Virtual Collaborative Care Versus Specialty Psychiatry Treatment for Depression or Anxiety.

Objective: While collaborative care is known to improve depressive and anxiety symptoms in primary care, comparative effectiveness studies of virtual collaborative care versus virtual specialty psychiatry treatment in real world settings are lacking. This study examined patient depressive and anxiety symptoms over 6 months in collaborative care versus specialty psychiatry.Methods: This was an observational study with target trial emulation in a large, community-based, integrated health care system. Participants were ≥18 years old with mild-moderate depressive or anxiety symptoms measured by the Patient Health Questionnaire-9 or Generalized Anxiety Disorder-7 Scale. Exclusion criteria included acute suicide risk. Patients were assigned to collaborative care or specialty psychiatry, and symptoms were measured 6 months after treatment initiation using linear mixed-effects regression with inverse probability of treatment weighting.Results: There were N = 10,380 patients (n = 1,607 in collaborative care; n = 8,773 in specialty psychiatry) with depressive disorders and N = 2,935 (n = 570 in collaborative care; n = 2,365 in specialty psychiatry) with anxiety disorders. Model effects at 6 months showed significant symptom improvement for patients in collaborative care (adjusted mean difference [AMD] = -9.0, 95% CI, -9.7, -8.4 for depression; -5.4, 95% CI, -6.2, -4.7 for anxiety) and in specialty psychiatry (AMD = -5.0, 95% CI, -5.6, -4.5 for depression; -2.8, 95% CI, -3.6, -2.1 for anxiety), with patients in collaborative care showing significantly greater improvement compared to those in specialty psychiatry (AMD = -4.0, 95% CI, -4.7, -3.3, P < .0001 for depression; AMD = -2.6, 95% CI, -3.4, -1.8, P < .0001 for anxiety).Conclusions: Virtual collaborative care was at least as effective as specialty psychiatry for depression and anxiety. Collaborative care implementation can support national guidelines regarding depression and anxiety screening and treatment.

Molecular Mechanisms of Coxiella burnetii Formalin Fixed Cellular Vaccine Reactogenicity.

Local and systemic reactogenic responses to Q-VAX® have prevented licensing of this vaccine outside of Australia. These reactogenic responses occur in previously sensitize individuals and have not been well defined at the cellular level, in part because many studies have been done in guinea pigs that have limited molecular tools. We previously characterized a mouse model of reactogenicity where local reactions sites showed an influx of CD8+ and IFNγ-expressing IL17a+ CD4+ T cells consistent with a Th1 delayed-type hypersensitivity. In this study we determined using depletion and adoptive transfer experiments that both anti- Coxiella antibodies and CD4+ T cells were essential for localized reactions at the site of vaccination. Furthermore, IFNγ depletion showed significant histological changes at the local reaction sites demonstrating the essential nature of this cytokine to reactogenicity. In addition to the cells and cytokines required for this response, we determined WCV material remained at the site of vaccination for at least 26 weeks post-injection. Transmission electron microscopy of these sites demonstrated intact rod-shaped bacteria at 2 weeks post-injection and partially degraded bacteria within macrophages at 26 weeks post-injection. Finally, since SCVs are an environmentally stable form, we determined that local reactions were more severe when the WCV material was prepared with higher levels of SCVs compared to typical WCV or with higher levels of LCV. These studies support the hypothesis that antigen persistence at the site of injection contributes to this reactogenicity and that anti- Coxiella antibodies, CD4+ T cells, and IFNγ each contribute to this process.

Navigating regulatory challenges, technical performance and circular economy integration of mineral-based waste materials for sustainable construction: A mini review in the European context.

The integration of mineral-based waste materials is crucial for achieving a sustainable and circular construction sector. Whilst technological and economic aspects receive attention, this mini review spotlights overlooked legal 'regulatory hurdles'. It explores major barriers within the European Union, aiming to compress the current ~30-year material development pipeline. Significant hurdles include the absence of harmonized end-of-waste criteria (Waste Framework Directive), the need for consensus-building in chemical risk assessments (REACH & CLP), scarcity of up-to-date harmonized product standards (Construction Products Regulation) and precision values for limit state analysis in structural codes (Eurocodes). This mini review serves as a practical manual, outlining the intricate regulatory landscape for industry experts, regulators and researchers. Emphasizing the parallel importance of environmental safety considerations and performance, our study presented in this mini-review, underscores the necessity for a multi-stakeholder approach to alleviate regulatory barriers. By illuminating regulatory intricacies, this mini review establishes the foundations for wider discussions and in-depth analysis as to the future outlook for consensus development procedures in a rapidly changing and challenging global construction sector. The manuscript also provides stakeholders with vital insights for informed decision-making, helping to facilitate the paradigm shift towards a sustainable and circular construction sector.

Pulsed Field Ablation: A Comprehensive Update.

One of the recent advancements in the field of cardiac electrophysiology is pulsed field ablation (PFA). PFA is a novel energy modality that does not rely on thermal processes to achieve ablation which, in turn, results in limited collateral damage to surrounding structures. In this review, we discuss the mechanisms, safety, efficacy, and clinical applications of PFA for the management of atrial and ventricular arrhythmias. We also summarize the published pre-clinical and clinical studies regarding this new technology.

Biofilm marker discovery with cloud-based dockerized metagenomics analysis of microbial communities.

In an environment, microbes often work in communities to achieve most of their essential functions, including the production of essential nutrients. Microbial biofilms are communities of microbes that attach to a nonliving or living surface by embedding themselves into a self-secreted matrix of extracellular polymeric substances. These communities work together to enhance their colonization of surfaces, produce essential nutrients, and achieve their essential functions for growth and survival. They often consist of diverse microbes including bacteria, viruses, and fungi. Biofilms play a critical role in influencing plant phenotypes and human microbial infections. Understanding how these biofilms impact plant health, human health, and the environment is important for analyzing genotype-phenotype-driven rule-of-life functions. Such fundamental knowledge can be used to precisely control the growth of biofilms on a given surface. Metagenomics is a powerful tool for analyzing biofilm genomes through function-based gene and protein sequence identification (functional metagenomics) and sequence-based function identification (sequence metagenomics). Metagenomic sequencing enables a comprehensive sampling of all genes in all organisms present within a biofilm sample. However, the complexity of biofilm metagenomic study warrants the increasing need to follow the Findability, Accessibility, Interoperability, and Reusable (FAIR) Guiding Principles for scientific data management. This will ensure that scientific findings can be more easily validated by the research community. This study proposes a dockerized, self-learning bioinformatics workflow to increase the community adoption of metagenomics toolkits in a metagenomics and meta-transcriptomics investigation. Our biofilm metagenomics workflow self-learning module includes integrated learning resources with an interactive dockerized workflow. This module will allow learners to analyze resources that are beneficial for aggregating knowledge about biofilm marker genes, proteins, and metabolic pathways as they define the composition of specific microbial communities. Cloud and dockerized technology can allow novice learners-even those with minimal knowledge in computer science-to use complicated bioinformatics tools. Our cloud-based, dockerized workflow splits biofilm microbiome metagenomics analyses into four easy-to-follow submodules. A variety of tools are built into each submodule. As students navigate these submodules, they learn about each tool used to accomplish the task. The downstream analysis is conducted using processed data obtained from online resources or raw data processed via Nextflow pipelines. This analysis takes place within Vertex AI's Jupyter notebook instance with R and Python kernels. Subsequently, results are stored and visualized in Google Cloud storage buckets, alleviating the computational burden on local resources. The result is a comprehensive tutorial that guides bioinformaticians of any skill level through the entire workflow. It enables them to comprehend and implement the necessary processes involved in this integrated workflow from start to finish. This manuscript describes the development of a resource module that is part of a learning platform named "NIGMS Sandbox for Cloud-based Learning" https://github.com/NIGMS/NIGMS-Sandbox. The overall genesis of the Sandbox is described in the editorial NIGMS Sandbox [1] at the beginning of this Supplement. This module delivers learning materials on the analysis of bulk and single-cell ATAC-seq data in an interactive format that uses appropriate cloud resources for data access and analyses.

Expanding the CRISPR base editing toolbox in Drosophila melanogaster.

CRISPR base editors can introduce point mutations into DNA precisely, and cytosine base editors (CBEs) catalyze C to T transitions. While CBEs have been thoroughly explored in cell culture and organisms such as mice, little is known about DNA base editing in insects. In this study, we evaluated germline editing rates of three different CBEs expressed under actin (ubiquitous) or nanos (germline) promoters utilizing Drosophila melanogaster. The original Rattus norvegicus-derived cytosine deaminase APOBEC1 (rAPO-1) displayed high base editing rates (~99%) with undetectable indel formation. Additionally, we show that base editors can be used for generating male sterility and female lethality. Overall, this study highlights the importance of promoter choice and sex-specific transmission for efficient base editing in flies while providing new insights for future genetic biocontrol designs in insects.

Blocked training facilitates learning of multiple schemas.

We all possess a mental library of schemas that specify how different types of events unfold. How are these schemas acquired? A key challenge is that learning a new schema can catastrophically interfere with old knowledge. One solution to this dilemma is to use interleaved training to learn a single representation that accommodates all schemas. However, another class of models posits that catastrophic interference can be avoided by splitting off new representations when large prediction errors occur. A key differentiating prediction is that, according to splitting models, catastrophic interference can be prevented even under blocked training curricula. We conducted a series of semi-naturalistic experiments and simulations with Bayesian and neural network models to compare the predictions made by the "splitting" versus "non-splitting" hypotheses of schema learning. We found better performance in blocked compared to interleaved curricula, and explain these results using a Bayesian model that incorporates representational splitting in response to large prediction errors. In a follow-up experiment, we validated the model prediction that inserting blocked training early in learning leads to better learning performance than inserting blocked training later in learning. Our results suggest that different learning environments (i.e., curricula) play an important role in shaping schema composition.

Scaling models of visual working memory to natural images.

Over the last few decades, psychologists have developed precise quantitative models of human recall performance in visual working memory (VWM) tasks. However, these models are tailored to a particular class of artificial stimulus displays and simple feature reports from participants (e.g., the color or orientation of a simple object). Our work has two aims. The first is to build models that explain people's memory errors in continuous report tasks with natural images. Here, we use image generation algorithms to generate continuously varying response alternatives that differ from the stimulus image in natural and complex ways, in order to capture the richness of people's stored representations. The second aim is to determine whether models that do a good job of explaining memory errors with natural images also explain errors in the more heavily studied domain of artificial displays with simple items. We find that: (i) features taken from state-of-the-art deep encoders predict trial-level difficulty in natural images better than several reasonable baselines; and (ii) the same visual encoders can reproduce set-size effects and response bias curves in the artificial stimulus domains of orientation and color. Moving forward, our approach offers a scalable way to build a more generalized understanding of VWM representations by combining recent advances in both AI and cognitive modeling.

Interfacial dynamics mediate surface binding events on supramolecular nanostructures.

The dynamic behavior of biological materials is central to their functionality, suggesting that interfacial dynamics could also mediate the activity of chemical events at the surfaces of synthetic materials. Here, we investigate the influence of surface flexibility and hydration on heavy metal remediation by nanostructures self-assembled from small molecules that are decorated with surface-bound chelators in water. We find that incorporating short oligo(ethylene glycol) spacers between the surface and interior domain of self-assembled nanostructures can drastically increase the conformational mobility of surface-bound lead-chelating moieties and promote interaction with surrounding water. In turn, we find the binding affinities of chelators tethered to the most flexible surfaces are more than ten times greater than the least flexible surfaces. Accordingly, nanostructures composed of amphiphiles that give rise to the most dynamic surfaces are capable of remediating thousands of liters of 50 ppb Pb2+-contaminated water with single grams of material. These findings establish interfacial dynamics as a critical design parameter for functional self-assembled nanostructures.

Incorporation of nitrogen in antinutritional Solanum alkaloid biosynthesis.

Steroidal glycoalkaloids (SGAs) are specialized metabolites produced by hundreds of Solanum species including food crops, such as tomato, potato and eggplant. Unlike true alkaloids, nitrogen is introduced at a late stage of SGA biosynthesis through an unknown transamination reaction. Here, we reveal the mechanism by which GLYCOALKALOID METABOLISM12 (GAME12) directs the biosynthesis of nitrogen-containing steroidal alkaloid aglycone in Solanum. We report that GAME12, a neofunctionalized γ-aminobutyric acid (GABA) transaminase, undergoes changes in both active site specificity and subcellular localization to switch from its renown and generic activity in core metabolism to function in a specialized metabolic pathway. Moreover, overexpression of GAME12 alone in engineered S. nigrum leaves is sufficient for de novo production of nitrogen-containing SGAs. Our results highlight how hijacking a core metabolism GABA shunt enzyme is crucial in numerous Solanum species for incorporating a nitrogen to a steroidal-specialized metabolite backbone and form defensive alkaloids.

Modeling the Clinical and Economic Burden of Therapeutic Inertia in People with Type 2 Diabetes in Saudi Arabia.

INTRODUCTION: Therapeutic inertia in type 2 diabetes, defined as a failure to intensify treatment despite poor glycemic control, can arise due to a variety of factors, despite evidence linking improved glycemic control with reductions in diabetes-related complications. The present study aimed to evaluate the health and economic burden of therapeutic inertia in people with type 2 diabetes in Saudi Arabia. METHODS: The IQVIA Core Diabetes Model (v.9.0) was used to evaluate outcomes. Baseline cohort characteristics were sourced from Saudi-specific data, with baseline glycated hemoglobin (HbA1c) tested at 8.0%, 9.0%, and 10.0%. Modeled subjects were brought to an HbA1c target of 7.0% immediately or after delays of 1-5 years across time horizons of 3-50 years. Outcomes were discounted annually at 3.0%. Costs were accounted from a societal perspective and expressed in 2023 Saudi Arabian Riyals (SAR). RESULTS: Immediate glycemic control was associated with improved or equal life expectancy and quality-adjusted life expectancy and cost savings in all scenarios compared with delays in achieving target HbA1c. Combined cost savings ranged from SAR 411 (EUR 102) per person with a baseline HbA1c of 8.0% versus a 1-year delay over a 3-year time horizon, to SAR 21,422 (EUR 5291) per person with a baseline HbA1c of 10.0% versus a 5-year delay over a 50-year time horizon. Discounted life expectancy and quality-adjusted life expectancy were projected to improve by up to 0.4 years and 0.5 quality-adjusted life years (QALYs), respectively, with immediate glycemic control. CONCLUSION: Therapeutic inertia was associated with a substantial health and economic burden in Saudi Arabia. Interventions and initiatives that can help to reduce therapeutic inertia are likely to improve health outcomes and reduce healthcare expenditure.

Surgical Treatment of Anterior Glenohumeral Instability: A Historical Review.

BACKGROUND: Glenohumeral instability is a common pathology, particularly in young, active patients. METHODS: A narrative review was performed to describe the history of surgical treatments for anterior shoulder instability. RESULTS: Open surgical techniques were first described by Bankart in 1923. Techniques include both anatomic soft tissue repairs and nonanatomic procedures to provide constraint to motion and dislocation. Osseous techniques to address glenoid bone loss include both autograft techniques, such as the Latarjet procedure, or the use of various allografts. Technological advances, particularly arthroscopy, have continued to drive the evolution of treatments. The concept of the glenoid track has furthered our understanding of this pathology to guide appropriate treatment to reduce recurrence. CONCLUSIONS: Surgical treatment for anterior shoulder instability continues to evolve in an effort to restore function and prevent additional injury.

Computational design of serine hydrolases.

Enzymes that proceed through multistep reaction mechanisms often utilize complex, polar active sites positioned with sub-angstrom precision to mediate distinct chemical steps, which makes their de novo construction extremely challenging. We sought to overcome this challenge using the classic catalytic triad and oxyanion hole of serine hydrolases as a model system. We used RFdiffusion 1 to generate proteins housing catalytic sites of increasing complexity and varying geometry, and a newly developed ensemble generation method called ChemNet to assess active site geometry and preorganization at each step of the reaction. Experimental characterization revealed novel serine hydrolases that catalyze ester hydrolysis with catalytic efficiencies ( k cat / K m ) up to 3.8 × 10 3 M -1 s -1 , closely match the design models (Cα RMSDs < 1 Å), and have folds distinct from natural serine hydrolases. In silico selection of designs based on active site preorganization across the reaction coordinate considerably increased success rates, enabling identification of new catalysts in screens of as few as 20 designs. Our de novo buildup approach provides insight into the geometric determinants of catalysis that complements what can be obtained from structural and mutational studies of native enzymes (in which catalytic group geometry and active site makeup cannot be so systematically varied), and provides a roadmap for the design of industrially relevant serine hydrolases and, more generally, for designing complex enzymes that catalyze multi-step transformations.

Chronic social defeat stress induces meningeal neutrophilia via type I interferon signaling.

Animal models of stress and stress-related disorders are also associated with blood neutrophilia. The mechanistic relevance of this to symptoms or behavior is unclear. We used cytometry, immunohistochemistry, whole tissue clearing, and single-cell sequencing to characterize the meningeal immune response to chronic social defeat (CSD) stress in mice. We find that chronic, but not acute, stress causes meningeal neutrophil accumulation, and CSD increases neutrophil trafficking in vascular channels emanating from skull bone marrow (BM). Transcriptional analysis suggested CSD increases type I interferon (IFN-I) signaling in meningeal neutrophils. Blocking this pathway via the IFN-I receptor (IFNAR) protected against the anhedonic and anxiogenic effects of CSD stress, potentially through reduced infiltration of IFNAR + neutrophils into the meninges from skull BM. Our identification of IFN-I signaling as a putative mediator of meningeal neutrophil recruitment may facilitate development of new therapies for stress-related disorders. One sentence summary: Type I interferon sensing neutrophils accumulate in meninges of psychosocially stressed mice via skull bone marrow channels and are associated with the negative behavioral sequelae of stress; blockade of this pathway inhibits neutrophil trafficking and improves behavioral outcomes.

Predictors of Long-Acting Injectable Antipsychotic Medication Use in Patients with Schizophrenia Spectrum, Bipolar, and Other Psychotic Disorders in a US Community-based, Integrated Health System.

Background and Hypothesis: Long-acting injectable (LAI) antipsychotics improve patient outcomes and are recommended by treatment guidelines for patients with limited medication adherence in schizophrenia spectrum, bipolar, and other psychotic disorders. Reports of LAI antipsychotic use in these disorders and if use aligns with treatment guidelines are lacking. This study aimed to report patient characteristics associated with LAI antipsychotic use in these disorders. Study Design: Retrospective observational study of patients ≥18-years-old with bipolar or psychotic disorders at a large, integrated, community-based health system. Patient demographic and clinical characteristics served as exposures for the main outcome of adjusted odds ratio (aOR) for LAI versus oral antipsychotic medication use from January 1, 2017 to December 31, 2023. Study Results: There were N = 2685 LAI and N = 31 531 oral antipsychotic users. Being non-white (aOR = 1.3-2.0; P < .0001), non-female (aOR = 1.5; P < .0001), from a high deprivation neighborhood (NDI, aOR = 1.3; P < .0007), having a higher body mass index (BMI, aOR = 1.3-1.7; P < .0009), having a schizophrenia/schizoaffective (aOR = 5.8-6.8; P < .0001), psychotic (aOR = 1.6, P < .0001), or substance use disorder (aOR = 1.4; P < .0001), and outpatient psychiatry (aOR = 2.3-7.5; P < .0001) or inpatient hospitalization (aOR = 2.4; P < .0001) utilization in the prior year with higher odds and age ≥40 (aOR = 0.4-0.7; P < .0001) or bipolar disorder (aOR = 0.9; P < .05) were associated with lower odds of LAI use. Non-white, non-female, age 18-39, and high NDI patients had higher LAI use regardless of treatment adherence markers. Smoking and cardiometabolic markers were also associated with LAI use. Conclusions: Demographic and clinical factors are associated with increased LAI use irrespective of treatment adherence. Research on utilization variation informing equitable formulation use aligned with treatment guideline recommendations is warranted.

Evaluating preoperative coagulation panels in dogs undergoing liver lobectomy for primary liver tumors: A multi-institutional retrospective study.

BACKGROUND: The objectives of this study were to: (i) Determine whether operable primary liver tumors were associated with prolongations in prothrombin time (PT) and activated partial thromboplastin time (aPTT) and (ii) determine if these secondary hemostatic abnormalities were more prevalent with specific liver tumors. STUDY DESIGN: Multi-institutional retrospective study. ANIMAL POPULATION: Dogs (n = 359) undergoing liver lobectomy for a primary liver tumor with a preoperative coagulation panel. METHODS: Data was identified via electronic medical record review at eight veterinary teaching hospitals. Baseline dog characteristics, coagulation panel values, platelet count, emergency versus non-emergency procedure, whether the dogs received transfusion(s) of a blood product, liver lobe removed, and histopathological diagnosis were extracted from the medical record. Chi-square analysis was used to compare categorical variables between groups. Continuous variables were assessed for normality using the Shapiro-Wilk test. RESULTS: A total of 74 of 359 dogs (20.6%) had a prolongation in either PT or aPTT preoperatively. A total of 20 of 359 dogs (5.6%) were found to have prolongation of both PT and aPTT. Hemangiosarcoma was the only histopathological diagnosis associated with concurrent prolongations of both PT and aPTT (p < .001) in 6/16 (37.5%) dogs. CONCLUSION: Coagulation panels including PT and aPTT are unlikely to detect substantial deficiencies in secondary hemostasis in most dogs with primary liver tumors except in dogs with a histopathological diagnosis of hemangiosarcoma. CLINICAL SIGNIFICANCE: PT and aPTT testing is low yield as an elective preoperative screening test in dogs with primary liver tumors except in dogs where there is a hemoabdomen or high suspicion for hepatic hemangiosarcoma.

Addressing sagittal plane imbalance in primary total knee arthroplasty.

Aims: Sagittal plane imbalance (SPI), or asymmetry between extension and flexion gaps, is an important issue in total knee arthroplasty (TKA). The purpose of this study was to compare SPI between kinematic alignment (KA), mechanical alignment (MA), and functional alignment (FA) strategies. Methods: In 137 robotic-assisted TKAs, extension and flexion stressed gap laxities and bone resections were measured. The primary outcome was the proportion and magnitude of medial and lateral SPI (gap differential > 2.0 mm) for KA, MA, and FA. Secondary outcomes were the proportion of knees with severe (> 4.0 mm) SPI, and resection thicknesses for each technique, with KA as reference. Results: FA showed significantly lower rates of medial and lateral SPI (2.9% and 2.2%) compared to KA (45.3%; p < 0.001, and 25.5%; p < 0.001) and compared to MA (52.6%; p < 0.001 and 29.9%; p < 0.001). There was no difference in medial and lateral SPI between KA and MA (p = 0.228 and p = 0.417, respectively). FA showed significantly lower rates of severe medial and lateral SPI (0 and 0%) compared to KA (8.0%; p < 0.001 and 7.3%; p = 0.001) and compared to MA (10.2%; p < 0.001 and 4.4%; p = 0.013). There was no difference in severe medial and lateral SPI between KA and MA (p = 0.527 and p = 0.307, respectively). MA resulted in thinner resections than KA in medial extension (mean difference (MD) 1.4 mm, SD 1.9; p < 0.001), medial flexion (MD 1.5 mm, SD 1.8; p < 0.001), and lateral extension (MD 1.1 mm, SD 1.9; p < 0.001). FA resulted in thinner resections than KA in medial extension (MD 1.6 mm, SD 1.4; p < 0.001) and lateral extension (MD 2.0 mm, SD 1.6; p < 0.001), but in thicker medial flexion resections (MD 0.8 mm, SD 1.4; p < 0.001). Conclusion: Mechanical and kinematic alignment (measured resection techniques) result in high rates of SPI. Pre-resection angular and translational adjustments with functional alignment, with typically smaller distal than posterior femoral resection, address this issue.