Verification, Analytical Validation, and Clinical Validation (V3): The Foundation of Determining Fit-for-Purpose for Biometric Monitoring Technologies (BioMeTs)

Digital medicine is an interdisciplinary field, drawing together stakeholders with expertize in engineering, manufacturing, clinical science, data science, biostatistics, regulatory science, ethics, patient advocacy, and healthcare policy, to name a few. Although this diversity is undoubtedly valuable, it can lead to confusion regarding terminology and best practices. There are many instances, as we detail in this paper, where a single term is used by different groups to mean different things, as well as cases where multiple terms are used to describe essentially the same concept. Our intent is to clarify core terminology and best practices for the evaluation of Biometric Monitoring Technologies (BioMeTs), without unnecessarily introducing new terms. We focus on the evaluation of BioMeTs as fit-for-purpose for use in clinical trials. However, our intent is for this framework to be instructional to all users of digital measurement tools, regardless of setting or intended use. We propose and describe a three-component framework intended to provide a foundational evaluation framework for BioMeTs. This framework includes (1) verification, (2) analytical validation, and (3) clinical validation. We aim for this common vocabulary to enable more effective communication and collaboration, generate a common and meaningful evidence base for BioMeTs, and improve the accessibility of the digital medicine field

Stability of Fe,Al-bearing bridgmanite in the lower mantle and synthesis of pure Fe-bridgmanite

The physical and chemical properties of Earth’s mantle, as well as its dynamics and evolution, heavily depend on the phase composition of the region. On the basis of experiments in laser-heated diamond anvil cells, we demonstrate that Fe,Al-bearing bridgmanite (magnesium silicate perovskite) is stable to pressures over 120 GPa and temperatures above 3000 K. Ferric iron stabilizes Fe-rich bridgmanite such that we were able to synthesize pure iron bridgmanite at pressures between ~45 and 110 GPa. The compressibility of ferric iron–bearing bridgmanite is significantly different from any known bridgmanite, which has direct implications for the interpretation of seismic tomography data

Extractive Separation of Scandium from Rare Earth Elements

The extractive separation of scandium and rare earth metals (REM) was studied. The extractants used are trialkylbenzylammonium di-2-ethylhexylphosphate (TABAC-D2EHPA, binary extractant) and trioctylphosphine oxide (TOPO). The effect of concentration and nature of mineral acids on the scandium recovery was studied. Changing the HNO3 concentration in the range of 0.01 – 2.0 mol/L does not affect the extraction of metals by binary extractant, extraction corresponds to the following row: La, Eu, Gd < Tb <Y < Er < Yb < Sc, Th, that allows to separate scandium from rare earth metals by single extraction. Extraction of scandium by trioctylphosphineoxide from HCl solution proceeds quantitatively in the range of 0.5 – 7.0 mol/L, an increased HNO3 concentration leads to the decrease in scandium extraction. The conditions for the extractive separation of scandium and REM using TOPO solution were determined: scandium can be isolated selectively at the HNO3 concentration of 0.5 mol/L REM are transferred into the organic phase at the HNO3 concentration of 5.0 mol/L. It was determined that the organic phase extracts the compounds of the following composition: (ScA3 + R3R′NCl) (HA - D2EHPA, R3R'NCl - TABAC) and [Sc(NO3)3·3TOPO]

Extractive Separation of Scandium from Rare Earth Elements

The extractive separation of scandium and rare earth metals (REM) was studied. The extractants used are trialkylbenzylammonium di-2-ethylhexylphosphate (TABAC-D2EHPA, binary extractant) and trioctylphosphine oxide (TOPO). The effect of concentration and nature of mineral acids on the scandium recovery was studied. Changing the HNO3 concentration in the range of 0.01 – 2.0 mol/L does not affect the extraction of metals by binary extractant, extraction corresponds to the following row: La, Eu, Gd < Tb <Y < Er < Yb < Sc, Th, that allows to separate scandium from rare earth metals by single extraction. Extraction of scandium by trioctylphosphineoxide from HCl solution proceeds quantitatively in the range of 0.5 – 7.0 mol/L, an increased HNO3 concentration leads to the decrease in scandium extraction. The conditions for the extractive separation of scandium and REM using TOPO solution were determined: scandium can be isolated selectively at the HNO3 concentration of 0.5 mol/L REM are transferred into the organic phase at the HNO3 concentration of 5.0 mol/L. It was determined that the organic phase extracts the compounds of the following composition: (ScA3 + R3R′NCl) (HA - D2EHPA, R3R'NCl - TABAC) and [Sc(NO3)3·3TOPO]

A new high-pressure phase transition in clinoferrosilite: In situ single-crystal X-ray diffraction study

Synchrotron-based high-pressure single-crystal X-ray diffraction experiments were conducted on synthetic pure clinoferrosilite, Fe$_2$Si$_2$O$_6$, at room temperature to a maximum pressure of 45 GPa. In addition to the previously described P2$_{1}$/c → C2/c phase transition between 1.48 and 1.75 GPa (Hugh-Jones et al. 1994), we observe further transition between 30 and 36 GPa into the high-pressure P2$_{1}$/c phase (HP-P2$_{1}$/c). The C2/c → HP-P2$_{1}$/c transition is induced by rearrangement of half of the layers of corner-sharing SiO$_4$ tetrahedra into layers of edge-sharing SiO$_6$ octahedra. The new configuration of VISi layers suggests a possibility of a progressive transformation of the pyroxene into an ilmenite-type structure. The persistence of metastable pyroxene up to pressures higher than expected and its feasible direct transformation to ilmenite are of special interest for understanding the dynamics of cold-subducting slabs. We report on structural and compressibility features of both high-pressure phases as well as address thermal stability of HP-P2$_{1}$/c

Discovery of Elgoresyite, (Mg,Fe)5Si2O9: Implications for Novel Iron Magnesium Silicates in Rocky Planetary Interiors

International audienceAs the most abundant material of rocky Planets, alhigh-pressure PolYmorPhs of iron- andinum. bearingmagnesium silicates have long been soughtbybuoth observations and experiments. Meanwhile, it wasrecently revealed that iron oxides form (Fe0.)m (Fe203),, bomologous series above -'10 GPa according to laboratory high-pressureexperiments. Here, we report a new high-pressure iron-magnesium silicate, recently approved by the International Mineralogical Association as a new mineral (No. 2020-086) and named elgoresy,ite,in a shock-induced melt vein ot., the Suizhou L6 chondrite with a chemistry of (mg,Fe) ironi209. The crystal structure of this new silicate is the same as the oxide Fe709, strongly suggesting that silicates also form ((Mg,Fe)) (SiO2), series that are isostructural to iron oxides via0,m +Si(Mg2+,Fe') 2Fe3' substitution. To test this hypothesis, the phase relationships of the silicates and iron oxides should further investigated at higher temperature conditions. Newly found iron -magnesium silicate is a potential constituent mineral rocky planets with relatively high Mg0 + Fe0 content

Reconsolidation of a context long-term memory in the terrestrial snail requires protein synthesis

We investigated the influence of the protein synthesis blocker anisomycin on contextual memory in the terrestrial snail Helix. Prior to the training session, the behavioral responses in two contexts were similar. Two days after a session of electric shocks (5 d) in one context only, the context conditioning was observed as the significant difference of behavioral response amplitudes in two contexts. On the day following testing of context learning, a session of “reminding” was performed, immediately after which the snails were injected with anisomycin or vehicle. Testing of long-term context memory has shown that only anisomycin injections impaired the context conditioning. In control series, the snails were injected after the training session with anisomycin/saline without reminding, and no impairment of the long-term context memory was observed, while injection of anisomycin during the training session completely abolished the long-term memory. No effects of anisomycin on the short-term memory were observed. Surprisingly, injection of anisomycin after the reminding combined with reinforcing stimuli elicited no effect on the context memory. Differences between single-trial and multisession learning are discussed

Compressibility of two Na-rich clinopyroxenes: A synchrotron single-crystal X-ray diffraction study

Synchrotron-based high-pressure single-crystal X-ray diffraction experiments were conducted on synthetic clinopyroxenes at room temperature to a maximum pressure of 40 GPa. We studied two crystals with different compositions. A Na-Ti-pyroxene with formula (Na0.86Mg0.14)(Mg0.57Ti0.43)Si2O6 synthesized at P = 7 GPa and T = 1700 °C, and a Na-pyroxene with composition (Na0.886Mg0.085Fe0.029) (Si0.442Mg0.390Fe0.168)Si2O6 synthesized at P = 15 GPa and T = 1500 °C. These phases were found to be monoclinic with the space group C2/c and exhibit KTo of 106.8(2), 121.8(4) GPa, respectively. Na-Tipyroxene is more compressible than Fe-bearing Na-Mg-Si-pyroxene, likely due to the fact that the FeO6 octahedron is significantly more rigid than MgO6 at high pressure. The formation of Na-rich pyroxenes in the deep mantle is related to crystallization of low-degree alkaline carbonate-silicate melts formed when the crust and mantle interact during the slab descent and its stagnation in the transition zone

Effect of composition on compressibility of skiagite-Fe-majorite garnet

Skiagite-Fe-majorite garnets were synthesized using a multianvil apparatus at 7.5–9.5 GPa and 1400–1600 K. Single-crystal X‑ray diffraction at ambient conditions revealed that synthesized garnets contain 23 to 76% of an Fe-majorite component. We found that the substitution of Fe$^{2+}$ and S$^{4+}$ for Fe$^{3+}$ in the octahedral site decreases the unit-cell volume of garnet at ambient conditions. Analysis of single-crystal X‑ray diffraction data collected on compression up to 90 GPa of garnets with different compositions reveals that with increasing majorite component the bulk modulus increases from 159(1) to 172(1) GPa. Our results and literature data unambiguously demonstrate that the total iron content and the Fe$^{3+}$/Fe$^{2+}$ ratio in (Mg,Fe)-majorites have a large influence on their elasticity. At pressures between 50 and 60 GPa we observed a significant deviation from a monotonic dependence of the molar volumes of skiagite-Fe-majorite garnet with pressure, and over a small pressure interval the volume dropped by about 3%. By combining results from single-crystal X‑ray diffraction and high-pressure synchrotron Mössbauer source spectroscopy we demonstrate that these changes in the compressional behavior are associated with changes of the electronic state of Fe in the octahedral site

Screening of the Promising Direct Thrombin Inhibitors from Haematophagous Organisms. Part I: Recombinant Analogues and Their Antithrombotic Activity In Vitro

The success in treatment of venous thromboembolism and acute coronary syndromes using direct thrombin inhibitors has stimulated research aimed at finding a new anticoagulant from haematophagous organisms. This study deals with the comparison between hirudin-1 from Hirudomedicinalis(desirudin), being the first-known and most well-studied natural anticoagulant, along with recombinant analogs of haemadin from the leech Haemadipsa sylvestris, variegin from the tick Amblyomma variegatum, and anophelin from Anopheles albimanus. These polypeptides were chosen due to their high specificity and affinity for thrombin, as well as their distinctive inhibitory mechanisms. We have developed a universal scheme for the biotechnological production of these recombinant peptides as pharmaceutical substances. The anticoagulant activities of these peptides were compared using the thrombin amidolytic activity assay and prolongation of coagulation time (thrombin time, prothrombin time, and activated partial thromboplastin time) in mouse and human plasma. The preliminary results obtained suggest haemadin as the closest analog of recombinant hirudin-1, the active substance of the medicinal product Iprivask (Aventis Pharmaceuticals, USA) for the prevention of deep venous thrombosis in patients undergoing elective hip or knee replacement surgery. In contrast, variegin can be regarded as a natural analog of bivalirudin (Angiomax, The Medicines Company), a synthetic hirudin-1 derivative certified for the treatment of patients undergoing percutaneous coronary intervention and of patients with unstable angina pectoris after percutaneous transluminal coronary angioplasty