High Lethality of Mycobacterium tuberculosis Infection in Mice Lacking the Phagocyte Oxidase and Caspase1/11.

Immune networks that control antimicrobial and inflammatory mechanisms have overlapping regulation and functions to ensure effective host responses. Genetic interaction studies of immune pathways that compare host responses in single and combined knockout backgrounds are a useful tool to identify new mechanisms of immune control during infection. For disease caused by pulmonary Mycobacterium tuberculosis (Mtb) infections, which currently lacks an effective vaccine, understanding the genetic interactions between protective immune pathways may identify new therapeutic targets or disease-associated genes. Previous studies have suggested a direct link between the activation of NLRP3-Caspase1 inflammasome and the NADPH-dependent phagocyte oxidase complex during Mtb infection. Loss of the phagocyte oxidase complex alone resulted in increased activation of Caspase1 and IL-1ß production during Mtb infection, resulting in failed disease tolerance during the chronic stages of disease. To better understand this interaction, we generated mice lacking both Cybb, a key subunit of the phagocyte oxidase, and Caspase1/11. We found that ex vivo Mtb infection of Cybb-/-Caspase1/11-/- macrophages resulted in the expected loss of IL-1ß secretion but an unexpected change in other inflammatory cytokines and bacterial control. Mtb infected Cybb-/-Caspase1/11-/- mice rapidly progressed to severe TB, succumbing within 4 weeks to disease characterized by high bacterial burden, increased inflammatory cytokines, and the recruitment of granulocytes that associated with Mtb in the lungs. These results uncover a key genetic interaction between the phagocyte oxidase complex and Caspase1/11 that controls protection against TB and highlight the need for a better understanding of the regulation of fundamental immune networks during Mtb infection.

Direct growth of crystalline SiGe nanowires on superconducting NbTiN thin films.

Novel heterostructures created by coupling one-dimensional semiconductor nanowires with a superconducting thin film show great potential toward next-generation quantum computing. Here, by growing high-crystalline SiGe nanowires on a NbTiN thin film, the resulting heterostructure exhibits Ohmic characteristics as well as a shift of the superconducting transition temperature (Tc). The structure was characterized at atomic resolution showing a sharp SiGe/NbTiN interface without atomic interdiffusion. Lattice spacing, as calculated from large-area x-ray diffraction experiments, suggests a potential preferredd-spacing matching between (200) NbTiN and (110) SiGe grains. The observed out-of-plane compressive strain within the NbTiN films coupled with SiGe nanowires explains the downward shift of the superconductivity behavior. The presented results post scientific insights toward functional heterostructures by coupling multi-dimensional materials, which could enable tunable superconductivity that benefits the quantum science applications.

An FBG Optical Approach to Thermal Expansion Measurements under Hydrostatic Pressure.

We report on an optical technique for measuring thermal expansion and magnetostriction at cryogenic temperatures and under applied hydrostatic pressures of 2.0 GPa. Optical fiber Bragg gratings inside a clamp-type pressure chamber are used to measure the strain in a millimeter-sized sample of CeRhIn5. We describe the simultaneous measurement of two Bragg gratings in a single optical fiber using an optical sensing instrument capable of resolving changes in length [dL/L = (L- L0)/L0] on the order of 10-7. Our results demonstrate the possibility of performing high-resolution thermal expansion measurements under hydrostatic pressure, a capability previously hindered by the small working volumes typical of pressure cells.

TGFß primes alveolar-like macrophages to induce type I IFN following TLR2 activation.

Alveolar macrophages (AMs) are key mediators of lung function and are potential targets for therapies during respiratory infections. TGFß is an important regulator of AM differentiation and maintenance, but how TGFß directly modulates the innate immune responses of AMs remains unclear. This shortcoming prevents effective targeting of AMs to improve lung function in health and disease. Here we leveraged an optimized ex vivo AM model system, fetal-liver derived alveolar-like macrophages (FLAMs), to dissect the role of TGFß in AMs. Using transcriptional analysis, we first globally defined how TGFß regulates gene expression of resting FLAMs. We found that TGFß maintains the baseline metabolic state of AMs by driving lipid metabolism through oxidative phosphorylation and restricting inflammation. To better understand inflammatory regulation in FLAMs, we next directly tested how TGFß alters the response to TLR2 agonists. While both TGFß (+) and TGFß (-) FLAMs robustly responded to TLR2 agonists, we found an unexpected activation of type I interferon (IFN) responses in FLAMs and primary AMs in a TGFß-dependent manner. Surprisingly, mitochondrial antiviral signaling protein and the interferon regulator factors 3 and 7 were required for IFN production by TLR2 agonists. Together, these data suggest that TGFß modulates AM metabolic networks and innate immune signaling cascades to control inflammatory pathways in AMs.

Sudden adiabaticity signals reentrant bulk superconductivity in UTe2.

There has been a recent surge of interest in UTe2 due to its unconventional magnetic field (H)-reinforced spin-triplet superconducting phases persisting at fields far above the simple Pauli limit for H∥[010]. Magnetic fields in excess of 35 T then induce a field-polarized magnetic state via a first-order-like phase transition. More controversially, for field orientations close to H∥[011] and above 40 T, electrical resistivity measurements suggest that a further superconducting state may exist. However, no Meissner effect or thermodynamic evidence exists to date for this phase making it difficult to exclude alternative scenarios. In this paper, we describe a study using thermal, electrical, and magnetic probes in magnetic fields of up to 55 T applied between the [010] (b) and [001] (c) directions. Our MHz conductivity data reveal the field-induced state of low or vanishing electrical resistance; our simultaneous magnetocaloric effect measurements (i.e. changes in sample temperature due to changing magnetic field) show the first definitive evidence for adiabaticity and thermal behavior characteristic of bulk field-induced superconductivity.

Rapid lethality of mice lacking the phagocyte oxidase and Caspase1/11 following Mycobacterium tuberculosis infection.

Immune networks that control antimicrobial and inflammatory mechanisms have overlapping regulation and functions to ensure effective host responses. Genetic interaction studies of immune pathways that compare host responses in single and combined knockout backgrounds are a useful tool to identify new mechanisms of immune control during infection. For disease caused by pulmonary Mycobacterium tuberculosis infections, which currently lacks an effective vaccine, understanding genetic interactions between protective immune pathways may identify new therapeutic targets or disease-associated genes. Previous studies suggested a direct link between the activation of NLRP3-Caspase1 inflammasome and the NADPH-dependent phagocyte oxidase complex during Mtb infection. Loss of the phagocyte oxidase complex alone resulted in increased activation of Caspase1 and IL1ß production during Mtb infection, resulting in failed disease tolerance during the chronic stages of disease. To better understand this interaction, we generated mice lacking both Cybb , a key subunit of the phagocyte oxidase, and Caspase1/11 . We found that ex vivo Mtb infection of Cybb -/- Caspase1/11 -/- macrophages resulted in the expected loss of IL1ß secretion but an unexpected change in other inflammatory cytokines and bacterial control. Mtb infected Cybb -/- Caspase1/11 -/- mice rapidly progressed to severe TB, succumbing within four weeks to disease characterized by high bacterial burden, increased inflammatory cytokines, and the recruitment of granulocytes that associated with Mtb in the lungs. These results uncover a key genetic interaction between the phagocyte oxidase complex and Caspase1/11 that controls protection against TB and highlight the need for a better understanding of the regulation of fundamental immune networks during Mtb infection.

Macrophage Infection Models for Mycobacterium tuberculosis.

Mycobacterium tuberculosis colonizes, survives, and grows inside macrophages. In vitro macrophage infection models, using both primary macrophages and cell lines, enable the characterization of the pathogen response to macrophage immune pressure and intracellular environmental cues. We describe methods to propagate and infect primary murine bone marrow-derived macrophages, HoxB8 conditionally immortalized myeloid cells, Max Planck Institute alveolar macrophage-like cells, and J774 and THP-1 macrophage-like cell lines. We also present methods on the characterization of M. tuberculosis intracellular survival and the preparation of infected macrophages for imaging.

Creating and sharing clinical decision support content with Web 2.0: Issues and examples.

Clinical decision support is a powerful tool for improving healthcare quality and patient safety. However, developing a comprehensive package of decision support interventions is costly and difficult. If used well, Web 2.0 methods may make it easier and less costly to develop decision support. Web 2.0 is characterized by online communities, open sharing, interactivity and collaboration. Although most previous attempts at sharing clinical decision support content have worked outside of the Web 2.0 framework, several initiatives are beginning to use Web 2.0 to share and collaborate on decision support content. We present case studies of three efforts: the Clinfowiki, a world-accessible wiki for developing decision support content; Partners Healthcare eRooms, web-based tools for developing decision support within a single organization; and Epic Systems Corporation's Community Library, a repository for sharing decision support content for customers of a single clinical system vendor. We evaluate the potential of Web 2.0 technologies to enable collaborative development and sharing of clinical decision support systems through the lens of three case studies; analyzing technical, legal and organizational issues for developers, consumers and organizers of clinical decision support content in Web 2.0. We believe the case for Web 2.0 as a tool for collaborating on clinical decision support content appears strong, particularly for collaborative content development within an organization.

The economics of integrated electronic medical record systems.

The decision to adopt electronic medical record systems in private practices is usually based on factors specific to the practice--the cost, cost and timesaving, and impact on quality of care. As evident by the low adoption rates, providers have not found these evaluations compelling. However, it is recognized that the widespread adoption of EMR systems would greatly benefit the health care system as a whole. One explanation for the lack of adoption is that there is a misalignment of the costs and benefits of EMR systems across the health care system. In this paper we present an economic model of the adoption of EMR systems that explicitly represents the distribution of costs and benefits across stakeholders (physicians, hospitals, insurers, etc.). We discuss incentive systems for balancing the costs and benefits and, thus, promoting the faster adoption of EMR systems. Finally, we describe our plan to extend the model and to use real-world data to evaluate our model.

Comparison of practice patterns of hospitalists and community physicians in the care of patients with congestive heart failure.

OBJECTIVE: The objective of the present study was to compare the practice patterns of hospitalists and community physicians in the care of patients with congestive heart failure. DESIGN/PARTICIPANTS/SETTING: The study was a retrospective chart review of 342 patients treated for congestive heart failure at a community-based teaching hospital. MEASUREMENTS: Use of established therapeutic modalities for congestive heart failure and utilization of resources by hospitalists and nonhospitalists were compared. Outcome measures were adjusted length of stay (LOS), costs per case, in-hospital mortality, acute renal failure rate, and readmission rate. RESULTS: The patients of hospitalist were more likely to receive ACE-I or ARB therapy within 24 hours of admission (86% vs. 72%; P = .003), intravenous diuretics (90% vs. 73%; P < .001), and social work consultation (48% vs. 29%; P < .001). They were less likely to have had serial chest radiographs (4% vs. 13%; P = .01) and multiple consultants (8% vs. 16%; P = .03). Hospitalists' patients with an illness whose severity was categorized as minor had a 40% reduction in LOS, those with a moderately severe illness had a 20% reduction, and those with an extremely severe illness had a 13% reduction (P = .002). Costs per case were reduced by $1000-$3100 across all severity categories (P < .001). Rates of acute renal failure and readmission were similar between the groups. CONCLUSIONS: Early use of ACE-I/ARB, aggressive approach to diuresis, greater involvement of social work services and decreased use of chest radiographs and medical consultants were identified as distinct practices of hospitalists in this medical center. These practices may have led to a shorter LOS and lower costs while preserving quality of care and possibly improving clinical outcomes.

Jumping the CPOE generation gap: Queen's Epic Installation.

The Queen's Medical Center has been a pioneer in the use of information technology for clinical care, especially for a community hospital. Queen's had demonstrated a high rate of success with CPOE dating to 1995. In 2003, Queen's took another pioneering step by choosing to upgrade its clinical systems with a single vendor solution. Additionally, a big-bang, all at once roll out was chosen. Despite this ambitious and high-risk project, Queen's has experienced success with its roll out of its next generation clinical system.

The characteristics of personal order sets in a computerized physician order entry system at a community hospital.

Personal order sets (POS) have been touted as important for the success of a computerized physician order entry (CPOE) system. However, POS may systematize practice variability and are difficult to centrally administer. Few studies have looked at the characteristics and use of POS in a community hospital. We examined how POS are used at the Queen's Medical Center (QMC). POS are an important part of the success of the QMC CPOE, but have definite disadvantages.

A successful technique for removing names in pathology reports using an augmented search and replace method.

The ability to access large amounts of de-identified clinical data would facilitate epidemiologic and retrospective research. Previously described de-identification methods require knowledge of natural language processing or have not been made available to the public. We take advantage of the fact that the vast majority of proper names in pathology reports occur in pairs. In rare cases where one proper name is by itself, it is preceded or followed by an affix that identifies it as a proper name (Mrs., Dr., PhD). We created a tool based on this observation using substitution methods that was easy to implement and was largely based on publicly available data sources. We compiled a Clinical and Common Usage Word (CCUW) list as well as a fairly comprehensive proper name list. Despite the large overlap between these two lists, we were able to refine our methods to achieve accuracy similar to previous attempts at de-identification. Our method found 98.7% of 231 proper names in the narrative sections of pathology reports. Three single proper names were missed out of 1001 pathology reports (0.3%, no first name/last name pairs). It is unlikely that identification could be implied from this information. We will continue to refine our methods, specifically working to improve the quality of our CCUW and proper name lists to obtain higher levels of accuracy.