Au-Pd separation enhances bimetallic catalysis of alcohol oxidation.

In oxidation reactions catalysed by supported metal nanoparticles with oxygen as the terminal oxidant, the rate of the oxygen reduction can be a limiting factor. This is exemplified by the oxidative dehydrogenation of alcohols, an important class of reactions with modern commercial applications1-3. Supported gold nanoparticles are highly active for the dehydrogenation of the alcohol to an aldehyde4 but are less effective for oxygen reduction5,6. By contrast, supported palladium nanoparticles offer high efficacy for oxygen reduction5,6. This imbalance can be overcome by alloying gold with palladium, which gives enhanced activity to both reactions7,8,9; however, the electrochemical potential of the alloy is a compromise between that of the two metals, meaning that although the oxygen reduction can be improved in the alloy, the dehydrogenation activity is often limited. Here we show that by separating the gold and palladium components in bimetallic carbon-supported catalysts, we can almost double the reaction rate compared with that achieved with the corresponding alloy catalyst. We demonstrate this using physical mixtures of carbon-supported monometallic gold and palladium catalysts and a bimetallic catalyst comprising separated gold and palladium regions. Furthermore, we demonstrate electrochemically that this enhancement is attributable to the coupling of separate redox processes occurring at isolated gold and palladium sites. The discovery of this catalytic effect-a cooperative redox enhancement-offers an approach to the design of multicomponent heterogeneous catalysts.

Lithium-Directed Transformation of Amorphous Iridium (Oxy)hydroxides To Produce Active Water Oxidation Catalysts.

The oxygen evolution reaction (OER) is crucial to future energy systems based on water electrolysis. Iridium oxides are promising catalysts due to their resistance to corrosion under acidic and oxidizing conditions. Highly active iridium (oxy)hydroxides prepared using alkali metal bases transform into low activity rutile IrO2 at elevated temperatures (>350 °C) during catalyst/electrode preparation. Depending on the residual amount of alkali metals, we now show that this transformation can result in either rutile IrO2 or nano-crystalline Li-intercalated IrOx. While the transition to rutile results in poor activity, the Li-intercalated IrOx has comparative activity and improved stability when compared to the highly active amorphous material despite being treated at 500 °C. This highly active nanocrystalline form of lithium iridate could be more resistant to industrial procedures to produce PEM membranes and provide a route to stabilize the high populations of redox active sites of amorphous iridium (oxy)hydroxides.

Monocyte migration profiles define disease severity in acute COVID-19 and unique features of long COVID.

BACKGROUND: COVID-19 is associated with a dysregulated immune response but it is unclear how immune dysfunction contributes to the chronic morbidity persisting in many COVID-19 patients during convalescence (long COVID). METHODS: We assessed phenotypical and functional changes of monocytes in COVID-19 patients during hospitalisation and up to 9 months of convalescence following COVID-19, respiratory syncytial virus or influenza A. Patients with progressive fibrosing interstitial lung disease were included as a positive control for severe, ongoing lung injury. RESULTS: Monocyte alterations in acute COVID-19 patients included aberrant expression of leukocyte migration molecules, continuing into convalescence (n=142) and corresponding with specific symptoms of long COVID. Long COVID patients with unresolved lung injury, indicated by sustained shortness of breath and abnormal chest radiology, were defined by high monocyte expression of C-X-C motif chemokine receptor 6 (CXCR6) (p<0.0001) and adhesion molecule P-selectin glycoprotein ligand 1 (p<0.01), alongside preferential migration of monocytes towards the CXCR6 ligand C-X-C motif chemokine ligand 16 (CXCL16) (p<0.05), which is abundantly expressed in the lung. Monocyte CXCR6 and lung CXCL16 were heightened in patients with progressive fibrosing interstitial lung disease (p<0.001), confirming a role for the CXCR6-CXCL16 axis in ongoing lung injury. Conversely, monocytes from long COVID patients with ongoing fatigue exhibited a sustained reduction of the prostaglandin-generating enzyme cyclooxygenase 2 (p<0.01) and CXCR2 expression (p<0.05). These monocyte changes were not present in respiratory syncytial virus or influenza A convalescence. CONCLUSIONS: Our data define unique monocyte signatures that define subgroups of long COVID patients, indicating a key role for monocyte migration in COVID-19 pathophysiology. Targeting these pathways may provide novel therapeutic opportunities in COVID-19 patients with persistent morbidity.

Methanol synthesis from CO2 and H2 using supported Pd alloy catalysts.

A number of Pd based materials have been synthesised and evaluated as catalysts for the conversion of carbon dioxide and hydrogen to methanol, a useful platform chemical and hydrogen storage molecule. Monometallic Pd catalysts show poor methanol selectivity, but this is improved through the formation of Pd alloys, with both PdZn and PdGa alloys showing greatly enhanced methanol productivity compared with monometallic Pd/Al2O3 and Pd/TiO2 catalysts. Catalyst characterisation shows that the 1 : 1 ß-PdZn alloy is present in all Zn containing post-reaction samples, including PdZn/Ga2O3, with the Pd2Ga alloy formed for the Pd/Ga2O3 sample. The heat of mixing was calculated for a variety of alloy compositions with high values determined for both PdZn and Pd2Ga alloys, at ca. -0.6 eV per atom and ca. -0.8 eV per atom, respectively. However, ZnO is more readily reduced than Ga2O3, providing a possible explanation for the preferential formation of the PdZn alloy, rather than PdGa, when in the presence of Ga2O3.

N-Heterocyclic Carbene Modified Palladium Catalysts for the Direct Synthesis of Hydrogen Peroxide.

Heterogeneous palladium catalysts modified by N-heterocyclic carbenes (NHCs) are shown to be highly effective toward the direct synthesis of hydrogen peroxide (H2O2), in the absence of the promoters which are typically required to enhance both activity and selectivity. Catalytic evaluation in a batch regime demonstrated that through careful selection of the N-substituent of the NHC it is possible to greatly enhance catalytic performance when compared to the unmodified analogue and reach concentrations of H2O2 rivaling that obtained by state-of-the-art catalysts. The enhanced performance of the modified catalyst, which is retained upon reuse, is attributed to the ability of the NHC to electronically modify Pd speciation.

Glucocorticoids rapidly inhibit cell migration through a novel, non-transcriptional HDAC6 pathway.

Glucocorticoids (GCs) act through the glucocorticoid receptor (GR, also known as NR3C1) to regulate immunity, energy metabolism and tissue repair. Upon ligand binding, activated GR mediates cellular effects by regulating gene expression, but some GR effects can occur rapidly without new transcription. Here, we show that GCs rapidly inhibit cell migration, in response to both GR agonist and antagonist ligand binding. The inhibitory effect on migration is prevented by GR knockdown with siRNA, confirming GR specificity, but not by actinomycin D treatment, suggesting a non-transcriptional mechanism. We identified a rapid onset increase in microtubule polymerisation following GC treatment, identifying cytoskeletal stabilisation as the likely mechanism of action. HDAC6 overexpression, but not knockdown of αTAT1, rescued the GC effect, implicating HDAC6 as the GR effector. Consistent with this hypothesis, ligand-dependent cytoplasmic interaction between GR and HDAC6 was demonstrated by quantitative imaging. Taken together, we propose that activated GR inhibits HDAC6 function, and thereby increases the stability of the microtubule network to reduce cell motility. We therefore report a novel, non-transcriptional mechanism whereby GCs impair cell motility through inhibition of HDAC6 and rapid reorganization of the cell architecture.This article has an associated First Person interview with the first author of the paper.

Bottom-up Synthesis of Water-Soluble Gold Nanoparticles Stabilized by N-Heterocyclic Carbenes: From Structural Characterization to Applications.

N-heterocyclic carbenes (NHCs) have become attractive ligands for functionalizing gold nanoparticle surfaces with applications ranging from catalysis to biomedicine. Despite their great potential, NHC stabilized gold colloids (NHC@AuNPs) are still scarcely explored and further efforts should be conducted to improve their design and functionalization. Here, the 'bottom-up' synthesis of two water-soluble gold nanoparticles (AuNP-1 and AuNP-2) stabilized by hydrophilic mono- and bidentate NHC ligands is reported together with their characterization by various spectroscopic and analytical methods. The NPs showed key differences likely to be due to the selected NHC ligand systems. Transmission electron microscopy (TEM) images showed small quasi-spherical and faceted NHC@AuNPs of similar particle size (ca. 2.3-2.6 nm) and narrow particle size distribution, but the colloids featured different ratios of Au(I)/Au(0) by X-ray photoelectron spectroscopy (XPS). Furthermore, the NHC@AuNPs were supported on titania and fully characterized. The new NPs were studied for their catalytic activity towards the reduction of nitrophenol substrates, the reduction of resazurin and for their photothermal efficiency. Initial results on their application in photothermal therapy (PTT) were obtained in human cancer cells in vitro. The aforementioned reactions represent important model reactions towards wastewater remediation, bioorthogonal transformations and cancer treatment.

Stable amorphous georgeite as a precursor to a high-activity catalyst.

Copper and zinc form an important group of hydroxycarbonate minerals that include zincian malachite, aurichalcite, rosasite and the exceptionally rare and unstable--and hence little known and largely ignored--georgeite. The first three of these minerals are widely used as catalyst precursors for the industrially important methanol-synthesis and low-temperature water-gas shift (LTS) reactions, with the choice of precursor phase strongly influencing the activity of the final catalyst. The preferred phase is usually zincian malachite. This is prepared by a co-precipitation method that involves the transient formation of georgeite; with few exceptions it uses sodium carbonate as the carbonate source, but this also introduces sodium ions--a potential catalyst poison. Here we show that supercritical antisolvent (SAS) precipitation using carbon dioxide (refs 13, 14), a process that exploits the high diffusion rates and solvation power of supercritical carbon dioxide to rapidly expand and supersaturate solutions, can be used to prepare copper/zinc hydroxycarbonate precursors with low sodium content. These include stable georgeite, which we find to be a precursor to highly active methanol-synthesis and superior LTS catalysts. Our findings highlight the value of advanced synthesis methods in accessing unusual mineral phases, and show that there is room for exploring improvements to established industrial catalysts.

The role of surface oxidation and Fe-Ni synergy in Fe-Ni-S catalysts for CO2 hydrogenation.

Increasing carbon dioxide (CO2) emissions, resulting in climate change, have driven the motivation to achieve the effective and sustainable conversion of CO2 into useful chemicals and fuels. Taking inspiration from biological processes, synthetic iron-nickel-sulfides have been proposed as suitable catalysts for the hydrogenation of CO2. In order to experimentally validate this hypothesis, here we report violarite (Fe,Ni)3S4 as a cheap and economically viable catalyst for the hydrogenation of CO2 into formate under mild, alkaline conditions at 125 °C and 20 bar (CO2 : H2 = 1 : 1). Calcination of violarite at 200 °C resulted in excellent catalytic activity, far superior to that of Fe-only and Ni-only sulfides. We further report first principles simulations of the CO2 conversion on the partially oxidised (001) and (111) surfaces of stoichiometric violarite (FeNi2S4) and polydymite (Ni3S4) to rationalise the experimentally observed trends. We have obtained the thermodynamic and kinetic profiles for the reaction of carbon dioxide (CO2) and water (H2O) on the catalyst surfaces via substitution and dissociation mechanisms. We report that the partially oxidised (111) surface of FeNi2S4 is the best catalyst in the series and that the dissociation mechanism is the most favourable. Our study reveals that the partial oxidation of the FeNi2S4 surface, as well as the synergy of the Fe and Ni ions, are important in the catalytic activity of the material for the effective hydrogenation of CO2 to formate.

The interaction of CO with a copper(ii) chloride oxy-chlorination catalyst.

The interaction of CO with an attapulgite-supported, KCl modified CuCl2 catalyst has previously been examined using a combination of XANES, EXAFS and DFT calculations. Exposing the catalyst to CO at elevated temperatures leads to the formation of CO2 as the only identifiable product. However, phosgene production can be induced by a catalyst pre-treatment stage, where the supported CuCl2 sample is exposed to a diluted stream of dichlorine; subsequent CO exposure at ∼643 K then leads to phosgene production. This communication describes a series of FTIR based micro-reactor measurements, coupled with characterisation measurements utilising TEM, XRD and XPS to define the nature of the catalyst at different stages of the reaction coordinate. The CuCl2 catalyst is able to support Deacon activity , establishing this work with the possibility of utilising the oxy-chlorination of CO to produce phosgene. Continuous dosing of CO at elevated temperatures over the chlorine pre-dosed CuCl2 catalyst shows diminishing phosgene production as a function of time-on-stream, indicating surface chlorine supply to be rate-limiting under the reaction conditions studied. A pictorial reaction scheme is proposed to account for the surface chemistry observed.

Versailles Project on Advanced Materials and Standards interlaboratory study on intensity calibration for x-ray photoelectron spectroscopy instruments using low-density polyethylene.

We report the results of a Versailles Project on Advanced Materials and Standards interlaboratory study on the intensity scale calibration of x-ray photoelectron spectrometers using low-density polyethylene (LDPE) as an alternative material to gold, silver, and copper. An improved set of LDPE reference spectra, corrected for different instrument geometries using a quartz-monochromated Al Kα x-ray source, was developed using data provided by participants in this study. Using these new reference spectra, a transmission function was calculated for each dataset that participants provided. When compared to a similar calibration procedure using the NPL reference spectra for gold, the LDPE intensity calibration method achieves an absolute offset of ∼3.0% and a systematic deviation of ±6.5% on average across all participants. For spectra recorded at high pass energies (≥90 eV), values of absolute offset and systematic deviation are ∼5.8% and ±5.7%, respectively, whereas for spectra collected at lower pass energies (<90 eV), values of absolute offset and systematic deviation are ∼4.9% and ±8.8%, respectively; low pass energy spectra perform worse than the global average, in terms of systematic deviations, due to diminished count rates and signal-to-noise ratio. Differences in absolute offset are attributed to the surface roughness of the LDPE induced by sample preparation. We further assess the usability of LDPE as a secondary reference material and comment on its performance in the presence of issues such as variable dark noise, x-ray warm up times, inaccuracy at low count rates, and underlying spectrometer problems. In response to participant feedback and the results of the study, we provide an updated LDPE intensity calibration protocol to address the issues highlighted in the interlaboratory study. We also comment on the lack of implementation of a consistent and traceable intensity calibration method across the community of x-ray photoelectron spectroscopy (XPS) users and, therefore, propose a route to achieving this with the assistance of instrument manufacturers, metrology laboratories, and experts leading to an international standard for XPS intensity scale calibration.

A Modular Vaccine Platform Combining Self-Assembled Peptide Cages and Immunogenic Peptides.

Subunit vaccines use delivery platforms to present minimal antigenic components for immunization. The benefits of such systems include multivalency, self-adjuvanting properties, and more specific immune responses. Previously, the design, synthesis, and characterization of self-assembling peptide cages (SAGEs) have been reported. In these, de novo peptides are combined to make hubs that assemble into nanoparticles when mixed in aqueous solution. Here it is shown that SAGEs are nontoxic particles with potential as accessible synthetic peptide scaffolds for the delivery of immunogenic components. To this end, SAGEs functionalized with the model antigenic peptides tetanus toxoid632-651 and ovalbumin323-339 drive antigen-specific responses both in vitro and in vivo, eliciting both CD4+ T cell and B cell responses. Additionally, SAGEs functionalized with the antigenic peptide hemagglutinin518-526 from the influenza virus are also able to drive a CD8+ T cell response in vivo. This work demonstrates the potential of SAGEs to act as a modular scaffold for antigen delivery, capable of inducing and boosting specific and tailored immune responses.

Efficient Elimination of Chlorinated Organics on a Phosphoric Acid Modified CeO2 Catalyst: A Hydrolytic Destruction Route.

The development of efficient technologies to prevent the emission of hazardous chlorinated organics from industrial sources without forming harmful byproducts, such as dioxins, is a major challenge in environmental chemistry. Herein, we report a new hydrolytic destruction route for efficient chlorinated organics elimination and demonstrate that phosphoric acid-modified CeO2 (HP-CeO2) can decompose chlorobenzene (CB) without forming polychlorinated congeners under the industry-relevant reaction conditions. The active site and reaction pathway were investigated, and it was found that surface phosphate groups initially react with CB and water to form phenol and HCl, followed by deep oxidation. The high on-stream stability of the catalyst was due to the efficient generation of HCl, which removes Cl from the catalyst surface and ensures O2 activation and therefore deep oxidation of the hydrocarbons. Subsequent density functional theory calculations revealed a distinctly decreased formation energy of an oxygen vacancy at nearest (VO-1) and next-nearest (VO-2) surface sites to the bonded phosphate groups, which likely contributes to the high rate of oxidation observed over the catalyst. Significantly, no dioxins, which are frequently formed in the conventional oxidation route, were observed. This work not only reports an efficient route and corresponding phosphate active site for chlorinated organics elimination but also illustrates that the rational design of the reaction route can solve some of the most important challenges in environmental catalysis.

One pot microwave synthesis of highly stable AuPd@Pd supported core-shell nanoparticles.

A series of 1 wt% supported Au, Pd and AuPd nanoalloy catalysts were prepared via microwave assisted reduction of PdCl2 and HAuCl4 in a facile, one pot process. The resulting materials showed excellent activity for the direct synthesis of hydrogen peroxide from hydrogen and oxygen, with a synergistic effect observed on the addition of Au into a Pd catalyst. Detailed electron microscopy showed that the bimetallic particles exhibited a core-shell morphology, with an Au core surrounded by an Au-Pd shell, with a size between 10-20 nm. The presence of Au in the shell was confirmed by EDX studies, with corroborating data from XPS measurements showing a significant contribution of both Au and Pd in the spectra, with the Au signal increasing as the total Au content of the catalyst increased. No PdO was observed, suggesting a complete reduction of the metal chloride nanoparticles. Unlike similar catalysts prepared by sol-immobilisation methodology, the core-shell structures showed excellent stability during the hydrogen peroxide synthesis reaction, and no catalyst deactivation was observed over 4 reuse cycles. This is the first time the preparation of stable core-shell particles have been reported using microwave assisted reduction. The observation that these particles are core-shell, without the need of a complicated synthesis or high thermal treatment and form in just 15 minutes presents an exciting opportunity for this experimental technique.

Advance care planning documentation strategies; goals-of-care as an alternative to not-for-resuscitation in medical and oncology patients. A pre-post controlled study on quantifiable outcomes.

BACKGROUND: Health services in Tasmania, Victoria and now Western Australia are changing to goals-of-care (GOC) advance care planning (ACP) documentation strategies. AIM: To compare the clinical impact of two different health department-sanctioned ACP documentation strategies. METHODS: A non-blinded, pre-post, controlled study over two corresponding 6-month periods in 2016 and 2017 comparing the current discretional not-for-resuscitation (NFR) with a new, inclusive GOC strategy in two medical/oncology wards at a large private hospital. Main outcomes were the uptake of ACP forms per hospitalisation and the timing between hospital admission, ACP form completion and in-patient death. Secondary outcomes included utilisation of the rapid response team (RRT), palliative and critical care services. RESULTS: In total, 650 NFR and 653 GOC patients underwent 1885 admissions (mean Charlson Comorbidity Index = 3.7). GOC patients had a higher uptake of ACP documentation (346 vs 150 ACP forms per 1000 admissions, P < 0.0001) and a higher proportion of ACP forms completed within the first 48 h of admission (58 vs 39%, P = 0.0002) but a higher incidence of altering the initial ACP level of care (P = 0.003). All other measures, including ACP documentation within 48 h of death (P = 0.50), activation of RRT (P = 0.73) and admission to critical (P = 0.62) or palliative (P = 0.81) care services, remained similar. GOC documentation was often incomplete, with most sub-sections left blank between 74 and 87% of occasions. CONCLUSION: Despite an increased uptake of the GOC form, overall use remained low, written completion was poor, and most quantitative outcomes remained statistically unchanged. Further research is required before a wider GOC implementation can be supported in Australia's healthcare systems.

Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy.

The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily, which controls programs regulating cell proliferation, differentiation, and apoptosis. We have identified an unexpected role for GR in mitosis. We discovered that specifically modified GR species accumulate at the mitotic spindle during mitosis in a distribution that overlaps with Aurora kinases. We found that Aurora A was required to mediate mitosis-driven GR phosphorylation, but not recruitment of GR to the spindle. GR was necessary for mitotic progression, with increased time to complete mitosis, frequency of mitotic aberrations, and death in mitosis observed following GR knockdown. Complementation studies revealed an essential role for the GR ligand-binding domain, but no clear requirement for ligand binding in regulating chromosome segregation. The GR N-terminal domain, and specifically phosphosites S203 and S211, were not required. Reduced GR expression results in a cell cycle phenotype, with isolated cells from mouse and human subjects showing changes in chromosome content over prolonged passage. Furthermore, GR haploinsufficient mice have an increased incidence of tumor formation, and, strikingly, these tumors are further depleted for GR, implying additional GR loss as a consequence of cell transformation. We identified reduced GR expression in a panel of human liver, lung, prostate, colon, and breast cancers. We therefore reveal an unexpected role for the GR in promoting accurate chromosome segregation during mitosis, which is causally linked to tumorigenesis, making GR an authentic tumor suppressor gene.

How and why do countries differ in their governance and financing-related administrative expenditure in health care? An analysis of OECD countries by health care system typology.

INTRODUCTION: Administration is vital for health care. Its importance may increase as health care systems become more complex, but academic attention has remained minimal. We investigated trends in administrative expenditure across OECD countries, cross-country spending differences, spending differences between health care system typologies, and differences in the scale and scope of administrative functions across typologies. METHODS: We used OECD data, which include health system governance and financing-related administrative activities by regulators, governance bodies, and insurers (macrolevel), but exclude administrative expenditure by health care providers (mesolevel and microlevel). RESULTS: We find that governance and financing-related administrative spending at the macrolevel has remained stable over the last decade at slightly over 3% of total health spending. Cross-country differences range from 1.3% of health spending in Iceland to 8.3% in the United States. Voluntary private health insurance bears much higher administrative costs than compulsory schemes in all countries. Among compulsory schemes, multiple payers exhibit significantly higher administrative spending than single payers. Among single-payer schemes, those where entitlements are based on residency have significantly lower administrative spending than those with single social health insurance, albeit with a small difference. DISCUSSION: These differences can partially be explained because multi-payer and voluntary private health insurance schemes require additional administrative functions and enjoy less economies of scale. Studies in hospitals and primary care indicate similar differences in administrative costs across health system typologies at the mesolevel and microlevel of health care delivery, which warrants more research on total administrative costs at all the levels of health systems.

Characterisation of the cancer-associated glucocorticoid system: key role of 11ß-hydroxysteroid dehydrogenase type 2.

BACKGROUND: Recent studies have shown that production of cortisol not only takes place in several non-adrenal peripheral tissues such as epithelial cells but, also, the local inter-conversion between cortisone and cortisol is regulated by the 11ß-hydroxysteroid dehydrogenases (11ß-HSDs). However, little is known about the activity of this non-adrenal glucocorticoid system in cancers. METHODS: The presence of a functioning glucocorticoid system was assessed in human skin squamous cell carcinoma (SCC) and melanoma and further, in 16 epithelial cell lines from 8 different tissue types using ELISA, western blotting and immunofluorescence. 11ß-HSD2 was inhibited both pharmacologically and by siRNA technology. Naïve CD8+ T cells were used to test the paracrine effects of cancer-derived cortisol on the immune system in vitro. Functional assays included cell-cell adhesion and cohesion in two- and three-dimensional models. Immunohistochemical data of 11ß-HSD expression were generated using tissue microarrays of 40 cases of human SCCs as well as a database featuring 315 cancer cases from 15 different tissues. RESULTS: We show that cortisol production is a common feature of malignant cells and has paracrine functions. Cortisol production correlated with the magnitude of glucocorticoid receptor (GR)-dependent inhibition of tumour-specific CD8+ T cells in vitro. 11ß-HSDs were detectable in human skin SCCs and melanoma. Analyses of publicly available protein expression data of 11ß-HSDs demonstrated that 11ß-HSD1 and -HSD2 were dysregulated in the majority (73%) of malignancies. Pharmacological manipulation of 11ß-HSD2 activity by 18ß-glycyrrhetinic acid (GA) and silencing by specific siRNAs modulated the bioavailability of cortisol. Cortisol also acted in an autocrine manner and promoted cell invasion in vitro and cell-cell adhesion and cohesion in two- and three-dimensional models. Immunohistochemical analyses using tissue microarrays showed that expression of 11ß-HSD2 was significantly reduced in human SCCs of the skin. CONCLUSIONS: The results demonstrate evidence of a cancer-associated glucocorticoid system and show for the first time, the functional significance of cancer-derived cortisol in tumour progression.

Incidence and Risk Factors for Deliberate Self-harm, Mental Illness, and Suicide Following Bariatric Surgery: A State-wide Population-based Linked-data Cohort Study.

OBJECTIVE: Assess the incidence and determinants of hospitalization for deliberate self-harm and mental health disorders, and suicide after bariatric surgery. BACKGROUND: Limited recent literature suggests an increase in deliberate self-harm following bariatric surgery. METHODS: A state-wide, population-based, self-matched, longitudinal cohort study over a 5-year period between 2007 and 2011. Utilizing the Western Australian Department of Health Data Linkage Unit records, all patients undergoing bariatric surgery (n = 12062) in Western Australia were followed for an average 30.4 months preoperatively and 40.6 months postoperatively. RESULTS: There were 110 patients (0.9%) hospitalized for deliberate self-harm, which was higher than the general population [incidence rate ratio (IRR) 1.47, 95% confidence interval (CI) 1.11-1.94, P = 0.005]. Compared with before surgery, there was no significant increase in deliberate self-harm hospitalizations (IRR 0.79, 95% CI 0.54-1.16; P = 0.206) and a reduction in overall mental illness related hospitalizations (IRR 0.76, 95% CI 0.63-0.91; P = 0.002) after surgery. Younger age, no private-health insurance cover, a history of hospitalizations due to depression before surgery, and gastrointestinal complications after surgery were predictors for deliberate self-harm hospitalizations after bariatric surgery. Three suicides occurred during the follow-up period, a rate comparable to the general population during the same time period (IRR 0.61, 95% CI 0.11-2.27, P = 0.444). CONCLUSIONS: Hospitalization for deliberate self-harm in bariatric patients was more common than the general population, but an increased incidence of deliberate self-harm after bariatric surgery was not observed. Hospitalization for depression before surgery and major postoperative gastrointestinal complications after bariatric surgery are potentially modifiable risk factors for deliberate self-harm after bariatric surgery.

Lenalidomide augments actin remodeling and lowers NK-cell activation thresholds.

As multiple myeloma (MM) progresses, natural killer (NK)-cell responses decline against malignant plasma cells. The immunomodulatory drug lenalidomide is widely used for treatment of MM but its influence on NK-cell biology is unclear. Here, we report that lenalidomide lowers the threshold for NK-cell activation, causing a 66% decrease in the 50% effective concentration (EC50) for activation through CD16, and a 38% decrease in EC50 for NK group 2 member D (NKG2D)-mediated activation, allowing NK cells to respond to lower doses of ligand. In addition, lenalidomide augments NK-cell responses, causing a twofold increase in the proportion of primary NK cells producing interferon-γ (IFN-γ), and a 20-fold increase in the amount of IFN-γ produced per cell. Importantly, lenalidomide did not trigger IFN-γ production in unstimulated NK cells. Thus, lenalidomide enhances the NK-cell arm of the immune response, without activating NK cells inappropriately. Of particular clinical importance, lenalidomide also allowed NK cells to be activated by lower doses of rituximab, an anti-CD20 monoclonal antibody (mAb) widely used to treat B-cell malignancies. This supports combined use of lenalidomide and rituximab in a clinical setting. Finally, superresolution microscopy revealed that lenalidomide increased the periodicity of cortical actin at immune synapses, resulting in an increase in the area of the actin mesh predicted to be penetrable to vesicles containing IFN-γ. NK cells from MM patients also responded to lenalidomide in this way. This indicates that nanometer-scale rearrangements in cortical actin, a recently discovered step in immune synapse assembly, are a potential new target for therapeutic compounds.