The psychedelic renaissance: the next trip for psychiatry?

The psychedelic research renaissance is gaining traction. Preliminary clinical studies of the hallucinogenic fungi, psilocybin, with psychological support, have indicated improvements in mood, anxiety and quality of life. A seminal, open-label study demonstrated marked reductions in depression symptoms in participants with treatment-resistant depression (TRD). The associated neurobiological processes involve alterations in brain connectivity, together with altered amygdala and default mode network activity. At the cellular level, psychedelics promote synaptogenesis and neural plasticity. Prompted by the promising preliminary studies, a randomized, double-blind trial has recently been launched across Europe and North America to investigate the efficacy of psilocybin in TRD. One of these centres is based in Ireland - CHO Area 7 and Tallaght University Hospital. The outcome of this trial will determine whether psilocybin with psychological support will successfully translate into the psychiatric clinic for the benefit of patients.

Psychedelic science in post-COVID-19 psychiatry.

The medium- to long-term consequences of COVID-19 are not yet known, though an increase in mental health problems are predicted. Multidisciplinary strategies across socio-economic and psychological levels may be needed to mitigate the mental health burden of COVID-19. Preliminary evidence from the rapidly progressing field of psychedelic science shows that psilocybin therapy offers a promising transdiagnostic treatment strategy for a range of disorders with restricted and maladaptive habitual patterns of cognition and behaviour, notably depression, addiction and obsessive compulsive disorder. The COMPASS Pathways (COMPASS) phase 2b double-blind trial of psilocybin therapy in antidepressant-free, treatment-resistant depression (TRD) is underway to determine the safety, efficacy and optimal dose of psilocybin. Results from the Imperial College London Psilodep-RCT comparing the efficacy and mechanisms of action of psilocybin therapy to the selective serotonin reuptake inhibitor (SSRI) escitalopram will soon be published. However, the efficacy and safety of psilocybin therapy in conjunction with SSRIs in TRD is not yet known. An additional COMPASS study, with a centre in Dublin, will begin to address this question, with potential implications for the future delivery of psilocybin therapy. While at a relatively early stage of clinical development, and notwithstanding the immense challenges of COVID-19, psilocybin therapy has the potential to play an important therapeutic role for various psychiatric disorders in post-COVID-19 clinical psychiatry.

Dimensional thinking in psychiatry in the era of the Research Domain Criteria (RDoC).

The biological mechanisms underlying psychiatric diagnoses are not well defined. Clinical diagnosis based on categorical systems exhibit high levels of heterogeneity and co-morbidity. The Research Domain Criteria (RDoC) attempts to reconceptualize psychiatric disorders into transdiagnostic functional dimensional constructs based on neurobiological measures and observable behaviour. By understanding the underlying neurobiology and pathophysiology of the relevant processes, the RDoC aims to advance biomarker development for disease prediction and treatment response. This important evolving dimensional framework must also consider environmental factors. Emerging evidence suggests that gut microbes (microbiome) play a physiological role in brain diseases by modulating neuroimmune, neuroendocrine and neural signalling pathways between the gut and the brain. The integration of the gut microbiome signature as an additional dimensional component of the RDoC may enhance precision psychiatry.

Examining stress: an investigation of stress, mood and exercise in medical students.

OBJECTIVES: Stress is an event that threatens homoeostasis and thus causes physiological and behavioural responses to reinstate equilibrium. Excessive and/or chronic stress can be psychologically and physiologically detrimental. Examinations can represent a significant source of stress for students. The hypothalamic-pituitary-adrenal axis (HPA) is the core endocrine stress system. Investigations into the HPA response to examinations have yielded inconsistent results. The aim of this study is to further explore the relationship between examination stress, HPA axis activity, mood, sleep and exercise in students undergoing a naturalistic examination period stressor. METHODS: In total, 16 medical students participated. Students completed self-reported stress, anxiety, mood, sleep and physical activity questionnaires, and provided saliva samples during an examination-free period and an examination period 1 month later. The cortisol awakening response, representative of HPA activity, was determined from saliva samples by enzyme-linked immunosorbent assay. RESULTS: Anxiety levels increased (p=0.04) and mood decreased (p=0.05) during the examination period. There was concomitant decease in physical activity levels (p=0.02). There was no significant increase in HPA activity during the examination period (p=0.29). Sleep quality did not significantly worsen (p=0.55) during the examination period. CONCLUSIONS: Examination periods are associated with increased anxiety levels, lower mood and decreased physical activity. Future studies incorporating examination results and cognitive function may help to identify potential protective interventional strategies, while optimising performance.

ADM guidance-ceramics: Fatigue principles and testing.

BACKGROUND: Clinical failure of dental ceramics is usually reported as partial fracture of the restoration (chipping) or as catastrophic fracture of the whole structure. In contrast to metals, ceramics are linear-elastic, brittle materials exhibiting extremely low damage tolerance to failure. Well documented clinical and lab reports have shown this fracture event often occurs at loads far below their fracture strength due to intrinsic fatigue degradation via slow crack growth or cyclic fatigue mechanisms. The presence and development of surface flaws have a dominant role in damage accumulation and lifetime reduction of ceramic structures. AIMS: This ADM guidance document aims to summarize the aspects related to fatigue degradation of dental ceramics, reviewing the concepts of fatigue testing and furthermore aims to provide practical guidance to young scientists entering into fatigue related research. The description of fatigue strength is always accompanied by a clear understanding of the underlying fracture mechanisms.

Emerging ceramic-based materials for dentistry.

Our goal is to give an overview of a selection of emerging ceramics and issues for dental or biomedical applications, with emphasis on specific challenges associated with full-contour zirconia ceramics, and a brief synopsis on new machinable glass-ceramics and ceramic-based interpenetrating phase composites. Selected fabrication techniques relevant to dental or biomedical applications such as microwave sintering, spark plasma sintering, and additive manufacturing are also reviewed. Where appropriate, the authors have added their opinions and guidance.

Ceramic materials in dentistry: historical evolution and current practice.

Dental ceramics are presented within a simplifying framework allowing for facile understanding of their development, composition and indications. Engineering assessments of clinical function are dealt with and literature is reviewed on the clinical behaviour of all-ceramic systems. Practical aspects are presented regarding the choice and use of dental ceramics to maximize aesthetics and durability, emphasizing what we know and how we know it.

Simple solutions of multilayered discs subjected to biaxial moment loading.

OBJECTIVES: The purpose of this study was to derive a simple closed-form solution for the stress distribution through the thickness of multilayered discs subjected to biaxial moment loading, such that it can be used readily to evaluate the biaxial strength of multilayered dental ceramics using biaxial flexure tests. METHODS: A simple analytical model was developed to derive the stress distribution through the thickness of multilayered discs subjected to biaxial moment loading. The accuracy of the solution was verified by comparing with previous rigorous analytical solutions and finite element results. The results obtained from Roark's formulas for bilayered discs were also included for comparison. RESULTS: Examples of porcelain/zirconia bilayered discs subjected to ring-on-ring and piston-on-ring loadings were used for comparison among different analyses. Despite the simplicity in deriving the present solution, it is sufficiently accurate in comparing with previous rigorous solutions and finite element results. Also, if the biaxial stresses on the top and the bottom surfaces of the disc can be measured during testing, the biaxial stress/strain through the entire thickness of the multilayered disc can be determined using equations derived in the present model. SIGNIFICANCE: International Organization for Standardization has selected piston-on-three-ball tests to establish ISO 6872 for dentistry-ceramic materials. However, monolayered specimens are considered in tests for this standard. While dental materials are usually fabricated into layered structures, modification of the current standard is essential. Our simple closed-form solution serves as a basis for extending the current standard to multilayered systems.

Levitation, lift, and bidirectional motion of colloidal particles in an electrically driven nematic liquid crystal.

We study electric-field-induced dynamics of colloids in a nematic cell, experimentally and by computer simulations. Solid particles in the nematic bulk create director distortions of dipolar type. Elastic repulsion from the walls keeps the particles in the middle of cell. The ac electric field reorients the dipoles and lifts them to top or bottom, depending on dipole orientation. Once near the walls, the colloids are carried along two antiparallel horizontal directions by nematic backflow. Computer simulations of the backflow agree with the experiment.

Electrorotation of colloidal particles in liquid crystals.

We present the first observations of dc electric-field-induced rotational motion of finite particles in liquid crystals. We show that the electrorotation is essentially identical to the well-known Quincke rotation, which in liquid crystals triggers an additional translational motion at higher fields. In the smectic phase the translational motion is confined to the two-dimensional geometry of smectic layers, in contrast to the isotropic and nematic phases, where the particles can move in all three dimensions. We demonstrate that by a proper analysis of the electrorotation, one can determine the in-plane viscosity of smectic liquid crystals. This method needs only a small amount of material, does not require uniform alignment over large areas, and enables probing rheological properties locally.

Switchable broadband achromatic half-wave plate with nematic liquid crystals.

We describe a broadband achromatic half-wave retarder for normally incident light of arbitrary polarization. The device consists of a stack of one nematic liquid-crystal cell with uniform alignment sandwiched between two twisted nematic layers that have identical twist angles (135 degrees) but different orientations of their surface alignment. As a specific application, for light with linear polarization at 45 degrees to the optic axis of the homogeneous cell the stack functions efficiently as an optical switch. The switch rotates the incident linear polarization by 90 degrees in the absence of an electric field. When sufficiently high voltage is applied to all three layers, the device produces a near-zero effect on the incident polarization. An achromatic response in the spectral range 400-700 nm is achieved for both activated and quiescent states.

Restoration of p53 function in anaplastic Wilms' tumor.

BACKGROUND/PURPOSE: Recent studies have reported a high incidence of p53 mutations in anaplastic Wilms' tumors (WT). Restoration of the normal p53 state by current gene therapy techniques is thus an attractive potential mode of therapy for this tumor, which is poorly responsive to standard therapy. The purpose of this study is to determine whether gene delivery of normal p53 is possible and to characterize the subsequent effect of restoring the wild-type p53 state. METHODS: Anaplastic WT RM1 cells (mutant p53) were transduced with replication-deficient adenoviral vectors containing either the wild-type p53 gene (rAd-p53) or the gene encoding a green fluorescent protein (rAd-GFP). The transduction efficiency of adenovirus for RM1 cells was determined by flow cytometric analysis of rAd-GFP-transduced cells. The effect of p53 transduction on cell viability was evaluated using a colorimetric proliferation assay. Apoptosis was evaluated by labeling DNA breaks using a TUNEL assay (Apo-Direct kit). RESULTS: Cells treated with increasing concentrations of viral particles relative to tumor cells (multiplicity of infection-MOI) showed a dose-dependent increase in the number of cells transduced. Twenty-four hours after viral treatment, the percentage of cells transduced for MOIs of 10, 50, 100, and 500 was 29.5, 60.9, 74.6, and 92.4, respectively; at 48 hours the percentage of cells transduced increased to 70.8, 90.7, 93. 7, and 96.3, respectively. Viral treatment at an MOI of 50 reduced cell proliferation by 10% at 17 hours and 97% at 5 days; at an MOI of 100, the relative reduction in proliferation was 15% and 99.8%, respectively. When assayed, 30% of cells became apoptotic at an MOI of 50, and 48% at an MOI of 100. CONCLUSIONS: Highly efficient delivery of the p53 tumor suppressor gene by adenoviral vector to anaplastic WT is possible. Subsequent restoration of the normal p53 state results in reduced viability and increased apoptosis. Gene replacement of p53 may represent a novel therapeutic agent for anaplastic Wilms' tumors.

Asymmetric transmissive behavior of liquid-crystal diffraction gratings.

We have used computer simulations to predict that the beam-steering efficiency of a common liquid-crystal diffraction grating will depend on which side is presented to the incident beam. The finite-difference time-domain method and the Helmholtz-Kirchhoff diffraction integral were utilized to simulate the performance of an idealized configuration of the grating.

A study to examine the accuracy of potassium measurements in clinical laboratories across Canada.

OBJECTIVE: To assess the accuracy of potassium measurements in clinical laboratories across Canada. DESIGN AND METHOD: The flame atomic emission spectrophotometry reference method for the determination of potassium was established at the Canadian Reference Laboratory by using National Institute of Science and Technology standard reference materials. The method was subsequently used to assign target values for potassium to Canadian Reference Laboratory's External Quality Assessment human-serum-based testing material. A total of 503 laboratories participated and 9,279 individual External Quality Assessment test results were included in the study. Bias was determined by using difference plots. RESULTS: Clinically significant bias (>1.6%) was observed in 45.9% of the laboratories. Bias ranged from 0.34 mmol/L to -0.54 mmol/L. At low concentrations (<3.5 mmol/L) a positive bias was most frequently observed (14.7% of analytical systems). At high potassium concentrations (>5.1 mmol/L) a negative bias was most frequently observed (31.4% of analytical systems). CONCLUSION: Inaccuracy in potassium results can contribute to test redundancy and mismanagement of patients, while prohibiting the merger of laboratory data from disparate testing sites for the purpose of trending and consolidation within a "universal health record." Inaccurate test results and the lack of standardization among laboratories adversely impact our ability to establish common reference intervals and critical limits. This inability has an adverse effect on medical decisions and patient care.

Multiple selectin blockade with a small molecule inhibitor downregulates liver chemokine expression and neutrophil infiltration after hemorrhagic shock.

BACKGROUND: The purpose of this study was to investigate the regulatory effect of a small molecule selectin inhibitor in the liver by examining the functional, structural, and survival response of animals subjected to hemorrhagic shock and to determine the liver infiltration of neutrophils and the regulation of chemokine expression. Selectins play an important role in the development of the lesions associated with ischemia/reperfusion and hemorrhagic shock. Blocking individually the selectin family of adhesion molecules with monoclonal antibodies has resulted in better organ function and survival. To our knowledge, there are no studies demonstrating the beneficial effect of multiple selectin blockade with a small molecule inhibitor under conditions of hemorrhagic shock. METHODS: Forty-eight Sprague-Dawley rats were subjected to hemorrhagic shock. Three groups of animals were included (n = 16/group), i.e., the sham, control, and treated groups, which received a small molecule selectin inhibitor (TBC-1269) at 25 mg/kg body weight after the bleeding began. The following parameters were evaluated: fluid requirements during resuscitation, liver injury tests (aspartate aminotransferase, alanine aminotransferase), liver histology and myeloperoxidase, and macrophage inflammatory protein-2 mRNA and cytokine-induced neutrophil chemoattractant mRNA in liver tissue, and animal survival at 3 days. Statistical analysis included Student's t test and analysis of variance when indicated. RESULTS: Significant improvement in liver function and histology was noted in the treated group. Survival was also improved, although it is not known whether liver failure was the most proximate cause of lethality. Infiltration of neutrophils, measured by tissue myeloperoxidase, was significantly decreased in livers of treated animals. No significant changes were noted in fluid requirements. The small molecule selectin inhibitor group showed a down-regulating effect on liver macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant mRNA expression associated with less accumulation of neutrophils in the liver. CONCLUSION: This study supports the role that selectins play in the pathogenesis of hemorrhagic shock. The mechanism of protection seen after multiple selectin blockade (TBC-1269) centered, in part, around the infiltration of liver neutrophils, probably dependent on the induction of macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant mRNA expression in liver tissue.

Load-bearing behavior of a simulated craniofacial structure fabricated from a hydroxyapatite cement and bioresorbable fiber-mesh.

Calcium phosphate cements (CPC) have proven successful in the repair of small, non-stress bearing skeletal defects. These cements do not have sufficient tensile strength or fracture toughness to allow their use in stress-bearing applications. It was hypothesized that a bioresorbable fiber mesh would improve the load-bearing behavior of shell structures fabricated of CPC. This study used a biaxial flexure fixture to compare the work-to-fracture values of discs made of: (1) CPC; (2) CPC reinforced with a bioresorbable two-dimensionally oriented poly(glactin) fiber-mesh; and (3) poly(methyl methacrylate) (PMMA) that were immersed in a serum-like solution for 0-28 days. CPC-mesh and PMMA discs were indistinguishable at 0, 1 and 7 days, based on work-to-fracture data. CPC and CPC-mesh discs were indistinguishable at day 28, because of fiber hydrolysis. The knitted fiber-mesh was effective in improving load-bearing behavior of a calcium phosphate cement for potential structural repair of bone defects.

Upregulation of lung chemokines associated with hemorrhage is reversed with a small molecule multiple selectin inhibitor.

BACKGROUND: Hemorrhage can modify the leukocyte-endothelial cell response leading to tissue injury. The selectin family of adhesion molecules and chemokines mediate the leukocyte-endothelial cell interaction, resulting in neutrophil sequestration and activation. This work studies whether a small molecule inhibitor of selectins can ameliorate the effect of hemorrhage on chemokine expression and neutrophil infiltration in the lung. We also aimed to assess the regulatory effect of this small molecule inhibitor of selectins in the lung functional and structural response of animals subjected to hemorrhagic shock. STUDY DESIGN: We subjected 36 Sprague-Dawley rats to uncontrolled hemorrhagic shock for a period of 150 minutes. Three groups of animals were included (n = 12 per group)-the sham, control, and treated groups, with the latter receiving a small molecule selectin inhibitor (TBC-1269) at 25 mg/kg, which was given after tail artery transection. The following measurements were evaluated: fluid requirements during resuscitation for 150 minutes; PO2/FIO2 ratio, lung water, and lung histology, lung myeloperoxidase and lung macrophage inflammatory protein-2 (MIP-2) mRNA and cytokine induced neutrophil chemoattractant mRNA at 6 hours. Statistical analysis included Student's t-test and ANOVA. RESULTS: There was significant improvement in lung function as expressed by PO2/FIO2 ratio and wet to dry lung water ratio in the treated group. There were no significant changes in fluid requirements between the three groups. Neutrophil infiltration, measured by tissue myeloperoxidase, was significantly (p < 0.05) decreased in the lungs of the treated animals. Lung histology was considerably improved in the treated group. The small molecule selectin inhibitor had a profound downregulating effect on macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant as expressed in lung tissue. CONCLUSIONS: Our study confirms the key role that selectins play in the pathogenesis of hemorrhagic shock. The multiple selectin blockade allowed for better function and structure of the lung. The mechanism of protection may be secondary to the downregulation of chemokine expression and neutrophil infiltration.

Clinically relevant approach to failure testing of all-ceramic restorations.

STATEMENT OF PROBLEM: One common test of single-unit restorations involves applying loads to clinically realistic specimens through spherical indenters, or equivalently, loading curved incisal edges against flat compression platens. As knowledge has become available regarding clinical failure mechanisms and the behavior of in vitro tests, it is possible to constructively question the clinical validity of such failure testing and to move toward developing more relevant test methods. PURPOSE: This article reviewed characteristics of the traditional load-to-failure test, contrasted these with characteristics of clinical failure for all-ceramic restorations, and sought to explain the discrepancies. Literature regarding intraoral conditions was reviewed to develop an understanding of how laboratory testing could be revised. Variables considered to be important in simulating clinical conditions were described, along with their recent laboratory evaluation. CONCLUSIONS: Traditional fracture tests of single unit all-ceramic prostheses are inappropriate, because they do not create failure mechanisms seen in retrieved clinical specimens. Validated tests are needed to elucidate the role(s) that cement systems, bonding, occlusion, and even metal copings play in the success of fixed prostheses and to make meaningful comparisons possible among novel ceramic and metal substructures. Research over the past 6 years has shown that crack systems mimicking clinical failure can be produced in all-ceramic restorations under appropriate conditions.