Trial of Psilocybin versus Escitalopram for Depression Carhart-Harris, Robin; Giribaldi, Bruna; Watts, Rosalind ...
New England journal of medicine/The New England journal of medicine,
04/2021, Volume:
384, Issue:
15
Journal Article
Peer reviewed
Open access
Psilocybin may have antidepressant properties, but direct comparisons between psilocybin and established treatments for depression are lacking.
In a phase 2, double-blind, randomized, controlled ...trial involving patients with long-standing, moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, a selective serotonin-reuptake inhibitor, over a 6-week period. Patients were assigned in a 1:1 ratio to receive two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo (psilocybin group) or two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram (escitalopram group); all the patients received psychological support. The primary outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating greater depression) at week 6. There were 16 secondary outcomes, including QIDS-SR-16 response (defined as a reduction in score of >50%) and QIDS-SR-16 remission (defined as a score of ≤5) at week 6.
A total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean scores on the QIDS-SR-16 at baseline were 14.5 in the psilocybin group and 16.4 in the escitalopram group. The mean (±SE) changes in the scores from baseline to week 6 were -8.0±1.0 points in the psilocybin group and -6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval CI, -5.0 to 0.9) (P = 0.17). A QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group and in 48% of those in the escitalopram group, for a between-group difference of 22 percentage points (95% CI, -3 to 48); QIDS-SR-16 remission occurred in 57% and 28%, respectively, for a between-group difference of 28 percentage points (95% CI, 2 to 54). Other secondary outcomes generally favored psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons. The incidence of adverse events was similar in the trial groups.
On the basis of the change in depression scores on the QIDS-SR-16 at week 6, this trial did not show a significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients. Secondary outcomes generally favored psilocybin over escitalopram, but the analyses of these outcomes lacked correction for multiple comparisons. Larger and longer trials are required to compare psilocybin with established antidepressants. (Funded by the Alexander Mosley Charitable Trust and Imperial College London's Centre for Psychedelic Research; ClinicalTrials.gov number, NCT03429075.).
The tuberous sclerosis complex (TSC) tumor suppressors form the TSC1-TSC2 complex, which limits cell growth in response to poor growth conditions. Through its GTPase-activating protein (GAP) activity ...toward Rheb, this complex inhibits the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a key promoter of cell growth. Here, we identify and biochemically characterize TBC1D7 as a stably associated and ubiquitous third core subunit of the TSC1-TSC2 complex. We demonstrate that the TSC1-TSC2-TBC1D7 (TSC-TBC) complex is the functional complex that senses specific cellular growth conditions and possesses Rheb-GAP activity. Sequencing analyses of samples from TSC patients suggest that TBC1D7 is unlikely to represent TSC3. TBC1D7 knockdown decreases the association of TSC1 and TSC2 leading to decreased Rheb-GAP activity, without effects on the localization of TSC2 to the lysosome. Like the other TSC-TBC components, TBC1D7 knockdown results in increased mTORC1 signaling, delayed induction of autophagy, and enhanced cell growth under poor growth conditions.
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► TBC1D7 is a ubiquitous, stably associated third core subunit of the TSC1-TSC2 complex ► TSC1 binds to and stabilizes both TSC2 and TBC1D7 within the trimeric complex ► The TSC1-TSC2-TBC1D7 (TSC-TBC) complex is the functional Rheb-GAP upstream of mTORC1 ► As part of the TSC-TBC complex, TBC1D7 inhibits mTORC1 and downstream functions
The post-thrombotic syndrome frequently develops in patients with proximal deep-vein thrombosis despite treatment with anticoagulant therapy. Pharmacomechanical catheter-directed thrombolysis ...(hereafter "pharmacomechanical thrombolysis") rapidly removes thrombus and is hypothesized to reduce the risk of the post-thrombotic syndrome.
We randomly assigned 692 patients with acute proximal deep-vein thrombosis to receive either anticoagulation alone (control group) or anticoagulation plus pharmacomechanical thrombolysis (catheter-mediated or device-mediated intrathrombus delivery of recombinant tissue plasminogen activator and thrombus aspiration or maceration, with or without stenting). The primary outcome was development of the post-thrombotic syndrome between 6 and 24 months of follow-up.
Between 6 and 24 months, there was no significant between-group difference in the percentage of patients with the post-thrombotic syndrome (47% in the pharmacomechanical-thrombolysis group and 48% in the control group; risk ratio, 0.96; 95% confidence interval CI, 0.82 to 1.11; P=0.56). Pharmacomechanical thrombolysis led to more major bleeding events within 10 days (1.7% vs. 0.3% of patients, P=0.049), but no significant difference in recurrent venous thromboembolism was seen over the 24-month follow-up period (12% in the pharmacomechanical-thrombolysis group and 8% in the control group, P=0.09). Moderate-to-severe post-thrombotic syndrome occurred in 18% of patients in the pharmacomechanical-thrombolysis group versus 24% of those in the control group (risk ratio, 0.73; 95% CI, 0.54 to 0.98; P=0.04). Severity scores for the post-thrombotic syndrome were lower in the pharmacomechanical-thrombolysis group than in the control group at 6, 12, 18, and 24 months of follow-up (P<0.01 for the comparison of the Villalta scores at each time point), but the improvement in quality of life from baseline to 24 months did not differ significantly between the treatment groups.
Among patients with acute proximal deep-vein thrombosis, the addition of pharmacomechanical catheter-directed thrombolysis to anticoagulation did not result in a lower risk of the post-thrombotic syndrome but did result in a higher risk of major bleeding. (Funded by the National Heart, Lung, and Blood Institute and others; ATTRACT ClinicalTrials.gov number, NCT00790335 .).
Abstract Once damaged, cardiac muscle has little intrinsic repair capability due to the poor regeneration potential of remaining cardiomyocytes. One method of overcoming this issue is to deliver ...functional cells to the injured myocardium to promote repair. To address this limitation we sought to test the hypothesis that electroactive carbon nanotubes (CNT) could be employed to direct mesenchymal stem cell (MSC) differentiation towards a cardiomyocyte lineage. Using a two-pronged approach, MSCs exposed to medium containing CNT and MSCs seeded on CNT based polylactic acid scaffolds were electrically stimulated in an electrophysiological bioreactor. After electrical stimulation the cells reoriented perpendicular to the direction of the current and adopted an elongated morphology. Using qPCR, an upregulation in a range of cardiac markers was detected, the greatest of which was observed for cardiac myosin heavy chain (CMHC), where a 40-fold increase was observed for the electrically stimulated cells after 14 days, and a 12-fold increase was observed for the electrically stimulated cells seeded on the PLA scaffolds after 10 days. Differentiation towards a cardioprogenitor cell was more evident from the western blot analysis, where upregulation of Nkx2.5, GATA-4, cardiac troponin t (CTT) and connexin43 (C43) was seen to occur. This was echoed in immunofluorescent staining, where increased levels of CTT, CMHC and C43 protein expression were observed after electrical stimulation for both cells and cell-seeded scaffolds. More interestingly, there was evidence of increased cross talk between the cells as shown by the pattern of C43 staining after electrical stimulation. These results establish a paradigm for nanoscale biomimetic cues that can be readily translated to other electroactive tissue repair applications.
Estimates from claims-based analyses suggest that the incidence of sepsis is increasing and mortality rates from sepsis are decreasing. However, estimates from claims data may lack clinical fidelity ...and can be affected by changing diagnosis and coding practices over time.
To estimate the US national incidence of sepsis and trends using detailed clinical data from the electronic health record (EHR) systems of diverse hospitals.
Retrospective cohort study of adult patients admitted to 409 academic, community, and federal hospitals from 2009-2014.
Sepsis was identified using clinical indicators of presumed infection and concurrent acute organ dysfunction, adapting Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) criteria for objective and consistent EHR-based surveillance.
Sepsis incidence, outcomes, and trends from 2009-2014 were calculated using regression models and compared with claims-based estimates using International Classification of Diseases, Ninth Revision, Clinical Modification codes for severe sepsis or septic shock. Case-finding criteria were validated against Sepsis-3 criteria using medical record reviews.
A total of 173 690 sepsis cases (mean age, 66.5 SD, 15.5 y; 77 660 42.4% women) were identified using clinical criteria among 2 901 019 adults admitted to study hospitals in 2014 (6.0% incidence). Of these, 26 061 (15.0%) died in the hospital and 10 731 (6.2%) were discharged to hospice. From 2009-2014, sepsis incidence using clinical criteria was stable (+0.6% relative change/y 95% CI, -2.3% to 3.5%, P = .67) whereas incidence per claims increased (+10.3%/y 95% CI, 7.2% to 13.3%, P < .001). In-hospital mortality using clinical criteria declined (-3.3%/y 95% CI, -5.6% to -1.0%, P = .004), but there was no significant change in the combined outcome of death or discharge to hospice (-1.3%/y 95% CI, -3.2% to 0.6%, P = .19). In contrast, mortality using claims declined significantly (-7.0%/y 95% CI, -8.8% to -5.2%, P < .001), as did death or discharge to hospice (-4.5%/y 95% CI, -6.1% to -2.8%, P < .001). Clinical criteria were more sensitive in identifying sepsis than claims (69.7% 95% CI, 52.9% to 92.0% vs 32.3% 95% CI, 24.4% to 43.0%, P < .001), with comparable positive predictive value (70.4% 95% CI, 64.0% to 76.8% vs 75.2% 95% CI, 69.8% to 80.6%, P = .23).
In clinical data from 409 hospitals, sepsis was present in 6% of adult hospitalizations, and in contrast to claims-based analyses, neither the incidence of sepsis nor the combined outcome of death or discharge to hospice changed significantly between 2009-2014. The findings also suggest that EHR-based clinical data provide more objective estimates than claims-based data for sepsis surveillance.
The implications of the declining energy return on investment of oil production Murphy, David J.
Philosophical transactions - Royal Society. Mathematical, Physical and engineering sciences/Philosophical transactions - Royal Society. Mathematical, physical and engineering sciences,
01/2014, Volume:
372, Issue:
2006
Journal Article
Peer reviewed
Open access
Declining production from conventional oil resources has initiated a global transition to unconventional oil, such as tar sands. Unconventional oil is generally harder to extract than conventional ...oil and is expected to have a (much) lower energy return on (energy) investment (EROI). Recently, there has been a surge in publications estimating the EROI of a number of different sources of oil, and others relating EROI to long-term economic growth, profitability and oil prices. The following points seem clear from a review of the literature: (i) the EROI of global oil production is roughly 17 and declining, while that for the USA is 11 and declining; (ii) the EROI of ultra-deep-water oil and oil sands is below 10; (iii) the relation between the EROI and the price of oil is inverse and exponential; (iv) as EROI declines below 10, a point is reached when the relation between EROI and price becomes highly nonlinear; and (v) the minimum oil price needed to increase the oil supply in the near term is at levels consistent with levels that have induced past economic recessions. From these points, I conclude that, as the EROI of the average barrel of oil declines, long-term economic growth will become harder to achieve and come at an increasingly higher financial, energetic and environmental cost.
Humans strongly impact the dynamics of coastal systems, yet surprisingly few studies mechanistically link management of anthropogenic stressors and successful restoration of nearshore habitats over ...large spatial and temporal scales. Such examples are sorely needed to ensure the success of ecosystem restoration efforts worldwide. Here, we unite 30 consecutive years of watershed modeling, biogeochemical data, and comprehensive aerial surveys of Chesapeake Bay, United States to quantify the cascading effects of anthropogenic impacts on submersed aquatic vegetation (SAV), an ecologically and economically valuable habitat. We employ structural equation models to link land use change to higher nutrient loads, which in turn reduce SAV cover through multiple, independent pathways. We also show through our models that high biodiversity of SAV consistently promotes cover, an unexpected finding that corroborates emerging evidence from other terrestrial and marine systems. Due to sustained management actions that have reduced nitrogen concentrations in Chesapeake Bay by 23% since 1984, SAV has regained 17,000 ha to achieve its highest cover in almost half a century. Our study empirically demonstrates that nutrient reductions and biodiversity conservation are effective strategies to aid the successful recovery of degraded systems at regional scales, a finding which is highly relevant to the utility of environmental management programs worldwide.
Highly prevalent among the elderly, hip osteoarthritis (OA) carries a heavy burden of disease. Guidelines for the management of hip OA are often extrapolated from knee OA research, despite clear ...differences in the etiopathogenesis and response to treatments of OA at these sites. We propose that hip OA requires specific attention separate from other OA phenotypes. Our understanding of the etiopathogenesis of hip OA has seen significant advance over the last 15 years, since Ganz and colleagues proposed femoroacetabular impingement (FAI) as an important etiological factor. This narrative review summarizes the current understanding of the etiopathogenesis of hip OA and identifies areas requiring further research. Therapeutic approaches for hip OA are considered in light of the condition’s etiopathogenesis. The evidence for currently adopted management strategies is considered, especially those approaches that may have disease-modifying potential. We propose that shifting the focus of hip OA research and public health intervention to primary prevention and early detection may greatly improve the current management paradigm.
Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer-related death. The immune-rich contexture of the HCC microenvironment makes this tumour an appealing target for immune-based ...therapies. Here, we discuss how the functional characteristics of the liver microenvironment can potentially be harnessed for the treatment of HCC. We will review the evidence supporting a therapeutic role for vaccines, cell-based therapies and immune-checkpoint inhibitors and discuss the potential for patient stratification in an attempt to overcome the series of failures that has characterised drug development in this disease area.
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