Comparison of ultrasound‐guided core biopsy versus fine‐needle aspiration biopsy in the evaluation of salivary gland lesions

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100263/1/hed23193.pd

Alveolar Microfluidic Systems for Study of Barrier Function, Cell Damage, and Migration at the Air-Blood Barrier.

The exchange of oxygen and carbon dioxide occurs across the air-blood barrier (or alveolar-capillary barrier). This barrier must be sufficiently thin to allow the passive diffusion, yet sufficiently strong to maintain a dry alveolar environment. When solid and fluid mechanical stresses damage the air-blood barrier’s integrity, edema fills this normally air-filled alveolar environment and pathology results. The specific mechanisms by which these stresses impact the cells of the air-blood barrier remain poorly understood. The role of solid mechanical stress (cyclic stretch) has been explored through traditional, culture techniques, but only recently have microfluidic systems allowed systematic exploration on combined solid and fluid stresses. Although such systems can be tailored to the biological phenomena being studied, key design parameters include: (i) two-layered channel design (to mimic “alveolar” and “endothelial” compartments), (ii) ability to convey combined solid and fluid stresses, (iii) co-culture, and (iv) the integration of biological sensors to detect real-time changes. A microfluidic “Alveoli-on-a-Chip” system was designed and fabricated. By varying the degree of fluid-filling within the “alveolar” channel, differential strain conditions were applied to alveolar epithelial cells. Experiments using this system, demonstrated significant increases in cell death and detachment in alveolar cell populations exposed to fluid and solid mechanical stresses compared to populations exposed solely to solid mechanical stresses. Because nearly all pathological processes of alveoli alter barrier permeability, detection of changes to the integrity of this barrier is an essential feature in alveolar models. A technique for embedding Ag/AgCl recording electrodes within a two-layered PDMS microsystem, allowing impedance to be measured across a porous cell culture membrane was also developed. This fabrication technique eliminated the need for direct deposition of recording electrodes onto the elastomer, avoiding the frequent and deep cracking pattern resulting from the modulus mismatch between conductive metals and PDMS polymer. The impact of mechanical stresses on the alveolar immune response was also studied by patterning alveolar macrophages onto confluent monolayers of alveolar epithelial cells using aqueous two-phase (ATPS) printing. Using this technique, increased migration rates in co-cultures experiencing physiologic stretch levels were demonstrated compared to migration in static cultures.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/97972/1/ndouvill_1.pd

Genetic predisposition may not improve prediction of cardiac surgery-associated acute kidney injury

Background: The recent integration of genomic data with electronic health records has enabled large scale genomic studies on a variety of perioperative complications, yet genome-wide association studies on acute kidney injury have been limited in size or confounded by composite outcomes. Genome-wide association studies can be leveraged to create a polygenic risk score which can then be integrated with traditional clinical risk factors to better predict postoperative complications, like acute kidney injury.Methods: Using integrated genetic data from two academic biorepositories, we conduct a genome-wide association study on cardiac surgery-associated acute kidney injury. Next, we develop a polygenic risk score and test the predictive utility within regressions controlling for age, gender, principal components, preoperative serum creatinine, and a range of patient, clinical, and procedural risk factors. Finally, we estimate additive variant heritability using genetic mixed models.Results: Among 1,014 qualifying procedures at Vanderbilt University Medical Center and 478 at Michigan Medicine, 348 (34.3%) and 121 (25.3%) developed AKI, respectively. No variants exceeded genome-wide significance (p < 5 × 10−8) threshold, however, six previously unreported variants exceeded the suggestive threshold (p < 1 × 10−6). Notable variants detected include: 1) rs74637005, located in the exonic region of NFU1 and 2) rs17438465, located between EVX1 and HIBADH. We failed to replicate variants from prior unbiased studies of post-surgical acute kidney injury. Polygenic risk was not significantly associated with post-surgical acute kidney injury in any of the models, however, case duration (aOR = 1.002, 95% CI 1.000–1.003, p = 0.013), diabetes mellitus (aOR = 2.025, 95% CI 1.320–3.103, p = 0.001), and valvular disease (aOR = 0.558, 95% CI 0.372–0.835, p = 0.005) were significant in the full model.Conclusion: Polygenic risk score was not significantly associated with cardiac surgery-associated acute kidney injury and acute kidney injury may have a low heritability in this population. These results suggest that susceptibility is only minimally influenced by baseline genetic predisposition and that clinical risk factors, some of which are modifiable, may play a more influential role in predicting this complication. The overall impact of genetics in overall risk for cardiac surgery-associated acute kidney injury may be small compared to clinical risk factors

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Fracture of metal coated elastomers

Polydimethylsiloxane (PDMS) substrates were coated with thin layers of gold varying in thickness between 40 nm and 160 nm. Arrays of parallel cracks formed when a tensile strain was applied to the coated system, with the spacing between the cracks being approximately inversely proportional to the strain. When the crack profiles were examined, it was noted that the cracks extended deep into the substrate-to depths up to two orders of magnitude greater than the film thickness. This extension of the cracks into the substrate is the result of the large mismatch in elastic properties between the metal and soft substrate, and plays a role in the development of the cracking pattern. Despite the relatively large strains that can be applied through the elastomeric substrate, there was no evidence of macroscopic plasticity in the metal films, and numerical analyses showed that the crack profiles were consistent with elastic deformation of the metal. A quantitative comparison of the crack depth and spacing with the predictions of a companion mechanics analysis indicated that the observed spacing and depth were consistent with the metal film being much tougher than the elastomeric substrate. However, for this level of toughness to be exhibited in a metal film would require plastic deformation over a scale much larger than would be expected in such a geometry. This inconsistency may be resolved by recognizing that rupture of a thin metal film can be associated with shear localization that results in a mode-II failure, rather than by classical mode-I crack propagation. This results in a failure mechanism for a metal film that is a high-strain, but low-energy process, with substrate cracking absorbing the excess elastic energy available upon rupture of the film. Such a failure mechanism is consistent with earlier observations for the failure of thin metal films, and this work suggests that failure of an elastomeric substrate may contribute to an additional loss of constraint enhancing this localizationclose171

Tropical influence on boreal summer mid-latitude stationary waves

International audienceWhile organized tropical convection is a well-known source of extratropical planetary waves, state-of-the-art climate models still show serious deficiencies in simulating accurately the atmospheric response to tropical sea surface temperature (SST) anomalies and the associated teleconnections. In the present study, the remote influence of the tropical atmospheric circulation is evaluated in ensembles of global boreal summer simulations in which the Arpege-Climat atmospheric General Circulation Model (GCM) is nudged towards 6-h reanalyses. The nudging is applied either in the whole tropical band or in a regional summer monsoon domain. Sensitivity tests to the experimental design are first conducted using prescribed climatological SST. They show that the tropical relaxation does not improve the zonal mean extratropical climatology but does lead to a significantly improved representation of the mid-latitude stationary waves in both hemispheres. Low-pass filtering of the relaxation fields has no major effect on the model response, suggesting that high-frequency tropical variability is not responsible for extratropical biases. Dividing the nudging strength by a factor 10 only decreases the magnitude of the response. Model errors in each monsoon domain contribute to deficiencies in the model's mid-latitude climatology, although an exaggerated large-scale subsidence in the central equatorial Pacific appears as the main source of errors for the representation of stationary waves in the Arpege-Climat model. Case studies are then conducted using either climatological or observed SST. The focus is first on summer 2003 characterized by a strong and persistent anticyclonic anomaly over western Europe. This pattern is more realistic in nudging experiments than in simulations only driven by observed SST, especially when the nudging domain is centred over Central America. Other case studies also show a significant tropical forcing of the summer mid-latitude stationary waves and suggest a weak influence of prescribed observed SST in the northern extratropics. Results therefore indicate that improving the tropical divergent circulation and its response to tropical SST anomalies remains a key issue for increasing the skill of extratropical seasonal predictions, not only in the winter hemisphere but also in the boreal summer hemisphere where the prediction of heatwave and drought likelihood is expected to become an important challenge with increasing concentrations of greenhouse gases

Volume of packed red blood cells and fresh frozen plasma is associated with intraoperative hypocalcaemia during large volume intraoperative transfusion

BackgroundSevere hypocalcaemia is associated with increased transfusion in the trauma population. Furthermore, trauma patients developing severe hypocalcaemia have higher mortality and coagulopathy. Electrolyte abnormalities associated with massive transfusion have been less studied in the surgical population. Here, we tested the primary hypothesis that volume of packed red blood cells and fresh frozen plasma transfused intraoperatively is associated with lower nadir ionised calcium in the surgical population receiving massive resuscitation.MethodsWe performed a retrospective observational study at an academic quaternary care centre to characterise hypocalcaemia following large volume (4 or more units packed red blood cells) intraoperative transfusion. We used multivariable linear regression to assess if volume of transfusion with packed red blood cells and fresh frozen plasma were independently associated with a lower ionised calcium. We then used multivariable logistic regressions to assess the association between ionised calcium and transfusion with: (i) mortality, (ii) acute kidney injury, and (iii) postoperative coagulopathy.ResultsHypocalcaemia following large volume resuscitation in the operating room is a very frequent occurrence (70% of cases). After controlling for demographic variables and intraoperative variables, the volume transfused intraoperative was independently associated with hypocalcaemia on multivariable linear regression. Hypocalcaemia, intraoperative transfusion of packed red blood cells, and intraoperative transfusion of fresh frozen plasma were not shown to be associated with clinical outcomes.ConclusionsHypocalcaemia was associated with increased transfusion volume in this single‐centre study. Unlike the trauma population, hypocalcaemia was not associated with increased mortality during surgical care. Our findings suggest that despite improved practice patterns of calcium supplementation, intraoperative hypocalcaemia occurs with relatively high frequency following large volume intraoperative transfusion.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/171170/1/tme12798.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/171170/2/tme12798_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/171170/3/tme12798-sup-0001-Supinfo.pd

Intraoperative risk factors of acute kidney injury following liver transplantation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/173103/1/lt26477.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/173103/2/lt26477_am.pd

New chronological data at South African Middle Stone Age sites applying femtosecond laser ablation – ICPMS for u-series dating of marine shells, snail shells, ostrich eggshells and tooth enamels.

International audienc