Heat engines provide most of our mechanical power and are essential for transportation on the macroscopic scale. However, although significant progress has been made in the miniaturization of ...electrostatic engines, it has proved difficult to reduce the size of liquid- or gas-driven heat engines below 107 μm3. Here we demonstrate that a crystalline silicon structure operates as a cyclic piezoresistive heat engine when it is driven by a sufficiently high d.c. current. A 0.34 μm3 engine beam draws heat from the d.c. current using the piezoresistive effect and converts it into mechanical work by expansion and contraction at different temperatures. This mechanical power drives a silicon resonator of 1.1×103 μm3 into sustained oscillation. Even below the oscillation threshold the engine beam continues to amplify the resonator's Brownian motion. When its thermodynamic cycle is inverted, the structure is shown to reduce these thermal fluctuations, therefore operating as a refrigerator. PUBLICATION ABSTRACT
Introduction
Ipilimumab, a cytotoxic T lymphocyte-associated antigen-4 blocking antibody, has improved overall survival (OS) in metastatic melanoma in phase III trials. However, about 80 % of ...patients fail to respond, and no predictive markers for benefit from therapy have been identified. We analysed a ‘real world’ population of patients treated with ipilimumab to identify markers for treatment benefit.
Methods
Patients with advanced cutaneous melanoma were treated in the Netherlands (NL) and the United Kingdom (UK) with ipilimumab at 3 mg/kg. Baseline characteristics and peripheral blood parameters were assessed, and patients were monitored for the occurrence of adverse events and outcomes.
Results
A total of 166 patients were treated in the Netherlands. Best overall response and disease control rates were 17 and 35 %, respectively. Median follow-up was 17.9 months, with a median progression-free survival of 2.9 months. Median OS was 7.5 months, and OS at 1 year was 37.8 % and at 2 years was 22.9 %. In a multivariate model, baseline serum lactate dehydrogenase (LDH) was demonstrated to be the strongest predictive factor for OS. These findings were validated in an independent cohort of 64 patients from the UK.
Conclusion
In both the NL and UK cohorts, long-term benefit of ipilimumab treatment was unlikely for patients with baseline serum LDH greater than twice the upper limit of normal. In the absence of prospective data, clinicians treating melanoma may wish to consider the data presented here to guide patient selection for ipilimumab therapy.
The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency, and increases morbidity and duration of hospital stay. To date, the nature of ...diaphragm weakness and its underlying pathophysiologic mechanisms are poorly understood.
We hypothesized that diaphragm muscle fibers of mechanically ventilated critically ill patients display atrophy and contractile weakness, and that the ubiquitin-proteasome pathway is activated in the diaphragm.
We obtained diaphragm muscle biopsies from 22 critically ill patients who received mechanical ventilation before surgery and compared these with biopsies obtained from patients during thoracic surgery for resection of a suspected early lung malignancy (control subjects). In a proof-of-concept study in a muscle-specific ring finger protein-1 (MuRF-1) knockout mouse model, we evaluated the role of the ubiquitin-proteasome pathway in the development of contractile weakness during mechanical ventilation.
Both slow- and fast-twitch diaphragm muscle fibers of critically ill patients had approximately 25% smaller cross-sectional area, and had contractile force reduced by half or more. Markers of the ubiquitin-proteasome pathway were significantly up-regulated in the diaphragm of critically ill patients. Finally, MuRF-1 knockout mice were protected against the development of diaphragm contractile weakness during mechanical ventilation.
These findings show that diaphragm muscle fibers of critically ill patients display atrophy and severe contractile weakness, and in the diaphragm of critically ill patients the ubiquitin-proteasome pathway is activated. This study provides rationale for the development of treatment strategies that target the contractility of diaphragm fibers to facilitate weaning.
As nuclear and particle physics facilities move to higher intensities, the detectors used there must be more radiation tolerant. Diamond is in use at many facilities due to its inherent radiation ...tolerance and ease of use. In this article we present our radiation tolerance measurements of the highest quality polycrystalline Chemical Vapor Deposition (pCVD) diamond material for irradiations from a range of proton energies, pions and neutrons up to a fluence of 2×1016particles/cm2. We have measured the damage constant as a function of energy and particle species and compared it with theoretical models. We also present measurements of the rate dependence of pulse height for non-irradiated and irradiated pCVD diamond pad and pixel detectors, including detectors tested over a range of particle fluxes up to 20 MHz/cm2 with both pad and pixel readout electronics. Our test beam results indicate a 2% upper limit to the pulse height dependence of unirradiated and neutron irradiated pCVD diamond detectors leading to the conclusion that the pulse height in pCVD diamond detectors is, at most, minimally dependent on the particle flux.
Among esophagogastric cancer patients, the probability of having undergone treatment with curative intent has been shown to vary, depending on the hospital of diagnosis. However, little is known ...about the factors that contribute to this variation. In this study, we sought to understand the organization of clinical pathways and their association with variation in practice.
A mixed-method study using quantitative and qualitative data was conducted. Quantitative data were obtained from the Netherlands Cancer Registry (e.g., outpatient clinic consultations and diagnostic procedures). For qualitative data, thematic content analysis was performed using semi-structured interviews (n = 30), observations of outpatient clinic consultations (n = 26), and multidisciplinary team meetings (MDTM, n = 16) in eight hospitals, to assess clinicians' perspectives regarding the clinical pathways.
Quantitative analyses showed that patients more often underwent surgical consultation prior to the MDTM in hospitals associated with a high probability of receiving treatment with curative intent, but more often consulted with a geriatrician in hospitals associated with a low probability of such treatment. The organization of clinical pathways was analyzed quantitatively at three levels: regional, local, and patient levels. At a regional level, hospitals differed in terms of the number of patients discussed during the MDTM. At the local level, the revision of radiological images and restaging after neoadjuvant treatment varied. At the patient level, some hospitals routinely conduct fitness tests, whereas others estimated the patient's physical fitness during an outpatient clinic consultation. Few clinicians performed a standard geriatric consultation in older patients to assess their mental fitness and frailty.
Surgical consultation prior to MDTM was more often conducted in hospitals associated with a high probability of receiving treatment with curative intent, whereas a geriatrician was consulted more often in hospitals associated with a low probability of receiving such treatment.
The suitability of type IIa diamonds prepared by High Pressure High Temperature (HPHT) in cubic presses at New Diamond Technology was assessed as substrates for the growth of thick detector-grade ...quality Chemically Vapour Deposited (CVD) diamond films. The substrates were found to possess a moderate dislocation density of about 103cm−2 and a reduced amount of residual impurities as compared to standard type Ib crystals. Using these diamonds as seeds for homoepitaxial growth, CVD films with improved structural characteristics were obtained although extended defects could not be completely prevented from forming and propagating. Their performance as detectors for β radiation was however improved leading to almost full charge collection which shows significant improvement as compared to CVD films grown under the same conditions on standard Ib HPHT diamonds. The availability of this new material source opens the way to the fabrication of higher quality CVD material for electronics applications.
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•Thick intrinsic CVD films are grown and retrieved from type IIa diamond substrates.•NDT's type IIa substrates have reduced impurity content and dislocation densities.•CVD films grown on NDT substrates show improved characteristics as compared to standard material.•A thick freestanding CVD plate with almost 100% charge collection efficiency is demonstrated.
The continuing miniaturization of microelectronics raises the prospect of nanometre-scale devices with mechanical and electrical properties that are qualitatively different from those at larger ...dimensions. The investigation of these properties, and particularly the increasing influence of quantum effects on electron transport, has therefore attracted much interest. Quantum properties of the conductance can be observed when 'breaking' a metallic contact: as two metal electrodes in contact with each other are slowly retracted, the contact area undergoes structural rearrangements until it consists in its final stages of only a few bridging atoms. Just before the abrupt transition to tunnelling occurs, the electrical conductance through a monovalent metal contact is always close to a value of 2e2/h ( 12.9 Ω−1), where e is the charge on an electron and h is Planck's constant. This value corresponds to one quantum unit of conductance, thus indicating that the 'neck' of the contact consists of a single atom. In contrast to previous observations of only single-atom necks, here we describe the breaking of atomic-scale gold contacts, which leads to the formation of gold chains one atom thick and at least four atoms long. Once we start to pull out a chain, the conductance never exceeds 2e2/h, confirming that it acts as a one-dimensional quantized nanowire. Given their high stability and the ability to support ballistic electron transport, these structures seem well suited for the investigation of atomic-scale electronics.
Chemical Vapour Deposition (CVD) diamond is being considered as a material for particle detectors in a harsh radiation environment. This article presents beam test results of 3D pixel detectors ...fabricated with poly-crystalline CVD diamonds. The cells of the devices had a size of 50µm×50µm with columns 2.6µm in diameter. The cells were ganged in a 3×2 and 5×1 pattern to match the layouts of the pixel read-out electronics currently used in the CMS and ATLAS experiments at the Large Hadron Collider, respectively. In beam tests, using tracks reconstructed with a high precision tracking telescope, a tracking efficiency of 99.3% was achieved. The efficiency of both devices plateaus at a bias voltage of 30V. Also irradiated poly-crystalline CVD diamond pad detectors were investigated. In high rate beam tests with particle fluxes up to 20MHz/cm2 and irradiations up to 8 ⋅ 1015n/cm2 it was shown that the pulse height of irradiated poly-crystalline CVD diamonds does not depend on flux to the O2%.
Endotheliopathy plays a role in the development of acute kidney and lung injury in COVID-19, probably due to inflammation, endothelial permeability, vascular leakage and edema formation. This study ...examined alterations in the circulation of patients with mild and severe COVID-19 on in vitro endothelial permeability and its relation to the endothelial angiopoietin/Tie2 system, which is involved in the regulation of endothelial permeability. Plasma was obtained from COVID-19 patients admitted to the ward (
n
= 14) or ICU (
n
= 20) at admission and after 1 and 2 weeks and healthy controls (
n
= 5). Human kidney and lung endothelial cells were exposed to patient plasma and treated with recombinant angiopoietin-1. In vitro endothelial barrier function was assessed using electric cell-substrate impedance sensing. Circulating markers of the angiopoietin/Tie2 system, endothelial dysfunction and glycocalyx degradation were measured by ELISA. Plasma from COVID-19 patients reduced endothelial resistance compared to healthy controls, but COVID-19 plasma-induced drop in endothelial resistance did not differ between ward and ICU patients. Circulating angiopoietin-2, soluble Tie2 and soluble Tie1 levels increased over time in ICU patients, whereas levels remained stable in ward patients. The increase in angiopoietin-2 was able to predict 90-day mortality (AUC = 0.914,
p
< 0.001). Treatment with recombinant angiopoietin-1 did not restore COVID-19 plasma-induced hyperpermeability. In conclusion, these results suggest that indirect effects of the virus represented in the circulation of COVID-19 patients induced endothelial hyperpermeability irrespective of disease severity and changes in the endothelial angiopoietin/Tie2 system. Nonetheless, angiopoietin-2 might be of interest in the context of organ injury and patient outcome in COVID-19.
We have measured the radiation tolerance of poly-crystalline and single-crystalline diamonds grown by the chemical vapor deposition (CVD) process by measuring the charge collected before and after ...irradiation in a 50 m pitch strip detector fabricated on each diamond sample. We irradiated one group of sensors with 800 MeV protons, and a second group of sensors with 24 GeV protons, in steps, to protons cm−2 and protons cm−2 respectively. We observe the sum of mean drift paths for electrons and holes for both poly-crystalline CVD diamond and single-crystalline CVD diamond decreases with irradiation fluence from its initial value according to a simple damage curve characterized by a damage constant for each irradiation energy and the irradiation fluence. We find for each irradiation energy the damage constant, for poly-crystalline CVD diamond to be the same within statistical errors as the damage constant for single-crystalline CVD diamond. We find the damage constant for diamond irradiated with 24 GeV protons to be and the damage constant for diamond irradiated with 800 MeV protons to be . Moreover, we observe the pulse height decreases with fluence for poly-crystalline CVD material and within statistical errors does not change with fluence for single-crystalline CVD material for both 24 GeV proton irradiation and 800 MeV proton irradiation. Finally, we have measured the uniformity of each sample as a function of fluence and observed that for poly-crystalline CVD diamond the samples become more uniform with fluence while for single-crystalline CVD diamond the uniformity does not change with fluence.
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