine-tuning decisively matters. In this study, we fine-tuned GPT-4o-mini using a unique corpus of online comments annotated by diverse groups of coders with varying annotation quality: research assistants, activists, two kinds of crowd workers, and citizen scientists. We find that only annotations from those groups of annotators that are better than zero-shot GPT-4o-mini in recognizing hate speech improve the classification performance of the fine-tuned LLM. Specifically, fine-tuning using the highest-quality annotator group – trained research assistants – boosts classification performance by increasing the model’s precision without notably sacrificing the good recall of zero-shot GPT-4o-mini. In contrast, lower-quality annotations do not improve and may even decrease the ability to identify hate speech. By examining tasks reliant on human judgment and context, we offer insights that go beyond hate speech detection.
Surveillance activities are emerging as exemplar use cases for large language models (LLMs) in health care. The aim of this study was to evaluate the potential for LLMs to support the expansion of surveillance activities to include cardiovascular implantable electronic device (CIED) procedures.
Methods:
A validated machine learning-based infection flagging tool was applied to a cohort of VA CIED procedures from 7/1/2021 to 9/30/2023; cases with ≥10% probability of CIED infection underwent manual review. Then, a weighted random sample of 50 infected and 50 uninfected cases was reviewed with generative artificial intelligence (GenAI) assistance. GenAI prompts were iteratively refined to extract and classify all components of infection-related variables from clinical notes. Data extracted by GenAI were compared with manual chart reviews to assess infection status and extraction consistency.
Results:
Among 12,927 CIED procedures, 334 (2.58%) had ≥10% probability of CIED infection. Among 100 sampled cases, 50 of 50 uninfected cases were correctly categorized. Among 50 infection cases, GenAI identified all CIED infections, but the timing of events and the attribution to a preceding procedure were incorrect in 7 of 50 cases. The overall specificity of the GenAI-assisted process was 100% and the sensitivity for accurately classifying timing and attribution of CIED infection events was 82%. Errors in timing improved with iterative prompt updates. Manual chart reviews averaged 25 minutes per chart; the GenAI-assisted process averaged 5–7 minutes per chart.
Conclusions:
LLMs can help streamline the review process for healthcare-associated infection surveillance, but manual adjudication of output is needed to ensure the correct timeline of events and attribution.
This article focuses on the occurrence of 3-point configurations in subsets of $\mathbb {R}^d$ of sufficient thickness. We prove that a compact set $A\subset \mathbb {R}^d$ contains a similar copy of any linear $3$-point configuration (such as a $3$-point arithmetic progression) provided that A satisfies a mild Yavicoli-thickness condition and an r-uniformity condition for $d\geq 2$; or, when $d=1$, the result holds provided that the Newhouse thickness of A is at least $1$. Moreover, we prove that compact sets $A\subset \mathbb {R}^2$ contain the vertices of an equilateral triangle (and more generally, the vertices of a similar copy of any given triangle) provided A satisfies a mild Yavicoli-thickness condition and an r-uniformity condition. Further, $C\times C$ contains the vertices of an equilateral triangle (and more generally the vertices of a similar copy of any given 3-point configuration) provided the Newhouse thickness of C is at least $1$. These are among the first results in the literature to give explicit criteria for the occurrence of 3-point configurations in the plane.
In 1968 the inhabitants of the Chagos Islands were forcibly displaced by the British to set up a US military base on Diego Garcia, in an act which Chagossians have contested for over 50 years. At the time, and to the present, the UK Foreign and Commonwealth Office (FCO) attempted to legitimise the displacement by disingenuously claiming that the Chagossians were a mobile population of contract workers. Through archival analysis, this paper addresses the FCO representation of the islanders as a mobile ‘floating population’ of ‘contract workers’, linked to the figure of the ‘migrant’. At the same time, it problematises the legal contestation of the islanders’ displacement through a politicisation of stasis, linked to claims to ‘indigenous’ status based on long-held ties with the islands, as well as a discrete ‘Ilois’ or ‘Chagossian’ identity category. It argues that these debates reproduce distinctions between ‘migrants’ and ‘natives’ which obscure mobile political relations, including the imperial mobilities that constitute ‘national’ polities, as well as the histories of enforced mobility of enslaved and indentured labourers. Drawing on Glissant’s concept of errantry, the paper highlights the need to multiply conceptual and legal frameworks and create additional frameworks that can recognise mobile forms of rootedness.
The study is the first to examine the effects of children’s and therapists’ in-session behaviors on later therapeutic alliance (TA; i.e., relational bond, task collaboration) as rated by children and therapists in an intervention for children with aggressive behavior. One hundred eighty children (ages 9.3–11.8; 69% male; 78% Black), screened as having aggressive behavior by teacher and parent ratings, received a 32-session group-based cognitive-behavioral intervention (Coping Power) at their schools. TA ratings were collected from children and therapists at mid- and end-of-intervention using the Therapeutic Alliance Scale for Children. Children’s and therapists’ behaviors during the first 16 sessions were coded by independent observers. Children’s negative in-session behaviors predicted lower child- and therapist-rated TA (averaged across mid- and end-of-intervention). Children’s in-session positive behaviors, at both the individual and group-wide level, predicted higher later TA. Therapists’ efforts to manage deviant behavior predicted stronger child-reported ratings of the relational bond and of child- and therapist-rated task collaboration. Exploratory analyses indicate that the effect of children’s in-session behaviors on later TA is moderated by therapists’ skills in managing the group and in managing deviant talk and behavior in sessions. Clinical and research implications of the findings are discussed.
Language impairments are common in affective and psychotic disorders, yet their patterns and underlying pathomechanisms remain insufficiently understood. A transdiagnostic perspective provides a framework for identifying shared and disorder-specific language alterations across diagnostic boundaries. Combining natural language processing (NLP) with network analysis enables the investigation of complex associations between linguistic, cognitive, and psychopathological features.
Methods
Spontaneous speech from N = 372 participants (119 MDD, 27 BD, 48 SSD and 178 HC) was elicited using four Thematic Apperception Test pictures (~12 min per participant). NLP models were applied to extract latent linguistic variables across various levels, including lexical diversity, syntactic complexity, semantic coherence, and disfluencies. Network analysis was used to relate linguistic variables, psychopathology (SAPS, SANS, HAM-A, HAM-D, YMRS, TLI, GAF), and cognitive performance (attention, verbal memory, recognition, and verbal fluency).
Results
Linguistic variables formed the densest network cluster, with type–token ratio, mean length of utterance, and syntactic complexity emerging as central nodes. Psychopathology variables were less cohesive, while TLI “Impoverishment”, coherence mean, and executive functioning bridged linguistic, cognitive, and psychopathological domains. Network comparison tests revealed no significant differences in linguistic–cognitive network structure across HC, MDD, BD, and SSD.
Conclusions
Linguistic networks show high structural consistency across healthy individuals and patients, whereas psychopathological symptom networks reflect transdiagnostic profiles. These findings support a dimensional and transdiagnostic framework underscore shared language–cognition mechanisms, and highlight executive functioning as key cross-domain connection, which opens up new avenues for dimensional research into the pathophysiological and etiological mechanisms underlying language dysfunctions.
Over the past two decades, there has been growing interest in analyzing the effects of educational programs on outcomes using process data from computer-based testing and learning environments. However, most analyses focus on final outcomes at the end of a test or session, overlooking their functional nature over time and neglecting causal mechanisms. To address this gap, this article proposes a novel causal mediation framework for identifying and estimating functional natural direct effects, functional natural indirect effects, and functional total effects, along with their subgroup effects. We define these effects using potential outcomes and provide nonparametric identification strategies depending on whether post-treatment covariates are present or not. We then develop estimation methods using generalized additive models, a flexible and robust tool for analyzing functional data. Through a simulation study, we assess the finite-sample performance of the proposed approach by comparing it to parametric regression methods. We also demonstrate our approach by examining the effects of extended time accommodations on two functional outcomes using process data from the National Assessment of Educational Progress. Our mediation approach with functional outcomes effectively captures dynamic causal mechanisms underlying the program’s effects and pinpoints when and for whom each effect manifests throughout the testing period.
The current study presents an HPSG analysis for deliminative verbal reduplication in Mandarin Chinese. We provide a detailed description of the phenomenon. After discussing reduplication’s interaction with verb classes and aspect markers, we argue that it is better analyzed as a morphological rather than a syntactic process. We put forward a lexical rule for verbal reduplication in Mandarin Chinese, and the different forms of reduplication are captured in an inheritance hierarchy. The interaction between verbal reduplication and aspect marking is handled by multiple inheritance. This analysis covers all forms of deliminative verbal reduplication in Mandarin Chinese and has none of the shortcomings of previous analyses.
The Latent Position Model (LPM) is a popular approach for the statistical analysis of network data. A central aspect of this model is that it assigns nodes to random positions in a latent space, such that the probability of an interaction between each pair of individuals or nodes is determined by their distance in this latent space. A key feature of this model is that it allows one to visualize nuanced structures via the latent space representation. The LPM can be further extended to the Latent Position Cluster Model (LPCM), to accommodate the clustering of nodes by assuming that the latent positions are distributed following a finite mixture distribution. In this paper, we extend the LPCM to accommodate missing network data and apply this to non-negative discrete weighted social networks. By treating missing data as “unusual” zero interactions, we propose a combination of the LPCM with the zero-inflated Poisson distribution. Statistical inference is based on a novel partially collapsed Markov chain Monte Carlo algorithm, where a Mixture-of-Finite-Mixtures (MFM) model is adopted to automatically determine the number of clusters and optimal group partitioning. Our algorithm features a truncated absorb-eject move, which is a novel adaptation of an idea commonly used in collapsed samplers, within the context of MFMs. Another aspect of our work is that we illustrate our results on 3-dimensional latent spaces, maintaining clear visualizations while achieving more flexibility than 2-dimensional models. The performance of this approach is illustrated via three carefully designed simulation studies, as well as four different publicly available real networks, where some interesting new perspectives are uncovered.
We analyse the monetary-fiscal policy mix in post-war Europe, focusing on France and Italy, to trace the historical dynamics of debt and inflation. Using a Markov-switching DSGE model, we identify distinct policy regimes: a Passive Monetary-Active Fiscal (PM/AF) regime before the late 1980s/early 1990s, an Active Monetary-Passive Fiscal (AM/PF) regime associated with central bank independence and EMU convergence, and a third regime marked by the ELB and active fiscal measures aimed at recovery. Simulations reveal that the PM/AF regime in France led to price volatility but stabilised debt, while AM/PF curbed inflation at the cost of rising debt. In contrast, Italy’s procyclical fiscal policy in downturns exacerbated imbalances, aggregate volatility, and low growth. We further assess the implications of policy credibility and uncertainty.
Previous literature has shown that the introduction of homogeneous perforation on plates and cylinders decreases aerodynamic drag. Here, it is shown that the opposite is true for a sphere; drag can increase with porosity. Hollow porous spheres exposed to a uniform free stream are studied experimentally using force and flow field measurements. The parameter space encompasses moderate to high Reynolds numbers ($5 \times 10^4 \leq \textit{Re} \leq 4 \times 10^5$) and porosities ranging from $0\,\%$ to $80\,\%$. The main conclusion is that drag increases with porosity, at super-critical Reynolds numbers, for all studied porosities. At low porosities (less than $9\,\%$), the effect of porosity on drag can be explained by shifts in the separation point. At higher porosities the drag increase cannot be explained by separation shifts, and instead is explained by two competing forms of kinetic energy dissipation: (i) shear on the macro-scale of the body, and (ii) hole losses from flow through the pores. The former generally decreases with porosity, as bleeding flow passing through the body decreases the characteristic velocity difference in the body-scale wake. In a sphere, hole losses increase with porosity sufficiently fast to overcome decreasing body-scale shear losses, in contrast to plates and cylinders where this is not the case. Relatively weak wake vortex structures, and associated low drag coefficient at zero porosity, for a sphere reduce the impact of wake bleeding. Moreover, fluid entering the fore of a sphere can exit perpendicular to the free stream, further reducing wake bleeding while still contributing to hole losses.
Major depression (MDD) is linked to neuro-immune, metabolic, and oxidative stress (NIMETOX) pathways. The gut microbiome may contribute to these pathways via leaky gut and immune-metabolic processes.
Aims:
To identify gut microbial alterations in MDD and to quantify functional pathways and enzyme gene families and integrate these with the clinical phenome and immune–metabolic biomarkers of MDD.
Methods:
Shotgun metagenomics with taxonomic profiling was performed in MDD versus controls using MetaPhlAn v4.0.6, and functional profiling was conducted using HUMAnN v3.9, aligning microbial reads to species-specific pangenomes (Bowtie2 v2.5.4) followed by alignment to the UniRef90 v201901 protein database (DIAMOND v2.1.9).
Results:
Gut microbiome diversity, both species richness and evenness, is quite similar between MDD and controls. The top enriched taxa in the multivariate discriminant profile of MDD reflect gut dysbiosis associated with leaky gut and NIMETOX mechanisms, i.e., Ruminococcus gnavus, Veillonella rogosaem and Anaerobutyricum hallii. The top four protective taxa enriched in controls indicate an anti-inflammatory ecosystem and microbiome resilience, i.e., Vescimonas coprocola, Coprococcus, Faecalibacterium prausnitzii, and Faecalibacterium parasitized. Pathway analysis indicates loss of barrier protection, antioxidants and short-chain fatty acids, and activation of NIMETOX pathways. The differential abundance of gene families suggests that there are metabolic distinctions between both groups, indicating aberrations in purine, sugar, and protein metabolism. The gene and pathway scores explain a larger part of the variance in suicidal ideation, recurrence of illness, neurocognitive impairments, immune functions, and atherogenicity.
Conclusion:
The gut microbiome changes might contribute to activated peripheral NIMETOX pathways in MDD.
To investigate the extent to which the associations of socio-economic position (SEP) with stunting and wasting are mediated by minimum acceptable diet (MAD) and a family care indicator (FCI) in Sri Lanka.
Design:
Secondary data analysis of children from the 2016 Sri Lanka Demographic and Health Survey. The outcomes were stunting and wasting, the exposure was a composite measure combining maternal education and household wealth, and the mediators were binary MAD and FCI variables (adequate v. inadequate). Analyses were performed using counterfactual mediation models adjusted for age, sex and place of residence.
Setting:
A nationally representative sample of children from Sri Lanka.
Participants:
Mothers/caregivers of children under 36 months (4325).
Results:
Twenty per cent of children were stunted, and 14 % were wasted. Lower SEP was associated with higher odds of stunting and wasting and inadequate MAD and FCI. Inadequate FCI was associated with higher odds of stunting (OR = 1·47, 95 % CI = 1·24, 1·74) but not wasting (OR = 1·14, 95 % CI = 0·94, 1·38), whereas MAD was not associated with stunting or wasting. Neither MAD nor FCI significantly mediated the relationship between SEP and stunting and wasting. All mediation estimates were statistically non-significant at the 5 % level. For example, the proportion mediated by FCI on the association between the lowest composite SEP and stunting was 13 % (mean difference = 0·13, 95 % CI = < 0·00, 0·26).
Conclusion:
We did not find consistent or strong evidence that the associations of SEP with childhood stunting and wasting in Sri Lanka are mediated by MAD and FCI. Research with larger samples is needed for more precise estimates.
The generalized Gompertz distribution—an extension of the standard Gompertz distribution as well as the exponential distribution and the generalized exponential distribution—offers more flexibility in modeling survival or failure times as it introduces an additional parameter, which can account for different shapes of hazard functions. This enhances its applicability in various fields such as actuarial science, reliability engineering and survival analysis, where more complex survival models are needed to accurately capture the underlying processes. The effect of heterogeneity has generated increased interest in recent times. In this article, multivariate chain majorization methods are exploited to develop stochastic ordering results for extreme-order statistics arising from independent heterogeneous generalized Gompertz random variables with increased degree of heterogeneity.
Large biobanks offer unprecedented data for psychiatric genomic research, but concerns exist about representativeness and generalizability. This study examined depression prevalence and polygenic risk score (PRS) associations in the All of Us data to assess potential impacts of nonrepresentative sampling.
Methods
Depression prevalence and correlates were analyzed in two subsamples: those with self-reported personal medical history (PMH) data (N = 185,232 overall; N = 114,739 with genetic data) and those with electronic health record (EHR) data (N = 287,015 overall; N = 206,175 with genetic data). PRS weights were estimated across ancestry groups. Associations of PRS with depression were examined by state and ancestry.
Results
Depression prevalence varied across states in both PMH (16.7–35.9%) and EHR (0.2–45.8%) data. Concordance between PMH and EHR diagnoses was low (kappa: 0.29, 95% CI: 0.30–0.30). Overall, one standard deviation increase in depression PRS was associated with lifetime depression based on PMH (odds ratio [OR] = 1.05, 95% confidence interval [CI]: 1.04–1.07) and EHR (OR = 1.05, 95% CI: 1.04–1.07). Results were generally consistent by ancestry, with the strongest signal for European ancestry (PMH: OR = 1.10, 95% CI: 1.08–1.12; EHR: OR = 1.07, 95% CI: 1.05–1.10). Associations between PRS and lifetime depression were largely consistent and significant associations varied minimally (ORs = 1.06–1.45) by state of residence in both subsamples.
Conclusions
Recorded depression prevalence by state in All of Us demonstrates a wide range, likely reflecting recruitment differences, EHR data completeness, and true geographic variation; yet PRS associations remained relatively stable. As studies like All of Us expand, accounting for sample composition and measurement approaches will be crucial for generating actionable findings.
Guidelines urge that infected fluid or tissue obtained during surgery be submitted for microbiologic study directly rather than via swab. A prospective study of operative specimens showed concordance in 64.7% of cases with better yield from abscess fluid, but swab cultures sometimes identified important pathogens missed by fluid culture.
The chronology of Late Pleistocene and Holocene aeolian sand activity in midcontinent North America provides important insight into paleoenvironmental change and associated surface processes. Near the limit of Marine Isotope Stage 2 glaciation of the Huron-Erie Lobe (Laurentide Ice Sheet) in south-central Indiana, aeolian sand deposits found along the eastern margin of outwash plains in the East Fork and West Fork White River valleys provide an opportunity to test the causal mechanisms for aeolian sand activity. Twenty-five optically stimulated luminescence ages on aeolian sand and four radiocarbon ages on gastropod shells document two phases of aeolian sand activity. The first phase, between 26 and 19 ka, records deflation from active outwash plains in the East Fork and West Fork White River valleys during and after the local glacial maximum. These ages overlap with the chronology of Huron-Erie Lobe advance into and out of the White River drainage basin based on a radiocarbon-dated slackwater succession. The second phase, between 16 and 12 ka, records reworking of older aeolian sand and outwash during a period of no-analog vegetation during the Bølling-Allerød/Younger Dryas and is in general agreement with the timing of dune activity from previous studies in the Great Lakes region.
The wheels of decolonization and reparatory justice in Africa are slow. Each gain is fundamentally instrumental, resolute and instructive. In its judgment in John Ssempebwa v Kampala Capital City Authority, the High Court of Uganda resisted the applicants' compelling attempt to constitutionalize reparation for colonial legacies but exercised judicial activism in obliging the authorities to proactively embrace reparatory justice approaches. Names of public infrastructure especially in a capital city are symbols of a nation; they should promote positive memory and sustainable futures. The succinct ruling avoided spatial politics and the historical sensibilities that characterized colonialism such as the construct of racial superiority that negated the rights of African Ugandans. This omission undervalues the ruling at a time when multisectoral efforts such as legislating reparatory justice are required to advance Africa’s reparations agenda. Reparation and decolonization of public memory by Africans for Africans in Africa is critical amidst ongoing global efforts.