A Clinical Rationale for Assessing the Impact of Childhood Sexual Abuse on Adjunctive Subcutaneous Esketamine for Treatment-Resistant Depression

Background: A history of child sexual abuse (CSA) is related to higher suicide rates and poor treatment outcomes in depressed adult patients. Twenty years after the first study investigating the effects of ketamine/esketamine on depression and suicide, there is a lack of data on the CSA effects on this emerging treatment. Here, we assess the impact of CSA on adjunctive subcutaneous (SC) esketamine for treatment-resistant depression (TRD). Methods: A directed acyclic graphic (DAG) was designed to identify clinical confounders between CSA and esketamine predictors of response. The confounders were applied in a statistical model to predict depression symptom trajectory in a sample of 67 TRD outpatients. Results: The patient sample had a relatively high prevalence rate of CSA (35.82%). Positive family history of first-degree relatives with alcohol use disorder and sex were clinical mediators of the effects of esketamine in a CSA adult population. Overall, the presence of at least one CSA event was unrelated to esketamine symptom reduction. Conclusions: Unlike responses to conventional antidepressants and psychotherapy, CSA does not appear to predict poor response to esketamine.publishedVersio

Circulating Mitochondrial DNA in Patients in the ICU as a Marker of Mortality: Derivation and Validation

Background: Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients. Methods and Findings: Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6–15.8, p = 1×10−7) and ME ARDS (OR 8.4, 95% CI 2.9–24.2, p = 9×10−5) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10−4) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers. Conclusions: Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients. Please see later in the article for the Editors' Summar

Protein Disulfide Isomerase Modulates the Activation of Thyroid Hormone Receptors

Thyroid hormone receptors (TRs) are responsible for mediating thyroid hormone (T3 and T4) actions at a cellular level. They belong to the nuclear receptor (NR) superfamily and execute their main functions inside the cell nuclei as hormone-regulated transcription factors. These receptors also exhibit so-called “non-classic” actions, for which other cellular proteins, apart from coregulators inside nuclei, regulate their activity. Aiming to find alternative pathways of TR modulation, we searched for interacting proteins and found that PDIA1 interacts with TRβ in a yeast two-hybrid screening assay. The functional implications of PDIA1—TR interactions are still unclear; however, our co-immunoprecipitation (co-IP) and fluorescence assay results showed that PDI was able to bind both TR isoforms in vitro. Moreover, T3 appears to have no important role in these interactions in cellular assays, where PDIA1 was able to regulate transcription of TRα and TRβ-mediated genes in different ways depending on the promoter region and on the TR isoform involved. Although PDIA1 appears to act as a coregulator, it binds to a TR surface that does not interfere with coactivator binding. However, the TR:PDIA1 complex affinity and activation are different depending on the TR isoform. Such differences may reflect the structural organization of the PDIA1:TR complex, as shown by models depicting an interaction interface with exposed cysteines from both proteins, suggesting that PDIA1 might modulate TR by its thiol reductase/isomerase activity

Efeito da neurocognição basal na mudança de severidade de sintomas depressivos ao longo de múltiplas injeções subcutâneas de escetamina no tratamento de depressão resistente

Strong evidence supports the rapid antidepressant and antisuicidal effects of ketamine for treatment-resistant unipolar and bipolar depression; however, it is important to determine which patients will benefit from this drug. The aim of the current study was to characterize the effects of baseline neurocognition on changes in depression severity throughout six subcutaneous esketamine injections in treatmentresistant depression (TRD) patients. Method: This was a retrospective analysis of a large case series of 70 patients with treatment-resistant unipolar or bipolar depression who received adjuvant treatment of six subcutaneous esketamine injections once per week. Processing speed, attention, working memory, verbal learning, executive function, and depression severity were assessed at baseline. Severity of depression was re-assessed after 24 h following esketamine administration. To determine appropriate confounding variables in the statistical analyses, we used a directed acyclic graph. Results: The moderation analyses found no significant associations between changes in depressive symptoms and the five baseline neurocognitive domains. Conclusion: In the current study, baseline neurocognitive profile did not moderate changes in the severity of depressive symptoms throughout six subcutaneous esketamine injections in TRD patients. Future studies are needed to investigate the effect of cognition on response to esketamine for personalized TRD.Evidências robustas embasam o efeito antidepressivo e antisuicida da cetamina no tratamento da depressão unipolar e bipolar resistente; no entanto, é importante identificar quais são os pacientes que irão se beneficiar dessa medicação. O objetivo do atual estudo é caracterizar o efeito da neurocognição basal na mudança da severidade de depressão ao longo de seis injeções de escetamina subcutânea na depressão resistente ao tratamento. Método: Esta é uma análise retrospectiva de uma série de 70 pacientes com depressão unipolar ou bipolar resistente que receberam um tratamento adjuvante com seis injeções subcutâneas de escetamina na frequência de uma vez por semana. Velocidade de processamento, atenção, memória de trabalho, aprendizado verbal, função executiva e severidade de depressão foram avaliadas antes de cada injeção. A severidade de depressão foi reavaliada após 24 horas da administração da escetamina. Para determinar e controlar os confundidores na análise estatística, nós usamos o directed acyclic graph. Resultados: As análises de moderação não identificaram possíveis interações do passar do tempo e os cinco domínios cognitivos basais na mudança da severidade dos sintomas depressivos. Conclusão: No presente estudo, a neurocognição basal não se mostrou um moderador de mudança na severidade de sintomas depressivos ao longo de seis injeções subcutâneas de escetamina na DRT. Estudos futuros são necessários para investigar o impacto da cognição basal na resposta à escetamina para um tratamento personalizado da DRT.Dados abertos - Sucupira - Teses e dissertações (2020

Stability and Metastability of Li3YCl6 and Li3HoCl6

Metastable solid electrolytes exhibit superior conductivity compared to stable ones, making them a subject of considerable interest. However, solid-state synthesis of the metastable phase is affected by multiple thermodynamic and kinetic parameters, leading to ambiguity in the categorization of stability and metastability. This study categorizes remnant and intermediate metastability based on thermodynamic principles. The intermediate metastable phase, which is less stable than the temperature-independent stable phase, typically transforms into the stable phase(s) at high temperatures. In contrast, the remnant metastable phase, such as the high-temperature stable phase obtained by fast cooling, becomes the most stable phase, and annealing of the remnant metastable phase causes the phase transition to the low-temperature stable phase. Investigating Li+ conducting chlorides, Li3MCl6 (M = Y and Ho), this study shows that heating starting materials to approximately 600 K produced low-temperature Li3MCl6 phase with one formula unit; high-temperature Li3MCl6 with three formula units were observed by further heating. Annealing of quenched Li3MCl6 at 573 K resulted in a phase transition from high-temperature to low-temperature, indicating that the high-temperature phase was remnant metastable at low temperatures. XRD patterns of low-temperature phases suggest the presence of stacking faults that stabilize low-temperature structures with high symmetry

Impact of Repeated Doses of Subcutaneous Esketamine on Acute Dissociative Symptoms in Treatment-Resistant Depression

Background: Esketamine has been approved by the US Food and Drug Administration (FDA) as an adjunctive treatment for use in conjunction with an oral antidepressant for patients with treatment-resistant depression (TRD), but dissociative symptoms are common adverse effects. Methods: A retrospective analysis of 394 subcutaneous esketamine injections given to 70 patients with TRD that were administered once a week during a six-week trial in conjunction with oral antidepressant therapy. Doses between 0.5 to 1.0 mg/kg were administered according to the patient’s response. Dissociative symptoms were assessed using the Clinician-Administered Dissociative States Scale (CADSS) 30 and 60 min after every weekly treatment (day 1, 8, 15, 22, 29 and 36). Results: Seventy patients received a total of 394 subcutaneous esketamine injections over six weeks. Over time, the evolution of CADSS scores demonstrated a significant mean difference of CADSS at 60 min post-injection (p = 0.010) throughout the six infusions. The mean CADSS scores at 60 min on day 22, 29 and 36 were similar. There were no differences between mean CADSS scores 30 min after the injections, no clinical correlation between response and dissociative symptoms, no correlation between time and demographic and clinical characteristics and no interactions between time and combined medication. Conclusions: Our results suggest that repeated subcutaneous esketamine doses are safe and well-tolerated regarding their acute dissociative and psychotomimetic symptoms. Symptoms usually peak at 30 min and decrease at 60 min post-injection, returning to their pretreatment levels at 120 min. Dissociative symptoms do not correlate with antidepressant response

A Clinical Rationale for Assessing the Impact of Childhood Sexual Abuse on Adjunctive Subcutaneous Esketamine for Treatment-Resistant Depression

Background: A history of child sexual abuse (CSA) is related to higher suicide rates and poor treatment outcomes in depressed adult patients. Twenty years after the first study investigating the effects of ketamine/esketamine on depression and suicide, there is a lack of data on the CSA effects on this emerging treatment. Here, we assess the impact of CSA on adjunctive subcutaneous (SC) esketamine for treatment-resistant depression (TRD). Methods: A directed acyclic graphic (DAG) was designed to identify clinical confounders between CSA and esketamine predictors of response. The confounders were applied in a statistical model to predict depression symptom trajectory in a sample of 67 TRD outpatients. Results: The patient sample had a relatively high prevalence rate of CSA (35.82%). Positive family history of first-degree relatives with alcohol use disorder and sex were clinical mediators of the effects of esketamine in a CSA adult population. Overall, the presence of at least one CSA event was unrelated to esketamine symptom reduction. Conclusions: Unlike responses to conventional antidepressants and psychotherapy, CSA does not appear to predict poor response to esketamine