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Further research is needed to help improve both the standard of care and the outcome for patients with treatment-resistant depression. A particularly critical evidence gap exists with respect to whether pharmacological or non-pharmacological augmentation is superior to antidepressant switch, or vice-versa. The objective of this study was to compare the effectiveness of augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to the antidepressant venlafaxine XR (or duloxetine for those not eligible to receive venlafaxine) for treatment-resistant depression. In this multi-site, 8-week, randomized, open-label study, 278 subjects (196 females and 82 males, mean age 45.6 years (SD 15.3)) with treatment-resistant depression were assigned in a 1:1:1 fashion to treatment with either of these three interventions; 235 subjects completed the study. 260 randomized subjects with at least one post-baseline Montgomery-Asberg Depression Rating (MADRS) assessment were included in the analysis. Repetitive transcranial magnetic stimulation (score change (standard error (se)) = -17.39 (1.3) (p = 0.015) but not aripiprazole augmentation (score change (se) = -14.9 (1.1) (p = 0.069) was superior to switch (score change (se) = -13.22 (1.1)) on the MADRS. Aripiprazole (mean change (se) = -37.79 (2.9) (p = 0.003) but not repetitive transcranial magnetic stimulation augmentation (mean change (se) = -42.96 (3.6) (p = 0.031) was superior to switch (mean change (se) = -34.45 (3.0)) on the symptoms of depression questionnaire. Repetitive transcranial magnetic stimulation augmentation was shown to be more effective than switching antidepressants in treatment-resistant depression on the study primary measure. In light of these findings, clinicians should consider repetitive transcranial magnetic stimulation augmentation early-on for treatment-resistant depression.Trial registration: ClinicalTrials.gov, NCT02977299.
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Major depressive disorder (MDD) is highly prevalent in adolescents and is a major risk factor for suicidality. Recent evidence shows that accelerated cellular senescence/aging is associated with psychiatric illness, including depression, in adults. The present study examined if the relationships of telomere length (TL) and mitochondrial DNA copy number (mtDNAcn), two critical indicators of cellular senescence/aging, are altered in depressed adolescents and whether these alterations are associated with suicidality, early-life adversities, and other co-occuring factors. In genomic DNA isolated from 53 adolescents (ages 16-19, 19 MDD with suicide attempt/suicidal ideation [MDD + SI/SA], 14 MDD without SA/SI [MDD-SI/SA], and 20 healthy controls [HC]), TL and mtDNAcn were measured as the ratio between the number of telomere repeats and that of a single-copy nuclear-hemoglobin [HBG] gene or the amount of mtDNA (NADH dehydrogenase, subunit 1) relative to HBG. Our data show that TL was significantly lower, and mtDNAcn was significantly higher in the total MDD group than HC. TL was significantly lower and mtDNAcn was significantly higher in the MDD + SA/SI group than in the HC, whereas there were no differences in the MDD-SI/SA group. TL was positively correlated with mtDNAcn in both HC and MDD-SA/SI groups; however, TL was negatively correlated with mtDNAcn in MDD + SA/SI. Furthermore, TL was negatively correlated with the severity of both depression and anxiety, while mtDNAcn was positively correlated with the severity of prior emotional abuse. Our study indicates that cellular senescence is more advanced in depressed adolescents with suicidal ideation and that childhood emotional abuse may participate in such a process.
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Transtorno Depressivo Maior , Suicídio , Adulto , Humanos , Adolescente , Criança , Ideação Suicida , Transtorno Depressivo Maior/genética , Variações do Número de Cópias de DNA/genética , DNA Mitocondrial/genética , Telômero/genéticaRESUMO
AIM: The present study examined the leaching and cytotoxicity of bismuth from ProRoot MTA and aimed to identify whether bismuth leaching was affected by the cement base and the immersion regime used. METHODOLOGY: The leaching profile of bismuth was examined from ProRoot MTA and compared with hydroxyapatite containing 20% bismuth oxide as well as hydroxyapatite and tricalcium silicate to investigate whether bismuth release changed depending on the cement base. Bismuth leaching was determined after 30 and 180 days of ageing immersed in Dulbecco's modified Eagle's medium (DMEM) using mass spectroscopy (ICP-MS). The media were either unchanged or regularly replenished. The pH, surface microstructure and phase changes of aged materials were assessed. Wistar rat femoral bone marrow stromal cells (BMSCs) and cutaneous fibroblasts were isolated, cultured and seeded for cell counting (trypan blue live/dead) after exposure to non-aged, 30- and 180-days-aged samples in regularly replenished DMEM. Aged DMEM in contact with materials was also used to culture BMSCs to investigate the effect of material leachates on the cells. Gene expression analysis was also carried out after direct exposure of cells to non-aged materials. Differences between groups were statistically tested at a significance level of 5%. RESULTS: All materials exhibited alterations after immersion in DMEM and this increased with longer exposure times. The bismuth leached from ProRoot MTA as detected by ICP-MS. Aged ProRoot MTA samples exhibited a black discolouration and surface calcium carbonate deposition. ProRoot MTA influenced cell counts after direct exposure and its 180-days leachates reduced BMSC viability. After direct BMSC contact with non-aged ProRoot MTA an upregulation of metallothionein (MT1 and MT2A) expression and down-regulation of collagen-1a (Col-1a) and bone sialoprotein (BSP) expression was identified. CONCLUSIONS: Bismuth leaching was observed throughout 180-days observation period from all materials containing bismuth oxide. This negatively influenced cell viability and gene expression associated with bismuth exposure. This is the first study to report that metallothionein gene expression was influenced by exposure to ProRoot MTA.
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Bismuto , Compostos de Cálcio , Combinação de Medicamentos , Óxidos , Ratos Wistar , Materiais Restauradores do Canal Radicular , Silicatos , Bismuto/toxicidade , Animais , Silicatos/toxicidade , Compostos de Cálcio/toxicidade , Compostos de Cálcio/farmacologia , Compostos de Cálcio/química , Ratos , Óxidos/toxicidade , Materiais Restauradores do Canal Radicular/toxicidade , Teste de Materiais , Fibroblastos/efeitos dos fármacos , Compostos de Alumínio/toxicidade , Células Cultivadas , Durapatita , Células-Tronco Mesenquimais/efeitos dos fármacosRESUMO
Sphingosine-1-phosphate (S1P) is a lipid mediator and its binding to the S1P receptor 2 (S1PR2) is reported to regulate cytoskeletal organization. Epidermal growth factor (EGF) has been shown to induce migration and invasion in tumour cells. Since binding of S1P to S1PR2 and EGF to the EGF receptors exhibit some overlapping functionality, this study aimed to determine whether S1PR2 was involved in EGF-induced migration and invasion of oral squamous cell carcinoma (OSCC) lines and to identify any potential crosstalk between the two pathways. Migration was investigated using the scratch wound assay while invasion was studied using the transwell invasion and multicellular tumour spheroid (MCTS) assays. Activity of Rac1, a RhoGTPase, was measured using G-LISA (small GTPase activation assays) while S1P production was indirectly measured via the expression of sphingosine kinase (Sphk). S1PR2 inhibition with 10 µM JTE013 reduced EGF-induced migration, invasion and Rac1 activity, however, stimulation of S1PR2 with 10 µM CYM5478 did not enhance the effect of EGF on migration, invasion or Rac1 activity. The data demonstrated a crosstalk between EGF/EGFR and S1P/S1PR2 pathways at the metabolic level. S1PR2 was not involved in EGF production, but EGF promoted S1P production through the upregulation of Sphk1. In conclusion, OSCC lines could not migrate and invade without S1PR2 regulation, even with EGF stimulation. EGF also activated S1PR2 by stimulating S1P production via Sphk1. The potential for S1PR2 to control cellular motility may lead to promising treatments for OSCC patients and potentially prevent or reduce metastasis.
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Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD.
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Transtorno Depressivo Maior , Transtorno Depressivo Resistente a Tratamento , Depressão , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , HumanosRESUMO
OBJECTIVE: Patients with bipolar disorder treated with lithium often require additional antipsychotics or anticonvulsants. However, the comparative effectiveness and safety of these agents as add-on to lithium has not been studied. METHODS: This secondary analysis combined two similar 24-week trials on outpatients with bipolar disorder randomized to lithium (target serum level 0.4-0.6 mEq/L). Guideline-based adjunctive antipsychotics (Li+AP) and anticonvulsants (Li+AC) could be used if clinically indicated and was assessed at every study visit. Response was measured on the Clinical Global Impression scale and we performed adjusted mixed effects linear regression analyses. Analysis of variance tests compared metabolic measures including a binary diagnosis of metabolic syndrome before and after 24 weeks of treatment. RESULTS: Among 379 outpatients (57% female, mean age 38 years, mean Clinical Global Impression 4.4), users of Li+AP (N = 50, primarily quetiapine and aripiprazole) improved to a similar degree (mean Clinical Global Impression improvement = 1.6, standard deviation = 1.5) as those using lithium-only (i.e. without adjunctive antipsychotics or anticonvulsants, N = 149, mean Clinical Global Impression improvement = 1.7, standard deviation = 1.4) (p = 0.59). Users of Li+AC (N = 107, primarily lamotrigine and valproate, mean Clinical Global Impression improvement = 1.2, standard deviation = 1.3) and users of Li+AP+AC (N = 73, mean Clinical Global Impression improvement = 1.1, standard deviation = 1.3) showed worse response compared to lithium-only users (all p < 0.01). When comparing Li+AP to Li+AC, users of Li+AP improved slightly better on general (p = 0.05) and manic symptoms (p = 0.01), but showed a worse development of glucose, triglycerides, and metabolic syndrome. CONCLUSION: Despite treatment-by-indication confounding, these findings are relevant for real-world treatment settings and emphasize the need for randomized trials on this clinically important topic.
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Anticonvulsivantes , Antipsicóticos , Transtorno Bipolar , Lítio , Síndrome Metabólica , Adulto , Feminino , Humanos , Masculino , Anticonvulsivantes/efeitos adversos , Antimaníacos/uso terapêutico , Antipsicóticos/efeitos adversos , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/induzido quimicamente , Quimioterapia Combinada , Lítio/uso terapêutico , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/tratamento farmacológico , Ácido Valproico/efeitos adversosRESUMO
OBJECTIVES: This study aims to assess the obturation efficacy of sealers placed with different techniques using microcomputed tomography (µCT) and assess the influence of µCT testing parameters on the obturation data obtained. MATERIALS AND METHODS: Incisors and mesial roots of lower molars with standardized root length were scanned using µCT, and one tooth of each type was 3D printed in acrylic. Two obturation techniques (warm vertical and single cone) and 4 sealer types (AH Plus, BioRoot RCS, Totalfill BC, and Bio-C Sealers) were assessed following storage in Hank's balanced salt solution for 3 and 6 months by assessing gap and void volume percentages on both natural and replica incisor and molar roots. The storage solution was analysed to assess calcium ion leaching. The influence of temperature, tooth positioning, and moisture content of the teeth while µCT scanning was also investigated. RESULTS: The obturation quality in the incisor group was the same using both natural teeth and replicas (p > 0.05). No changes in void volume were identified when comparing the same sealer using different obturation techniques. The premixed sealers used in single-cone obturation exhibited high void volume in the 3D printed replicas in the long term. The temperature, positioning, and moisture content of the teeth did not affect the outcome of µCT testing. CONCLUSIONS: BioRoot RCS, Totalfill BC, and Bio-C Sealers are suitable for obturation of both complex and simple root canal systems using different obturation techniques with BioRoot RCS exhibiting the highest calcium ion release. 3D printed acrylic teeth can be used to assess the obturation quality in uncomplicated root canal systems. µCT parameters had no significant effect on the µCT measurement. CLINICAL RELEVANCE: The single-cone obturation technique with hydraulic sealer is a simple technique that can be used for obturation of all root canal systems.
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Materiais Restauradores do Canal Radicular , Resinas Epóxi , Cálcio , Microtomografia por Raio-X , Compostos de Cálcio , Teste de Materiais , Obturação do Canal Radicular/métodos , Silicatos , Cavidade PulparRESUMO
OBJECTIVE: The aim of the study was to evaluate the ability of a combinatorial pharmacogenomic test to predict medication blood levels and relative clinical improvements in a selected pediatric population. METHODS: This study enrolled patients between ages 3 to 18 years who presented to a pediatric emergency department with acute psychiatric, behavioral, or mental health crisis and/or concerns, and had previously been prescribed psychotropic medications. Patients received combinatorial pharmacogenomic testing with medications categorized according to gene-drug interactions (GDIs); medications with a GDI were considered "incongruent," and medications without a GDI were considered "congruent." Blood levels for escitalopram, fluoxetine, aripiprazole, and clonidine were evaluated according to level of GDI. Relative clinical improvements in response to the prescribed psychotropic medications were measured using a parent-rated Clinical Global Impression of Improvement (CGI-I) assessment, where lower scores corresponded with greater improvement. RESULTS: Of the 100 patients enrolled, 73% reported taking ≥1 incongruent medication. There was no significant difference in CGI-I scores between patients prescribed congruent versus incongruent medications (3.37 vs 3.68, P = 0.343). Among patients who presented for depression or suicidal ideation, those prescribed congruent medications had significantly lower CGI-I scores compared with those taking incongruent medications ( P = 0.036 for depression, P = 0.018 for suicidal ideation). There was a significant association between medication GDI and blood levels for aripiprazole (n = 15, P = 0.01) and escitalopram (n = 10, P = 0.01). CONCLUSIONS: Our preliminary findings suggest that combinatorial pharmacogenomic testing can predict medication blood levels and relative outcomes based on medication congruency in children presenting to an emergency department with acute psychiatric/behavioral crises. Additional studies will be needed to confirm these findings.
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Escitalopram , Farmacogenética , Humanos , Criança , Pré-Escolar , Adolescente , Aripiprazol/uso terapêutico , Psicotrópicos/uso terapêutico , Serviço Hospitalar de EmergênciaRESUMO
BACKGROUND: Childhood trauma affects the course of mood disorders. Researchers are now considering childhood trauma as an influential factor in the treatment of mood disorders. However, the role of childhood trauma in the treatment of bipolar disorder remains understudied. METHODS: The effect of childhood trauma on treatment outcomes was evaluated among participants randomised to treatment with lithium or quetiapine in the Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study by clinician assessment. Mixed effects linear regression models were used to analyse rates of improvement in symptom severity (assessed with the Bipolar Inventory of Symptoms Scale and the Clinical Global Impression Scale for Bipolar Disorder) and functional impairment (assessed with the Longitudinal Interval Follow-up Evaluation-Range of Impaired Functioning Tool). RESULTS: A history of any childhood trauma was reported by 52.7% of the sample (N = 476). Although participants with a history of any childhood trauma presented with greater symptom severity and functional impairment at most study visits, participants with and without a history of any childhood trauma showed similar rates of improvement in symptom severity and functional impairment over the 24 weeks of treatment. CONCLUSION: This is the first study to explore the association between childhood trauma and treatment outcomes during treatment with lithium or quetiapine in the context of a randomised trial. In Bipolar CHOICE, a history of childhood trauma did not inhibit improvement in symptom severity or functional impairment. Nevertheless, these findings need replication across different settings.
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Experiências Adversas da Infância , Antipsicóticos , Transtorno Bipolar , Antipsicóticos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Humanos , Lítio/uso terapêutico , Pacientes Ambulatoriais , Fumarato de Quetiapina/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVE: To assess the likelihood of attaining response/remission of depressive symptoms with esketamine nasal spray (ESK) plus standard of care (SoC) vs placebo nasal spray (PBO) plus SoC at 4 weeks in patients with major depressive disorder and active suicidal ideation with intent (MDSI) without early response. METHODS: A post hoc analysis of pooled data from ASPIRE I and ASPIRE II evaluated ESK plus SoC vs PBO plus SoC in adults with MDSI without response (≥50% improvement from baseline in Montgomery-Åsberg Depression Rating Scale [MADRS] score) at 24 hours after the first dose or at week 1 after the first two doses (ie, 24-hour and week 1 nonresponders). Response and remission (MADRS score ≤ 12) rates were assessed on day 25. RESULTS: The analysis included 362 patients (n = 182, ESK plus SoC; n = 180, PBO plus SoC). Among 24-hour nonresponders, more patients receiving ESK plus SoC vs PBO plus SoC achieved response (63.9% vs 48.0%, P = .010) and remission (35.1% vs 24.4%, P = .074) at day 25. Odds of response/remission were higher with ESK plus SoC vs PBO plus SoC (response: 1.89, 95% CI, 1.17-3.05; remission: 1.48, 95% CI, 0.93-2.35). Similar findings were observed among week 1 nonresponders for response (48.4% vs 34.5%, P = .075), remission (25.0% vs 13.1%, P = .060), and odds of response/remission (response: 2.03, 95% CI, 1.22-3.40; remission: 1.63, 95% CI, 1.01-2.62). CONCLUSIONS: Patients with MDSI not responding within the first week of treatment with ESK plus SoC may still benefit from a full 4-week treatment course.
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BACKGROUND: Adjunctive antidepressants are frequently used for bipolar depression but their clinical efficacy has been studied in few trials and little is known about how co-occurring manic symptoms affect treatment response. METHODS: Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (N = 482) and Lithium Treatment Moderate-Dose Use Study (N = 281) were similar comparative effectiveness trials on outpatients with bipolar disorder comparing four different randomized treatment arms with adjunctive personalized guideline-based treatment for 24 weeks. Adjunctive antidepressant treatment could be used if clinically indicated and was assessed at every study visit. Adjusted mixed effects linear regression analyses compared users of antidepressants to nonusers overall and in different subcohorts. RESULTS: Of the 763 patients, 282 (37.0%) used antidepressant drugs during the study. Antidepressant users had less improvement compared to nonusers on the Clinical Global Impression Scale for Bipolar Disorder and on measures of depression. This was particularly true among patients with co-occurring manic symptoms. Exclusion of individuals begun on antidepressants late in the study (potentially due to overall worse response) resulted in no differences between users and nonusers. We found no differences in treatment effects on mania scales. CONCLUSIONS: In this large cohort of outpatients with bipolar disorder, clinically indicated and guideline-based adjunctive antidepressant treatment was not associated with lower depressive symptoms or higher mania symptoms. The treatment-by-indication confounding due to the nonrandomized design of the trials complicates causal interpretations, but no analyses indicated better treatment effects of adjunctive antidepressants.
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Transtorno Bipolar , Antidepressivos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/epidemiologia , Humanos , Pacientes AmbulatoriaisRESUMO
INTRODUCTION: Adherence to smoking cessation medications remains suboptimal, particularly among low-income smokers. Guided, experiential sampling of nicotine replacement therapies (NRTs) may increase NRT adherence and smoking cessation over gold standard counseling plus NRT. The present pilot study aimed to examine feasibility, acceptability, and preliminary efficacy of a novel experiential intervention. AIMS AND METHODS: This pilot randomized controlled trial (N = 83) compared gold standard smoking cessation treatment (four weekly sessions of behavioral counseling followed by self-selected combination NRT in week 5) to a novel experiential approach (ie, In Vivo; four weekly sessions of sampling each short form of NRT-gum, lozenge, inhaler, nasal spray-in-session while wearing the nicotine patch followed by NRT selection in week 5). Both groups received 8 weeks of nicotine patch plus their selected additional short form NRT for smoking cessation followed by a 1-month assessment. RESULTS: Screening and enrollment rates supported feasibility. In Vivo was comparable in acceptability with the gold standard of care intervention; however, there was greater attrition in the In Vivo group compared with the gold standard of care group. Results suggested higher medication adherence and improvements in smoking behavior in the In Vivo intervention; with generally small-to-medium effect sizes. CONCLUSIONS: This experiential approach to sampling NRT is feasible and acceptable to low-income people who smoke. This intervention may increase adherence and reduce harmful smoking behavior but needs to be tested on a larger scale. IMPLICATIONS: Medication adherence remains a significant impediment to the successful smoking cessation. The results of this study suggest that guided sampling of NRT products improves adherence among low-income smokers. Additionally, this approach yielded greater improvements in smoking behavior compared with gold standard smoking cessation treatment. This intervention shows promise as a feasible smoking cessation treatment for low-income smokers.
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Abandono do Hábito de Fumar , Humanos , Adesão à Medicação , Projetos Piloto , Fumantes , Dispositivos para o Abandono do Uso de TabacoRESUMO
Hydrogels constructed from naturally derived polymers provide an aqueous environment that encourages cell growth, however, mechanical properties are poor and degradation can be difficult to predict. Whilst, synthetic hydrogels exhibit some improved mechanical properties, these materials lack biochemical cues for cells growing and have limited biodegradation. To produce hydrogels that support 3D cell cultures to form tissue mimics, materials must exhibit appropriate biological and mechanical properties. In this study, novel organic-inorganic hybrid hydrogels based on chitosan and silica were prepared using the sol-gel technique. The chemical, physical and biological properties of the hydrogels were assessed. Statistical analysis was performed using One-Way ANOVAs and independent-sample t-tests. Fourier transform infrared spectroscopy showed characteristic absorption bands including amide II, Si-O and Si-O-Si confirming formation of hybrid networks. Oscillatory rheometry was used to characterise the sol to gel transition and viscoelastic behaviour of hydrogels. Furthermore, in vitro degradation revealed both chitosan and silica were released over 21 days. The hydrogels exhibited high loading efficiency as total protein loading was released in a week. There were significant differences between TC2G and C2G at all-time points (p < 0.05). The viability of osteoblasts seeded on, and encapsulated within, the hydrogels was >70% over 168 h culture and antimicrobial activity was demonstrated against Pseudomonas aeruginosa and Enterococcus faecalis. The hydrogels developed here offer alternatives for biopolymer hydrogels for biomedical use, including for application in drug/cell delivery and for bone tissue engineering.
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Encapsulamento de Células/métodos , Quitosana/química , Sistemas de Liberação de Medicamentos/métodos , Hidrogéis/química , Dióxido de Silício/química , Antibacterianos/química , Antibacterianos/farmacologia , Técnicas de Cultura de Células em Três Dimensões/métodos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Enterococcus faecalis/efeitos dos fármacos , Humanos , Hidrogéis/farmacologia , Microscopia Eletrônica de Varredura , Transição de Fase , Espectroscopia de Prótons por Ressonância Magnética , Pseudomonas aeruginosa/efeitos dos fármacos , Espectroscopia de Infravermelho com Transformada de Fourier , Engenharia Tecidual/métodosRESUMO
A 25-year-old runner received a single-lead, VDD pacemaker after ablation of AV nodal reentrant tachycardia complicated by intermittent AV block. The rate-adaptive AV delay algorithm (RAAV), which shortens the sensed AV interval (SAV) at faster atrial rates, was programmed to provide a physiologic SAV with exercise. She developed repetitive, atypical, long-RP pacemaker-mediated tachycardia (PMT) because the RAAV shortened the antegrade SAV and retrograde conduction occurred over the slow AV nodal pathway. PMT was refractory to usual programming solutions. Using high-density electroanatomic mapping, we were able to ablate the retrograde limb of PMT without further damaging AV conduction.
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Bloqueio Atrioventricular/terapia , Estimulação Cardíaca Artificial/efeitos adversos , Ablação por Cateter/efeitos adversos , Sistema de Condução Cardíaco/cirurgia , Marca-Passo Artificial , Taquicardia Ventricular/cirurgia , Potenciais de Ação , Adulto , Bloqueio Atrioventricular/diagnóstico , Bloqueio Atrioventricular/etiologia , Bloqueio Atrioventricular/fisiopatologia , Eletrocardiografia Ambulatorial , Técnicas Eletrofisiológicas Cardíacas , Feminino , Sistema de Condução Cardíaco/fisiopatologia , Frequência Cardíaca , Humanos , Reoperação , Corrida , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/fisiopatologia , Fatores de Tempo , Resultado do TratamentoRESUMO
This cross-sectional study was designed to determine what role race plays in the relationship between obesity and child maltreatment (CM), which is currently unknown. One hundred fifteen participants successfully completed the study, including Whites (n = 60) and Blacks (n = 55) of both sexes. CM was assessed using the Childhood Trauma Questionnaire. Total fat, trunk/total fat ratio, visceral adipose tissue (VAT), and VAT/trunk ratio, were measured through Dual Energy X-ray Absorptiometry (DXA) and Corescan software estimation. A significant interaction between identifying as White and having a history of CM was found to predict body mass index (BMI) (ß = 5.02, p = .025), total fat (kg) (ß = 9.81, p = .036), and VAT (kg) (ß = 0.542, p = .025), whereas race by itself was an insignificant predictor. An interaction between having history of physical abuse and identifying as White was found to predict BMI (ß = 6.993, p = .003), total fat (ß = 12.683, p = .010), and VAT (ß = 0.591, p = .018). An interaction between having multiple CM subtypes and identifying as White predicts increased total fat (ß = 5.667, p = .034) and VAT (ß = 0.335, p = .014). Our findings indicate that the relationship between CM and obesity, measured through BMI, total body fat, and VAT, is seen in Whites but not in Blacks. Future research should investigate the nature of this racial influence to guide obesity prevention and target at-risk populations.
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Maus-Tratos Infantis/etnologia , Obesidade/etiologia , Absorciometria de Fóton , Adulto , Índice de Massa Corporal , Criança , Estudos Transversais , Feminino , Humanos , Gordura Intra-Abdominal , Masculino , Fatores de Risco , Adulto JovemRESUMO
OBJECTIVE: Evaluate the clinical utility of combinatorial pharmacogenomic testing for informing medication selection among older adults who have experienced antidepressant medication failure for major depressive disorder (MDD). DESIGN: Post hoc analysis of data from a blinded, randomized controlled trial comparing two active treatment arms. SETTING: Psychiatry specialty and primary care clinics across 60 U.S. community and academic sites. PARTICIPANTS: Adults age 65 years or older at baseline (nâ¯=â¯206), diagnosed with MDD and inadequate response to at least one medication on the combinatorial pharmacogenomic test report during the current depressive episode. INTERVENTION: Combinatorial pharmacogenomic testing to inform medication selection (guided-care), compared with treatment as usual (TAU). OUTCOMES: Mean percent symptom improvement, response rate, and remission rateat week 8, measured using the 17-item Hamilton Depression Rating Scale; medication switching; and comorbidity moderator analysis. RESULTS: At week 8, symptom improvement was not significantly different for guided-care than for TAU (∆â¯=â¯8.1%, tâ¯=â¯1.64, dfâ¯=â¯187; pâ¯=â¯0.102); however, guided-care showed significantly improved response (∆â¯=â¯13.6%, tâ¯=â¯2.16, dfâ¯=â¯187; pâ¯=â¯0.032) and remission (∆â¯=â¯12.7%, tâ¯=â¯2.49, dfâ¯=â¯189; pâ¯=â¯0.014) relative to TAU. By week 8, more than twice as many patients in guided-care than in TAU were on medications predicted to have no gene-drug interactions (χ2â¯=â¯19.3, dfâ¯=â¯2; p <0.001). Outcomes in the guided-care arm showed consistent improvement through the end of the open-design 24-week trial, indicating durability of the effect. Differences in outcomes between arms were not significantly impacted by comorbidities. CONCLUSIONS: Combinatorial pharmacogenomic test-informed medication selection improved outcomes over TAU among older adults with depression.
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Antidepressivos , Transtorno Depressivo Maior , Testes Farmacogenômicos/métodos , Idoso , Antidepressivos/administração & dosagem , Antidepressivos/classificação , Antidepressivos/farmacocinética , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Substituição de Medicamentos , Feminino , Humanos , Masculino , Avaliação de Resultados em Cuidados de Saúde , Seleção de Pacientes , Escalas de Graduação Psiquiátrica , Falha de TratamentoRESUMO
BACKGROUND: Depressed patients presenting to emergency departments with acute suicidal ideation are a major public health concern. Ketamine, a rapidly acting antidepressant with antisuicidal properties, might offer relief. METHODS: In a randomized, double-blind, placebo-controlled, proof-of-concept trial, 18 depressed subjects with acute suicidal ideation, who required hospitalization, were randomized to either an intravenous ketamine 0.2 mg/kg group or a saline placebo group. Safety and efficacy evaluations were scheduled for 15, 30, 60, 90, 120, 180, and 240 min, and on Days 1, 2, 3, 7, and 14 after infusion. The main outcome measure was suicidal ideation with secondary measures of depression. RESULTS: Nine subjects were randomized to each group. There were no differences between groups at baseline in any demographic or assessment scales. A reduction in suicidal ideation was noted at 90-180 min (p < .05). Ninety minutes after infusion, 88% of the ketamine group had achieved remission of suicidal ideation compared with 33% in the placebo group (p < .05). No serious adverse events were noted. CONCLUSIONS: Ketamine was safe and effective for rapid reduction in suicidal ideation in depressed, highly suicidal subjects presenting to the emergency department. Our results support further study of ketamine for acute suicidal ideation.
Assuntos
Transtorno Depressivo Maior , Antagonistas de Aminoácidos Excitatórios , Ketamina , Ideação Suicida , Transtorno Depressivo Maior/tratamento farmacológico , Método Duplo-Cego , Serviço Hospitalar de Emergência , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Humanos , Ketamina/uso terapêutico , Escalas de Graduação PsiquiátricaRESUMO
BACKGROUND: Sexual dysfunction is common among patients with major depressive disorder (MDD). In the CLARITY study, the safety and efficacy of adjunctive pimavanserin, an inverse agonist at 5-HT2A receptors, were demonstrated when added to existing treatment for MDD. This analysis provides a detailed assessment of the effects of pimavanserin on sexual function from the CLARITY study. METHODS: Patients with a diagnosis of MDD in a depressive episode, inadequate response to ongoing antidepressant therapy, and a Montgomery-Åsberg Depression Rating Scale total score >20 were randomized to pimavanserin 34 mg/day or placebo added to ongoing treatment with an immediate revision of all selective serotonin or serotonin-norepinephrine for 5 weeks (Stage 1), and nonresponders (<50% improvement from baseline in Hamilton Depression Rating Scale [HAMD-17]) were re-randomized for an additional 5 week (Stage 2). Effects of pimavanserin on the Massachusetts General Hospital Sexual Functioning Index (MGH-SFI) and HAMD-17 Item 14 (sexual interest) were examined. RESULTS: Among 203 patients (51 on pimavanserin; 152 on placebo), pimavanserin demonstrated significant improvement from baseline to Week 5 on the MGH-SFI (least square [LS]mean difference -0.634, 95% confidence interval [CI] [-0.964, -0.304]; p = .0002; effect size [ES], Cohen's d: .614). Across Stages 1 and 2, the weighted LSmean difference was -0.468 (95% CI [-0.720, -0.216]; p = .0003) for pimavanserin versus placebo. Mean changes from baseline to Week 5 for MGH-SFI Items 1, 2, 3, and 5 and HAMD Item 14 were significantly (p < .05) greater with pimavanserin versus placebo. CONCLUSIONS: Adjunctive pimavanserin improved sexual function in patients with MDD. Adding pimavanserin to ongoing treatment for MDD may be especially useful for patients experiencing sexual dysfunction.
Assuntos
Antidepressivos/uso terapêutico , Antipsicóticos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Norepinefrina/uso terapêutico , Piperidinas/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Serotonina/uso terapêutico , Ureia/análogos & derivados , Adulto , Transtorno Depressivo Maior/diagnóstico , Método Duplo-Cego , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Disfunções Sexuais Fisiológicas , Resultado do Tratamento , Ureia/uso terapêuticoRESUMO
BACKGROUND: Kappa-opioid antagonism may possess antidepressant properties. We assessed, in a proof-of-concept pilot trial among patients with major depressive disorder with inadequate response to antidepressants, the efficacy of adjunctive CERC-501 (formerly LY2456302), a kappaselective opioid receptor antagonist. METHODS: In a Sequential Parallel Comparison Design study, patients were pre-randomized to: a) 10 mg/d of CERC-501 for 6 days, b) 20 mg/d of CERC-501 for 6 days, c) placebo for 3 days followed by 10 mg/d of CERC- 501 for 3 days, d) placebo for 3 days followed by 20 mg/d of CERC-501 for 3 days, or e) placebo for 6 days. RESULTS: The study was terminated early by the National Institute of Mental Health due to slow enrollment (N = 8). The weighted mean difference of changes (drug vs placebo) in the 6-item Hamilton Depression Rating Scale (HAMD-6) (primary outcome measure) (1.28), Montgomery-Åsberg Depression Rating Scale (MADRS) (2.33), Perceived Stress Scale (1.01), Symptoms of Depression Questionnaire (9.17), Positive Affect Scale (PAS) (6.39), Symptom Questionnaire (SQ) Depression scale (2.94), SQ Anger- Hostility scale (1.67), and Patient-Reported Outcomes Measurement Information System Satisfaction with Participation in Discretionary Social Activities (4.67) scores were all numerically but not statistically greater for CERC-501 than for placebo. CONCLUSIONS: Although the small sample size limits the ability to draw conclusions, results suggest that CERC-501 may have antidepressant effects. Additional studies are necessary to further explore these effects of CERC-501.
Assuntos
Benzamidas/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Antagonistas de Entorpecentes/uso terapêutico , Pirrolidinas/uso terapêutico , Receptores Opioides kappa , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Resultado do TratamentoRESUMO
BACKGROUND: Patients with depression who are treated with esketamine nasal spray may commonly experience dysgeusia (bad/metallic/bitter taste) and related side effects such as nausea and vomiting. While pretreatment with antiemetics can mitigate or prevent nausea and vomiting, it may not address dysgeusia as a contributing factor. Alternative interventions could help to manage vomiting due to dysgeusia following administration of esketamine nasal spray in those patients who are affected. CASE PRESENTATION: A 40-year-old man presented to the emergency department with depression and started treatment with an oral antidepressant. After providing informed consent to participate in a clinical trial evaluating the efficacy and safety of esketamine for major depressive disorder with active suicidal ideation with intent, he received 84 mg of esketamine nasal spray twice per week for 4 weeks. On the first 2 days of esketamine administration, the patient reported dysgeusia lasting several hours and intermittent retching lasting approximately 20 min. The patient was then given a fruit punch-flavored powdered drink (Crystal Light Fruit Punch™) approximately 25 min after nasal spray administration during the study period. The use of a fruit punch drink resulted in notable improvement of dysgeusia and associated vomiting, with time to resolution occurring within 30 min of the report of the adverse event. CONCLUSIONS: A fruit punch-flavored powdered drink mix taken shortly after administration of esketamine nasal spray may rapidly manage and prevent vomiting due to dysgeusia.