Low-hysteresis shape-memory ceramics designed by multimode modelling.

Zirconia ceramics exhibit a martensitic phase transformation that enables large strains of order 10%, making them prospects for shape-memory and superelastic applications at high temperature1-5. Similarly to other martensitic materials, this transformation strain can be engineered by carefully alloying to produce a more commensurate transformation with reduced hysteresis (difference in transformation temperature on heating and cooling)6-11. However, such 'lattice engineering' in zirconia is complicated by additional physical constraints: there is a secondary need to manage a large transformation volume change12, and to achieve transformation temperatures high enough to avoid kinetic barriers6. Here we present a method of augmenting the lattice engineering approach to martensite design to address these additional constraints, incorporating modern computational thermodynamics and data science tools to span complex multicomponent spaces for which no data yet exist. The result is a new zirconia composition with record low hysteresis of 15 K, which is about ten times less transformation hysteresis compared to typical values (and approximately five times less than the best values reported so far). This finding demonstrates that zirconia ceramics can exhibit hysteresis values of the order of those of widely deployed shape-memory alloys, paving the way for their use as viable high-temperature shape-memory materials.

Diagnosis of latent tuberculosis infection is associated with reduced HIV viral load and lower risk for opportunistic infections in people living with HIV.

Approximately 28% of the human population have been exposed to Mycobacterium tuberculosis (MTB), with the overwhelming majority of infected individuals not developing disease (latent TB infection (LTBI)). While it is known that uncontrolled HIV infection is a major risk factor for the development of TB, the effect of underlying LTBI on HIV disease progression is less well characterized, in part because longitudinal data are lacking. We sorted all participants of the Swiss HIV Cohort Study (SHCS) with at least 1 documented MTB test into one of the 3 groups: MTB uninfected, LTBI, or active TB. To detect differences in the HIV set point viral load (SPVL), linear regression was used; the frequency of the most common opportunistic infections (OIs) in the SHCS between MTB uninfected patients, patients with LTBI, and patients with active TB were compared using logistic regression and time-to-event analyses. In adjusted models, we corrected for baseline demographic characteristics, i.e., HIV transmission risk group and gender, geographic region, year of HIV diagnosis, and CD4 nadir. A total of 13,943 SHCS patients had at least 1 MTB test documented, of whom 840 (6.0%) had LTBI and 770 (5.5%) developed active TB. Compared to MTB uninfected patients, LTBI was associated with a 0.24 decreased log HIV SPVL in the adjusted model (p < 0.0001). Patients with LTBI had lower odds of having candida stomatitis (adjusted odds ratio (OR) = 0.68, p = 0.0035) and oral hairy leukoplakia (adjusted OR = 0.67, p = 0.033) when compared to MTB uninfected patients. The association of LTBI with a reduced HIV set point virus load and fewer unrelated infections in HIV/TB coinfected patients suggests a more complex interaction between LTBI and HIV than previously assumed.

Use of a Contained Mycobacterium tuberculosis Mouse Infection Model to Predict Active Disease and Containment in Humans.

Previous studies have identified whole-blood transcriptional risk and disease signatures for tuberculosis; however, several lines of evidence suggest that these signatures primarily reflect bacterial burden, which increases before symptomatic disease. We found that the peripheral blood transcriptome of mice with contained Mycobacterium tuberculosis infection (CMTI) has striking similarities to that of humans with active tuberculosis and that a signature derived from these mice predicts human disease with accuracy comparable to that of signatures derived directly from humans. A set of genes associated with immune defense are up-regulated in mice with CMTI but not in humans with active tuberculosis, suggesting that their up-regulation is associated with bacterial containment. A signature comprising these genes predicts both protection from tuberculosis disease and successful treatment at early time points where current signatures are not predictive. These results suggest that detailed study of the CMTI model may enable identification of biomarkers for human tuberculosis.

Intracardiac MR imaging (ICMRI) guiding-sheath with amplified expandable-tip imaging and MR-tracking for navigation and arrythmia ablation monitoring: Swine testing at 1.5 and 3T.

PURPOSE: Develop a deflectable intracardiac MR imaging (ICMRI) guiding-sheath to accelerate imaging during MR-guided electrophysiological (EP) interventions for radiofrequency (500 kHz) ablation (RFA) of arrythmia. Requirements include imaging at three to five times surface-coil SNR in cardiac chambers, vascular insertion, steerable-active-navigation into cardiac chambers, operation with ablation catheters, and safe levels of MR-induced heating. METHODS: ICMRI's 6 mm outer-diameter (OD) metallic-braided shaft had a 2.6 mm OD internal lumen for ablation-catheter insertion. Miniature-Baluns (MBaluns) on ICMRI's 1 m shaft reduced body-coil-induced heating. Distal section was a folded "star"-shaped imaging-coil mounted on an expandable frame, with an integrated miniature low-noise-amplifier overcoming cable losses. A handle-activated movable-shaft expanded imaging-coil to 35 mm OD for imaging within cardiac-chambers. Four MR-tracking micro-coils enabled navigation and motion-compensation, assuming a tetrahedron-shape when expanded. A second handle-lever enabled distal-tip deflection. ICMRI with a protruding deflectable EP catheter were used for MR-tracked navigation and RFA using a dedicated 3D-slicer user-interface. ICMRI was tested at 3T and 1.5T in swine to evaluate (a) heating, (b) cardiac-chamber access, (c) imaging field-of-view and SNR, and (d) intraprocedural RFA lesion monitoring. RESULTS: The 3T and 1.5T imaging SNR demonstrated >400% SNR boost over a 4 × 4 × 4 cm3 FOV in the heart, relative to body and spine arrays. ICMRI with MBaluns met ASTM/IEC heating limits during navigation. Tip-deflection allowed navigating ICMRI and EP catheter into atria and ventricles. Acute-lesion long-inversion-time-T1-weighted 3D-imaging (TWILITE) ablation-monitoring using ICMRI required 5:30 min, half the time needed with surface arrays alone. CONCLUSION: ICMRI assisted EP-catheter navigation to difficult targets and accelerated RFA monitoring.

Contained Mycobacterium tuberculosis infection induces concomitant and heterologous protection.

Progress in tuberculosis vaccine development is hampered by an incomplete understanding of the immune mechanisms that protect against infection with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. Although the M72/ASOE1 trial yielded encouraging results (54% efficacy in subjects with prior exposure to Mtb), a highly effective vaccine against adult tuberculosis remains elusive. We show that in a mouse model, establishment of a contained and persistent yet non-pathogenic infection with Mtb ("contained Mtb infection", CMTB) rapidly and durably reduces tuberculosis disease burden after re-exposure through aerosol challenge. Protection is associated with elevated activation of alveolar macrophages, the first cells that respond to inhaled Mtb, and accelerated recruitment of Mtb-specific T cells to the lung parenchyma. Systems approaches, as well as ex vivo functional assays and in vivo infection experiments, demonstrate that CMTB reconfigures tissue resident alveolar macrophages via low grade interferon-γ exposure. These studies demonstrate that under certain circumstances, the continuous interaction of the immune system with Mtb is beneficial to the host by maintaining elevated innate immune responses.

Chronic aseptic meningitis caused by enterovirus in a humorally immunosuppressed adult patient presenting with sensorineural hearing loss: a case report.

BACKGROUND: Enterovirus has been described as a cause of aseptic meningitis in humorally immunosuppressed patients. CASE PRESENTATION: A 67-year-old female with a history of mantle cell lymphoma on rituximab therapy presented with subacute hepatitis, myalgias, and sensorineural hearing loss several months after an initial febrile illness. She was diagnosed with enterovirus infection by CSF PCR as a unifying etiology of her presentation, representing an unusual presentation of disease. DISCUSSION AND CONCLUSIONS: This patient's unique presentation and clinical course presents important implications in the care of similarly immunosuppressed patients with cryptic complaints.

Reducing the use of empiric antibiotic therapy in COVID-19 on hospital admission.

BACKGROUND: Empiric antibiotics for community acquired bacterial pneumonia (CABP) are often prescribed to patients with COVID-19, despite a low reported incidence of co-infections. Stewardship interventions targeted at facilitating appropriate antibiotic prescribing for CABP among COVID-19 patients are needed. We developed a guideline for antibiotic initiation and discontinuation for CABP in COVID-19 patients. The purpose of this study was to assess the impact of this intervention on the duration of empiric CABP antibiotic therapy among patients with COVID-19. METHODS: This was a single-center, retrospective, quasi-experimental study of adult patients admitted between 3/1/2020 to 4/25/2020 with COVID-19 pneumonia, who were initiated on empiric CABP antibiotics. Patients were excluded if they were initiated on antibiotics > 48 h following admission or if another source of infection was identified. The primary outcome was the duration of antibiotic therapy (DOT) prior to the guideline (March 1 to March27, 2020) and after guideline implementation (March 28 to April 25, 2020). We also evaluated the clinical outcomes (mortality, readmissions, length of stay) among those initiated on empiric CABP antibiotics. RESULTS: A total of 506 patients with COVID-19 were evaluated, 102 pre-intervention and 404 post-intervention. Prior to the intervention, 74.5% (n = 76) of patients with COVID-19 received empiric antibiotics compared to only 42% of patients post-intervention (n = 170), p < 0.001. The median DOT in the post-intervention group was 1.3 days shorter (p < 0.001) than the pre-intervention group, and antibiotics directed at atypical bacteria DOT was reduced by 2.8 days (p < 0.001). More patients in the post-intervention group were initiated on antibiotics based on criteria consistent with our guideline (68% versus 87%, p = 0.001). There were no differences between groups in terms of clinical outcomes. CONCLUSION: Following the implementation of a guideline outlining recommendations for initiating and discontinuing antibiotics for CABP among COVID-19 inpatients, we observed a reduction in antibiotic prescribing and DOT. The guideline also resulted in a significant increase in the rate of guideline-congruent empiric antibiotic initiation.

Assessing the completeness of periodontal disease documentation in the EHR: a first step in measuring the quality of care.

BACKGROUND: Our objective was to measure the proportion of patients for which comprehensive periodontal charting, periodontal disease risk factors (diabetes status, tobacco use, and oral home care compliance), and periodontal diagnoses were documented in the electronic health record (EHR). We developed an EHR-based quality measure to assess how well four dental institutions documented periodontal disease-related information. An automated database script was developed and implemented in the EHR at each institution. The measure was validated by comparing the findings from the measure with a manual review of charts. RESULTS: The overall measure scores varied significantly across the four institutions (institution 1 = 20.47%, institution 2 = 0.97%, institution 3 = 22.27% institution 4 = 99.49%, p-value < 0.0001). The largest gaps in documentation were related to periodontal diagnoses and capturing oral homecare compliance. A random sample of 1224 charts were manually reviewed and showed excellent validity when compared with the data generated from the EHR-based measure (Sensitivity, Specificity, PPV, and NPV > 80%). CONCLUSION: Our results demonstrate the feasibility of developing automated data extraction scripts using structured data from EHRs, and successfully implementing these to identify and measure the periodontal documentation completeness within and across different dental institutions.

Structural stability of Co-V intermetallic phases and thermodynamic description of the Co-V system.

The Co-V system has been reviewed. Density functional theory (DFT) calculations using the generalized gradient approximation (GGA) were used to obtain the energies for the end-members for all three intermediate phases, Co3V, σ and CoV3. Results from DFT calculations considering spin polarization were used to evaluate the CALPHAD (Calculation of phase diagrams) model parameters. The method to evaluate the contribution of the magnetism to the energies of Co-rich compounds that was introduced in our previous work is presented in more detail in the present work. For the description of the σ phase, the magnetic part of the total energy is included in the description of the pure Co end-member compound resulting in a non-linear description of the magnetic contribution over composition. The calculated phase diagram obtained from the present CALPHAD description is in good agreement with the experimental data. The metastable FCC-L12 phase diagram was calculated and compared with experimental data.

Thermodynamic analysis of the topologically close packed σ phase in the Co-Cr system.

Density functional theory (DFT) calculations show that it is essential to consider the magnetic contribution to the total energy for the end-members of the σ phase. A more straightforward method to use the DFT results in a CALPHAD (Calculation of phase diagrams) description has been applied in the present work. It was found that only the results from DFT calculations considering spin-polarization are necessary to obtain a reliable description of the σ phase. The benefits of this method are: the DFT calculation work can be reduced and the CALPHAD description of the magnetic contribution is more reliable. A revised thermodynamic description of the Co-Cr system is presented which gives improved agreement with experimental phase boundary data for the σ phase.

Thermodynamic assessment of the Co-Ta system.

The Co-Ta system has been reviewed and the thermodynamic description was re-assessed in the present work. DFT (density functional theory) calculations considering spin polarization were performed to obtain the energies for all end-member configurations of the C14, C15, C36 and µ phases for the evaluation of the Gibbs energies of these phases. The phase diagram calculated with the present description agrees well with the experimental and theoretical data. Considering the DFT results was essential for giving a better description of the µ phase at lower temperatures.

Prediction of seebeck coefficient for compounds without restriction to fixed stoichiometry: A machine learning approach.

The regression model-based tool is developed for predicting the Seebeck coefficient of crystalline materials in the temperature range from 300 K to 1000 K. The tool accounts for the single crystal versus polycrystalline nature of the compound, the production method, and properties of the constituent elements in the chemical formula. We introduce new descriptive features of crystalline materials relevant for the prediction the Seebeck coefficient. To address off-stoichiometry in materials, the predictive tool is trained on a mix of stoichiometric and nonstoichiometric materials. The tool is implemented into a web application (http://info.eecs.northwestern.edu/SeebeckCoefficientPredictor) to assist field scientists in the discovery of novel thermoelectric materials. © 2017 Wiley Periodicals, Inc.

Electron tomography of HIV-1 infection in gut-associated lymphoid tissue.

Critical aspects of HIV-1 infection occur in mucosal tissues, particularly in the gut, which contains large numbers of HIV-1 target cells that are depleted early in infection. We used electron tomography (ET) to image HIV-1 in gut-associated lymphoid tissue (GALT) of HIV-1-infected humanized mice, the first three-dimensional ultrastructural examination of HIV-1 infection in vivo. Human immune cells were successfully engrafted in the mice, and following infection with HIV-1, human T cells were reduced in GALT. Virions were found by ET at all stages of egress, including budding immature virions and free mature and immature viruses. Immuno-electron microscopy verified the virions were HIV-1 and showed CD4 sequestration in the endoplasmic reticulum of infected cells. Observation of HIV-1 in infected GALT tissue revealed that most HIV-1-infected cells, identified by immunolabeling and/or the presence of budding virions, were localized to intestinal crypts with pools of free virions concentrated in spaces between cells. Fewer infected cells were found in mucosal regions and the lamina propria. The preservation quality of reconstructed tissue volumes allowed details of budding virions, including structures interpreted as host-encoded scission machinery, to be resolved. Although HIV-1 virions released from infected cultured cells have been described as exclusively mature, we found pools of both immature and mature free virions within infected tissue. The pools could be classified as containing either mostly mature or mostly immature particles, and analyses of their proximities to the cell of origin supported a model of semi-synchronous waves of virion release. In addition to HIV-1 transmission by pools of free virus, we found evidence of transmission via virological synapses. Three-dimensional EM imaging of an active infection within tissue revealed important differences between cultured cell and tissue infection models and furthered the ultrastructural understanding of HIV-1 transmission within lymphoid tissue.

Particulate accumulations in the vital organs of wild Brevoortia patronus from the northern Gulf of Mexico after the Deepwater Horizon oil spill.

Histopathologic lesions were observed in the commercially important filter-feeding fish, Brevoortia patronus (Gulf menhaden), along the Louisiana Gulf Coast. Menhaden collected from Louisiana waters in 2011 and 2012, 1 and 2 years following the Deepwater Horizon oil spill, showed varying severities of gill lesions as well as an unusual accumulation of black particulates visible at necropsy in the heart and stomach vasculature. The PAH derived particulates were typically 1-4 µm in diameter, but larger aggregates were observed in the coronary vessels on the ventricle surfaces and their location and size was confirmed by light microscopy. Composited particulate composition was consistent with weathered petrogenic polycyclic aromatic hydrocarbon (PAH) mixtures based on GC-MS analysis. Particulates were present in 63 and 80% of fish hearts and 70 and 89% of stomach muscularis collected in 2011 and 2012, respectively. Tissue embedded particulates can lead to localized cellular damage from bioavailable compounds, as well as chronic effects from occlusion of sensitive tissues' blood flow. The PAH derived particulates appeared to act as emboli in small capillaries, and could associated with localized inflammation, focal necrosis and inappropriate collagen and fibroblast tissue repair. We believe large volume filter feeding teleosts, such as menhaden (up to 3 million gallons per year/fish) with high lipid content, have a higher exposure risk and greater potential for toxicity from toxic particulates than other higher trophic level finfish. Suspended PAH derived particulates following an oil spill therefore, should be considered when assessing long-term ecological impacts and not be limited to physical contact (coating) or water soluble fractions for assessing toxicity (gill and neurologic).

Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction.

Innate immune cells play important roles in tissue injury and repair following acute myocardial infarction (MI). Although reprogramming of macrophage metabolism has been observed during inflammation and resolution phases, the mechanistic link to macrophage phenotype is not fully understood. In this study, we found that myeloid-specific deletion (mKO) of mitochondrial complex I protein, encoded by Ndufs4, reproduced the proinflammatory metabolic profile in macrophages and exaggerated the response to LPS. Moreover, mKO mice showed increased mortality, poor scar formation, and worsened cardiac function 30 days after MI. We observed a greater inflammatory response in mKO mice on day 1 followed by increased cell death of infiltrating macrophages and blunted transition to the reparative phase during post-MI days 3-7. Efferocytosis was impaired in mKO macrophages, leading to lower expression of antiinflammatory cytokines and tissue repair factors, which suppressed the proliferation and activation of myofibroblasts in the infarcted area. Mitochondria-targeted ROS scavenging rescued these impairments, improved myofibroblast function in vivo, and reduced post-MI mortality in mKO mice. Together these results reveal a critical role of mitochondria in inflammation resolution and tissue repair via modulation of efferocytosis and crosstalk with fibroblasts. These findings have potential significance for post-MI recovery as well as for other inflammatory conditions.

Transferred mitochondria accumulate reactive oxygen species, promoting proliferation.

Recent studies reveal that lateral mitochondrial transfer, the movement of mitochondria from one cell to another, can affect cellular and tissue homeostasis. Most of what we know about mitochondrial transfer stems from bulk cell studies and have led to the paradigm that functional transferred mitochondria restore bioenergetics and revitalize cellular functions to recipient cells with damaged or non-functional mitochondrial networks. However, we show that mitochondrial transfer also occurs between cells with functioning endogenous mitochondrial networks, but the mechanisms underlying how transferred mitochondria can promote such sustained behavioral reprogramming remain unclear. We report that unexpectedly, transferred macrophage mitochondria are dysfunctional and accumulate reactive oxygen species in recipient cancer cells. We further discovered that reactive oxygen species accumulation activates ERK signaling, promoting cancer cell proliferation. Pro-tumorigenic macrophages exhibit fragmented mitochondrial networks, leading to higher rates of mitochondrial transfer to cancer cells. Finally, we observe that macrophage mitochondrial transfer promotes tumor cell proliferation in vivo. Collectively these results indicate that transferred macrophage mitochondria activate downstream signaling pathways in a ROS-dependent manner in cancer cells, and provide a model of how sustained behavioral reprogramming can be mediated by a relatively small amount of transferred mitochondria in vitro and in vivo.

An Observational Retrospective Study of Adverse Events and Behavioral Outcomes During Pediatric Dental Sedation.

Purpose: The purpose of this study was to examine a university-based dental electronic health records (EHR) database to identify sedation-related adverse events (AEs) and assess patients' behavioral outcomes during routine pediatric dental sedations (PDSs) in a dental school clinic. Methods: A database was screened for patients younger than 18 years old who had received dental sedation in 2019. The qualifying EHRs were then accessed and sedations were reviewed for AEs, which were categorized using a 12-point classification system and the Tracking and Reporting Outcomes of Procedural Sedation Tool. Patient behaviors were assessed using provider progress notes and categorized as presence/ absence of agitation. Results: A total of 690 sedations were reviewed, yielding 28 AEs. Emesis was the most common AE observed in 1.3 percent of sedations. Respiratory and cardiovascular AEs were observed in 0.7 percent and 0.6 percent of sedations, respectively. Agitation was identified in 47.5 percent of sedations, while 34.1 percent of agitations resulted in the documented suspension of dental treatment. Agitation was mainly observed for nitrous oxide and oral sedation resulting in one failed sedation out of five sedations for each method. Conclusions: Potentially serious adverse effects were identified during pediatric dental sedations, but their incidence was low. A significant proportion of the sedated children experienced agitation, resulting in some sedation failures. Such events need to be tracked and examined for risk assessment reduction and quality-of-care improvement.

Genetic Modification of Primary Human Myeloid Cells to Study Cell Migration, Activation, and Organelle Dynamics.

Myeloid dendritic cells (DCs) and macrophages are mononuclear phagocytes with key roles in the immune system. As antigen-presenting cells, they link innate detection of microbes with programming adaptive immune responses. Myeloid DCs and macrophages also play critical roles in development, promote tissue homeostasis, and direct repair in response to injury and inflammation. As cellular migration and organelle dynamics are intimately connected with these processes, it is necessary to develop tools to track myeloid cell behavior and function. Here, we build on previously established protocols to isolate primary human myeloid cells from peripheral blood and report an optimized method for their genetic modification with lentiviral vectors to study processes related to cell migration, activation, and organelle dynamics. Specifically, we provide a protocol for delivering genetically encoded fluorescent markers into primary monocyte-derived DCs (MDDCs) and monocyte-derived macrophages (MDMs) to label mitochondria, peroxisomes, and whole cells. We describe the isolation of primary CD14+ monocytes from peripheral blood using positive selection with magnetic beads and, alternatively, isolation based on plastic adherence. Isolated CD14+ cells can be transduced with lentiviral vectors and subsequently cultured in the presence of cytokines to derive MDDCs or MDMs. This protocol is highly adaptable for cotransduction with vectors to knock down or overexpress genes of interest. These tools enable mechanistic studies of genetically modified myeloid cells through flow cytometry, fluorescence microscopy, and other downstream assays. © 2022 Wiley Periodicals LLC. Basic Protocol: Transduction of MDDCs and MDMs with lentiviral vectors encoding fluorescent markers Alternate Protocol 1: Isolation of monocytes by plastic adhesion Alternate Protocol 2: Transduction of MDDCs and MDMs with lentiviral vectors to knock down or overexpress genes of interest Support Protocol 1: Production and purification of lentiviral vectors for transduction into primary human myeloid cells Support Protocol 2: Flow cytometry of MDDCs and MDMs Support Protocol 3: Fixed and live-cell imaging of fluorescent markers in MDMs and MDDCs.

Caries Risk Documentation And Prevention: eMeasures For Dental Electronic Health Records.

BACKGROUND: Longitudinal patient level data available in the electronic health record (EHR) allows for the development, implementation, and validations of dental quality measures (eMeasures). OBJECTIVE: We report the feasibility and validity of implementing two eMeasures. The eMeasures determined the proportion of patients receiving a caries risk assessment (eCRA) and corresponding appropriate risk-based preventative treatments for patients at elevated risk of caries (appropriateness of care [eAoC]) in two academic institutions and one accountable care organization, in the 2019 reporting year. METHODS: Both eMeasures define the numerator and denominator beginning at the patient level, populations' specifications, and validated the automated queries. For eCRA, patients who completed a comprehensive or periodic oral evaluation formed the denominator, and patients of any age who received a CRA formed the numerator. The eAoC evaluated the proportion of patients at elevated caries risk who received the corresponding appropriate risk-based preventative treatments. RESULTS: EHR automated queries identified in three sites 269,536 patients who met the inclusion criteria for receiving a CRA. The overall proportion of patients who received a CRA was 94.4% (eCRA). In eAoC, patients at elevated caries risk levels (moderate, high, or extreme) received fluoride preventive treatment ranging from 56 to 93.8%. For patients at high and extreme risk, antimicrobials were prescribed more frequently site 3 (80.6%) than sites 2 (16.7%) and 1 (2.9%). CONCLUSION: Patient-level data available in the EHRs can be used to implement process-of-care dental eCRA and AoC, eAoC measures identify gaps in clinical practice. EHR-based measures can be useful in improving delivery of evidence-based preventative treatments to reduce risk, prevent tooth decay, and improve oral health.