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Inline vertical separators are commonly employed in natural gas transmission facilities (e.g., receipt stations) to filter liquid contaminants such as compressor oil, glycol, and free water from the gas stream. Manufacturers of these separators have claimed liquid removal efficiencies of 98–99% for droplet sizes ≥ 8 μm. However, these contaminants have been found invariably in piping systems downstream of these separators, suggesting inadequate separator performance. Currently, there is a lack of ability to verify manufacturer claims due to difficulties in quantifying liquid contaminants and droplet characteristics. The potential consequences of having such contaminants include lower gas quality, impaired gas metering accuracy, corrosion and damage to equipment/instrumentation, and adverse impacts on industrial and residential end users. This paper presents performance testing of a mesh-vane-type vertical separator conducted on high pressure, pipeline quality, natural gas in the range of 4–5 MPa and flow velocity in the range of 1.3–13 m/s in the DN150 separator inlet (hence turndown ratio of 10:1). Four different spray nozzles were used to inject and atomize industrial compressor oil with a liquid-to-gas mass loading ratio of 0.06–1.8%. Test results revealed that the average bulk efficiency separation performance for this separator is approximately 90.34%. This was found to be independent of the liquid-to-gas mass loading ratio. The effective Souders–Brown K-factor was found to be 0.15 m/s. This is below literature published data in the range of 0.27–0.3 m/s for horizontal flow, vane-pack-type separators. Liquid separation tests were also conducted following the injection of solid glass beads. Liquid separation efficiency decreased by approximately 9%, following the injection of 7 kg of industrial glass beads over a period of approximately 4 h. This was attributed to accumulation of solids in the vane pack.

Conventional photon radiation therapy (RT) for breast cancer is associated with a reduction in global longitudinal strain (GLS) and an increase in troponin, N-terminal pro hormone B-type natriuretic peptide (NT-proBNP), and incident heart failure. The cardiac radiation exposure with proton-RT is much reduced and thus may be associated with less cardiotoxicity. The objective was to test the effect of proton-RT on GLS, troponin, and NT-proBNP.We conducted a prospective, observational, single-center study of 70 women being treated with proton-RT for breast cancer. Serial measurements of GLS, high-sensitivity troponin I, and NT-proBNP were performed at prespecified intervals (before proton-RT, 4 weeks after completion of proton-RT, and again at 2 months after proton-RT).The mean age of the patients was 46 ± 11 years, and the mean body mass index was 25.6 ± 5.2 kg/mProton-RT did not affect LV function and was not associated with an increase in biomarkers. These data support the potential cardiac benefits of proton-RT compared with conventional RT.

γ-Irradiation of crystalline hexaaquamagnesium trans-2-butenoate dihydrate affords rel-(3S,4R)-1-hexene-3,4-dicarboxylate by a single-crystal-to-single-crystal reaction. The reaction proceeds by a ...

Background The relationship between von Willebrand factor antigen (VWF:Ag), VWF propeptide (VWFpp), VWFpp/VWF:Ag ratio, ADAMTS13 activity, and microembolic signal (MES) status in carotid stenosis is unknown. Methods This prospective, multicenter study simultaneously assessed plasma VWF:Ag levels, VWFpp levels and ADAMTS13 activity, and their relationship with MES in asymptomatic versus symptomatic moderate-to-severe (≥50–99%) carotid stenosis patients. One-hour transcranial Doppler ultrasound of the middle cerebral arteries classified patients as MES+ve or MES−ve. Results Data from 34 asymptomatic patients were compared with 43 symptomatic patients in the “early phase” (≤4 weeks) and 37 patients in the “late phase” (≥3 months) after transient ischemic attack (TIA)/ischemic stroke. VWF:Ag levels were higher (p = 0.049) and VWFpp/VWF:Ag ratios lower (p = 0.006) in early symptomatic than in asymptomatic patients overall, and in early symptomatic versus asymptomatic MES−ve subgroups (p ≤0.02). There were no intergroup differences in VWFpp expression or ADAMTS13 activity (p ≥0.05). VWF:Ag levels and ADAMTS13 activity decreased (p ≤ 0.048) and VWFpp/VWF:Ag ratios increased (p = 0.03) in symptomatic patients followed up from the early to late phases after TIA/stroke. Although there were no differences in the proportions of symptomatic and asymptomatic patients with blood group O, a combined analysis of early symptomatic and asymptomatic patients revealed lower median VWF:Ag levels in patients with blood group O versus those without blood group O (9.59 vs. 12.32 µg/mL, p = 0.035). Discussion VWF:Ag expression, a marker of endothelial ± platelet activation, is enhanced in recently symptomatic versus asymptomatic carotid stenosis patients, including in MES−ve patients, and decreases with ADAMTS13 activity over time following atherosclerotic TIA/ischemic stroke.

Solid solutions of aripiprazole (APZ) and its active metabolite, dehydro-aripiprazole (dAPZ), have been prepared as free form (neat or nonsolvated), hydrated, or alcohol- solvated modifications wit...

Introduction: According to the 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, admitting orders for the patient with STEMI should include a serum lipid profile in laboratory tests. Subsequently, the 2018 Guideline on the Management of Blood Cholesterol guidelines state that in primary prevention statins are recommended for patients with severe hypercholesterolemia and in adults 40 to 75 years of age either with diabetes mellitus or at higher ASCVD risk. Methods: A baseline review of data from Get With The Guidelines® - CAD across 10 pilot sites was conducted. An initial 430 patients were excluded from the Ezetimibe Considered for Very High-Risk Patients measure due to missing data fields. Interviews were conducted with participating sites to determine the root cause of the incomplete data. Results: The root cause analyses resulting from these interviews and case studies revealed that lipid profiles were not consistently performed. Further, only two patients were included in the numerator for the Ezetimibe Considered for Very High-Risk Patients measure. An analysis of 455 eligible patients showed that 70% of AMI patients seen by these hospitals were not presenting on any statin therapy prior to their acute event. Conclusions: Despite the clinical guideline recommendations for lipid management for both acute and secondary prevention, there remains much room for improvement. Preliminary results from this learning collaborative highlight the need for improved lipid profiling practices in the acute setting for STEMI patients and an opportunity for intervention through modifiable risk factor reduction in the form of statin therapy in the outpatient setting. We have identified a gap in AMI patient care, which presents the opportunity to improve long-term patient outcomes through heightened lipid profile collection sensitivity. At a systemic level, further research needs to be conducted to determine why patients are presenting with severe acute coronary events without prior management of their blood cholesterol levels. We hope through continued studies with the pilot sites we will observe a shift in practice patterns and improved non-statin lipid-lowering medication consideration for very high-risk ASCVD patients.

Background Conventional photon radiotherapy (RT) for breast cancer is associated with reduction in global longitudinal strain (GLS), an increase in both troponin and N-terminal pro-B type natriuretic peptide (NT-proBNP), and incident heart failure. The cardiac radiation exposure with proton-RT is reduced and, thus may be associated with less cardiotoxicity. Objectives To test the effect of proton-RT on GLS, troponin and NT-proBNP. Methods A prospective observational single center study of 69 women being treated with proton-RT for breast cancer. Serial measurements of GLS, high-sensitivity cardiac troponin-I (hs-cTnI), and NT-proBNP were performed at pre-specified intervals (pre proton-RT, 4 weeks after completion of proton-RT and again at 2 months post proton-RT). Results The mean age was 46±11 years, BMI was 25.6±5.2 kg/m2, 32% had hypertension and mean radiation dose to the heart and left ventricle (LV) were 0.44 Gy and 0.12 Gy respectively. There was no change in LV ejection fraction (pre proton-RT vs. 4-weeks post proton-RT vs. 2 months post proton-RT, 65±5 vs. 66±5 vs. 64±4%, p=0.15), global GLS (−21.7±2.7 vs. −22.7±2.3 vs. −22.8±2.1%, p=0.24) or segmental GLS from pre-to post proton-RT. Similarly, there was no change in hs-cTnI or NT-proBNP with proton-RT. However, post proton-RT, we found that patients with a history of hypertension had lower GLS when compared to women without hypertension (−21.3±3.5 vs. −24.0±2.4%, p=0.006). Conclusion Proton-RT did not impact LV function, or associate with an increase in biomarkers. These data support the potential cardiac benefits of proton-RT compared to conventional RT. Funding Acknowledgement Type of funding sources: None.

Long-acting injectable (LAI) antipsychotics are an important treatment option for patients with schizophrenia. Advances and variability in formulation technology have provided several LAI antipsychotic treatment options for schizophrenia, with a wide range of doses and dose intervals. However, clinical reviews of LAIs have not focused on formulation development despite its clinical relevance to injection safety and technique. This article reviews the relationship between formulation technology and clinical practices for LAIs, with a focus on aripiprazole lauroxil, a long-acting atypical antipsychotic indicated for the treatment of schizophrenia. The formulation developed for aripiprazole lauroxil is an aqueous-based suspension suitable for use as a prefilled syringe that, after injection, will release aripiprazole slowly into the plasma. The clinical relationship between the aripiprazole lauroxil formulation and proper injection techniques is explained, including why tapping and shaking the syringe to resuspend the drug particles and rapid injection speed are key steps for best injection practices for this formulation.

Introduction Shoulder dislocation is a painful injury best treated by early closed reduction. Patients often require intravenous sedation, with airway monitoring in a safe setting. We implemented methoxyflurane inhalational analgesia (Penthrox) to aid shoulder dislocation reduction without the need for sedation and evaluated the effectiveness and adverse events. Method Patients presenting to the minor injury’s unit at Wrexham Maelor Hospital between 01/04/2020 and 26/05/2020 with only shoulder dislocation were included. Patients had Penthrox and underwent closed reduction. Pre and post reduction shoulder radiographs were reviewed to determine reduction success and time between radiographs was evaluated. Adverse events were recorded. Reduction success and times between radiographs were compared to a consecutive retrospective cohort of patients who underwent closed shoulder dislocation reduction with sedation before implementing Penthrox. Results 22 patients were included. Mean patient age was 44.6 years. Majority were male (72%). Penthrox was used in 11 patients. All patients had their shoulder dislocation reduced successfully. Mean time between reduction radiographs for the Penthrox group was 40.8 min (95%CI 27.4 to 54.3). This was shorter than the intravenous sedation group mean 157.7 minutes (95%CI 92.3 to 223.2, p = 0.0026). No documented adverse events with Penthrox. Conclusions Simple shoulder dislocations can be reduced safely, quickly, and effectively using Penthrox.

Introduction It has been shown that direct fixation of the posterior malleolus improves functional outcomes. Our aim was to audit the functional outcome of patients with these fractures which were fixed with an isolated posterolateral approach. Method A consecutive case series of patients who underwent direct fixation of the posterior malleolus using a posterolateral approach between 20/12/2012 and 23/1/2020 was identified. Fractures were classified according to Mason and Molloy classification based on preoperative CT. Type 2a and 2b fractures were included. Functional outcome was assessed using Olerud-Molander score. Result 18 patients were included. Mean age at time of surgery was 52 years (range 20 to 75 years). 56% (n = 10) were female. Mean follow up was 18.1 months (range 4.2 months to 7.2 years). OMAS score for type 2a fractures (n = 9) was 71.1 (95% CI 65.3 to 77.0). OMAS score for type 2b fractures (n = 9) was 67.8 (95% CI 54.6 to 81.0). There was no significant difference between groups (p = 0.65). Conclusions Fixation of Mason and Molloy Type 2 fractures using an isolated posterolateral approach results in satisfactory functional results for the majority of patients. Further prospective comparative study is needed to identify which patients benefit most from alternative approaches.

Clinical and experimental data suggest that pathogenesis in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is driven by ANCA-mediated activation of neutrophils and monocytes. While the role of neutrophils has been extensively investigated, the function of monocytes remains relatively understudied. We have previously demonstrated that stimulation of monocytes with anti-myeloperoxidase (MPO), but not anti-proteinase-3 (PR3), antibodies results in production of the pro-inflammatory cytokine IL-1β. Changes in cellular metabolism, particularly a switch to glycolysis, have recently been linked to activation of immune cells and production of IL-1β. Therefore, we investigated the metabolic profile of monocytes following ANCA stimulation. We found a significant increase in glucose uptake in anti-MPO stimulated monocytes. Interestingly, both anti-MPO and anti-PR3 stimulation resulted in an immediate increase in glycolysis, measured by Seahorse extracellular flux analysis. However, this increase in glycolysis was sustained (for up to 4 h) in anti-MPO- but not anti-PR3-treated cells. In addition, only anti-MPO-treated cells exhibited increased oxidative phosphorylation, a metabolic response that correlated with IL-1β production. These data indicate that monocyte metabolism is altered by ANCA, with divergent responses to anti-MPO and anti-PR3 antibodies. These metabolic changes may underlie pathologic immune activation in ANCA associated vasculitis, as well as potentially contributing to the differing clinical phenotype between PR3- and MPO-ANCA positive patients. These metabolic pathways may therefore be potential targets for therapeutic intervention.

The phase behavior and characterization of two forms of naltrexone hydrochloride dihydrate are presented. A metastable form was isolated first in the solid state under kinetically controlled conditions, namely dehydration of a higher hydrate followed by exposure to ∼38% relative humidity. The second, more thermodynamically stable polymorph was isolated from an aqueous slurry at an elevated temperature. The phase transition boundaries between naltrexone hydrochloride anhydrate and the metastable hydrate species are established through a combination of slurry and moisture sorption experiments to provide a detailed mechanistic understanding of the hydration/dehydration behavior.

Brexpiprazole (BPZ) is an atypical antipsychotic drug indicated for the treatment of schizophrenia and depression. Crystal form screening of BPZ resulted in the formation of three polymorphs (I, II, and III), two methanol solvates, a toluene hemisolvate, and a dihydrate. Thermal analysis and solvent-mediated conversion experiments of the three unsolvated polymorphs established that Form I is the thermodynamically stable form at ambient temperature. All three polymorphs are monotropically related, whereby Forms I and II are the most and least stable forms, respectively. Structural diversity of BPZ was compared with two chemically related analogues, aripiprazole (APZ) and its active metabolite dehydro-aripiprazole (dAPZ). Like APZ and dAPZ, BPZ was shown to form a thermodynamically stable, hydrated crystal form when exposed to an aqueous environment; however, while APZ and dAPZ were characterized as monohydrates, BPZ is a dihydrate. The crystal structure of BPZ dihydrate (S2H2O) showed two water molecules c...

Summary Innate lymphocyte populations, such as innate lymphoid cells (ILCs), γδ T cells, invariant natural killer T (iNK T) cells and mucosal-associated invariant T (MAIT) cells are emerging as important effectors of innate immunity and are involved in various inflammatory and autoimmune diseases. The aim of this study was to assess the frequencies and absolute numbers of innate lymphocytes as well as conventional lymphocytes and monocytes in peripheral blood from a cohort of anti-neutrophil cytoplasm autoantibody (ANCA)-associated vasculitis (AAV) patients. Thirty-eight AAV patients and 24 healthy and disease controls were included in the study. Patients with AAV were sampled both with and without immunosuppressive treatment, and in the setting of both active disease and remission. The frequencies of MAIT and ILC2 cells were significantly lower in patients with AAV and in the disease control group compared to healthy controls. These reductions in the AAV patients remained during remission. B cell count and frequencies were significantly lower in AAV in remission compared to patients with active disease and disease controls. Despite the strong T helper type 2 (Th) preponderance of eosinophilic granulomatosis with polyangiitis, we did not observe increased ILC2 frequency in this cohort of patients. The frequencies of other cell types were similar in all groups studied. Reductions in circulating ILC2 and MAIT cells reported previously in patients with AAV are not specific for AAV, but are more likely to be due to non-specific manifestations of renal impairment and chronic illness. Reduction in B cell numbers in AAV patients experiencing remission is probably therapy-related.

Poor myeloid engraftment remains a barrier to experimental use of humanized mice. Focusing primarily on peripheral blood cells, we compared the engraftment profile of NOD-scid-IL2Rγc(-/-) (NSG) mice with that of NSG mice transgenic for human membrane stem cell factor (hu-mSCF mice), NSG mice transgenic for human interleukin (IL)-3, granulocyte-macrophage-colony stimulating factor (GM-CSF), and stem cell factor (SGM3 mice). hu-mSCF and SGM3 mice showed enhanced engraftment of human leukocytes compared to NSG mice, and this was reflected in the number of human neutrophils and monocytes present in these strains. Importantly, discrete classical, intermediate, and nonclassical monocyte populations were identifiable in the blood of NSG and hu-mSCF mice, while the nonclassical population was absent in the blood of SGM3 mice. Granulocyte-colony stimulating factor (GCSF) treatment increased the number of blood monocytes in NSG and hu-mSCF mice, and neutrophils in NSG and SGM3 mice; however, this effect appeared to be at least partially dependent on the stem cell donor used to engraft the mice. Furthermore, GCSF treatment resulted in a preferential expansion of nonclassical monocytes in both NSG and hu-mSCF mice. Human tubulointerstitial CD11c(+) cells were present in the kidneys of hu-mSCF mice, while monocytes and neutrophils were identified in the liver of all strains. Bone marrow-derived macrophages prepared from NSG mice were most effective at phagocytosing polystyrene beads. In conclusion, hu-mSCF mice provide the best environment for the generation of human myeloid cells, with GCSF treatment further enhancing peripheral blood human monocyte cell numbers in this strain.

A specific biomarker that can separate active renal vasculitis from other causes of renal dysfunction is lacking, with a kidney biopsy often being required. Soluble CD163 (sCD163), shed by monocytes and macrophages, has been reported as a potential biomarker in diseases associated with excessive macrophage activation. Thus, we hypothesized that urinary sCD163 shed by crescent macrophages correlates with active glomerular inflammation. We detected sCD163 in rat urine early in the disease course of experimental vasculitis. Moreover, microdissected glomeruli from patients with small vessel vasculitis (SVV) had markedly higher levels of CD163 mRNA than did those from patients with lupus nephritis, diabetic nephropathy, or nephrotic syndrome. Both glomeruli and interstitium of patients with SVV strongly expressed CD163 protein. In 479 individuals, including patients with SVV, disease controls, and healthy controls, serum levels of sCD163 did not differ between the groups. However, in an inception cohort, including 177 patients with SVV, patients with active renal vasculitis had markedly higher urinary sCD163 levels than did patients in remission, disease controls, or healthy controls. Analyses in both internal and external validation cohorts confirmed these results. Setting a derived optimum cutoff for urinary sCD163 of 0.3 ng/mmol creatinine for detection of active renal vasculitis resulted in a sensitivity of 83%, specificity of 96%, and a positive likelihood ratio of 20.8. These data indicate that urinary sCD163 level associates very tightly with active renal vasculitis, and assessing this level may be a noninvasive method for diagnosing renal flare in the setting of a known diagnosis of SVV.

The purpose of this review is to examine the proposed role of immune modulation in the development and progression of diabetic kidney disease (DKD). Diabetic kidney disease has not historically been considered an immune-mediated disease; however, increasing evidence is emerging in support of an immune role in its pathophysiology. Both systemic and local renal inflammation have been associated with DKD. Infiltration of immune cells, predominantly macrophages, into the kidney has been reported in a number of both experimental and clinical studies. In addition, increased levels of circulating pro-inflammatory cytokines have been linked to disease progression. Consequently, a variety of therapeutic strategies involving modulation of the immune response are currently being investigated in diabetic kidney disease. Although no current therapies for DKD are directly based on immune modulation many of the therapies in clinical use have anti-inflammatory effects along with their primary actions. Macrophages emerge as the most likely beneficial immune cell target and compounds which reduce macrophage infiltration to the kidney have shown potential in both animal models and clinical trials.

Clinicians using long-acting injectable (LAI) antipsychotics may assume that there is uniformity in the injection technique for all LAIs. However, because LAIs have significant differences in their formulation, each requires a specific administration procedure. Here, we focus on how the formulation properties of the atypical LAI aripiprazole lauroxil impact its administration.The history of LAI formulations is presented as a background to recent advances in formulation technology. A shared challenge for new LAIs is to adapt the formulation of insoluble drugs to aqueous-based suspensions.The early LAIs kept the drug product dissolved as oil-based solutions, which were stable and did not require mixing prior to injection. However, oil-based solutions tend to be viscous and cause injection-site reactions (ISRs).New LAI formulations tend to be aqueous-based suspensions and need to be resuspended or reconstituted before injection. Beyond this common element, formulation properties lead to differences in administration for each of the available LAIs.We reviewed the formulations of LAIs indicated for the treatment of schizophrenia and how they impact instructions for use, with a focus on aripiprazole lauroxil.Aripiprazole monohydrate and olanzapine pamoate are lyophilized powders that require reconstitution before administration and should be injected slowly. Risperidone is formulated as microspheres in powder form that require reconstitution before injection, although the injection speed is not specified. Paliperidone palmitate is a ready-to-use aqueous suspension of crystalline particles and should be injected slowly. Aripiprazole lauroxil is an aqueous-based, ready-to-use suspension of crystalline particles. Unlike other LAIs, the formulation of aripiprazole lauroxil contains particles that are loosely associated to facilitate resuspension. Because loosely associated suspensions are shear-thinning, meaning the viscosity of the formulation decreases with higher injection force, the injection must be given rapidly. Vigorous shaking and rapid injection are key aspects of administration and have been accepted by patients and investigators in clinical trials. In a pivotal phase 3 study of aripiprazole lauroxil, the incidence of ISRs was low (3.9% and 5.8% for aripiprazole lauroxil 441mg and 882mg , respectively) and mostly associated with the first injection.Advances in formulation technology have increased LAI options for patients with schizophrenia. The aripiprazole lauroxil formulation differs from other LAIs in that the particles are loosely associated to support use as a ready-to-use pre-filled syringe. Because the suspension is shear-thinning, aripiprazole lauroxil requires rapid injection, which is not required when using other LAIs. An understanding of the differences in formulation design and how they impact the specific techniques associated with an LAI is essential for successful administration.Funding Acknowledgements: This study was funded by Alkermes, Inc.

Background Obtaining family consent to organ donation is a significant obstacle to improving further Australian deceased organ donation rates. Currently, neither the consent rates for donors eligible to donate after circulatory death, nor factors that influence decision to decline or consent to donation in general are known in Australia. Methods This study at four university teaching hospitals in Melbourne, Victoria, examined consecutive patients where organ donation was discussed with the family Results A total of 123 cases were identified; the family consent rate was 52.8%, and 34.1% proceeded to donation. Consent to donation was related to potential donor factors such as country of birth, cultural background in Australia, a non-religious or Christian background and registration on the Australian Organ Donor Register. Family-related factors included being English speaking and having knowledge of the deceased's wishes about organ donation. Family of donation after circulatory death-eligible donors were less likely to consent to donation than the family of donation after brain death-eligible donors, although not reaching statistical significance. Among consented potential donors, those eligible for donation after brain death and with a shorter length of stay were more likely to proceed to donating organs for transplantation. Conclusion Despite a small sample size, these findings describe current consent and donation rates and associated factors and may assist in improving conversations about organ donation.

A new polymorph of aripiprazole has been discovered, making it the most polymorphic drug to date with twelve reported anhydrous forms, and a record-breaking ninth solved crystal structure. The new form was induced by seeding with crystals of the active metabolite dehydro-aripiprazole.

Current therapies for treating antineutrophil cytoplasm autoantibody (ANCA)-associated vasculitis include cyclophosphamide and corticosteroids. Unfortunately, these agents are associated with severe adverse effects, despite inducing remission in most patients. Histone deacetylase inhibitors are effective in rodent models of inflammation and act synergistically with many pharmacological agents, including alkylating agents like cyclophosphamide. EDO-S101 is an alkylating fusion histone deacetylase inhibitor molecule combining the DNA alkylating effect of Bendamustine with a pan-histone deacetylase inhibitor, Vorinostat. Here we studied the effects of EDO-S101 in two established rodent models of ANCA-associated vasculitis: a passive mouse model of anti-myeloperoxidase IgG-induced glomerulonephritis and an active rat model of myeloperoxidase-ANCA microscopic polyangiitis. Although pretreatment with EDO-S101 reduced circulating leukocytes, it did not prevent the development of passive IgG-induced glomerulonephritis in mice. On the other hand, treatment in rats significantly reduced glomerulonephritis and lung hemorrhage. EDO-S101 also significantly depleted rat B and T cells, and induced DNA damage and apoptosis in proliferating human B cells, suggesting a selective effect on the adaptive immune response. Thus, EDO-S101 may have a role in treatment of ANCA-associated vasculitis, operating primarily through its effects on the adaptive immune response to the autoantigen myeloperoxidase.

Tapered THz coplanar waveguides (CPWs) formed from Co/Cu multilayers with embedded low-temperature-grown gallium arsenide photoconductive switches were designed in order to observe giant magnetoresistance (GMR). Pulsed THz radiation was excited using the switches, and was transmitted through both straight and tapered CPWs. GMR-induced changes in the transmitted THz pulse amplitude were demonstrated.

Objectives To determine Australian emergency department clinicians' cultural and religious barriers to organ and tissue donation (OTD). Method A national cross-sectional survey of physicians and nurses working in Australian emergency departments. An online questionnaire of 133 items was delivered via e-mail. Results Responses were received from 599 of 2969 (20%) physicians and 212 of 1026 (21%) nurses. Respondents were generally representative of the colleges. Participants were from 26 cultures and 9 religious groups. Self-rated competence in OTD tasks was low for some minority groups: South American, Caribbean, and Pacific Islanders reported little competence in identifying, referring, and caring for potential donors, introducing OTD to families, and approaching distressed families. Those of Arabic, Jewish, North African, and Middle Eastern background reported low competence in referring and caring for potential donors and comforting distressed families. They reported low support for OTD after cardiac death, low familiarity with OTD processes after cardiac death, and poor familiarity with the coroner's process. Those of Southern Asian background reported low comfort in undertaking OTD processes, poor familiarity with the coroner's process, and low competence in caring for potential donors. Those of Islamic faith reported low competence in identifying potential donors, low support for OTD after cardiac death, and thought that the emergency department was an inappropriate location to identify potential donors. Those of Buddhist and Hindu faiths reported low competence in identifying potential donors. Respondent numbers for members of minority groups were low, thereby limiting the statistical accuracy of results. Conclusions Among clinicians working in Australian emergency departments, religion and culture may be barriers to facilitating OTD in emergency departments because of the perceptions and attitudes held by particular religious and cultural groups. Improving access to education may address these differences.

TGF-β1 is a prototypic profibrotic cytokine and major driver of fibrosis in the kidney and other organs. Induced in high glucose-1 (IHG-1) is a mitochondrial protein which we have recently reported to be associated with renal disease. IHG-1 amplifies responses to TGF-β1 and regulates mitochondrial biogenesis by stabilising the transcriptional co-activator peroxisome proliferator-activated receptor gamma coactivator-1-alpha. Here we report that the mitochondrial localisation of IHG-1 is pivotal in the amplification of TGF-β1 signalling. We demonstrate that IHG-1 expression is associated with repression of the endogenous TGF-β1 inhibitor Smad7. Intriguingly, expression of a non-mitochondrial deletion mutant of IHG-1 (Δmts-IHG-1) repressed TGF-β1 fibrotic signalling in renal epithelial cells. In cells expressing Δmts-IHG-1 fibrotic responses including CCN2/connective tissue growth factor, fibronectin and jagged-1 expression were reduced following stimulation with TGF-β1. Δmts-IHG-1 modulation of TGF-β1 signalling was associated with increased Smad7 protein expression. Δmts-IHG-1 modulated TGF-β1 activity by increasing Smad7 protein expression as it failed to inhibit TGF-β1 transcriptional responses when endogenous Smad7 expression was knocked down. These data indicate that mitochondria modulate TGF-β1 signal transduction and that IHG-1 is a key player in this modulation.

Immune modulation is now known to contribute to the development of glomerulosclerosis, tubulointerstitial fibrosis and end-stage renal disease in a large number of kidney diseases. Similarly, diabetic nephropathy is increasingly considered an inflammatory disease, with immune modulation being involved in both the development and progression of the disease. Infiltration of immune cells including macrophages, T cells, B cells and mast cells into the kidney has been reported. A number of pro-inflammatory cytokines and chemokines also play a major role in pathogenesis of diabetic nephropathy. Consequently, a variety of therapeutic strategies involving modulation of the immune response are currently being investigated in diabetic kidney disease.

To improve organ donation processes and outcomes, many Australian hospitals have introduced donation after cardiac death (DCD) following the 2010 publication of the National Protocol for DCD. As emergency clinicians play a significant role in identifying potential DCD donors, it is critical to assess their support and knowledge. Although many support DCD, most are unaware of the protocol or procedures regarding DCD. Education is needed and desired by many emergency clinicians.

Crystal form exploration of dehydro-aripiprazole (dAPZ), the active metabolite of the antipsychotic drug aripiprazole (APZ), elucidated five polymorphs (I, II, III, IV, and V), two methanol solvates, and a monohydrate. The forms were characterized by thermal microscopy, differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), single and powder X-ray diffraction (SCXRD and PXRD), and infrared spectroscopy. DSC analysis showed monotropic relationships among polymorphs I, II, III, and IV and enantiotropic relationships for the two form pairs I ↔ V and II ↔ V. Solvent-mediated conversion experiments indicated that Form V is the thermodynamically stable form in the temperature range 5–60 °C and Form I is the stable form at ≥70 °C, where a transition temperature lies between 60 and 70 °C. Two polymorphs of the methanol solvate (SMeOH1 and SMeOH2) were crystallized from methanol solutions in 1:1 dAPZ/methanol molar ratio. SMeOH2 is the thermodynamically stable form of the two methanol solvate...

Purpose of review This review focuses on the role of the mitochondrial protein induced in high glucose 1 (IHG-1) in kidney fibrosis. Recent findings Diabetic nephropathy is the most common cause of end-stage renal disease. Transforming growth factor-β1 (TGF-β1) is a pivotal mediator of fibrosis and diabetic nephropathy. IHG-1 was identified in a screen for genes differentially expressed in renal cells exposed to high glucose. Here we review the biology of this novel functionally uncharacterized gene transcript. Data from human biopsy material and experimental models indicate increased expression of IHG-1 is a critical component of fibrogenesis as it amplifies TGF-β1 signalling. IHG-1 is expressed in mitochondria, stabilizes PGC-1α protein and increases mitochondrial biogenesis. Recently the crystal structure of IHG-1 has been determined revealing structural homology with canonical 5'→ 3' DNA polymerases and adenylyl/guanylyl cyclases, whereas the closely related yeast homologue has been shown to function as a tRNA(HIS) guanyltransferase. Summary IHG-1 is a transcript up-regulated in renal cells exposed to high glucose, in animal models of renal fibrosis and in human diabetic nephropathy. IHG-1 encodes a mitochondrial protein that amplifies fibrotic responses to TGF-β1 and promotes mitochondrial biogenesis. Investigation of the functional significance of the highly conserved domains of IHG-1 may lead to new therapeutic strategies.

Current biomarkers of renal disease in systemic vasculitis lack predictive value and are insensitive to early damage. To identify novel biomarkers of renal vasculitis flare, we analysed the longitudinal urinary metabolomic profile of a rat model of anti-neutrophil cytoplasmic antibody (ANCA) vasculitis. Wistar-Kyoto (WKY) rats were immunised with human myeloperoxidase (MPO). Urine was obtained at regular intervals for 181 days, after which relapse was induced by re-challenge with MPO. Urinary metabolites were assessed in an unbiased fashion using nuclear magnetic resonance (NMR) spectroscopy, and analysed using partial least squares discriminant analysis (PLS-DA) and partial least squares regression (PLS-R). At 56 days post-immunisation, we found that rats with vasculitis had a significantly different urinary metabolite profile than control animals; the observed PLS-DA clusters dissipated between 56 and 181 days, and re-emerged with relapse. The metabolites most altered in rats with active or relapsing vasculitis were trimethylamine N-oxide (TMAO), citrate and 2-oxoglutarate. Myo-inositol was also moderately predictive. The key urine metabolites identified in rats were confirmed in a large cohort of patients using liquid chromatography–mass spectrometry (LC-MS). Hypocitraturia and elevated urinary myo-inositol remained associated with active disease, with the urine myo-inositol:citrate ratio being tightly correlated with active renal vasculitis.

A specific biomarker that can separate active renal vasculitis from other causes of renal dysfunction is lacking, with a kidney biopsy often being required. Soluble CD163 (sCD163), shed by monocytes and macrophages, has been reported as a potential biomarker in diseases associated with excessive macrophage activation. Thus, we hypothesized that urinary sCD163 shed by crescent macrophages correlates with active glomerular inflammation. We detected sCD163 in rat urine early in the disease course of experimental vasculitis. Moreover, microdissected glomeruli from patients with small vessel vasculitis (SVV) had markedly higher levels of CD163 mRNA than did those from patients with lupus nephritis, diabetic nephropathy, or nephrotic syndrome. Both glomeruli and interstitium of patients with SW strongly expressed CD163 protein. In 479 individuals, including patients with SW, disease controls, and healthy controls, serum levels of sCD163 did not differ between the groups. However, in an inception cohort, including 177 patients with SW, patients with active renal vasculitis had markedly higher urinary sCD163 levels than did patients in remission, disease controls, or healthy controls. Analyses in both internal and external validation cohorts confirmed these results. Setting a derived optimum cutoff for urinary sCD163 of 0.3 ng/mmol creatinine for detection of active renal vasculitis resulted in a sensitivity of 83%, specificity of 96%, and a positive likelihood ratio of 20.8. These data indicate that urinary sCD163 level associates very tightly with active renal vasculitis, and assessing this level may be a noninvasive method for diagnosing renal flare in the setting of a known diagnosis of SW.

Objectives: In 2010 the Australian Organ and Tissue Authority introduced a nationally consistent indicator, the GIVE Clinical Trigger, for early identification of potential organ and tissue donors in EDs and intensive care units. This national survey of emergency clinicians aimed to assess emergency clinicians’ perceptions and use of the Trigger. Methods: National cross-sectional survey of Australasian College for Emergency Medicine (ACEM) fellows and trainees and members of the College of Emergency Nursing Australia (CENA); online questionnaire; 12 items addressing implementation of the GIVE Trigger; graded and free-text responses. Results: Five hundred and ninety-nine (20.2%) of 2969 ACEM members and 212 (20.7%) of 1026 CENA members responded. Four hundred and seventy-four respondents (62.7%) were familiar with the Trigger; 472 (63.8%) agreed it was easy to recognise patients who activated the Trigger; 490 (64.9%) had sufficient time to use the Trigger; 511 (67.7%) felt they had the necessary competence and knowledge to identify a potential donor; 464 (61.5%) felt competent and 501 (66.4%) felt comfortable referring a potential donor when identified. Overall 587 (77.7%) ED clinicians supported the use of the Trigger, but most (587 [77.7%]) perceived barriers to its use; 628 (80%) had never activated the Trigger and 557 (71%) had never referred a potential donor to relevant authorities. Conclusion: Most Australian emergency clinicians are familiar with and support the GIVE Clinical Trigger, and feel they have the necessary skills to use the Trigger; however, most perceive barriers to its use and have not yet used the Trigger.

Pharmaceutical cocrystals have gained increased attention at least in part because of their potential for enhancing physicochemical and biopharmaceutical properties of existing drugs. As a result, design, screening, and large-scale preparation of pharmaceutical cocrystals have been emphasized in recent research. The design of pharmaceutical cocrystals has focused primarily on determining the empirical guidelines regarding the hierarchy of supramolecular synthons. However, this approach is typically less predictive when considering drugs that are complex in nature, such as those having a multiplicity of functional groups and/or numerous degrees of conformational flexibility. In this manuscript, we report a crystal engineering design strategy to facilitate the synthesis of multicomponent crystal forms of the atypical antipsychotic drug olanzapine, marketed as a drug product under the trade name Zyprexa. Comprehensive analysis and data mining of existing crystal structures of olanzapine were followed by grou...

Objective: The ED is emerging as a priority for efforts to improve rates of organ and tissue donation (OTD) in Australia, but little is known of ED clinicians' attitudes, education or practices in the area. We aimed to determine the attitudes and OTD-related educational background and practices of Australian ED clinicians. Methods: This was a national cross-sectional survey of members of the Australasian College for Emergency Medicine (ACEM) and the College of Emergency Nursing Australasia (CENA); online questionnaire of 133 items, graded responses using Likert and ordinal multi-category scales, plus open-ended qualitative questions. Results: Of 2969 ACEM members, 599 (20.2%) responded; of 1026 CENA members, 212 (20.7%) responded. Respondents were broadly representative of the membership, with male trainee specialists underrepresented. Most ED staff supported OTD, although many were not certain that facilitating OTD was their role, or that the ED was the right place to identify donors. Around a quarter of medical and nursing staff had received no education regarding OTD. Having received education was related to professional status, cultural background, place of work and years of experience, and was significantly associated with attitude towards OTD and whether staff participated in OTD-related tasks. Conclusions: More education on OTD is needed and requested by ED clinicians in Australia, particularly on OTD after cardiac death, management of a donor, brain death and obtaining consent. Postgraduate curricula should reflect this need for more OTD-related education in emergency medicine and nursing.

The critical involvement of TGF-β1 (transforming growth factor-β1) in DN (diabetic nephropathy) is well established. However, the role of CTGF (connective tissue growth factor) in regulating the complex interplay of TGF-β1 signalling networks is poorly understood. The purpose of the present study was to investigate co-operative signalling between CTGF and TGF-β1 and its physiological significance. CTGF was determined to bind directly to the TβRIII (TGF-β type III receptor) and antagonize TGF-β1-induced Smad phosphorylation and transcriptional responses via its N-terminal half. Furthermore, TGF-β1 binding to its receptor was inhibited by CTGF. A consequent shift towards non-canonical TGF-β1 signalling and expression of a unique profile of differentially regulated genes was observed in CTGF/TGF-β1-treated mesangial cells. Decreased levels of Smad2/3 phosphorylation were evident in STZ (streptozotocin)-induced diabetic mice, concomitant with increased levels of CTGF. Knockdown of TβRIII restored TGF-β1-mediated Smad signalling and cell contractility, suggesting that TβRIII is key for CTGF-mediated regulation of TGF-β1. Comparison of gene expression profiles from CTGF/TGF-β1-treated mesangial cells and human renal biopsy material with histological diagnosis of DN revealed significant correlation among gene clusters. In summary, mesangial cell responses to TGF-β1 are regulated by cross-talk with CTGF, emphasizing the potential utility of targeting CTGF in DN.

Insulin receptor substrate (IRS) proteins comprise a family of adaptor molecules that integrate extracellular signals from insulin and other ligands to intracellular effectors such as phosphoinositide 3-kinase and mitogen-activated protein kinase. The predominant forms of IRS protein in humans, IRS1 and IRS2, are widely expressed. Despite structural similarities, IRS1 and IRS2 display distinct signalling modalities, and mice lacking these proteins present with distinct phenotypes. Transforming growth factor (TGF)-β1 is the primary cytokine shown to induce epithelial–mesenchymal transition. Recent data have demonstrated a role for IRS1 in TGF-β1-induced epithelial–mesenchymal transition in lung epithelial cells. In the present study, we report data showing that TGF-β1 signals via IRS2 in kidney epithelial cells. Small interfering RNA (siRNA)-mediated targeting of IRS2 increased E-cadherin expression, although it did not alter TGF-β1-mediated E-cadherin repression. Phosphorylation of the downstream target of IRS2/Akt signalling, FoxO3a, was induced on Ser253 and, to a lesser extent, on Thr32. Transfection of FoxO3aThr32Ala mutant for 24 h greatly reduced FoxO3a phosphorylation on Ser253 but over-expression of FoxO3a Ser253Ala did not effect Thr32 phosphorylation, suggesting that a distinct order of phosphorylation of FoxO3a is required for physiological function in cells. Transfection of FoxO3a Ser253Ala mutant partially inhibited TGF-β1-mediated E-cadherin repression at 24 h. Taken together, these data highlight novel roles for IRS2 and FoxO3a in the regulation of kidney epithelial cells by E-cadherin.

Reconstituted parenteral solutions of three surface-active anti-infective small-molecule drugs and solutions of sodium dodecyl sulfate (SDS, a model surfactant) were studied to quantify the impact of sample preparation and handling on particle counts. Turbidimetry and light obscuration profiles were recorded as a function of agitation and shearing with and without the introduction of foam into the solutions. SDS solutions at concentrations above the critical micelle concentration (CMC) show significantly greater sensitivity to shear and foam presence than SDS solution below the CMC: Values of >10 μm particles increased 8 fold over control (an unsheared sample) in the micellar solution vs. 4 fold particle count increase over control at a sub-micellar concentration. An even more significant increase in the ratio of particle count in sheared/unsheared solution is seen for >25 μm unit counts, due to the increased interference of foam with the measurement. Two commercial products, injection formulations of teicoplanin and cefotaxime sodium, as well as an investigational compound 1, showed an increase in scattering as a function of foam production. The impact of foaming was significant, resulting in an increase of turbidity and light obscuration measurements in all solutions. The results illustrate some of the challenges that are inherent to optically clear, homogeneous pharmaceutical injections containing compounds which have a tendency toward self-association and surfactant-like behavior.

Crystalline hydrates and propylene glycol solvates of celecoxib sodium salt (Cel-Na) were prepared and characterized with the aim of improving oral drug absorption by breaking up the H-bonding interactions present in crystals of the poorly soluble marketed form of the drug (Cel-III). The hydrate grows rapidly from aqueous alkaline solution, forming a thick slurry of thin plates. Thicker plates for structure determination were successfully grown by adding up to 1% benzyl alcohol to the solution. The structure of the pentahydrate of the sodium salt is comprised of a bilayer motif where three waters are coordinated to sodium ions in a discrete layer, while the other two waters reside in a one-dimensional channel. At a given temperature, the hydration state changes rapidly and reversibly as a function of relative humidity (RH). The hydrated salt is physically stable in a sealed vial, but reverts rapidly to the crystalline free base if exposed to ambient CO2 in air at 40% RH or higher. The propylene glycol (PG) solvate of Cel-Na exists in an anhydrous and trihydrate form. The trihydrated PG solvate of Cel-Na is physically stable above ∼15% RH and does not react measurably with CO2 at 66% RH over 4 days, making it the most suitable form for use in solid pharmaceutical formulations.

60Co γ-irradiation of bis(trans-2-butenoato)calcium (4) and triaquabis(trans-2-butenoato)magnesium (11) affords cyclodimerization products cis,trans- and trans,trans-nepetic acids (5 and 15), respectively. The products are produced in high yield, based upon conversion, by a γ-ray induced radical chain pathway and provide unprecedented, stereospecific, one-pot syntheses of two of the four possible nepetic acid diastereomers, adding significant generality to the synthetic scope of the γ-ray induced reactions of crystalline metal trans-2-butenoates. Stereochemical analysis of the products from the analogous trans-2-butenoato-3-d complexes 19 and 27 establishes unequivocally that hydrogen atom transfer is also stereospecific and not part of a random process. The stereochemistry of the diastereomers is that predicted by the analysis of crystal packing, consistent with the least-motion principles of the topochemical postulate. Analysis of the crystal structures, with respect to the nearest neighbors, is consistent with the hypothesis that the formation of both carbon–carbon bonds and hydrogen atom transfer are topochemical and controlled by the crystal lattice. Analysis of the packing diagrams provides a pathway for chain propagation throughout the crystal that consumes all the molecules in the unit cell.

We consider regular semigroups S that are the disjoint union of those local submonoids eSe for which the idempotent e is regularity-preserving. The structure of these is given in terms of Rees matrix semigroups over regular monoids, and a description of certain RP-dominated regular semigroups is obtained as a special case.

Cocrystallization experiments were carried out to study the efficacy of Benzo-[18]crown-6 (B18C6) as a cocrystallizing agent (CA). Traditional solution cocrystallization, high-throughput cocrystallization, dry grinding and solvent-drop grinding cocrystallization have led to the discovery of five new cocrystals of B18C6 with urea, thiourea, and their derivatives. The cocrystals have been characterized by a variety of methods, including X-ray diffraction, vibrational spectroscopy (infrared), and optical microscopy (HSM). We have also examined the structures in order to determine the viability and the reproducibility of the R21(6) motif between the donor hydrogen and the ether group of B18C6.

Since the early observation that similarities between thyroiditis and insulitis existed, the important role played by inflammation in the development of diabetes has been appreciated. More recently, experiments have shown that inflammation also plays a prominent role in the development of target organ damage arising as complications, with both elements of the innate and the adaptive immune system being involved, and that cytokines contributing to local tissue damage may arise from both infiltrating and resident cells. This review will discuss the experimental evidence that shows that inflammatory cell-mediated apoptosis contributes to target organ damage, from beta cell destruction to both micro- and macro-vascular disease complications, and also how alterations in leukocyte turnover affects immune function.

One stable form (Form I) and two metastable forms (Forms II and IV) of p-methylchalcone have been obtained, with Form II having previously been reported to be a disappearing polymorph. To prevent the conversion of Form II, which has a melting point of 89-91 °C, into the stable form it was produced in conditions free from seeds of the stable form. Form IV was discovered serendipitously as a single crystal that appeared in the preparation of a powder of Form II. Forms I and II have also been characterized by optical microscopy, differential scanning calorimetry (DSC), variable temperature powder X-ray diffraction, and spectroscopic analysis. The crystal structures of these three forms have been solved, Forms I and IV by single-crystal methods and Form II from synchrotron powder diffraction. This investigation highlights the fact that the challenges of reproducing experimental results (i.e., the production of a particular crystal form) may be overcome by a systematic search for new conditions under which previously obtained results can be regained.

The search for co-crystals of amines as bifunctional hydrogen-bond donors with bidentate oxygens as bifunctional hydrogen-bond acceptors, as part of a program to investigate the utility of using the (8) hydrogen-bonding motif, has yielded three co-crystals of benzidine with p-benzoquinone, diphenyl sulfoxide, and triphenylphosphine oxide. The crystal structures for all three materials are reported. Only the co-crystal structure of benzidine/diphenyl sulfoxide/water reveals the desired motif.