PRN OPINION PAPER: Application of precision medicine across pharmacy specialty areas

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149551/1/jac51107_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149551/2/jac51107.pd

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Harmonization and standardization of nucleus pulposus cell extraction and culture methods

Background: In vitro studies using nucleus pulposus (NP) cells are commonly used to investigate disc cell biology and pathogenesis, or to aid in the development of new therapies. However, lab‐to‐lab variability jeopardizes the much‐needed progress in the field. Here, an international group of spine scientists collaborated to standardize extraction and expansion techniques for NP cells to reduce variability, improve comparability between labs and improve utilization of funding and resources. Methods: The most commonly applied methods for NP cell extraction, expansion, and re‐differentiation were identified using a questionnaire to research groups worldwide. NP cell extraction methods from rat, rabbit, pig, dog, cow, and human NP tissue were experimentally assessed. Expansion and re‐differentiation media and techniques were also investigated. Results: Recommended protocols are provided for extraction, expansion, and re‐differentiation of NP cells from common species utilized for NP cell culture. Conclusions: This international, multilab and multispecies study identified cell extraction methods for greater cell yield and fewer gene expression changes by applying species‐specific pronase usage, 60–100 U/ml collagenase for shorter durations. Recommendations for NP cell expansion, passage number, and many factors driving successful cell culture in different species are also addressed to support harmonization, rigor, and cross‐lab comparisons on NP cells worldwide

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Ingénierie aux échelles nanométriques de matériaux chalcogénures à changement de phase pour les mémoires à changement de phase du futur

In terms of performance, cost and functional speed, phase-change memories are playing a key role in data storage technologies. Leveraging the properties of some chalcogenide materials, phase-change materials (PCMs) present unique features, mainly: fast and reversible switching between amorphous and crystalline states with significant optical and electrical contrasts between the both states. However, for an improved performance, the elevated power consumption due to the high programming current must be reduced, and the crystallization temperature also has to be increased. In this context, we have developed new multilayer systems of [GeTe/C]n and [Ge2Sb2Te5/C]n. The aim is to obtain, in a controlled and reproducible manner, a thin layer of nanostructured PCM with dimensions less than 10 nm. The multilayers were produced by the magnetron sputtering deposition technique in a 200 mm industrial equipment with a multi-cathode chamber. The multilayers are amorphous after deposition. Ion beam techniques permitted to check periodicity and composition of the multilayers. The sheet resistance and reflectivity as a function of temperature were measured in situ. The crystallization temperature of PCM in the multilayer structure increases and is dependent on the thickness of the PCM layer and that of the carbon films. The kinetics and magnitude of the amorphous-crystal transition of PCM in the multilayers are also significantly affected. The impact of the multilayer structure on the crystallization of GeTe versus Ge2Sb2Te5 is then compared and discussed with respect to their crystallization mechanism. We show that the initially amorphous multilayer structure is retained even after PCM crystallization during an annealing that is identical to the one used for the manufacture of memory devices (300 °C for 15 min). Thus, it is possible to obtain nanocrystalline grains of PCM in amorphous C on the order of 4 nm vertically and 20-30 nm in the layer plane. These results are compared with the microstructure of C-doped GeTe and Ge2Sb2Te5 films. Finally, by using X-ray diffraction measurements in the laboratory and by in situ experiments at the SOLEIL synchrotron, we were able to follow the evolution of the structure of these multilayers during annealing. For example, we reported that a local percolation effect of the GeTe grains between the layers of C occurs above a certain temperature.En terme de performance, de coût et de vitesse de fonctionnement, les mémoires à changement de phase occupent une place importante dans les technologies de stockage de données. Elles utilisent les propriétés de certains matériaux à changement de phase (PCM), principalement des alliages de matériaux chalcogénures, qui présentent des caractéristiques uniques : commutation rapide et réversible entre un état amorphe et un état cristallin avec un contraste optique et électrique important entre les deux états. Cependant, pour de meilleures performances, la consommation d’énergie due aux courants de programmation élevés doit être réduite et la température de cristallisation augmentée. Dans ce contexte, nous avons élaboré de nouveaux systèmes de multicouches de [GeTe/C]n et [Ge2Sb2Te5/C]n. Le but est d’obtenir de manière contrôlée et reproductible une couche mince de PCM nanostructuré avec une ou des dimensions caractéristiques inférieures à 10 nm. Les multicouches ont été élaborées par la technique de dépôt par pulvérisation cathodique magnétron dans un bâti de dépôt industriel 200 mm équipé d’une chambre multi-cathodes. Les multicouches sont amorphes après dépôt. Des analyses par faisceaux d’ions ont permis de contrôler la périodicité et la composition des multicouches ainsi élaborées. Des mesures de résistivité et de réflectivité en température montrent que la température de cristallisation du PCM dans la structure multicouche augmente et dépend de l’épaisseur du PCM et des films de carbone. Aussi, la cinétique et l’amplitude de la transition amorphe-cristal du PCM dans la multicouche est aussi largement affectée. L’impact de la structure multicouche sur la cristallisation du GeTe et du Ge2Sb2Te5 est alors comparée et discutée au regard de la nature de leur mécanisme de cristallisation. Nous montrons que la structure multicouche initialement amorphe est conservée même après cristallisation du PCM lors d’un recuit identique à celui utilisé pour la fabrication des dispositifs mémoires (300 °C pendant 15 min). Ainsi, il est possible d’obtenir des grains nanocristallins de PCM dans du C amorphe de l’ordre de 4 nm verticalement et de 20-30 nm dans le plan des couches. Ces résultats sont comparés à la microstructure de films de GeTe et Ge2Sb2Te5 dopés avec du C. Enfin, l’analyse de l’évolution de la structure de ces multicouches par des mesures de diffraction de rayons X en laboratoire et par des mesures in situ au cours d’un recuit au synchrotron SOLEIL a été réalisée. Ceci a permis par exemple de mettre en évidence au-delà d’une certaine température la percolation locale des grains de GeTe entre les couches de C

Nano-engineering of chalcogenide phase-change materials for ultimate phase-change memories

En terme de performance, de coût et de vitesse de fonctionnement, les mémoires à changement de phase occupent une place importante dans les technologies de stockage de données. Elles utilisent les propriétés de certains matériaux à changement de phase (PCM), principalement des alliages de matériaux chalcogénures, qui présentent des caractéristiques uniques : commutation rapide et réversible entre un état amorphe et un état cristallin avec un contraste optique et électrique important entre les deux états. Cependant, pour de meilleures performances, la consommation d’énergie due aux courants de programmation élevés doit être réduite et la température de cristallisation augmentée. Dans ce contexte, nous avons élaboré de nouveaux systèmes de multicouches de [GeTe/C]n et [Ge2Sb2Te5/C]n. Le but est d’obtenir de manière contrôlée et reproductible une couche mince de PCM nanostructuré avec une ou des dimensions caractéristiques inférieures à 10 nm. Les multicouches ont été élaborées par la technique de dépôt par pulvérisation cathodique magnétron dans un bâti de dépôt industriel 200 mm équipé d’une chambre multi-cathodes. Les multicouches sont amorphes après dépôt. Des analyses par faisceaux d’ions ont permis de contrôler la périodicité et la composition des multicouches ainsi élaborées. Des mesures de résistivité et de réflectivité en température montrent que la température de cristallisation du PCM dans la structure multicouche augmente et dépend de l’épaisseur du PCM et des films de carbone. Aussi, la cinétique et l’amplitude de la transition amorphe-cristal du PCM dans la multicouche est aussi largement affectée. L’impact de la structure multicouche sur la cristallisation du GeTe et du Ge2Sb2Te5 est alors comparée et discutée au regard de la nature de leur mécanisme de cristallisation. Nous montrons que la structure multicouche initialement amorphe est conservée même après cristallisation du PCM lors d’un recuit identique à celui utilisé pour la fabrication des dispositifs mémoires (300 °C pendant 15 min). Ainsi, il est possible d’obtenir des grains nanocristallins de PCM dans du C amorphe de l’ordre de 4 nm verticalement et de 20-30 nm dans le plan des couches. Ces résultats sont comparés à la microstructure de films de GeTe et Ge2Sb2Te5 dopés avec du C. Enfin, l’analyse de l’évolution de la structure de ces multicouches par des mesures de diffraction de rayons X en laboratoire et par des mesures in situ au cours d’un recuit au synchrotron SOLEIL a été réalisée. Ceci a permis par exemple de mettre en évidence au-delà d’une certaine température la percolation locale des grains de GeTe entre les couches de C.In terms of performance, cost and functional speed, phase-change memories are playing a key role in data storage technologies. Leveraging the properties of some chalcogenide materials, phase-change materials (PCMs) present unique features, mainly: fast and reversible switching between amorphous and crystalline states with significant optical and electrical contrasts between the both states. However, for an improved performance, the elevated power consumption due to the high programming current must be reduced, and the crystallization temperature also has to be increased. In this context, we have developed new multilayer systems of [GeTe/C]n and [Ge2Sb2Te5/C]n. The aim is to obtain, in a controlled and reproducible manner, a thin layer of nanostructured PCM with dimensions less than 10 nm. The multilayers were produced by the magnetron sputtering deposition technique in a 200 mm industrial equipment with a multi-cathode chamber. The multilayers are amorphous after deposition. Ion beam techniques permitted to check periodicity and composition of the multilayers. The sheet resistance and reflectivity as a function of temperature were measured in situ. The crystallization temperature of PCM in the multilayer structure increases and is dependent on the thickness of the PCM layer and that of the carbon films. The kinetics and magnitude of the amorphous-crystal transition of PCM in the multilayers are also significantly affected. The impact of the multilayer structure on the crystallization of GeTe versus Ge2Sb2Te5 is then compared and discussed with respect to their crystallization mechanism. We show that the initially amorphous multilayer structure is retained even after PCM crystallization during an annealing that is identical to the one used for the manufacture of memory devices (300 °C for 15 min). Thus, it is possible to obtain nanocrystalline grains of PCM in amorphous C on the order of 4 nm vertically and 20-30 nm in the layer plane. These results are compared with the microstructure of C-doped GeTe and Ge2Sb2Te5 films. Finally, by using X-ray diffraction measurements in the laboratory and by in situ experiments at the SOLEIL synchrotron, we were able to follow the evolution of the structure of these multilayers during annealing. For example, we reported that a local percolation effect of the GeTe grains between the layers of C occurs above a certain temperature

Calculus at Georgia State University

Calculus continues to be a challenge for many students. We have pursued a multifaceted approach to supporting students that involves a) a drop-in tutorial center, b) Supplemental Instruction, c) weekly graded homework, d) online practice using ALEKS, and e) a new Calculus for the Life Science course sequence. The influences of these various support mechanisms will be discussed

Nanocomposites of chalcogenide phase-change materials: from C-doping of thin films to advanced multilayers

International audienceEngineering of chalcogenide phase-change materials at the nanoscale is required to improve the performances of ultimate size memory devices and reduce their power consumption. Amorphous C-doped GeTe thin films and innovative multilayers consisting of periodic stacks of a few nm thick GeTe, or Ge$_2$Sb$_2$Te$_5$, and C layers with a thickness between 0.5 and 2 nm are deposited by magnetron sputtering at room temperature. The phase-change material is then crystallized by heat treatment. In C-doped GeTe films, the phase separation of C and GeTe during the GeTe crystallization leads to the spontaneous formation of a nanocomposite, consisting of amorphous C located at the grain boundaries of GeTe crystallites, but the resulting nanostructure is highly disordered. In contrast, the deposition of multilayers allows control of the nanostructure and the interfaces between the phase-change material and the C phase. Transmission electron microscopy and X-ray diffraction at room temperature and as a function of temperature during annealing show that the multilayer structure is maintained after crystallization of the phase-change material, even when the thickness of the C layer is as low as 0.5 nm. GeTe and Ge$_2$Sb$_2$Te$_5$ crystallites are anisotropic, their size in the direction perpendicular to the layers being determined by the design of the multilayer. The crystallisation temperature of the GeTe and Ge2Sb2Te5 layers depends on the structure of the stack, revealing scaling and stress effects. The results presented show that GeTe/C and Ge$_2$Sb$_2$Te$_5$/C MLs are promising for applications in memory devices and also in photonic and thermoelectric devices

Stress Buildup Upon Crystallization of GeTe Thin Films: Curvature Measurements and Modelling

International audiencePhase change materials are attractive materials for non-volatile memories because of their ability to switch reversibly between an amorphous and a crystal phase. The volume change upon crystallization induces mechanical stress that needs to be understood and controlled. In this work, we monitor stress evolution during crystallization in thin GeTe films capped with SiOx, using optical curvature measurements. A 150 MPa tensile stress buildup is measured when the 100 nm thick film crystallizes. Stress evolution is a result of viscosity increase with time and a tentative model is proposed that renders qualitatively the observed features

Mental disorders, disability and treatment gap in a protracted refugee setting

Studies have shown high levels of distress and mental disorder among people living in refugee camps, yet none has confirmed diagnosis through clinical reappraisal