Transport Rates and Prehospital Intervals for an EMS Telemedicine Intervention.

INTRODUCTION: Emergency medical services (EMS) facilitated telemedicine encounters have been proposed as a strategy to reduce transports to hospitals for patients who access the 9-1-1 system. It is unclear which patient impressions are most likely able to be treated in place. It is also unknown if the increased time spent facilitating the telemedicine encounter is offset by the time saved from reducing the need for transport. The objective of this study was to determine the association between the impressions of EMS clinicians of the patients' primary problems and transport avoidance, and to describe the effects of telemedicine encounters on prehospital intervals. METHODS: This was a retrospective review of EMS records from two commercial EMS agencies in New York and Tennessee. For each EMS call where a telemedicine encounter occurred, a matched pair was identified. Clinicians' impressions were mapped to the corresponding category in the International Classification of Primary Care, 2nd edition (ICPC-2). Incidence and rates of transport avoidance for each category were determined. Prehospital interval was calculated as the difference between the time of ambulance dispatch and back-in-service time. RESULTS: Of the 463 prehospital telemedicine evaluations performed from March 2021 to April 2022, 312 (67%) avoided transports to the hospital. Respiratory calls were most likely to result in transport avoidance (p = 0.018); no other categories had statistically significant transport rates. Four hundred sixty-one (99.6%) had matched pairs identified and were included in the analysis. When compared to the matched pair, telemedicine without transport was associated with a prehospital interval reduction in 68% of the cases with a median reduction of 16 min; this is significantly higher than telemedicine with transport when compared to the matched pair with a median interval increase in 27 min. Regardless of transport status, the prehospital interval was a median of 4 min shorter for telemedicine encounters than non-telemedicine encounters (p = 0.08). CONCLUSION: In this study, most telemedicine evaluations resulted in ED transport avoidance, particularly for respiratory issues. Telemedicine interventions were associated with a median four-minute decrease in prehospital interval per call. Future research should investigate the long-term effects of telemedicine on patient outcomes.

Palliative care needs and models of care for people who use drugs and/or alcohol: A mixed methods systematic review.

BACKGROUND: Providing palliative care for individuals who use alcohol and/or drugs poses a multi-faceted challenge. In addition to clinical and social needs, individuals may endure mental health problems, co-morbidities and homelessness, thus requiring a multi-disciplinary, flexible approach to care. AIM: To identify the palliative care needs and models of care for people who use drugs and/or alcohol. DESIGN: A mixed-methods systematic review was conducted using the JBI Manual for Evidence Synthesis. DATA SOURCES: Six databases were searched to identify relevant studies. Full text review and quality appraisal were completed independently and in-duplicate by two reviewers with conflicts resolved by a third reviewer. Qualitative and quantitative data were tabulated together using narrative synthesis, then categorised according to outcomes of interest, with similar and divergent findings reported accordingly. RESULTS: Thirteen studies were included, nine qualitative and four quantitative, using a range of data collection methods, across various settings. The difficulties for individuals who use alcohol and/or drugs as well as their formal and informal carers, in relation to end-of-life care were examined, revealing access, care and skills issues. Three themes emerged which could underpin the development of a model of care: interpersonal/organisational relationships; holistic care; and collaborating with other services and training. CONCLUSION: Despite end-of-life needs of this population being different to others, challenges include creating inclusive policies, sensitising staff to distinctive individual needs and training exchanges for staff working in both drug and alcohol services and palliative care.

The Many Faces of Cytokine Release Syndrome-Related Coagulopathy.

Cytokine release syndrome (CRS) has been increasingly recognized in various conditions including the coronavirus disease 2019 (COVID-19). It is not only associated with systemic inflammatory symptoms, but also hematological complications such as coagulopathy. CRS can affect various components of the coagulation pathway, including the endothelial cells, platelets, coagulation cascade, and fibrinolytic system. Different causes of CRS, such as primary hemophagocytic lymphohistocytosis (HLH), chimeric antigen receptor (CAR) T-cell therapy, and COVID-19, have different cytokine profiles and coagulopathy presentations, with microvascular thrombosis surfacing as a common pathology. HLH shares many features with severe CRS, and is characterized by severe consumptive coagulopathy, frequent disseminated intravascular coagulation and an increased bleeding risk. CAR T-cell therapy is characterized by frequent and mild consumptive coagulopathy, as well as an increased risk of thrombosis. While consumptive coagulopathy is rare in COVID-19, it is associated with an increased thrombotic risk. The differences can be explained by the severity of CRS and underlying conditions associated with coagulopathy. Various treatments, including cytokine inhibitors, plasma exchange, Janus kinases inhibitors, complement blockade, and corticosteroids are being studied to mitigate CRS-related coagulopathy.

Nanofluid Development Using Silver Nanoparticles and Organic-Luminescent Molecules for Solar-Thermal and Hybrid Photovoltaic-Thermal Applications.

Exploiting solar energy using photo-thermal (PT) and/or hybridised photovoltaic/thermal (PVT) systems can represent a viable alternative to the growing demand for renewable energy. For large-scale implementation, such systems require thermal fluids able to enhance the combined conversion efficiency achievable by controlling the 'thermal' and 'electrical' components of the solar spectrum. Nanofluids are typically employed for these purposes and they should exhibit high heat-transfer capabilities and optical properties tuned towards the peak performance spectral window of the photovoltaic (PV) component. In this work, novel nanofluids, composed of highly luminescent organic molecules and Ag nanoparticles dispersed within a base fluid, were tested for PT and PVT applications. These nanofluids were designed to mimic the behaviour of luminescent down-shifting molecules while offering enhanced thermo-physical characteristics over the host base fluid. The nanofluids' conversion efficiency was evaluated under a standard AM1.5G weighted solar spectrum. The results revealed that the Ag nanoparticles' inclusion in the composite fluid has the potential to improve the total solar energy conversion. The nanoparticles' presence minimizes the losses in the electrical power component of the PVT systems as the thermal conversion increases. The enhanced performances recorded suggest that these nanofluids could represent suitable candidates for solar energy conversion applications.

Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS).

The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.

Caspase-11 Modulates Inflammation and Attenuates Toxoplasma gondii Pathogenesis.

Toxoplasma gondii is an obligate intracellular parasite that is the etiologic agent responsible for toxoplasmosis. Infection with T. gondii results in activation of nucleotide binding domain and leucine rich repeat containing receptors (NLRs). NLR activation leads to inflammasome formation, the activation of caspase-1, and the subsequent cleavage of IL-1ß and IL-18. Recently, a noncanonical inflammasome has been characterized which functions through caspase-11 and appears to augment many biological functions previously considered to be dependent upon the canonical inflammasome. To better elucidate the function of this noncanonical inflammasome in toxoplasmosis, we utilized Asc (-/-) and Casp11 (-/-) mice and infected these animals with T. gondii. Our data indicates that caspase-11 modulates the innate immune response to T. gondii through a mechanism which is distinct from that currently described for the canonical inflammasome. Asc (-/-) mice demonstrated increased disease pathogenesis during the acute phase of T. gondii infection, whereas Casp11 (-/-) mice demonstrated significantly attenuated disease pathogenesis and reduced inflammation. This attenuated host response was associated with reduced local and systemic cytokine production, including diminished IL-1ß. During the chronic phase of infection, caspase-11 deficiency resulted in increased neuroinflammation and tissue cyst burden in the brain. Together, our data suggest that caspase-11 functions to protect the host by enhancing inflammation during the early phase of infection in an effort to minimize disease pathogenesis during later stages of toxoplasmosis.

Down shifting in poly(vinyl alcohol) gels doped with terbium complex.

Novel poly(vinyl alcohol) (PVA) based soft gels with luminescent properties are detailed in this contribution. Lanthanide complex of terbium ions with anthranilic acid, Tb(ant)3·2H2O, was synthesized and incorporated into a DMSO/water solution, followed by addition of PVA, to attain soft gels at room temperature. Morphological and thermal analyses revealed homogeneous distribution of Tb(ant)3·2H2O into the PVOH/DMSO/water gel, and that incorporation of the terbium complex does not alter the thermal properties of the gels. The gels are transparent and luminescent, as they exhibit Large Stokes shift down shifting (LSS DS) up to 400nm, with very high emission quantum yield, that was found to be function of Tb complex concentration.

Discovery of Highly Isoform Selective Thiazolopiperidine Inhibitors of Phosphoinositide 3-Kinase γ.

A series of high affinity second-generation thiazolopiperidine inhibitors of PI3Kγ were designed based on some general observations around lipid kinase structure. Optimization of the alkylimidazole group led to inhibitors with higher levels of PI3Kγ selectivity. Additional insights into PI3K isoform selectivity related to sequence differences in a known distal hydrophobic pocket are also described.

Friends, social networks, and progressive chronic kidney disease.

A report by Dunkler et al. reminds us that social factors are relevant for today's clinical scientist and practitioner. They report that an increasing number of friends reduces the incidence and progression of chronic kidney disease in type 2 diabetes. The observation that 'friends don't let friends' develop kidney disease suggests that social factors, as well as biomarkers, may be relevant in developing 'personalized renal medicine' and may identify areas for future nephrology research and education.

IL-6-driven STAT signalling in circulating CD4+ lymphocytes is a marker for early anticitrullinated peptide antibody-negative rheumatoid arthritis.

OBJECTIVES: A previously identified signal transduction and activator of transcription-3 (STAT3) target-enriched gene signature in circulating CD4+ T cells of patients with early rheumatoid arthritis (RA) was prominent in autoantibody-negative individuals. Here, interleukin (IL)-6-mediated STAT signalling was investigated in circulating lymphocytes of an independent early arthritis patient cohort, seeking further insight into RA pathogenesis and biomarkers of potential clinical utility. METHODS: Constitutive and IL-6-induced expression of phosphorylated STAT1 (pSTAT1) and pSTAT3 was determined in T and B cells using Phosflow cytometric analysis in patients with RA and controls. Contemporaneous levels of serum cytokines were measured by immunoassay. Induced gene expression was measured in cultured CD4+T cells by quantitative real-time PCR. RESULTS: Among circulating lymphocytes of 187 patients with early arthritis, constitutive pSTAT3 correlated with serum IL-6 levels maximally in CD4+ T cells. Increased constitutive pSTAT3, but not pSTAT1, was observed in circulating CD4+ T cells of patients with early anticitrullinated peptide autoantibody (ACPA)-negative RA compared with disease controls, and these levels decreased alongside markers of disease activity with IL-6R-targeted treatment. Among patients presenting with seronegative undifferentiated arthritis (UA) the ratio of constitutive pSTAT3:pSTAT1 in CD4+ T cells contributed substantially to an algorithm for predicting progression to classifiable RA during a median of 20 months follow-up (area under receiver operator characteristic curve=0.84; p<0.001). CONCLUSIONS: Our findings support a particular role for IL-6-driven CD4+ T cell activation via STAT3 during the induction of RA, particularly as a feature of ACPA-negative disease. CD4+ T cell pSTAT measurements show promise as biomarkers of UA-RA progression and now require independent validation.

Structural basis for isoform selectivity in a class of benzothiazole inhibitors of phosphoinositide 3-kinase γ.

Phosphoinositide 3-kinase γ (PI3Kγ) is an attractive target to potentially treat a range of disease states. Herein, we describe the evolution of a reported phenylthiazole pan-PI3K inhibitor into a family of potent and selective benzothiazole inhibitors. Using X-ray crystallography, we discovered that compound 22 occupies a previously unreported hydrophobic binding cleft adjacent to the ATP binding site of PI3Kγ, and achieves its selectivity by exploiting natural sequence differences among PI3K isoforms in this region.

Thermoreversible luminescent organogels doped with Eu(TTA)3phen complex.

This manuscript details the preparation and characterization of luminescent organogels in toluene. Gels were prepared by using 12-hydroxystearic acid (12HSA) as gelator and different amounts of thenoyltrifluoroacetonato 1,10-phenanthroline europium(III) complex (Eu(TTA)3phen). The gelation properties and the thermoreversible behavior from solid-like to liquid systems were investigated by differential scanning calorimetry. At higher concentration, an interaction of Eu complex with the polar group of the gelator was revealed by DSC and FTIR analyses. The spectroscopic behavior of the complex was investigated in toluene solution and in the gel state. TEM analysis revealed that 12HSA is able to solvate the Eu diketonate complex inducing a remarkable increase in the Eu-Eu distance. The Eu(TTA)3phen in the gel state exhibits a very high emission quantum yield, Φ, which was found to be independent of Eu complex concentration, at least for the composition range analyzed. These results indicate that 12HSA organogels containing Eu(TTA)3phen are promising materials for optical applications.

Management of hyperkalemia in hospitalized patients.

PURPOSE: The aim of this study was to determine the incidence of treatment of hyperkalemia in hospitalized patients. METHODS: This is a prospective chart review of adults in a tertiary care hospital with hyperkalemia (serum potassium [K] ≥5.1 mEq/L) over a 6-month period. The treatments and their effectiveness, causative factors and associated electrocardiographic (ECG) changes were examined. RESULTS: There were 154 hyperkalemic episodes, 32 with K ≥6.5 mEq/L and 122 with K<6.5 mEq/L. Overall, 97% received treatment for an average K of 5.9 mEq/L. Sodium polystyrene sulfonate (SPS) was included in 95% of the regimens. Incremental doses of SPS monotherapy yielded potassium reductions between 0.7 and 1.1 mEq/L, and inadequate responses (K <0.5 mEq/L) were less frequent with higher doses. There were no differences in the effectiveness of SPS among dialysis-dependent, chronic kidney disease, or nonchronic kidney disease patients. Greater reductions in potassium were observed using a combination of treatments. ECGs were performed in 44% of patients, and 50% showed no ECG changes despite K being ≥6.5 mEq/L. The most common abnormality, peaked T waves, was associated with a higher frequency of calcium administration but not with the number of K+-lowering therapies. CONCLUSIONS: Almost all the patients were treated for hyperkalemia. Oral SPS monotherapy was the predominant treatment with the best response at the highest dose. Some combination therapies had greater K reductions but were used infrequently. An ECG was obtained in about 50% of the cases, but two thirds showed no K-related changes. Reduced kidney function was associated with 70% of hyperkalemic episodes. Angiotensin-converting enzyme inhibitors and trimethoprim were the most commonly implicated medications.

Refolding and characterization of a soluble ectodomain complex of the calcitonin gene-related peptide receptor.

The calcitonin gene-related peptide (CGRP) receptor is a heterodimer of two membrane proteins: calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1). CLR is a class B G-protein-coupled receptor (GPCR), possessing a characteristic large amino-terminal extracellular domain (ECD) important for ligand recognition and binding. Dimerization of CLR with RAMP1 provides specificity for CGRP versus related agonists. Here we report the expression, purification, and refolding of a soluble form of the CGRP receptor comprising a heterodimer of the CLR and RAMP1 ECDs. The extracellular protein domains corresponding to residues 23-133 of CLR and residues 26-117 of RAMP1 were shown to be sufficient for formation of a stable, monodisperse complex. The binding affinity of the purified ECD complex for the CGRP peptide was significantly lower than that of the native receptor (IC(50) of 12 microM for the purified ECD complex vs 233 pM for membrane-bound CGRP receptor), indicating that other regions of CLR and/or RAMP1 are important for peptide agonist binding. However, high-affinity binding to known potent and specific nonpeptide antagonists of the CGRP receptor, including olcegepant and telcagepant (K(D) < 0.02 muM), as well as N-terminally truncated peptides and peptide analogues (140 nM to 1.62 microM) was observed.

ROCK enzymatic assay.

We describe the protocols for measuring Rho-associated coiled-coil-containing kinase (ROCK) activity in vitro. A His-tagged, constitutively active form of the protein (lacking C-terminal inhibitory domains) is expressed in baculovirus. The protein is purified by a combination of metal affinity, ion exchange, and size exclusion chromatography. Enzymatic activity is measured spectrophotometrically in a coupled assay format wherein a molecule of NADH is oxidized to NAD+ each time a phosphate is transferred by ROCK.

Once-weekly vancomycin for patients receiving high-flux hemodialysis.

PURPOSE: The effectiveness of a once-weekly vancomycin dosing protocol for patients receiving long-term high-flux hemodialysis (HFHD) in the outpatient setting was studied. METHODS: Eligible patients were at least 18 years old, required hemodialysis for at least two months before study enrollment, and were not known to have any active infection. All patients received outpatient dialysis at a 1000-bed urban teaching hospital three times per week through a high-flux synthetic dialyzer. All patients received vancomycin 35 mg/kg, rounded to the nearest 250 mg, administered during hemodialysis at a rate of 1 g/hr via an infusion pump and scheduled to end when the hemodialysis session was over. Vancomycin was infused either predialyzer or postdialyzer, and infusion pumps were used in patients who received vancomycin through the postdialyzer access port. Serum vancomycin levels were measured before the third hemodialysis session (study day 8) to evaluate the percentage of patients who maintained therapeutic vancomycin concentrations of >or=10 microg/mL. RESULTS: No patients achieved a vancomycin concentration of >or=10 microg/mL on study day 8 (mean serum concentration, 5.1 microg/mL). When patients were separated into two groups based on administration technique, six patients (83%) who received vancomycin predialyzer had undetectable vancomycin levels (<3.5 microg/mL) by study day 8 (n = 6). Patients who received vancomycin postdialyzer maintained a mean serum concentration of 6.4 microg/mL at day 8 (n = 3). CONCLUSION: A single dose of vancomycin 35 mg/kg administered during HFHD in oliguric patients with end-stage renal disease did not achieve the therapeutic serum concentration necessary for once-weekly dosing.

A rare cause of Cushing's syndrome demonstrates analytical discrepancies between the Roche E170 and Bayer Centaur testosterone assays.

The initial biochemical investigations of a female patient with suspected Cushing's syndrome revealed abnormal endocrine results, including a marked elevation of serum testosterone. Overnight and low-dose dexamethasone suppression tests confirmed the diagnosis of Cushing's syndrome. Imaging investigations revealed an appearance compatible with adrenocortical carcinoma with metastases in the lungs and liver. This tumour is a rare cause of Cushing's syndrome. Two different automated testosterone immunoassays were used during the investigation of this patient, and analytical discrepancies in the patient's testosterone results were found. The two assays used, as well as potential causes of the difference in results will be discussed.

Efficient expression in E. coli of an enantioselective nitrile hydratase from Rhodococcus erythropolis.

The genes encoding an enantioselective nitrile hydratase (NHase) from Rhodococcus erythropolis AJ270 have been cloned and an active NHase has been produced in Escherichia coli. Maximal activity was found when the genes encoding the alpha- and beta-subunits were transcribed as one unit and the gene encoding the P44k activator protein as a separate ORF on a single replicon. Addition of n-butyric acid and FeSO(4 )could improve NHase activity. Coexpression of the GroEL-GroES chaperone proteins increased activity in the absence of P44k protein but had no effect in the presence of P44k. The recombinant enzyme was highly enantioselective in the synthesis of S-(+)-3-benzoyloxy- 4-cyanobutyramide from the prochiral substrate 3-benzoyloxyglutaronitrile.