Improved implicit self-esteem is associated with extended antidepressant effects following a novel synergistic intervention.

INTRODUCTION: In a previously published randomized controlled trial, automated self-association training (ASAT), a novel digital intervention, was found to extend the rapid antidepressant effect of a single infusion of ketamine for at least 30 days. In this secondary analysis, we aimed to understand the potential role of implicit self-esteem in the combined antidepressant effect of ketamine and ASAT training, by investigating the novel synergistic treatment's effects on implicit self-associations and their relation to symptom improvement. METHODS: A total of 154 adults (ages 18-60) with treatment-resistant unipolar depression and lower-than-normative explicit self-esteem were randomized in a double-blind, parallel-arm design to receive one of three treatment allocations: an active/active treatment combination consisting of one infusion of ketamine (0.5 mg/kg) followed by four days of ASAT ( ~ 30-40 min/day), or one of two control arms that lacked either the active drug or the active behavioral component. The Implicit Association Test (IAT) was used to behaviorally assess the strength of association between self-related stimuli and negative concepts. Linear regression models were used to test the relationship between group assignment, IAT scores acquired immediately post-treatment, and both acute and extended clinical outcomes (% change in Montgomery-Asberg Depression Rating Scale scores, relative to pre-treatment baseline) in the trial. RESULTS: The group assigned to ketamine + ASAT intervention, compared to the other groups, had a pattern of IAT scores indicating more positive self-associations immediately after treatment relative to the control arms (F(1, 131) = 3.979; p = 0.048). In regression models, IAT scores tracked with concurrent (acute post-treatment) % change in MADRS scores across all treatment arms (p = 0.001), and mediated more extended (Day 30) depression improvements specifically for the ketamine+ASAT arm (group * IAT interaction term: ß = -0.201; p = 0.049). DISCUSSION: Our findings suggest that changing implicit self-worth during a post-ketamine 'plasticity window' is one key mechanism whereby the novel ketamine+ASAT treatment combination exerts its antidepressant benefit, confirming the intended treatment target at the level of implicit cognition. Future studies should seek to further enhance the reliability of the biobehavioral intervention's impact on implicit cognition, as this mechanism appears linked to the intervention's enduring clinical benefits.

Stochastic processes and changes in evolutionary rate are associated with diversification in a lineage of tropical hard pines (Pinus).

The study of the patterns of polymorphism and molecular evolution among closely related species is key to understanding the evolutionary forces involved in the diversification of lineages. This point is a big challenge in species with slow evolutionary rates, long life cycles, and ancient, shared polymorphisms such as conifers. Under the premise of divergence in a stepwise migration process, we expect clinal geographical patterns of purifying selection efficiency, and genetic structure related to latitude or longitude. If migration is accompanied by changes in the environment, we could further expect a role of positive selection in driving species divergence. Here, we infer patterns of polymorphism, efficiency of purifying selection, and molecular evolution using a dataset of 161 nuclear genes (∼71 Kb) in a lineage of hard pines from North America, the Caribbean, Mexico, and Central America presumed to have migrated from North America toward lower latitudes with tropical conditions. Under the premise of differences in selective pressures, we also look for possible signals of positive selection. To test our hypothesis, first we estimated different indices to infer patterns of polymorphism and efficiency of purifying selection (Ka, Ks, Ka/Ks, dN, dS, dN/dS, and dxy) and compared these metrics across five clades. Also, we investigated possible clinal patterns in these indices and morphological traits (needle length and cone length). Then we inferred genetic structure and environmental differences among species to test for possible signals of positive selection using phylogenetic methods in specific clades. We found differences among clades using Ka, Ks, and Ka/Ks with a relaxation of purifying selection, especially in the Elliotti and Patula clades. We also found environmental differences related to geographic distance, and among clades suggesting differences in selective pressures. The indices Ks, dxy, and needle length had relationships with geography but not ovulate cone length. Finally, we found that most analyzed genes are under purifying selection, but there was an exception of faster evolutionary rate in some pine species, suggesting the possible action of positive selection in divergence. Our study indicated that stochastic processes have played a key role in the diversification of the group, with a possible input of positive selection in pines from Mexico and Central America.

VEXAS syndrome: A review of cutaneous findings and treatments in an emerging autoinflammatory disease.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic mutation) syndrome is a novel autoinflammatory, late-onset, disorder first identified in 2020. It is caused by mutations in the UBA1 gene. The most prominent clinical features reported by VEXAS patients are cutaneous and haematological, having characteristic skin features reported as the initial presenting findings of the disease. VEXAS is a severe and treatment-resistant condition with high morbidity and mortality rates. Here, we examine all case reports and case series of VEXAS syndrome through March 2023 focusing on those presenting cutaneous manifestations. We discuss these manifestations and their reported treatment strategies. In many cases, it might be first suspected and diagnosed by dermatologists, highlighting their vital role in initiating timely multidisciplinary care.

The Characterization of a Novel PrMADS11 Transcription Factor from Pinus radiata Induced Early in Bent Pine Stem.

A novel MADS-box transcription factor from Pinus radiata D. Don was characterized. PrMADS11 encodes a protein of 165 amino acids for a MADS-box transcription factor belonging to group II, related to the MIKC protein structure. PrMADS11 was differentially expressed in the stems of pine trees in response to 45° inclination at early times (1 h). Arabidopsis thaliana was stably transformed with a 35S::PrMADS11 construct in an effort to identify the putative targets of PrMADS11. A massive transcriptome analysis revealed 947 differentially expressed genes: 498 genes were up-regulated, and 449 genes were down-regulated due to the over-expression of PrMADS11. The gene ontology analysis highlighted a cell wall remodeling function among the differentially expressed genes, suggesting the active participation of cell wall modification required during the response to vertical stem loss. In addition, the phenylpropanoid pathway was also indicated as a PrMADS11 target, displaying a marked increment in the expression of the genes driven to the biosynthesis of monolignols. The EMSA assays confirmed that PrMADS11 interacts with CArG-box sequences. This TF modulates the gene expression of several molecular pathways, including other TFs, as well as the genes involved in cell wall remodeling. The increment in the lignin content and the genes involved in cell wall dynamics could be an indication of the key role of PrMADS11 in the response to trunk inclination.

Gradually supply of isoamyl alcohol increases the isoamyl acetate production in solid-state fermentation.

Nowadays, isoamyl acetate production is carried out by chemical synthesis with a recent interest in developing biological producing processes, mainly based on microorganisms in submerged fermentation. This work assayed producing isoamyl acetate through solid-state fermentation (SSF), feeding the precursor in the gas phase. Polyurethane foam functioned as the inert support to contain 20 ml of a solution of molasses (10% w/v, pH 5.0). The yeast Pichia fermentans was inoculated at 3 × 107 cells per gram of initial dry weight. The airstream to supply oxygen also served to supply the precursor. Slow supply was obtained using an isoamyl alcohol solution of 5 g l-1 in the bubbling columns and an air stream of 50 ml min-1. For fast supply, fermentations were aerated using 10 g l-1 and 100 ml min-1 for isoamyl alcohol solution and air stream, respectively. It demonstrated the feasibility of isoamyl acetate production in SSF. Moreover, the slow supply of the precursor increased isoamyl acetate production up to 390 mg l-1, which is 12.5 times higher than that obtained without precursor (32 mg l-1). On the other hand, fast supply caused an evident inhibition of the growth and production capacity of the yeast.

Mechanistic Modelling of Biomass Growth, Glucose Consumption and Ethanol Production by Kluyveromyces marxianus in Batch Fermentation.

This paper presents results concerning mechanistic modeling to describe the dynamics and interactions between biomass growth, glucose consumption and ethanol production in batch culture fermentation by Kluyveromyces marxianus (K. marxianus). The mathematical model was formulated based on the biological assumptions underlying each variable and is given by a set of three coupled nonlinear first-order Ordinary Differential Equations. The model has ten parameters, and their values were fitted from the experimental data of 17 K. marxianus strains by means of a computational algorithm design in Matlab. The latter allowed us to determine that seven of these parameters share the same value among all the strains, while three parameters concerning biomass maximum growth rate, and ethanol production due to biomass and glucose had specific values for each strain. These values are presented with their corresponding standard error and 95% confidence interval. The goodness of fit of our system was evaluated both qualitatively by in silico experimentation and quantitative by means of the coefficient of determination and the Akaike Information Criterion. Results regarding the fitting capabilities were compared with the classic model given by the logistic, Pirt, and Luedeking-Piret Equations. Further, nonlinear theories were applied to investigate local and global dynamics of the system, the Localization of Compact Invariant Sets Method was applied to determine the so-called localizing domain, i.e., lower and upper bounds for each variable; whilst Lyapunov's stability theories allowed to establish sufficient conditions to ensure asymptotic stability in the nonnegative octant, i.e., R+,03. Finally, the predictive ability of our mechanistic model was explored through several numerical simulations with expected results according to microbiology literature on batch fermentation.

Expression of a ß-glucosidase from Trichoderma reesei in Escherichia coli using a synthetic optimized gene and stability improvements by immobilization using magnetite nano-support.

The enzymatic conversion of lignocellulosic biomass to fermentable sugars is determined by the enzymatic activity of cellulases; consequently, improving enzymatic activity has attracted great interest in the scientific community. Cocktails of commercial cellulase often have low ß-glucosidase content, leading to the accumulation of cellobiose. This accumulation inhibits the activity of the cellulolytic complex and can be used to determine the enzymatic efficiency of commercial cellulase cocktails. Here, a novel codon optimized ß-glucosidase gene (B-glusy) from Trichoderma reesei QM6a was cloned and expressed in three strains of Escherichia coli (E. coli). The synthetic sequence containing an open reading frame (ORF) of 1491 bp was used to encode a polypeptide of 497 amino acid residues. The ß-glucosidase recombinant protein that was expressed (57 kDa of molecular weight) was purified by Ni agarose affinity chromatography and visualized by SDS-PAGE. The recombinant protein was better expressed in E. coli BL21 (DE3), and its enzymatic activity was higher at neutral pH and 30 °C (22.4 U/mg). Subsequently, the ß-glucosidase was immobilized using magnetite nano-support, after which it maintained >65% of its enzymatic activity from pH 6 to 10, and was more stable than the free enzyme above 40 °C. The maximum immobilization yield had enzyme activity of 97.2%. In conclusion, ß-glucosidase is efficiently expressed in the microbial strain E. coli BL21 (DE3) grown in a simplified culture medium.

Methods of Bloodless Care, Clinical Outcomes, and Costs for Adult Patients Who Decline Allogeneic Transfusions.

BACKGROUND: Providing bloodless medical care for patients who wish to avoid allogeneic transfusion can be challenging; however, previous studies have demonstrated favorable outcomes when appropriate methods are used. Here, we report one of the largest series of patients receiving bloodless care, along with the methods used to provide such care, and the resulting outcomes. METHODS: In a retrospective cohort study, 1111 adult inpatients (age ≥18 years) at a single institution who declined allogeneic transfusion for religious or personal reasons between June 2012 and June 2016 were included, and the patient blood management methods are described. Patient characteristics, laboratory data, and transfusion rates, as well as clinical outcomes (morbidity, mortality, and length of stay) were compared to all other patients in the hospital who received standard care, including transfusions if needed (n = 137,009). Medical and surgical patients were analyzed as subgroups. The primary outcome was composite morbidity (any morbid event: infectious, thrombotic, ischemic, renal, or respiratory). Secondary outcomes included individual morbid events, in-hospital mortality, length of stay, total hospital charges, and costs. RESULTS: The bloodless cohort had more females and a lower case mix index, but more preadmission comorbidities. Mean nadir hemoglobin during hospitalization was lower in the bloodless (9.7 ± 2.6 g/dL) compared to the standard care (10.1 ± 2.4 g/dL) group (P < .0001). Composite morbidity occurred in 14.4% vs 16.0% (P = .16) of the bloodless and standard care patients, respectively. Length of stay and in-hospital mortality were similar between the bloodless and standard care patients. After Bonferroni adjustment for multiple comparisons, hospital-acquired infection occurred less frequently in the bloodless compared to the standard care cohort (4.3% vs 8.3%) (P < .0001) in the medical patient subgroup, but not in the surgical subgroup. After propensity score adjustment in a multivariable model and adjustment for multiple comparisons, bloodless care was associated with less risk of hospital-acquired infection (OR, 0.56; 95% CI, 0.35-0.83; P = .0074) in the medical subgroup, but not in the surgical subgroup. Median total hospital charges (by 8.5%; P = .0017) and costs (by 8.7%; P = .0001) were lower in the bloodless compared to the standard care cohort, when all patients were included. CONCLUSIONS: Overall, adult patients receiving bloodless care had similar clinical outcomes compared to patients receiving standard care. Medical (but not surgical) bloodless patients may be at less risk for hospital-acquired infection compared to those receiving standard care. Bloodless care is cost-effective and should be considered as high-value practice.

Non-adaptive evolutionary processes governed the diversification of a temperate conifer lineage after its migration into the tropics.

Constructing phylogenetic relationships among closely related species is a recurrent challenge in evolutionary biology, particularly for long-lived taxa with large effective population sizes and uncomplete reproductive isolation, like conifers. Conifers further have slow evolutionary rates, which raises the question of whether adaptive or non/adaptive processes were predominantly involved when they rapidly diversified after migrating from temperate regions into the tropical mountains. Indeed, fine-scale phylogenetic relationships within several conifer genus remain under debate. Here, we studied the phylogenetic relationships of endemic firs (Abies, Pinaceae) discontinuously distributed in the montane forests from the Southwestern United States to Guatemala, and addressed several hypotheses related to adaptive and non-adaptive radiations. We derived over 80 K SNPs from genotyping by sequencing (GBS) for 45 individuals of nine Mesoamerican species to perform phylogenetic analyses. Both Maximum Likelihood and quartets-inference phylogenies resulted in a well-resolved topology, showing a single fir lineage divided in four subgroups that coincided with the main mountain ranges of Mesoamerica; thus having important taxonomic implications. Such subdivision fitted a North-South isolation by distance framework, in which non-adaptive allopatric processes seemed the rule. Interestingly, several reticulations were observed within subgroups, especially in the central-south region, which may explain past difficulties for generating infrageneric phylogenies. Further evidence for non-adaptive processes was obtained from analyses of 21 candidate-gene regions, which exhibited diminishing values of πa/πs and Ka/Ks with latitude, thus indicating reduced efficiency of purifying selection towards the Equator. Our study indicates that non-adaptive allopatric processes may be key generators of species diversity and endemism in the tropics.

Assessing predictors of futility in patients receiving massive transfusions.

BACKGROUND: Massive transfusions are associated with a high mortality rate, but there is little evidence indicating when such efforts are futile. The purpose of this study was to identify clinical variables that could be used as futility indicators in massively transfused patients. METHODS: We retrospectively analyzed 138 adult surgical patients at our institution receiving a massive transfusion (2016-2019). Peak lactate and nadir pH within 24 h of massive transfusion initiation, along with other clinical variables, were assessed as predictors of the primary outcome, in-hospital mortality. RESULTS: The overall rate of in-hospital mortality among our patient population was 52.9% (n = 73). Increasing lactate and decreasing pH were associated with greater mortality among massively transfused patients. Mortality rates were ~2-fold higher for patients in the highest lactate category (≥10.0 mmol/L: 25 of 37; 67.6%) compared to the lowest category (0.0-4.9 mmol/L: 17 of 48; 35.4%) (p = .005), and ~2.5-fold higher for patients in the lowest pH category (<7.00: 8 of 9; 88.9%) compared to the highest category (≥7.40: 8 of 23; 34.7%) (p = .016). Increasing age was also associated with higher mortality (≥65 years: 24 of 33; 72.7%) when compared to younger patients (18-64 years: 49 of 105; 46.7%) (p = .010). CONCLUSIONS: Peak lactate ≥10.0 mmol/L, nadir pH <7.00, and age ≥65 years were significantly associated with higher rates of in-hospital mortality among massively transfused patients. Incorporating these clinical parameters into a futility index for massive transfusions will be useful in situations where blood products are scarce and/or mortality may be unavoidable.

Impact of body weight on hemoglobin increments in adult red blood cell transfusion.

BACKGROUND: Though weight is a major consideration when transfusing blood in pediatric patients, it is generally not considered when dosing transfusions in adults. We hypothesized that the change in hemoglobin (Hb) concentration is inversely proportional to body weight when transfusing red blood cells (RBC) in adults. METHODS: A total of 13,620 adult surgical patients at our institution were assessed in this retrospective cohort study (2009-2016). Patients were stratified based on total body weight (kg): 40-59.9 (16.6%), 60-79.9 (40.4%), 80-99.9 (28.8%), 100-119.9 (11.3%), and 120-139.9 (2.9%). The primary outcome was the change in Hb per RBC unit transfused. Subgroup analyses were performed after stratification by sex (male/female) and the total number of RBC units received (1/2/≥3 units). Multivariable models were used to assess the association between weight and change in Hb. RESULTS: As patients' body weight increased, there was a decrease in the mean change in Hb per RBC unit transfused (40-59.9 kg: 0.85 g/dL, 60-79.9 kg: 0.73 g/dL, 80-99.9 kg: 0.66 g/dL, 100-119.9 kg: 0.60 g/dL, 120-139.9 kg: 0.55 g/dL; p < .0001). This corresponded with a 35% difference in the change in Hb between the lowest and highest weight categories on univariate analysis. Similar trends were seen after subgroup stratification. On multivariable analysis, for every 20 kg increase in patient weight, there was a ~6.5% decrease in the change in Hb per RBC unit transfused (p < .0001). CONCLUSIONS: Patient body weight differentially impacts the change in Hb after RBC transfusion. These findings justify incorporating body weight into the clinical decision-making process when transfusing blood in adult surgical patients.

Balancing the Blood Component Transfusion Ratio for High- and Ultra High-Dose Cell Salvage Cases.

OBJECTIVE: To assess the ratio of non-red blood cell to red blood cell components required to avoid coagulopathy when transfusing large amounts of salvaged blood using laboratory test-guided therapy. DESIGN: Retrospective cohort study. SETTING: Single-center, academic hospital. PARTICIPANTS: Thoracoabdominal and abdominal open aortic surgery patients. MEASUREMENT AND MAIN RESULTS: Thirty-eight patients in whom at least 1,000 mL of salvaged red blood cells were transfused were identified and divided into the following 2 cohorts: 1,000-to-2,000 mL of salvaged red blood cells (high dose) (n = 20) and >2,000 mL of salvaged red blood cells (ultra-high dose) (n = 18). Compared with the high-dose cohort, the ultra high-dose cohort received ∼4 times more salvaged red blood cells (1,240 ± 279 mL v 5,550 ± 3,801 mL). With transfusion therapy guided by intraoperative coagulation tests and thromboelastography, the adjusted ratio of non-red blood cell to red blood cell components (plasma + platelets + cryoprecipitate:allogeneic + salvaged red blood cells) was 0.59 ± 0.66 in the high-dose and 0.93 ± 0.27 in the ultra high-dose cohorts. Multiple coagulation parameters were normal and similar between cohorts at the end of surgery, as determined by the mean, median, and 95% confidence intervals. CONCLUSIONS: When transfusing large volumes of salvaged blood, it is important to balance the ratio between non-red blood cell and red blood cell components. Through a laboratory test-guided approach, coagulopathy was not detected when transfusing blood in ratios of approximately 1:2 for patients receiving 1,000-to-2,000 mL of salvaged blood and 1:1 for patients receiving >2,000 mL of salvaged blood.

Effect of fermentation time and acid casein concentration as nitrogen source on microbial rennet production.

We evaluated the effects of fermentation time and acid casein content on the microbial rennet obtained by solid-state fermentation using wheat bran as the carbon source. The experiments used two fermentation times (72 and 96 h), while acid casein content was 1.5, 2.0, 2.5, and 3.0 g. Rennet strength from eight enzymatic extracts was measured using pasteurized whole milk. Rennet strength of samples from 72 h of fermentation showed an increase when acid casein content increased. The rennet strength increased at 96 h of fermentation with increasing amount of casein (up to 2.5 g), and then decreased with the largest addition (3.0 g) of casein. Coagulation time for the sample with highest rennet strength was 420 s.

Rare cutaneous adverse reactions associated with GLP-1 agonists: a review of the published literature.

Glucagon-like-peptide-1 (GLP-1) agonists are an emerging class of medications used to manage type 2 diabetes mellitus (T2DM) and weight loss, with demonstrated efficacy in reducing hemoglobin A1c levels, body mass index, and adverse cardiovascular events. While previous studies have reviewed notable cutaneous adverse effects with other antidiabetic medications, little is known about GLP-1 agonist-induced cutaneous reactions. Nevertheless, rare but significant cutaneous adverse reactions have been reported, including but not limited to dermal hypersensitivity reactions, eosinophilic panniculitis, bullous pemphigoid, and morbilliform drug eruptions. As GLP-1 induced cutaneous reactions are diverse, diagnosis requires clinical suspicion, thorough history-taking, and supportive histopathological findings when available. Management involves cessation of the offending agent with a tailored regimen to address inflammatory and/or immunogenic etiologies as well as irritative symptoms. This review aims to consolidate available information from case reports and case series regarding rare skin-related adverse outcomes due to GLP-1 use, aiming to provide a comprehensive overview of the presentation, pathogenesis, and management for dermatologists and other clinicians.

Management and clinical outcomes for patients with gastrointestinal bleeding who decline transfusion.

BACKGROUND: The national blood shortage and growing patient population who decline blood transfusions have created the need for bloodless medicine initiatives. This case series describes the management of gastrointestinal bleed patients who declined allogeneic blood transfusion. Understanding the effectiveness of bloodless techniques may improve treatment for future patients while avoiding the risks and cost associated with transfusion. STUDY DESIGN AND METHODS: A retrospective chart review identified 30 inpatient encounters admitted between 2016 to 2022 for gastrointestinal hemorrhage who declined transfusion due to religious or personal reasons. Clinical characteristics and patient blood management methods utilized during hospitalization were analyzed. Hemoglobin concentrations and clinical outcomes are reported. RESULTS: The most common therapy was intravenous iron (n = 25, 83.3%), followed by erythropoietin (n = 18, 60.0%). Endoscopy was the most common procedure performed (n = 23, 76.7%), and surgical intervention was less common (n = 4, 13.3%). Pre-procedure hemoglobin was <6 g/dL in 7 patients, and <5 g/dL in 4 patients. The median nadir hemoglobin was 5.6 (IQR 4.5, 7.0) g/dL, which increased post-treatment to 7.3 (IQR 6.2, 8.4) g/dL upon discharge. One patient (3.3%) with a nadir Hb of 3.7 g/dL died during hospitalization from sepsis. Nine other patients with nadir Hb <5 g/dL survived hospitalization. CONCLUSIONS: Gastrointestinal bleed patients can be successfully managed with optimal bloodless medicine techniques. Even patients with a nadir Hb <5-6 g/dL can be stabilized with aggressive anemia treatment and may safely undergo anesthesia and endoscopy or surgery for diagnostic or therapeutic purposes. Methods used for treating bloodless medicine patients may be used to improve clinical care for all patients.

Rapid neuroplasticity changes and response to intravenous ketamine: a randomized controlled trial in treatment-resistant depression.

Intravenous ketamine is posited to rapidly reverse depression by rapidly enhancing neuroplasticity. In human patients, we quantified gray matter microstructural changes on a rapid (24-h) timescale within key regions where neuroplasticity enhancements post-ketamine have been implicated in animal models. In this study, 98 unipolar depressed adults who failed at least one antidepressant medication were randomized 2:1 to a single infusion of intravenous ketamine (0.5 mg/kg) or vehicle (saline) and completed diffusion tensor imaging (DTI) assessments at pre-infusion baseline and 24-h post-infusion. DTI mean diffusivity (DTI-MD), a putative marker of microstructural neuroplasticity in gray matter, was calculated for 7 regions of interest (left and right BA10, amygdala, and hippocampus; and ventral Anterior Cingulate Cortex) and compared to clinical response measured with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptoms-Self-Report (QIDS-SR). Individual differences in DTI-MD change (greater decrease from baseline to 24-h post-infusion, indicative of more neuroplasticity enhancement) were associated with larger improvements in depression scores across several regions. In the left BA10 and left amygdala, these relationships were driven primarily by the ketamine group (group * DTI-MD interaction effects: p = 0.016-0.082). In the right BA10, these associations generalized to both infusion arms (p = 0.007). In the left and right hippocampus, on the MADRS only, interaction effects were observed in the opposite direction, such that DTI-MD change was inversely associated with depression change in the ketamine arm specifically (group * DTI-MD interaction effects: p = 0.032-0.06). The acute effects of ketamine on depression may be mediated, in part, by acute changes in neuroplasticity quantifiable with DTI.

Black-box and surrogate optimization for tuning spiking neural models of striatum plasticity.

The basal ganglia (BG) is a brain structure that has long been proposed to play an essential role in action selection, and theoretical models of spiking neurons have tried to explain how the BG solves this problem. A recently proposed functional and biologically inspired network model of the striatum (an important nucleus of the BG) is based on spike-timing-dependent eligibility (STDE) and captured important experimental features of this nucleus. The model can recognize complex input patterns and consistently choose rewarded actions to respond to such sensory inputs. However, model tuning is challenging due to two main reasons. The first is the expert knowledge required, resulting in tedious and potentially biased trial-and-error procedures. The second is the computational cost of assessing model configurations (approximately 1.78 h per evaluation). This study addresses the model tuning problem through numerical optimization. Considering the cost of assessing solutions, the selected methods stand out due to their low requirements for solution evaluations and compatibility with high-performance computing. They are the SurrogateOpt solver of Matlab and the RBFOpt library, both based on radial basis function approximations, and DIRECT-GL, an enhanced version of the widespread black-box optimizer DIRECT. Besides, a parallel random search serves as a baseline reference of the outcome of opting for sophisticated methods. SurrogateOpt turns out to be the best option for tuning this kind of model. It outperforms, on average, the quality of the configuration found by an expert and works significantly faster and autonomously. RBFOpt and the random search share the second position, but their average results are below the option found by hand. Finally, DIRECT-GL follows this line becoming the worst-performing method.

Racial Stress and Trauma and the Development of Adolescent Depression: A Review of the Role of Vigilance Evoked by Racism-Related Threat.

There are known disparities in the burden of illness and access/quality of care for African, Latino/a, Asian, and Native American (ALANA) patients diagnosed with depressive disorders, which may occur because of health inequities. Racial stress and trauma (RST), or the significant fear and distress that can be imparted from exposure to racism, is one such inequity linked to the development of depression. The current review summarizes past research examining the association between racism, RST, and depression, as well as avenues in which RST becomes biologically embedded in ALANA individuals. We describe multimodal research that supports vigilance as a potential mediator of the association between RST and depression and consider the nuanced role that vigilance plays during experiences with racism. Finally, we describe methodological advances in the assessment of vigilance evoked by RST and the clinical implications that may be generated by future improvements. In each of these areas, we present examples of how ongoing and future research can be leveraged to provide support for psychosocial programs that facilitate autonomous community healing and resilience, increase calls for public policy changes, and support clinical interventions that lessen the burden of racism on ALANA communities.

A Pilot Study of Ketamine Infusion after Suicide Attempt: New Frontiers in Treating Acute Suicidality in a Real-World Medical Setting.

Ketamine, in research settings, rapidly reduces suicidal thoughts 2-24 h after a single infusion in patients with high suicidal ideation. In this study, the authors investigate ketamine's effects on suicidality in a real-world sample of recent suicide attempters on a tertiary-care Consultation-Liaison (CL) psychiatry service. Using an open-label design, 16 transdiagnostic CL patients were recruited, 18-65 years old, to receive a single dose of intravenous ketamine (0.5 mg/kg) in the acute medical setting. All were psychiatrically hospitalized post-infusion. Baseline suicidality and depression measures were compared to ratings taken at 24 h, 5 days, 12 days, and 1, 3 and 6 months post-infusion using paired t-tests. Across all measures, rapid, statistically significant decreases (p's < 0.001) were observed with large to very large effect sizes (Cohen's d's: 1.7-8.8) at acute timepoints (24 h; 5 days). These gains were uniformly maintained to 6 months post-infusion. Open-label ketamine appeared to rapidly and robustly reduced suicidal symptoms in an ultra-high-risk, heterogeneous, real-world sample. Ketamine infusion may therefore be a safe, feasible, viable method to rapidly reduce suicidality among medically hospitalized patients after a suicide attempt, with potentially enduring benefits. The current pilot findings suggest ketamine could be readily integrated into the settings where high-risk CL patients already receive healthcare, with the potential to become an important and novel tool in the treatment of suicidality.

A Novel, Brief, Fully Automated Intervention to Extend the Antidepressant Effect of a Single Ketamine Infusion: A Randomized Clinical Trial.

OBJECTIVE: Intravenous ketamine, which displays rapid antidepressant properties, is posited to reverse depression by rapidly enhancing neuroplasticity. The authors tested whether an automated, computer-based approach could efficiently leverage enhanced neuroplasticity to extend the durability of rapid clinical response. METHODS: A total of 154 adults (ages 18-60) with treatment-resistant unipolar depression were randomized in a double-blind, parallel-arm design to receive an active/active treatment combination (ketamine plus active "automated self-association training" [ASAT]; N=53) or one of two control arms that lacked either the active drug component (saline plus active ASAT; N=51) or the active behavioral component (ketamine plus sham ASAT; N=50). One day after a single infusion of intravenous ketamine (0.5 mg/kg over 40 minutes) or inert placebo (saline), active ASAT-targeting self-worth through automated "evaluative conditioning" training delivered by computer-or sham ASAT (consisting of identical computer tasks that included no positive or self-referential stimuli) was given, delivered twice daily over 4 consecutive days (eight sessions, ≤20 minutes per session). The prespecified primary outcome measure throughout the main (30-day) study period was score on the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Ketamine rapidly and significantly reduced depression scores at 24 hours postinfusion (group-by-time interaction: standardized beta [ß]=-1.30, 95% CI=-1.89, -0.70; t=-4.29, df=150). In intent-to-treat linear mixed models, depression scores in the ketamine+ASAT group remained significantly and stably low over the 30-day study period relative to those of the saline+ASAT group (ß=-0.61, 95% CI=-0.95, -0.28; t=-3.62, df=148). By contrast, depression scores following ketamine+sham treatment followed a significant, increasing linear trajectory from 24 hours to 30 days, approaching the levels observed in the saline+ASAT group (group-by-time interaction relative to the saline+ASAT group: ß=0.015, 95% CI=0.003, 0.03; t=2.35, df=568). CONCLUSIONS: After priming the brain with ketamine, training positive self-associations could provide an efficient, low-cost, portable, noninvasive, and highly dissemination-ready strategy for leveraging and extending ketamine's rapid antidepressant effects.