Emerging data suggest that Electro-Convulsive Treatment (ECT) may reduce depressive symptoms by increasing the expression of Brain-Derived Neurotrophic Factor (BDNF). Yet, conflicting findings have ...been reported. For this reason we performed a systematic review and meta-analysis of the preclinical and clinical literature on the association between ECT treatment (ECS in animals) and changes in BDNF concentrations and their effect on behavior. In addition, regional brain expression of BDNF in mouse and human brains were compared using Allen Brain Atlas. ECS, over sham, increased BDNF mRNA and protein in animal brain (effect size Hedge's g: 0.38-0.54; 258 effect-size estimates, N = 4,284) but not in serum (g = 0.06, 95% CI = -0.05-0.17). In humans, plasma but not serum BDNF increased following ECT (g = 0.72 vs. g = 0.14; 23 effect sizes, n = 281). The gradient of the BDNF increment in animal brains corresponded to the gradient of the BDNF gene expression according to the Allen brain atlas. Effect-size estimates were larger following more ECT sessions in animals (r = 0.37, P < .0001) and in humans (r = 0.55; P = 0.05). There were some indications that the increase in BDNF expression was associated with behavioral changes in rodents, but not in humans. We conclude that ECS in rodents and ECT in humans increase BDNF concentrations but this is not consistently associated with changes in behavior.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although Li-rich layered oxides (Li1+xNiyCozMn1-x-y-zO2 > 250 mAh g(-1)) are attractive electrode materials providing energy densities more than 15% higher than today's commercial Li-ion cells, they ...suffer from voltage decay on cycling. To elucidate the origin of this phenomenon, we employ chemical substitution in structurally related Li2RuO3 compounds. Li-rich layered Li2Ru1-yTiyO3 phases with capacities of ~240 mAh g(-1) exhibit the characteristic voltage decay on cycling. A combination of transmission electron microscopy and X-ray photoelectron spectroscopy studies reveals that the migration of cations between metal layers and Li layers is an intrinsic feature of the charge-discharge process that increases the trapping of metal ions in interstitial tetrahedral sites. A correlation between these trapped ions and the voltage decay is established by expanding the study to both Li2Ru1-ySnyO3 and Li2RuO3; the slowest decay occurs for the cations with the largest ionic radii. This effect is robust, and the finding provides insights into new chemistry to be explored for developing high-capacity layered electrodes that evade voltage decay.
The energy density delivered by a Li-ion battery is a key parameter that needs to be significantly increased to address the global question of energy storage for the next 40 years. This quantity is ...directly proportional to the battery voltage (V) and the battery capacity (C) which are difficult to improve simultaneously when materials exhibit classical cationic redox activity. Recently, a cumulative cationic (M super(4+)/M super(5+)) and anionic (2O super(2-)/(O sub(2)) n-) redox activity has been demonstrated in the Li-rich Li sub(2)MO sub(3) family of compounds, therefore enabling doubling of the energy density with respect to high-potential cathodes such as transition metal phosphates and sulfates. This paper aims to clarify the origin of this extra capacity by addressing some fundamental questions regarding reversible anionic redox in high-potential electrodes for Li-ion batteries. First, the ability of the system to stabilize the oxygen holes generated by Li-removal and to achieve a reversible oxo- to peroxo-like (2O super(2-)/(O sub(2)) n-) transformation is elucidated by means of a metal-driven reductive coupling mechanism. The penchant of the system for undergoing this reversible anionic redox or releasing O sub(2) gas is then discussed with regards to experimental results for 3d- and 4d-based Li sub(2)MO sub(3) phases. Finally, robust indicators are built as tools to predict which materials in the Li-rich TM-oxide family will undergo efficient and reversible anionic redox. The present finding provides insights into new directions to be explored for the development of high-energy density materials for Li-ion batteries.
KRAS is the most frequently mutated oncogene in human cancer. In addition to holding this distinction, unsuccessful attempts to target this protein have led to the characterization of RAS as ...'undruggable'. However, recent advances in technology and novel approaches to drug discovery have renewed hope that a direct KRAS inhibitor may be on the horizon. In this Review, we provide an in-depth analysis of the structure, dynamics, mutational activation and inactivation, and signalling mechanisms of RAS. From this perspective, we then consider potential mechanisms of action for effective RAS inhibitors. Finally, we examine each of the many recent reports of direct RAS inhibitors and discuss promising avenues for further development.
Logical qubit encoding and quantum error correction (QEC) protocols have been experimentally demonstrated in various physical systems with multiple physical qubits, generally without reaching the ...break-even point, at which the lifetime of the quantum information exceeds that of the single best physical qubit within the logical qubit. Logical operations are challenging, owing to the necessary non-local operations at the physical level, making bosonic logical qubits that rely on higher Fock states of a single oscillator attractive, given their hardware efficiency. QEC that reaches the break-even point and single logical-qubit operations have been demonstrated using the bosonic cat code. Here, we experimentally demonstrate repetitive QEC approaching the break-even point of a single logical qubit encoded in a hybrid system consisting of a superconducting circuit and a bosonic cavity using a binomial bosonic code. This is achieved while simultaneously maintaining full control of the single logical qubit, including encoding, decoding and a high-fidelity universal quantum gate set with 97% average process fidelity. The corrected logical qubit has a lifetime 2.8 times longer than that of its uncorrected counterpart. We also perform a Ramsey experiment on the corrected logical qubit, reporting coherence twice as long as for the uncorrected case.Repeated error correction creates a logical qubit encoded in the hybrid state of a superconducting circuit and a bosonic cavity, which is shown to be fully controllable under a universal single-qubit gate set.
IMPORTANCE: The efficacy of endovascular thrombectomy (EVT) for symptomatic large anterior vessel occlusion (sLAVO) sharply decreases with time. Because EVT is restricted to comprehensive stroke ...centers, prehospital triage of patients with acute stroke codes for sLAVO is crucial, and although several prediction scales are already in use, external validation, head-to-head comparison, and feasibility data are lacking. OBJECTIVE: To conduct external validation and head-to-head comparisons of 7 sLAVO prediction scales in the emergency medical service (EMS) setting and to assess scale feasibility by EMS paramedics. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study was conducted between July 2018 and October 2019 in a large urban center in the Netherlands with a population of approximately 2 million people and included 2 EMSs, 3 comprehensive stroke centers, and 4 primary stroke centers. Participants were consecutive patients aged 18 years or older for whom an EMS-initiated acute stroke code was activated. Of 2812 acute stroke codes, 805 (28.6%) were excluded, because no application was used or no clinical data were available, leaving 2007 patients included in the analyses. EXPOSURES: Applications with clinical observations filled in by EMS paramedics for each acute stroke code enabling reconstruction of the following 7 prediction scales: Los Angeles Motor Scale (LAMS); Rapid Arterial Occlusion Evaluation (RACE); Cincinnati Stroke Triage Assessment Tool; Prehospital Acute Stroke Severity (PASS); gaze-face-arm-speech-time; Field Assessment Stroke Triage for Emergency Destination; and gaze, facial asymmetry, level of consciousness, extinction/inattention. MAIN OUTCOMES AND MEASURES: Planned primary and secondary outcomes were sLAVO and feasibility rates (ie, the proportion of acute stroke codes for which the prehospital scale could be reconstructed). Predictive performance measures included accuracy, sensitivity, specificity, the Youden index, and predictive values. RESULTS: Of 2007 patients who received acute stroke codes (mean SD age, 71.1 14.9 years; 1021 50.9% male), 158 (7.9%) had sLAVO. Accuracy of the scales ranged from 0.79 to 0.89, with LAMS and RACE scales yielding the highest scores. Sensitivity of the scales ranged from 38% to 62%, and specificity from 80% to 93%. Scale feasibility rates ranged from 78% to 88%, with the highest rate for the PASS scale. CONCLUSIONS AND RELEVANCE: This study found that all 7 prediction scales had good accuracy, high specificity, and low sensitivity, with LAMS and RACE being the highest scoring scales. Feasibility rates ranged between 78% and 88% and should be taken into account before implementing a scale.
Most individuals with dementia or mild cognitive impairment (MCI) have multiple chronic conditions (MCC). The combination leads to multiple medications and complex medication regimens and is ...associated with increased risk for significant treatment burden, adverse drug events, cognitive changes, hospitalization, and mortality. Optimizing medications through deprescribing (the process of reducing or stopping the use of inappropriate medications or medications unlikely to be beneficial) may improve outcomes for MCC patients with dementia or MCI.
With input from patients, family members, and clinicians, we developed and piloted a patient-centered, pragmatic intervention (OPTIMIZE) to educate and activate patients, family members, and primary care clinicians about deprescribing as part of optimal medication management for older adults with dementia or MCI and MCC. The clinic-based intervention targets patients on 5 or more medications, their family members, and their primary care clinicians using a pragmatic, cluster-randomized design at Kaiser Permanente Colorado. The intervention has two components: a patient/ family component focused on education and activation about the potential value of deprescribing, and a clinician component focused on increasing clinician awareness about options and processes for deprescribing. Primary outcomes are total number of chronic medications and total number of potentially inappropriate medications (PIMs). We estimate that approximately 2400 patients across 9 clinics will receive the intervention. A comparable number of patients from 9 other clinics will serve as wait-list controls. We have > 80% power to detect an average decrease of - 0.70 (< 1 medication). Secondary outcomes include the number of PIM starts, dose reductions for selected PIMs (benzodiazepines, opiates, and antipsychotics), rates of adverse drug events (falls, hemorrhagic events, and hypoglycemic events), ability to perform activities of daily living, and skilled nursing facility, hospital, and emergency department admissions.
The OPTIMIZE trial will examine whether a primary care-based, patient- and family-centered intervention educating patients, family members, and clinicians about deprescribing reduces numbers of chronic medications and PIMs for older adults with dementia or MCI and MCC.
NCT03984396. Registered on 13 June 2019.
Many patients with aggressive B-cell lymphomas and high clinical risk score still die of lymphoma after conventional R-CHOP chemoimmunotherapy. We hypothesized that intensified chemoimmunotherapy ...including systemic central nervous system (CNS) prophylaxis improves outcome and reduces the incidence of CNS-related events.
Inclusion criteria were age 18–65 years, primary diffuse large B-cell lymphoma or grade III follicular lymphoma without clinical signs of CNS disease and negative cerebrospinal fluid cytology, age-adjusted International Prognostic Index 2–3 and WHO performance score 0–3. Treatment consisted of six courses of R-CHOEP-14 followed by a course of high-dose cytarabine and a course of high-dose methotrexate. Primary end point was failure-free survival (FFS) at 3 years.
A total of 156 eligible patients with a median age of 54 years (range 20–64) were included. Three toxic deaths were observed. Three-year overall survival (OS) and FFS rates (median observation time 52 months for survivors) were 81% and 65%, respectively. Seven patients experienced CNS relapse, all within 6 months.
The results are promising with favorable 3-year OS and FFS rates, a low toxic death rate and a lower than expected number of CNS events. CNS progression might be further reduced by earlier CNS prophylaxis.
NCT01502982.
The active control of a molecular spin represents one of the main challenges in molecular spintronics. Up to now spin manipulation has been achieved through the modification of the molecular ...structure either by chemical doping or by external stimuli. However, the spin of a molecule adsorbed on a surface depends primarily on the interaction between its localized orbitals and the electronic states of the substrate. Here we change the effective spin of a single molecule by modifying the molecule/metal interface in a controlled way using a low-temperature scanning tunneling microscope. A nickelocene molecule reversibly switches from a spin 1 to 1/2 when varying the electrode-electrode distance from tunnel to contact regime. This switching is experimentally evidenced by inelastic and elastic spin-flip mechanisms observed in reproducible conductance measurements and understood using first principle calculations. Our work demonstrates the active control over the spin state of single molecule devices through interface manipulation.
To reduce widespread shortages, attempts are made to use more marginal livers for transplantation. Many of these grafts are discarded for fear of inferior survival rates or biliary complications. ...Recent advances in organ preservation have shown that ex vivo subnormothermic machine perfusion has the potential to improve preservation and recover marginal livers pretransplantation. To determine the feasibility in human livers, we assessed the effect of 3 h of oxygenated subnormothermic machine perfusion (21°C) on seven livers discarded for transplantation. Biochemical and microscopic assessment revealed minimal injury sustained during perfusion. Improved oxygen uptake (1.30 1.11–1.94 to 6.74 4.15–8.16 mL O2/min kg liver), lactate levels (4.04 3.70–5.99 to 2.29 1.20–3.43 mmol/L) and adenosine triphosphate content (45.0 70.6–87.5 pmol/mg preperfusion to 167.5 151.5–237.2 pmol/mg after perfusion) were observed. Liver function, reflected by urea, albumin and bile production, was seen during perfusion. Bile production increased and the composition of bile (bile salts/phospholipid ratio, pH and bicarbonate concentration) became more favorable. In conclusion, ex vivo subnormothermic machine perfusion effectively maintains liver function with minimal injury and sustains or improves various hepatobiliary parameters postischemia.
This study of human livers shows that subnormothermic machine perfusion can preserve hepatobiliary function and may be feasible for liver graft recovery pretransplantation.
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