The Psychedelic Future of Post-Traumatic Stress Disorder Treatment.

Post-traumatic stress disorder (PTSD) is a mental health condition that can occur following exposure to a traumatic experience. An estimated 12 million U.S. adults are presently affected by this disorder. Current treatments include psychological therapies (e.g., exposure-based interventions) and pharmacological treatments (e.g., selective serotonin reuptake inhibitors (SSRIs)). However, a significant proportion of patients receiving standard-of-care therapies for PTSD remain symptomatic, and new approaches for this and other trauma-related mental health conditions are greatly needed. Psychedelic compounds that alter cognition, perception, and mood are currently being examined for their efficacy in treating PTSD despite their current status as Drug Enforcement Administration (DEA)- scheduled substances. Initial clinical trials have demonstrated the potential value of psychedelicassisted therapy to treat PTSD and other psychiatric disorders. In this comprehensive review, we summarize the state of the science of PTSD clinical care, including current treatments and their shortcomings. We review clinical studies of psychedelic interventions to treat PTSD, trauma-related disorders, and common comorbidities. The classic psychedelics psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT) and DMT-containing ayahuasca, as well as the entactogen 3,4-methylenedioxymethamphetamine (MDMA) and the dissociative anesthetic ketamine, are reviewed. For each drug, we present the history of use, psychological and somatic effects, pharmacology, and safety profile. The rationale and proposed mechanisms for use in treating PTSD and traumarelated disorders are discussed. This review concludes with an in-depth consideration of future directions for the psychiatric applications of psychedelics to maximize therapeutic benefit and minimize risk in individuals and communities impacted by trauma-related conditions.

Public Interest in Psilocybin and Psychedelic Therapy in the Context of the COVID-19 Pandemic: Google Trends Analysis.

BACKGROUND: Psychedelic substances have demonstrated promise in the treatment of depression, anxiety, and substance use disorders. Significant media coverage has been dedicated to psychedelic medicine, but it is unclear whether the public associates psilocybin with its potential therapeutic benefits. The COVID-19 pandemic led to an increase in depression, anxiety, and substance abuse in the general population. OBJECTIVE: This study attempts to link increases in interest in these disorders with increases in interest in psilocybin using Google Trends. METHODS: Weekly interest-over-time Google Trends data for 4 years, from the week of March 11, 2018, to the week of March 6, 2022, were obtained for the following terms: "psilocybin," "psychedelic therapy," "cannabis," "cocaine," "antidepressant," "depression," "anxiety," and "addiction." Important psilocybin-related news and the declaration of the pandemic were noted. Trends data for each of the queried terms were plotted, and multiple regression analysis was performed to determine the slope of the prepandemic and postpandemic data with 95% CIs. Nonparametric Tau-U analysis was performed correcting for baseline trends. Results from this test were used to make inferences about the pre- and postpandemic trends and inferences about the change in overall level of searches between the 2 groups. RESULTS: Tau values for prepandemic data were significant for stable trends, all ranging -0.4 to 0.4. Tau values for postpandemic data showed positive trends for "psilocybin," "psychedelic therapy," and "antidepressant." All other trends remained stable in the range of -0.4 to 0.4. When comparing Tau values for pre- and postpandemic data, overall increases in relative search volume (RSV) were seen for "psilocybin," "psychedelic therapy," and "anxiety," and overall decreases in RSV were seen for "depression," "addiction," and "cocaine." Overall RSVs for "cannabis" and "antidepressant" remained stable as Tau values ranged between -0.4 and 0.4. In the immediate aftermath of the declaration of the pandemic, drop-offs in interest were seen for all terms except for "anxiety" and "cannabis." After the initial shock of a global pandemic, "psilocybin" and "psychedelic therapy" groups demonstrated increases in interest trends and overall RSV. CONCLUSIONS: These data suggest that overall interest in "psilocybin" and "psychedelic therapy" increased at higher rates and to higher levels after than before the declaration of the pandemic. This is consistent with our hypothesis that interest increased for these treatments after the pandemic as incidence of depression, anxiety, and addiction increased. However, there may be other drivers of interest for these topics, since interest in antidepressants-the typical pharmacologic treatments for depression and anxiety-followed the expected pattern of drop-off and accelerated interest back to prepandemic levels. Interest in "psilocybin" and "psychedelic therapy" may have also been partially driven by popular culture hype and novelty, explaining why interest increased at a higher rate post pandemic and continued to grow, surpassing prior interest.

Access to Hepatitis C Treatment during and after Incarceration in New Jersey, United States: A Qualitative Study.

Despite effective antiviral therapy for hepatitis C virus (HCV), people who are incarcerated and those returning to the community face challenges in obtaining HCV treatment. We aimed to explore facilitators and barriers to HCV treatment during and after incarceration. From July-November 2020 and June-July 2021, we conducted 27 semi-structured interviews with residents who were formerly incarcerated in jail or prison. The interviews were audio-recorded and professionally transcribed. We used descriptive statistics to characterize the study sample and analyzed qualitative data thematically using an iterative process. Participants included five women and 22 men who self-identified as White (n = 14), Latinx (n = 8), and Black (n = 5). During incarceration, a key facilitator was having sufficient time to complete HCV treatment, and the corresponding barrier was delaying treatment initiation. After incarceration, a key facilitator was connecting with reentry programs (e.g., halfway house or rehabilitation program) that coordinated the treatment logistics and provided support with culturally sensitive staff. Barriers included a lack of insurance coverage and higher-ranking priorities (e.g., managing more immediate reentry challenges such as other comorbidities, employment, housing, and legal issues), low perceived risk of harm related to HCV, and active substance use. Incarceration and reentry pose distinct facilitators and challenges to accessing HCV treatment. These findings signal the need for interventions to improve engagement in HCV care both during and after incarceration to assist in closing the gap of untreated people living with HCV.

Incorporating Paid Caregivers Into Medical Education to Enhance Medical Student Exposure to This Essential Workforce.

The implications of the COVID-19 pandemic underscored the utility of home-based health care due in part to social distancing requirements, curtailment of elective hospital procedures, and patient apprehension of the health care setting. The pandemic particularly accentuated the integral role of paid caregivers (eg, home health aides, personal care attendants, and other home care workers) in caring for patients with chronic health conditions. Given the paradigm shift toward community- and value-based health care models, paid caregivers are likely to play an even greater role as care team members. Despite the increasingly prominent role paid caregivers are assuming in health care, especially for patients who are chronically ill, in our experience as medical students, we have very little exposure to these care team members, with most interactions occurring in brief, chance encounters. Specifically, we advocate for increased medical student exposure to paid caregivers to facilitate their recognition as valuable care team members. We propose to achieve this through (1) classroom-based module learning with live paid caregivers and (2) plain language communication training to enhance reciprocal engagement.

Hydrogel-Embedded Poly(Lactic-co-Glycolic Acid) Microspheres for the Delivery of hMSC-Derived Exosomes to Promote Bioactive Annulus Fibrosus Repair.

OBJECTIVE: Intervertebral disk degeneration is a prevalent postoperative complication after discectomy, underscoring the need to develop preventative and bioactive treatment strategies that decelerate degeneration and seal annulus fibrosus (AF) defects. Human mesenchymal stem cell-derived exosomes (MSC-Exos) hold promise for cell-free bioactive repair; however, their ability to promote AF repair is poorly understood. The objective of this study was to evaluate the ability of MSC-Exos to promote endogenous AF repair processes and integrate MSC-Exos within a biomaterial delivery system. DESIGN: We characterize biophysical and biochemical properties of normoxic (Nx) and hypoxic (Hx) preconditioned MSC-Exos from young, healthy donors and examine their effects on AF cell proliferation, migration, and gene expression. We then integrate a poly(lactic-co-glycolic acid) microsphere (PLGA µSphere) delivery platform within an interpenetrating network hydrogel to facilitate sustained MSC-Exo delivery. RESULTS: Hx MSC-Exos led to a more robust response in AF cell proliferation and migration than Nx MSC-Exos and was selected for a downstream protection experiment. Hx MSC-Exos maintained a healthy AF cell phenotype under a TNFα challenge in vitro and attenuated catabolic responses. In all functional assays, AF cell responses were more sensitive to Hx MSC-Exos than Nx MSC-Exos. PLGA µSpheres released MSC-Exos over a clinically relevant timescale without affecting hydrogel modulus or pH upon initial embedment and µSphere degradation. CONCLUSIONS: This MSC-Exo treatment strategy may offer benefits of stem cell therapy without the need for exogenous stem cell transplantation by stimulating cell proliferation, promoting cell migration, and protecting cells from the degenerative proinflammatory microenvironment.

Extracellular Vesicles as an Emerging Treatment Option for Intervertebral Disc Degeneration: Therapeutic Potential, Translational Pathways, and Regulatory Considerations.

Emergent approaches in regenerative medicine look toward the use of extracellular vesicles (EVs) as a next-generation treatment strategy for intervertebral disc (IVD) degeneration (IVDD) because of their ability to attenuate chronic inflammation, reduce apoptosis, and stimulate proliferation in a number of tissue systems. Yet, there are no Food and Drug Administration (FDA)-approved EV therapeutics in the market with an indication for IVDD, which motivates this article to review the current state of the field and provide an IVD-specific framework to assess its efficacy. In this systematic review, 29 preclinical studies that investigate EVs in relation to the IVD are identified, and additionally, the regulatory approval process is reviewed in an effort to accelerate emerging EV-based therapeutics toward FDA submission and timeline-to-market. The majority of studies focus on nucleus pulposus responses to EV treatment, where the main findings show that stem cell-derived EVs can decelerate the progression of IVDD on the molecular, cellular, and organ level. The findings also highlight the importance of the EV parent cell's pathophysiological and differentiation state, which affects downstream treatment responses and therapeutic outcomes. This systematic review substantiates the use of EVs as a promising cell-free strategy to treat IVDD and enhance endogenous repair.

Evaluation of SLE arthritis using frequency domain optical imaging.

OBJECTIVES: Systemic lupus erythematosus (SLE) affects the joints in up to 95% of patients. The diagnosis and evaluation of SLE arthritis remain challenging in both practice and clinical trials. Frequency domain optical imaging (FDOI) has been previously used to assess joint involvement in inflammatory arthritis. The objective of this study was to evaluate FDOI in SLE arthritis. METHODS: Ninety-six proximal interphalangeal (PIP) joints from 16 patients with SLE arthritis and 60 PIP joints from 10 age-matched, gender-matched and race/ethnicity-matched controls were examined. A laser beam with a wavelength of 670 nm, 1 mm in diameter and intensity modulated at 300 MHz and 600 MHz was directed onto the dorsal surface of each joint, scanning across a sagittal plane. The transmitted light intensities and phase shifts were measured with an intensified charge-coupled device camera. The data were analysed using Discriminant Analysis and Support Vector Machine algorithms. RESULTS: The amplitude and phase of the transmitted light were significantly different between SLE and control PIPs (p<0.05). Receiver operating characteristic (ROC) analysis of cross-validated models showed an Area Under the ROC Curve (AUC)of 0.89 with corresponding sensitivity of 95%, specificity of 79%, and accuracy of 80%. CONCLUSION: This study is the first evaluation of optical methods in the assessment of SLE arthritis; there was a statistically significant difference in the FDOI signals between patients with SLE and healthy volunteers. The results show that FDOI may have the potential to provide an objective, user-independent, evaluation of SLE PIP joints arthritis.

The Functional Role of Interface Tissue Engineering in Annulus Fibrosus Repair: Bridging Mechanisms of Hydrogel Integration with Regenerative Outcomes.

Hydrogels are extraordinarily versatile by design and can enhance repair in diseased and injured musculoskeletal tissues. Biological fixation of these constructs is a significant determinant factor that is critical to the clinical success and functionality of regenerative technologies for musculoskeletal repair. In the context of an intervertebral disc (IVD) herniation, nucleus pulposus tissue protrudes through the ruptured annulus fibrosus (AF), consequentially impinging on spinal nerve roots and causing debilitating pain. Discectomy is the surgical standard of care to treat symptomatic herniation; however these procedures do not repair AF defects, and these lesions are a significant risk factor for recurrent herniation. Advances in tissue engineering utilize adhesive hydrogels as AF sealants; however these repair strategies have yet to progress beyond preclinical animal models because these biomaterials are often plagued by poor integration with AF tissue and lead to large variability in repair outcomes. These critical barriers to translation motivate this article to review the material composition of hydrogels that have been evaluated in situ for AF repair, proposed mechanisms of how these biomaterials interface with AF tissue, and their functional outcomes after treatment in order to inform the development of new hydrogels for AF repair. In this systematic review, we identify 18 hydrogel formulations evaluated for AF repair, all of which demonstrate large heterogeneity in their interfacing mechanisms and reported outcome measures to assess the effectiveness of repair. Hydrogels that covalently bond to AF tissue were found to be the most successful in improving IVD biomechanical properties from the injured state, but none were able to restore properties to the intact state suggesting that new repair strategies with innovative surface chemistries are an important future direction. We additionally review biomechanical evaluation methods and recommend standardization in the field of AF tissue engineering to establish mechanical benchmarks for translation and ensure clinical feasibility.

Development of a two-part biomaterial adhesive strategy for annulus fibrosus repair and ex vivo evaluation of implant herniation risk.

Intervertebral disc (IVD) herniation causes pain and disability, but current discectomy procedures alleviate pain without repairing annulus fibrosus (AF) defects. Tissue engineering strategies seal AF defects by utilizing hydrogel systems to prevent recurrent herniation, however current biomaterials are limited by poor adhesion to wetted tissue surfaces or low failure strength resulting in considerable risk of implant herniation upon spinal loading. Here, we developed a two-part repair strategy comprising a dual-modified (oxidized and methacrylated) glycosaminoglycan that can chemically adsorb an injectable interpenetrating network hydrogel composed of fibronectin-conjugated fibrin and poly (ethylene glycol) diacrylate (PEGDA) to covalently bond the hydrogel to AF tissue. We show that dual-modified hyaluronic acid imparts greater adhesion to AF tissue than dual-modified chondroitin sulfate, where the degree of oxidation is more strongly correlated with adhesion strength than methacrylation. We apply this strategy to an ex vivo bovine model of discectomy and demonstrate that PEGDA molecular weight tunes hydrogel mechanical properties and affects herniation risk, where IVDs repaired with low-modulus hydrogels composed of 20kDa PEGDA failed at levels at or exceeding discectomy, the clinical standard of care. This strategy bonds injectable hydrogels to IVD extracellular matrix proteins, is optimized to seal AF defects, and shows promise for IVD repair.

The Spectrum of Health Domains Important to Lupus Patients Early Development of a Disease Activity Patient Reported Outcome.

INTRODUCTION: Patients with systemic lupus erythematosus (SLE) face lifelong challenges from chronic and disabling symptoms. The toolkit for assessing patient progress lacks a simple, scalable index that includes both physician assessments and patient experiences. Clinician and patient reported outcomes (ClinROs and PROs) were developed in isolation and discrepancies in their results promote confusion. The Lupus Foundation of America-Rapid Evaluation of Activity in Lupus (LFA-REAL™) was designed as a simple, versatile instrument of simple additive scales. Dual physician and patient components allow for a complete evaluation of disease activity. This report presents the early development of the LFA-REAL™ PRO. METHODS: An initial focus group was conducted consisting of 10 SLE patients who ranked 32 areas of health and identified additional domains that are important to people with lupus. Subsequently, 19 domains were ranked by 100 consecutive patients with SLE from New York and Oklahoma City. RESULTS: The 10 focus group participants were female and had a mean age of 38.6. The dimensions they identified were generally in two categories: symptoms and impacts. The main symptoms were fatigue, joint and muscle pain, and general pain. The main impacts were sleep, drug side effects, and physical well-being. The 100 patients with SLE (90% female, mean age 37.5 years) ranked the 19 fields of health in order of importance. The top eight domains ranked were joint and muscle pain, fatigue, experience of quality of life, general pain, physical well-being, emotional well-being, organ involvement, and family life. Clinicians reviewed the data and decided on an instrument that would differentiate between lupus related symptoms and impact on quality of life as well as differentiate active symptoms from chronic damage. The disease activity instrument draft included all the identified symptoms: rash, joint symptoms (pains, stiffness, and swelling), muscle pain, fatigue, organ involvement symptoms (fever, chest pain, shortness of breath, leg swelling, and other), and hair loss. DISCUSSION: The PRO derived here is a composite disease activity instrument to accompany the physician reported assessment. The ClinRO and the PRO will provide the spectrum of lupus disease activity and bring the patient's experience and provide essential quantitative data to the evaluation of lupus in routine clinical care and clinical research.

Belatacept in kidney transplant patients with systemic lupus erythematosus.

OBJECTIVES: Lupus nephritis (LN) requires renal replacement therapy in 10%-30% of patients. About 30% of these patients receive a kidney transplant. Belatacept is a second-generation, selective, T-cell co-stimulator blocker (inhibits cytotoxic, T-lymphocyte antigen 4, CTLA-4) used as an alternative to calcineurin inhibitors (CNI) for maintenance regimens after kidney transplantation. The pathogenic relevance of CTLA-4 inhibition and the favourable cardiovascular profile of belatacept make it an attractive therapeutic option in systemic lupus erythematosus (SLE). Intravenous administration of belatacept ensures therapeutic adherence. METHODS: This retrospective, single-centre study evaluates the outcomes of LN kidney transplant recipients treated with belatacept for reasons not related to SLE at the Columbia University Lupus and Renal Transplant Cohort. RESULTS: Belatacept was started in six patients on CNI regimens at 15.5±17.1 months following transplantation for LN. In five patients, creatinine levels stabilised 6 months after belatacept, one returned to haemodialysis due to CNI toxicity and pyelonephritis and one relisted for a kidney transplant following acute cellular rejection and cortical necrosis. Five patients are followed for extrarenal lupus; no extrarenal manifestations were documented in the other two patients. Data on SLE disease activity pre-belatacept and post-belatacept were available and scored in three patients using the SLE Disease Activity Index Glucocorticosteroid Index (SLEDAI-2KG), which accounts for clinical and laboratory manifestations, as well as steroid dose. Mean SLEDAI-2KG decreased from 13 to 7.6. CONCLUSION: Belatacept in LN kidney transplant recipients may decrease extrarenal manifestations, attenuate CNI toxicity and stabilise allograft function, providing a better alternative to CNI regimens. Furthermore, these data suggest that belatacept, although initiated for reasons not related to SLE, might have a beneficial effect in SLE.