In a randomized trial involving 59 selected patients with depression, the change in depression scale scores from baseline to week 6 did not differ significantly between patients who received two ...doses of psilocybin and those who received daily escitalopram. Secondary outcomes generally favored psilocybin over escitalopram.
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
Patients with proximal deep-vein thrombosis were assigned to undergo anticoagulation either alone or combined with pharmacomechanical thrombolysis. After 6 to 24 months, there was no significant ...between-group difference in the incidence of the post-thrombotic syndrome.
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.
IMPORTANCE: 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. OBJECTIVE: To estimate the US national incidence of sepsis and trends using detailed clinical data from the electronic health record (EHR) systems of diverse hospitals. DESIGN, SETTING, AND POPULATION: Retrospective cohort study of adult patients admitted to 409 academic, community, and federal hospitals from 2009-2014. EXPOSURES: 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. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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). CONCLUSIONS AND RELEVANCE: 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.
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.
This study showed an association of loss-of-function mutations in
ANGPTL4
with low triglyceride levels and protection against coronary artery disease. Inhibition of Angptl4 in mice and monkeys with a ...monoclonal antibody reduced triglyceride levels.
The level of serum triglycerides is, in part, heritable, and elevated levels are associated with a risk of ischemic cardiovascular disease.
1
–
3
Mendelian randomization studies of genetically determined triglyceride levels have suggested that this association is causal.
4
Two lines of genetic evidence have further established a causal role for serum triglycerides in the risk of cardiovascular disease. First, inactivating mutations in the gene encoding apolipoprotein C3 (
APOC3
), a component of remnant particles, were reported to be associated with decreased serum triglyceride levels, a decreased burden of subclinical atherosclerosis, and a reduced risk of ischemic cardiovascular disease, which suggests . . .
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