Solution-processable mixed-anion cluster chalcohalide Rb6Re6S8I8 in a light-emitting diode.

Rhenium chalcohalide cluster compounds are a photoluminescent family of mixed-anion chalcohalide cluster materials. Here we report the new material Rb6Re6S8I8, which crystallizes in the cubic space group Fm[Formula: see text]m and contains isolated [Re6S8I6]4- clusters. Rb6Re6S8I8 has a band gap of 2.06(5) eV and an ionization energy of 5.51(3) eV, and exhibits broad photoluminescence (PL) ranging from 1.01 eV to 2.12 eV. The room-temperature PL exhibits a PL quantum yield of 42.7% and a PL lifetime of 77 µs (99 µs at 77 K). Rb6Re6S8I8 is found to be soluble in multiple polar solvents including N,N-dimethylformamide, which enables solution processing of the material into films with thickness under 150 nm. Light-emitting diodes based on films of Rb6Re6S8I8 were fabricated, demonstrating the potential for this family of materials in optoelectronic devices.

The 2D Halide Perovskite Rulebook: How the Spacer Influences Everything from the Structure to Optoelectronic Device Efficiency.

Two-dimensional (2D) halide perovskites have emerged as outstanding semiconducting materials thanks to their superior stability and structural diversity. However, the ever-growing field of optoelectronic device research using 2D perovskites requires systematic understanding of the effects of the spacer on the structure, properties, and device performance. So far, many studies are based on trial-and-error tests of random spacers with limited ability to predict the resulting structure of these synthetic experiments, hindering the discovery of novel 2D materials to be incorporated into high-performance devices. In this review, we provide guidelines on successfully choosing spacers and incorporating them into crystalline materials and optoelectronic devices. We first provide a summary of various synthetic methods to act as a tutorial for groups interested in pursuing synthesis of novel 2D perovskites. Second, we provide our insights on what kind of spacer cations can stabilize 2D perovskites followed by an extensive review of the spacer cations, which have been shown to stabilize 2D perovskites with an emphasis on the effects of the spacer on the structure and optical properties. Next, we provide a similar explanation for the methods used to fabricate films and their desired properties. Like the synthesis section, we will then focus on various spacers that have been used in devices and how they influence the film structure and device performance. With a comprehensive understanding of these effects, a rational selection of novel spacers can be made, accelerating this already exciting field.

Distance Dependence of Förster Resonance Energy Transfer Rates in 2D Perovskite Quantum Wells via Control of Organic Spacer Length.

Two-dimensional (2D) semiconductors are attractive candidates for a variety of optoelectronic applications owing to the unique electronic properties that arise from quantum confinement along a single dimension. Incorporating nonradiative mechanisms that enable directed migration of bound charge carriers, such as Förster resonance energy transfer (FRET), could boost device efficiencies provided that FRET rates outpace undesired relaxation pathways. However, predictive models for FRET between distinct 2D states are lacking, particularly with respect to the distance d between a donor and acceptor. We approach FRET in systems with binary mixtures of donor and acceptor 2D perovskite quantum wells (PQWs), and we synthetically tune distances between donor and acceptor by varying alkylammonium spacer cation lengths. FRET rates are monitored using transient absorption spectroscopy and ultrafast photoluminescence, revealing rapid picosecond lifetimes that scale with spacer cation length. We theoretically model these binary mixtures of PQWs, describing the emitters as classical oscillating dipoles. We find agreement with our empirical lifetimes and then determine the effects of lateral extent and layer thickness, establishing fundamental principles for FRET in 2D materials.

Narrow-Bandgap Mixed Lead/Tin-Based 2D Dion-Jacobson Perovskites Boost the Performance of Solar Cells.

The advent of the two-dimensional (2D) family of halide perovskites and their demonstration in 2D/three-dimensional (3D) hierarchical film structures broke new ground toward high device performance and good stability. The 2D Dion-Jacobson (DJ) phase halide perovskites are especially attractive in solar cells because of their superior charge transport properties. Here, we report on 2D DJ phase perovskites using a 3-(aminomethyl)piperidinium (3AMP) organic spacer for the fabrication of mixed Pb/Sn-based perovskites, exhibiting a narrow bandgap of 1.27 eV and a long carrier lifetime of 657.7 ns. Consequently, solar cells employing mixed 2D DJ 3AMP-based and 3D MA0.5FA0.5Pb0.5Sn0.5I3 (MA = methylammonium, FA = formamidinium) perovskite composites as light absorbers achieve enhanced efficiency and stability, giving a power conversion efficiency of 20.09% with a high open-circuit voltage of 0.88 V, a fill factor of 79.74%, and a short-circuit current density of 28.63 mA cm-2. The results provide an effective strategy to improve the performance of single-junction narrow-bandgap solar cells and, potentially, to give a highly efficient alternative to bottom solar cells in tandem devices.

Alternative Organic Spacers for More Efficient Perovskite Solar Cells Containing Ruddlesden-Popper Phases.

The halide perovskite Ruddlesden-Popper (RP) phases are a homologous layered subclass of solution-processable semiconductors that have aroused great attention, especially for developing long-term solar photovoltaics. They are defined as (A')2(A)n-1PbnX3n+1 (A' = spacer cation, A = cage cation, and X = halide anion). The orientation control of low-temperature self-assembled thin films is a fundamental issue associated with the ability to control the charge carrier transport perpendicular to the substrate. Here we report new chemical derivatives designed from a molecular perspective using a novel spacer cation 3-phenyl-2-propenammonium (PPA) with conjugated backbone as a low-temperature strategy to assemble more efficient solar cells. First, we solved and refined the crystal structures of single crystals with the general formula (PPA)2(FA0.5MA0.5)n-1PbnI3n+1 (n = 2 and 3, space group C2) using X-ray diffraction and then used the mixed halide (PPA)2(Cs0.05(FA0.88MA0.12)0.95)n-1Pbn(I0.88Br0.12)3n+1 analogues to achieve more efficient devices. While forming the RP phases, multiple hydrogen bonds between PPA and inorganic octahedra reinforce the layered structure. For films we observe that as the targeted layer thickness index increases from n = 2 to n = 4, a less horizontal preferred orientation of the inorganic layers is progressively realized along with an increased presence of high-n or 3D phases, with an improved flow of free charge carriers and vertical to substrate conductivity. Accordingly, we achieve an efficiency of 14.76% for planar p-i-n solar cells using PPA-RP perovskites, which retain 93.8 ± 0.25% efficiency with encapsulation after 600 h at 85 °C and 85% humidity (ISOS-D-3).

Global Analysis for Time and Spectrally Resolved Multidimensional Microscopy: Application to CH3NH3PbI3 Perovskite Thin Films.

The advancement of improved photoactive materials, such as those proposed for next-generation solar cells, low-power lighting, and lasing applications, requires a deep understanding of their correlated spatial, spectral, and temporal properties. In principle, correlated time-resolved microscopy techniques are capable of capturing such information. However, the large data sets that encapsulate temporal, spectral, and spatial information create the prodigious challenge of analyzing gigabytes of correlated data, which typically takes enormous computational resources. These challenges motivate the development of robust and efficient data analysis tools to realize fast spatial and spectral decomposition and to gain physical insights that arise from statistical analysis. Herein, we propose a reliable and fast global analysis method based on variable projection and subsampling methods, which exhibits exceptionally high sensitivity to buried spatial and spectral information in large and multidimensional microscopy data sets as compared to traditional methods. The reliability and robustness of this new method is tested on transient absorption and impulsive vibrational microscopy data sets acquired on polycrystalline CH3NH3PbI3 perovskite films.

(4NPEA)2PbI4 (4NPEA = 4-Nitrophenylethylammonium): Structural, NMR, and Optical Properties of a 3 × 3 Corrugated 2D Hybrid Perovskite.

(4NPEA)2PbI4 (4NPEA = 4-nitrophenylethylammonium) is the first 3 × 3 corrugated 2D organic-Pb/I perovskite. The nitro groups are involved in cation-cation and cation-iodide interactions. The structure contains both highly distorted and near-ideal PbI6 octahedra, consistent with the observation of two 207Pb NMR resonances, while the optical properties resemble those of other 2D perovskites with distorted PbI6 octahedra.

From 2D to 1D Electronic Dimensionality in Halide Perovskites with Stepped and Flat Layers Using Propylammonium as a Spacer.

Two-dimensional (2D) hybrid halide perovskites are promising in optoelectronic applications, particularly solar cells and light-emitting devices (LEDs), and for their increased stability as compared to 3D perovskites. Here, we report a new series of structures using propylammonium (PA+), which results in a series of Ruddlesden-Popper (RP) structures with the formula (PA)2(MA)n-1PbnI3n+1 (n = 3, 4) and a new homologous series of "step-like" (SL) structures where the PbI6 octahedra connect in a corner- and face-sharing motif with the general formula (PA)2m+4(MA)m-2Pb2m+1I7m+4 (m = 2, 3, 4). The RP structures show a blue-shift in bandgap for decreasing n (1.90 eV for n = 4 and 2.03 eV for n = 3), while the SL structures have an even greater blue-shift (2.53 eV for m = 4, 2.74 eV for m = 3, and 2.93 eV for m = 2). DFT calculations show that, while the RP structures are electronically 2D quantum wells, the SL structures are electronically 1D quantum wires with chains of corner-sharing octahedra "insulated" by blocks of face-sharing octahedra. Dark measurements for RP crystals show high resistivity perpendicular to the layers (1011 Ω cm) but a lower resistivity parallel to them (107 Ω cm). The SL crystals have varying resistivity in all three directions, confirming both RP and SL crystals' utility as anisotropic electronic materials. The RP structures show strong photoresponse, whereas the SL materials exhibit resistivity trends that are dominated by ionic transport and no photoresponse. Solar cells were made with n = 3 giving an efficiency of 7.04% (average 6.28 ± 0.65%) with negligible hysteresis.

Talazoparib has no clinically relevant effect on QTc interval in patients with advanced solid tumors.

The aims of this study were (i) to evaluate the effect of talazoparib (1 mg once daily) on cardiac repolarization in patients with advanced solid tumors by assessing corrected QT interval (QTc) and (ii) to examine the relationship between plasma talazoparib concentration and QTc. In this open-label phase 1 study, patients had continuous 12-lead ECG recordings at baseline followed by time-matched continuous ECG recordings and collection of talazoparib plasma pharmacokinetic samples predose and at 1, 2, 4, and 6 h postdose on treatment days 1 and 22 and before talazoparib administration on day 2. ECG recordings were submitted for independent central review where triplicate 10-s ECGs, extracted up to 15 min before pharmacokinetic samples, were assessed for RR, PR, QRS, and QT intervals and ECG morphology. QT interval was corrected for heart rate using Fridericia's (QTcF) and Bazett's (QTcB) formulae. Linear mixed-effects modeling was used to examine the relationship between QTc and RR interval change from baseline and plasma talazoparib concentration. Thirty-seven patients received talazoparib. Mean change in QTcF from time-matched baseline ranged from -3.5 to 6.9 ms, with the greatest change 1 h postdose on day 22. No clinically relevant changes in PR, QRS, QTcB, QTcF, or RR intervals, heart rate, or ECG morphology were observed. No concentration-dependent effect on heart rate or QTc was observed. No deaths, permanent treatment discontinuations due to adverse events were reported. Talazoparib (1 mg once daily) had no clinically relevant effects on cardiac repolarization.

Two-Dimensional Halide Perovskites Incorporating Straight Chain Symmetric Diammonium Ions, (NH3C mH2 mNH3)(CH3NH3) n-1Pb nI3 n+1 ( m = 4-9; n = 1-4).

Low-dimensional halide perovskites have recently attracted intense interest as alternatives to the three-dimensional (3D) perovskites because of their greater tunability and higher environmental stability. Herein, we present the new homologous 2D series (NH3C mH2 mNH3)(CH3NH3) n-1Pb nI3 n+1 ( m = 4-9; n = 1-4), where m represents the carbon-chain number and n equals layer-thickness number. Multilayer ( n > 1) 2D perovskites incorporating diammonium cations were successfully synthesized by the solid-state grinding method for m = 4 and 6 and by the solution method for m = 7-9. Structural characterization by single-crystal X-ray diffraction for the m = 8 and m = 9 series ( n = 1-4) reveals that these compounds adopt the Cc space group for even n members and Pc for odd n members. The optical bandgaps are 2.15 eV for two-layer ( n = 2), 2.01 eV for three-layer ( n = 3), and 1.90 eV for four-layer ( n = 4). The materials exhibit excellent solution processability, and casting thin-films of the n = 3 members was successfully accomplished. The films show a clear tendency for the higher- m members to have preferred orientation on the glass substrate, with m = 8 exhibiting almost perfect vertical layer orientation and m = 9 displaying both vertical and parallel layer orientation, as confirmed by grazing-incidence wide-angle X-ray scattering (GIWAXS) measurements. The vertical layer orientation for the (NH3C8H16NH3)(CH3NH3)2Pb3I10 member results in the best thermal, light, and air stability within this series, thus showing excellent potential for solar cell applications.

Palbociclib has no clinically relevant effect on the QTc interval in patients with advanced breast cancer.

The aim of this study was to assess the potential effects of palbociclib in combination with letrozole on QTc. PALOMA-2, a phase 3, randomized, double-blind, placebo-controlled trial, compared palbociclib plus letrozole with placebo plus letrozole in postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The study included a QTc evaluation substudy carried out as a definitive QT interval prolongation assessment for palbociclib. Time-matched triplicate ECGs were performed at 0, 2, 4, 6, and 8 h at baseline (Day 0) and on Cycle 1 Day 14. Additional ECGs were collected from all patients for safety monitoring. The QT interval was corrected for heart rate using Fridericia's correction (QTcF), Bazett's correction (QTcB), and a study-specific correction factor (QTcS). In total, 666 patients were randomized 2 : 1 to palbociclib plus letrozole or placebo plus letrozole. Of these, 125 patients were enrolled in the QTc evaluation substudy. No patients in the palbociclib plus letrozole arm of the substudy (N=77) had a maximum postbaseline QTcS or QTcF value of ≥ 480 ms, or a maximum increase from clock time-matched baseline for QTcS or QTcF values of ≥ 60 ms. The upper bounds of the one-sided 95% confidence interval for the mean change from time-matched baseline for QTcS, QTcF, and QTcB at all time points and at steady-state Cmax following repeated administration of 125 mg palbociclib were less than 10 ms. Palbociclib, when administered with letrozole at the recommended therapeutic dosing regimen, did not prolong the QT interval to a clinically relevant extent.

The Metal or the Ligand? The Preferred Locus for Redox Changes in Oxygen Atom Transfer Reactions of Rhenium Amidodiphenoxides.

The rhenium(V) oxo complex oxo(triphenylphosphine) (bis(3,5-di-tert-butyl-2-phenoxo)amido)rhenium(V), (ONOCat)ReO(PPh3), reacts with molecular oxygen to give triphenylphosphine oxide and the dimeric rhenium(VII) complex fac,anti-(ONOCat)Re(O)(µ-O)2Re(O)(ONOCat). The ONO ligand adopts an unusual fac geometry, presumably to maximize π donation to rhenium; strong π donation is substantiated by the intraligand bond distances (metrical oxidation state = -2.24(9)). Addition of the N-heterocyclic carbene ligand IMes to fac,anti-(ONOCat)Re(O)(µ-O)2Re(O)(ONOCat) cleaves the dimer into monomeric C1-symmetric fac-(ONOCat)ReO2(IMes). The monorhenium(VII) complex is deoxygenated by PMe2Ph to give the rhenium(V) compound (ONOCat)ReO(IMes), which can be independently prepared by ligand substitution of (ONOCat)ReO(PPh3). The degree of stereochemical rigidity exhibited by the dioxo compound, as established by dynamic NMR spectroscopy, excludes the intermediacy of mer-(ONOQ)ReVO2(IMes) in this oxygen atom transfer reaction. Thus, oxygen atom transfer takes place preferentially by direct reduction of the oxorhenium(VII) moiety (classical oxygen atom transfer) rather than through initial internal electron transfer and ligand-centered reduction of an oxorhenium(V)-iminoquinone.

Palbociclib Combined with Fulvestrant in Premenopausal Women with Advanced Breast Cancer and Prior Progression on Endocrine Therapy: PALOMA-3 Results.

BACKGROUND: The efficacy and safety of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, combined with fulvestrant and goserelin was assessed in premenopausal women with advanced breast cancer (ABC) who had progressed on prior endocrine therapy (ET). PATIENTS AND METHODS: One hundred eight premenopausal endocrine-refractory women ≥18 years with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) ABC were among 521 women randomized 2:1 (347:174) to fulvestrant (500 mg) ± goserelin with either palbociclib (125 mg/day orally, 3 weeks on, 1 week off) or placebo. This analysis assessed whether the overall tolerable safety profile and significant progression-free survival (PFS) improvement extended to premenopausal women. Potential drug-drug interactions (DDIs) and ovarian suppression with goserelin were assessed via plasma pharmacokinetics and biochemical analyses, respectively. (ClinicalTrials.gov identifier: NCT01942135) RESULTS: Median PFS for premenopausal women in the palbociclib (n = 72) versus placebo arm (n = 36) was 9.5 versus 5.6 months, respectively (hazard ratio, 0.50, 95% confidence interval: 0.29-0.87), and consistent with the significant PFS improvement in the same arms for postmenopausal women. Any-grade and grade ≤3 neutropenia, leukopenia, and infections were among the most frequent adverse events reported in the palbociclib arm with concurrent goserelin administration. Hormone concentrations were similar between treatment arms and confirmed sustained ovarian suppression. Clinically relevant DDIs were not observed. CONCLUSION: Palbociclib combined with fulvestrant and goserelin was an effective and well-tolerated treatment for premenopausal women with prior endocrine-resistant HR+/HER2- ABC. Inclusion of both premenopausal and postmenopausal women in pivotal combination ET trials facilitates access to novel drugs for young women and should be considered as a new standard for clinical trial design. IMPLICATIONS FOR PRACTICE: PALOMA-3, the first registrational study to include premenopausal women in a trial investigating a CDK4/6 inhibitor combined with endocrine therapy, has the largest premenopausal cohort reported in an endocrine-resistant setting. In pretreated premenopausal women with hormone receptor-positive advanced breast cancer, palbociclib plus fulvestrant and goserelin (luteinizing hormone-releasing hormone [LHRH] agonist) treatment almost doubled median progression-free survival (PFS) and significantly increased the objective response rate versus endocrine monotherapy, achieving results comparable to those reported for chemotherapy without apparently interfering with LHRH agonist-induced ovarian suppression. The significant PFS gain and tolerable safety profile strongly support use of this regimen in premenopausal women with endocrine-resistant disease who could possibly delay chemotherapy.

Development of highly potent protease-activated receptor 2 agonists via synthetic lipid tethering.

Protease-activated receptor-2 (PAR2) is a G-protein coupled receptor (GPCR) associated with a variety of pathologies. However, the therapeutic potential of PAR2 is limited by a lack of potent and specific ligands. Following proteolytic cleavage, PAR2 is activated through a tethered ligand. Hence, we reasoned that lipidation of peptidomimetic ligands could promote membrane targeting and thus significantly improve potency and constructed a series of synthetic tethered ligands (STLs). STLs contained a peptidomimetic PAR2 agonist (2-aminothiazol-4-yl-LIGRL-NH2) bound to a palmitoyl group (Pam) via polyethylene glycol (PEG) linkers. In a high-throughput physiological assay, these STL agonists displayed EC50 values as low as 1.47 nM, representing a ∼200 fold improvement over the untethered parent ligand. Similarly, these STL agonists were potent activators of signaling pathways associated with PAR2: EC50 for Ca(2+) response as low as 3.95 nM; EC50 for MAPK response as low as 9.49 nM. Moreover, STLs demonstrated significant improvement in potency in vivo, evoking mechanical allodynia with an EC50 of 14.4 pmol. STLs failed to elicit responses in PAR2(-/-) cells at agonist concentrations of >300-fold their EC50 values. Our results demonstrate that the STL approach is a powerful tool for increasing ligand potency at PAR2 and represent opportunities for drug development at other protease activated receptors and across GPCRs.

Image-based discrimination of the early stages of mesenchymal stem cell differentiation.

Mesenchymal stem cells (MSCs) are self-renewing, multipotent cells, which can be used in cellular and tissue therapeutics. MSCs cell number can be expanded in vitro, but premature differentiation results in reduced cell number and compromised therapeutic efficacies. Current techniques fail to discriminate the "stem-like" population from early stages (12 hours) of differentiated MSC population. Here, we imaged nuclear structure and actin architecture using immunofluorescence and used deep learning-based computer vision technology to discriminate the early stages (6-12 hours) of MSC differentiation. Convolutional neural network (CNN) models trained by nucleus and actin images have high accuracy in reporting MSC differentiation; nuclear images alone can identify early stages of differentiation. Concurrently, we show that chromatin fluidity and heterochromatin levels or localization change during early MSC differentiation. This study quantifies changes in cell architecture during early MSC differentiation and describes a novel image-based diagnostic tool that could be widely used in MSC culture, expansion and utilization.

Orientational analysis of atomic pair correlations in nanocrystalline indium oxide thin films.

The application of grazing-incidence total X-ray scattering (GITXS) for pair distribution function (PDF) analysis using >50 keV X-rays from synchrotron light sources has created new opportunities for structural characterization of supported thin films with high resolution. Compared with grazing-incidence wide-angle X-ray scattering, which is only useful for highly ordered materials, GITXS/PDFs expand such analysis to largely disordered or nanostructured materials by examining the atomic pair correlations dependent on the direction relative to the surface of the supporting substrate. A characterization of nanocrystalline In2O3-derived thin films is presented here with in-plane-isotropic and out-of-plane-anisotropic orientational ordering of the atomic structure, each synthesized using different techniques. The atomic orientations of such films are known to vary based on the synthetic conditions. Here, an azimuthal orientational analysis of these films using GITXS with a single incident angle is shown to resolve the markedly different orientations of the atomic structures with respect to the planar support and the different degrees of long-range order, and hence, the terminal surface chemistries. It is anticipated that orientational analysis of GITXS/PDF data will offer opportunities to extend structural analyses of thin films by providing a means to qualitatively determine the major atomic orientation within nanocrystalline and, eventually, non-crystalline films.

Mo3S13 Chalcogel: A High-Capacity Electrode for Conversion-Based Li-Ion Batteries.

Despite large theoretical energy densities, metal-sulfide electrodes for energy storage systems face several limitations that impact the practical realization. Here, we present the solution-processable, room temperature (RT) synthesis, local structures, and application of a sulfur-rich Mo3S13 chalcogel as a conversion-based electrode for lithium-sulfide batteries (LiSBs). The structure of the amorphous Mo3S13 chalcogel is derived through operando Raman spectroscopy, synchrotron X-ray pair distribution function (PDF), X-ray absorption near edge structure (XANES), and extended X-ray absorption fine structure (EXAFS) analysis, along with ab initio molecular dynamics (AIMD) simulations. A key feature of the three-dimensional (3D) network is the connection of Mo3S13 units through S-S bonds. Li/Mo3S13 half-cells deliver initial capacity of 1013 mAh g-1 during the first discharge. After the activation cycles, the capacity stabilizes and maintains 312 mAh g-1 at a C/3 rate after 140 cycles, demonstrating sustained performance over subsequent cycling. Such high-capacity and stability are attributed to the high density of (poly)sulfide bonds and the stable Mo-S coordination in Mo3S13 chalcogel. These findings showcase the potential of Mo3S13 chalcogels as metal-sulfide electrode materials for LiSBs.

Readmission following hospitalization for pneumonia: the impact of pneumonia type and its implication for hospitals.

BACKGROUND: Readmission rates following discharge after pneumonia are thought to represent the quality of care. Factors associated with readmission, however, remain poorly described. It is unclear if readmission rates vary based on pneumonia type. METHODS: We retrospectively identified adults admitted to an index hospital with non-nosocomial pneumonia (January through December 2010) and who survived to discharge. We only included patients with bacterial evidence of infection. Readmission in the 30 days following discharge to any of 9 hospitals comprising the index hospital's healthcare system served as the primary end point. We recorded demographics, severity of illness, comorbidities, and infection-related factors. We noted whether the patient had healthcare-associated pneumonia (HCAP) versus community-acquired pneumonia. We utilized logistic regression analysis to determine factors independently associated with readmission. RESULTS: The cohort included 977 subjects; 78.9% survived to discharge. The readmission rate equaled 20%. Neither disease severity nor the rate of initially inappropriate antibiotic therapy correlated with readmission. Subjects with HCAP were 7.5 (95% confidence interval [CI], 3.6-15.7) times more likely to be readmitted. Four HCAP criteria were independently associated with readmission: admission from long-term care (adjusted odds ratio [AOR], 2.2 [95% CI, 1.4-3.4]); immunosuppression (AOR, 1.9 [95% CI, 1.3-2.9]); prior antibiotics (AOR, 1.7 [95% CI, 1.2-2.6]); and prior hospitalization (AOR, 1.7 [95% CI, 1.1-2.5]). CONCLUSIONS: Readmission for pneumonia is common but varies based on pneumonia type. The variables associated with readmission do not reflect factors that hospitals directly control. Use of one rule to guide payment that fails to account for HCAP and the HCAP criteria on readmission seems inappropriate.

Determination of efavirenz in human dried blood spots by reversed-phase high-performance liquid chromatography with UV detection.

BACKGROUND: Previously published methods for determination of efavirenz (EFV) in human dried blood spots (DBS) use costly and complex liquid chromatography/mass spectrometry. We describe the validation and evaluation of a simple and inexpensive high-performance liquid chromatography method for EFV quantification in human DBS and dried plasma spots (DPS), using ultraviolet detection appropriate for resource-limited settings. METHODS: One hundred microliters of heparinized whole blood or plasma were spotted onto blood collection cards, dried, punched, and eluted. Eluates are injected onto a C-18 reversed phase high-performance liquid chromatography column. EFV is separated isocratically using a potassium phosphate and acetonitrile mobile phase. Ultraviolet detection is at 245 nm. Quantitation is by use of external calibration standards. Following validation, the method was evaluated using whole blood and plasma from HIV-positive patients undergoing EFV therapy. RESULTS: Mean recovery of drug from DBS is 91.5%. The method is linear over the validated concentration range of 0.3125-20.0 µg/mL. A good correlation (Spearman r = 0.96) between paired plasma and DBS EFV concentrations from the clinical samples was observed, and hematocrit level was not found to be a significant determinant of the EFV DBS level. The mean observed C DBS/C plasma ratio was 0.68. A good correlation (Spearman r = 0.96) between paired plasma and DPS EFV concentrations from the clinical samples was observed. The mean percent deviation of DPS samples from plasma samples is 1.68%. CONCLUSIONS: Dried whole blood spot or dried plasma spot sampling is well suited for monitoring EFV therapy in resource-limited settings, particularly when high sensitivity is not essential.

The protease-activated receptor-2-specific agonists 2-aminothiazol-4-yl-LIGRL-NH2 and 6-aminonicotinyl-LIGRL-NH2 stimulate multiple signaling pathways to induce physiological responses in vitro and in vivo.

Protease-activated receptor-2 (PAR(2)) is one of four protease-activated G-protein-coupled receptors. PAR(2) is expressed on multiple cell types where it contributes to cellular responses to endogenous and exogenous proteases. Proteolytic cleavage of PAR(2) reveals a tethered ligand that activates PAR(2) and two major downstream signaling pathways: mitogen-activated protein kinase (MAPK) and intracellular Ca(2+) signaling. Peptides or peptidomimetics can mimic binding of the tethered ligand to stimulate signaling without the nonspecific effects of proteases. The most commonly used peptide activators of PAR(2) (e.g. SLIGRL-NH(2) and SLIGKV-NH(2)) lack potency at the receptor. However, although the potency of 2-furoyl-LIGRLO-NH(2) (2-f-LIGRLO-NH(2)) underscores the use of peptidomimetic PAR(2) ligands as a mechanism to enhance pharmacological action at PAR(2), 2-f-LIGRLO-NH(2) has not been thoroughly evaluated. We evaluated the known agonist 2-f-LIGRLO-NH(2) and two recently described pentapeptidomimetic PAR(2)-specific agonists, 2-aminothiazol-4-yl-LIGRL-NH(2) (2-at-LIGRL-NH(2)) and 6-aminonicotinyl-LIGRL-NH(2) (6-an-LIGRL-NH(2)). All peptidomimetic agonists stimulated PAR(2)-dependent in vitro physiological responses, MAPK signaling, and Ca(2+) signaling with an overall rank order of potency of 2-f-LIGRLO-NH(2) ≈ 2-at-LIGRL-NH(2) > 6-an-LIGRL-NH(2) ≫ SLIGRL-NH(2). Because PAR(2) plays a major role in pathological pain conditions and to test potency of the peptidomimetic agonists in vivo, we evaluated these agonists in models relevant to nociception. All three agonists activated Ca(2+) signaling in nociceptors in vitro, and both 2-at-LIGRL-NH(2) and 2-f-LIGRLO-NH(2) stimulated PAR(2)-dependent thermal hyperalgesia in vivo. We have characterized three high potency ligands that can be used to explore the physiological role of PAR(2) in a variety of systems and pathologies.