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Background Sarcopenia is a progressive and systemic skeletal muscle disorder associated with an increased risk of hospitalization and adverse effects on survival. This study aims to investigate the prevalence and related risk factors of sarcopenia in people living with HIV using the revised European Working Group on Sarcopenia in Older People (EWGSOP2) definition.Methods This cross-sectional study comprising 379 patients with confirmed HIV infection evaluated the appendicular skeletal muscle mass by employing the bioelectrical impedance analysis method. Muscle strength and functional mobility were analyzed using the five-time sit-to-stand test and the timed “Up and Go” test.Results The prevalence rates of pre-sarcopenia and sarcopenia among people living with HIV were 3.4 % and 2.1 % according to the revised EWGSOP2 definition. Advanced age (Odds Ratio 1.07, p= .03), lower body mass index (Odds Ratio 0.79, p= .012) and CD4+T-cell count below 500/μl (Odds Ratio 2.22, p= .007) were identified as significant factors associated with sarcopenia. Sarcopenia was also identified as a significant correlate of frailty (p< .001).Conclusion This is the first study examining the prevalence of sarcopenia in people living with HIV according to the revised EWGSOP2 clinical algorithm. Advanced age, lower body mass index and a poor immune status are determined as promoting factors of sarcopenia. Sarcopenia significantly correlates with frailty. Standardized clinical algorithms are essential for reliable sarcopenia diagnosis in people living with HIV in order to promote intervention strategies and to prevent adverse health outcomes.

Background: Abiraterone (Abi) is an androgen receptor signaling inhibitor that significantly improves patients’ life expectancy in metastatic prostate cancer (PCa). Despite its beneficial effects, many patients have baseline or acquired resistance against Abi. The aim of this study was to identify predictive serum biomarkers for Abi treatment. Methods: We performed a comparative proteome analysis on three Abi sensitive (LNCaPabl, LAPC4, DuCaP) and resistant (LNCaPabl-Abi, LAPC4-Abi, DuCaP-Abi) PCa cell lines using liquid chromatography tandem mass spectrometry (LC-MS/MS) technique. Two bioinformatic selection workflows were applied to select the most promising candidate serum markers. Serum levels of selected proteins were assessed in samples of 100 Abi-treated patients with metastatic castration-resistant disease (mCRPC) using ELISA. Moreover, FSCN1 serum concentrations were measured in samples of 69 Docetaxel (Doc) treated mCRPC patients. Results: Our proteome analysis identified 68 significantly, at least two-fold upregulated proteins in Abi resistant cells. Using two filtering workflows four proteins (AMACR, KLK2, FSCN1 and CTAG1A) were selected for ELISA analyses. We found high baseline FSCN1 serum levels to be significantly associated with poor survival in Abi-treated mCRPC patients. Moreover, the multivariable analysis revealed that higher ECOG status (>1) and high baseline FSCN1 serum levels (>10.22 ng/ml by ROC cut-off) were independently associated with worse survival in Abi-treated patients (p&lt; 0.001 and p= 0.021, respectively). In contrast, no association was found between serum FSCN1 concentrations and overall survival in Doc-treated patients. Conclusions: Our analysis identified baseline FSCN1 serum levels to be independently associated with poor survival of Abi-treated, but not Doc-treated mCRPC patients, suggesting a therapy specific prognostic value for FSCN1.

Chronic recurrent angioedema without wheals (CRA) with normal C1 inhibitor (C1-INH) that is unresponsive to antihistamines may involve patients with recurrent angioedema of unknown cause (ie, so-called non-histaminergic idiopathic angioedema) as well as patients with hereditary angioedema with normal C1-INH (HAEnCI) when HAEnCI occurs in only one family member.

Spätpaläozoischer (Variszischer) Magmatismus ist in Mitteleuropa weit verbreitet. Eines der wichtigen Areale, die zum Verständnis der komplexen vulkano-tektonischen Prozesse am Übergang vom Pennsylvanium zum Cisuralium beitragen, ist die Chemnitz-Flöha-Vulkanzone (CFVZ). Letztere ist Teil des Saxothuringikums innerhalb der europäischen Varisziden. Für den zur CFVZ gehörigen Altenhain-Rhyolith präsentieren wir eine vollständige geochemische Gesamtgesteinsanalyse. Der kaliumreiche Altenhain-Rhyolith stammt aus einer hochdifferenzierten, kalkalkalischen, peraluminosen, A-typischen granitischen Schmelze. Es gibt starke geochemische Ähnlichkeiten zum Flöha-Ignimbrit und zum Zeisigwald-Tuff, die ebenfalls beide der CFVZ angehören. Das Vorkommen eines seltenen Minerals aus der Arsenogoyazit-/Arsenoflorencit-(Ce)-Festkörperlösungsreihe wird mitgeteilt.

Hintergrund: Infektionen mit antibiotikaresistenten Bakterien stellen eine hohe Gesundheitsbelastung dar, da sie mit erhöhter Letalität assoziiert sind und längerfristige dramatische Beeinträchtigungen der Lebensqualität hervorrufen können. In Deutschland erkranken jährlich etwa 54.500 Menschen an Infektionen durch antibiotikaresistente Erreger, von denen etwa 2400 Menschen versterben. Infektionen mit multiresistenten gramnegativen Bakterien (MRGN), insbesondere mit carbapenemresistenten Erregern, stellen ein besonderes Risiko dar, da nur eine begrenzte Zahl an Therapieoptionen verfügbar ist. Fragestellung: Wie sind die Ergebnisse aus Studien und Compassionate-Use-Programm mit dem neuen Siderophorantibiotikum Cefiderocol, das im April 2020 von der Europäischen Arzneimittel-Agentur (EMA) bei Erwachsenen zur Behandlung von Infektionen durch aerobe gramnegative Erreger zugelassen wurde, wenn nur begrenzte Behandlungsmöglichkeiten zur Verfügung stehen? Die Zulassung ist pathogenbasiert und fokusunabhängig [5]. Ergebnisse: Cefiderocol, das über einen innovativen Zelleintrittsmechanismus verfügt, ist als erstes β‑Laktam-Antibiotikum aus der Gruppe der Cephalosporine stabil gegenüber allen klinisch relevanten β‑Laktamasen, einschließlich Carbapenemasen, und hat eine hohe In-vitro-Wirksamkeit gegenüber carbapenemresistenten MRGN. Die Ergebnisse werden durch klinische Studien bei komplizierten Harnwegsinfektionen, nosokomialer Pneumonie/Beatmungspneumonie und schweren Infektionen durch carbapenemresistente Erreger bestätigt. Fazit: Klinische Studiendaten sowie die Ergebnisse aus den weltweiten Erfahrungsberichten zeigen, dass Cefiderocol eine vielversprechende Behandlungsoption für schwere Infektionen durch multiresistente, insbesondere carbapenemresistente gramnegative Bakterien darstellt.

Plastic scintillators are widely used as radiation detection media in homeland security and nuclear physics applications. Their attributes include low cost, scalability to large detector volumes, and additive compounding to enable additional material and detection features, such as pulse shape discrimination (PSD), gamma-ray spectroscopy, aging resistance, and coincidence timing. However, traditional chemically cured plastic scintillators (CCS) require long reaction times, and hazardous wet chemical procedures performed by specially trained personnel, and can leave residual monomer, resulting in deleterious optical and material properties. Here, we synthesize melt blended scintillators (MBSs) in 2.5 days using easily accessible solid-state compounding of commercially-available poly(styrene) with 30–60 wt% fluorene-based compound “P2” to create monolithic detectors with < 100 ppm residual monomer, in several form factors. The best scintillation performance was recorded for 60 wt% P2 in Styron 665, including gamma-ray light yield 139% of EJ- 200 commercial scintillator and PSD figure of merit (FOM) value of 2.65 at 478 keVee, approaching P2 organic glass scintillator (OGS). The capability of MBS to generate fog-resistant scintillators and poly(methyl methacrylate) (PMMA)-based scintillators for use in challenging environments is also demonstrated.

Low-coordinate titanium(III) amido complexes were readily prepared via treatment of β-TiCl3with 1 or 2 equiv of Li[N(SiiPr3)DIPP] (DIPP = 2,6-di-iso-propylphenyl) to form dinuclear [{Ti(N(SiiPr3)DIPP)Cl(μ-Cl)}2] (1) or mononuclear Ti[N(SiiPr3)DIPP]2Cl (2), respectively. Both complexes were characterized by a variety of methods, including NMR spectroscopy, Evans method magnetic susceptibility, and single-crystal X-ray diffraction studies. Complex 1was shown to be a versatile precursor for salt metathesis reactions to form heteroleptic complexes bearing alkoxide or silyl ligands. Alternatively, 1formed adducts with Lewis bases such as 4-dimethylaminopyridine (DMAP) that are paramagnetic, mononuclear species. The base-stabilized complex 5was alkylated with 1 or 2 equiv of LiCH2SiMe3to form mono- or dialkyl products, respectively. In contrast, treatment of complex 1in the absence of DMAP with 2 equiv of LiCH2SiMe3results in the ultimate formation of a dinuclear cyclometalated complex 9bearing a [Ti2(μ-Cl)2(μ:η1-CH2SiMe2CH2-)] core. This study demonstrates the convenient synthesis of a family of low-coordinate titanium(III) amido complexes possessing a variety of neutral and monoanionic ligands.

The randomized, controlled STOP-IgAN trial in patients with IgA nephropathy (IgAN) and substantial proteinuria showed no benefit of immunosuppression added on top of supportive care on renal function over three years. As a follow-up we evaluated renal outcomes in patients over a follow-up of up to ten years in terms of serum creatinine, proteinuria, end-stage kidney disease (ESKD), and death. The adapted primary endpoint was the time to first occurrence of a composite of death, ESKD, or a decline of over 40% in the estimated glomerular filtration rate (eGFR) compared to baseline at randomization into STOP-IgAN. Data were analyzed by Cox-regression models. Follow-up data were available for 149 participants, representing 92% of the patients originally randomized. Median follow-up was 7.4 years (inter quartile range 5.7 to 8.3 years). The primary endpoint was reached in 36 of 72 patients randomized to supportive care and 35 of 77 patients randomized to additional immunosuppression (hazard ratio 1.20; 95% confidence interval 0.75 to 1.92). ESKD occurred in 17 of the patients with supportive care and in 20 of the patients with additional immunosuppression. Additionally, the rates of eGFR loss over 40% and annual eGFR loss did not differ between groups. Two patients died with supportive care and three with additional immunosuppression. Thus, within the limitations of a retrospective study, over a follow-up of up to ten years, and using an adapted primary endpoint, we failed to detect differences in key clinical outcomes in IgAN patients randomized to receive added immunosuppression on top of supportive care versus supportive care alone.

Hintergrund: Vaskulitiden können zahlreiche unterschiedliche Organsysteme betreffen. Gastrointestinale Manifestationen kommen regelhaft bei Vaskulitiden vor und müssen spezifisch behandelt werden. Hepatitis-B/-C-Virus-Infektionen können bestimmte Vaskulitisformen auslösen. Ziel: Diese Übersichtarbeit beleuchtet die interdisziplinären Herausforderungen in der Diagnose und Therapie von Vaskulitiden. Schlussfolgerung: Insbesondere gastrointestinale Läsionen infolge einer ANCA(antineutrophile zytoplasmatische Antikörper)-Vaskulitis bedürfen einer konsequenten immunsuppressiven Behandlung, und infektiöse Komplikationen wie eine CMV(Zytomegalievirus)-Kolitis müssen von vaskulitischen Manifestationen unterschieden werden.

Supplemental Digital Content is available in the text.

Digital media have become increasingly important in recent years and can offer new possibilities for mathematics education in elementary schools. From our point of view, geometry and geometric objects seem to be suitable for the use of computer-aided design software in mathematics classes. Based on the example of Tinkercad, the use of CAD software — a new and challenging context in elementary schools — is discussed within the approach of domains of subjective experience and the Toulmin model. An empirical study examined the influence of Tinkercad on fourth-graders’ development of a model of a geometric solid and related reasoning processes in mathematics classes.

Supplemental Digital Content is available in the text.

This is a randomized trial (ATHENA study) in de novokidney transplant patients to compare everolimus versus mycophenolic acid (MPA) with similar tacrolimus exposure in both groups, or everolimus with concomitant tacrolimus or cyclosporine (CsA), in an unselected population. In this 12-month, multicenter, open-label study, de novokidney transplant recipients were randomized to everolimus with tacrolimus (EVR/TAC), everolimus with CsA (EVR/CsA) or MPA with tacrolimus (MPA/TAC), with similar tacrolimus exposure in both groups. Non-inferiority of the primary end point (estimated glomerular filtration rate [eGFR] at month 12), assessed in the per-protocol population of 338 patients, was not shown for EVR/TAC or EVR/CsA versus MPA/TAC. In 123 patients with TAC levels within the protocol-specified range, eGFR outcomes were comparable between groups. The mean increase in eGFR during months 1 to 12 post-transplant, analyzed post hoc, was similar with EVR/TAC or EVR/CsA versus MPA/TAC. The incidence of treatment failure (biopsy proven acute rejection, graft loss or death) was not significant for EVR/TAC but significant for EVR/CsA versus MPA/TAC. Most biopsy-proven acute rejection events in this study were graded mild (BANFF IA). There were no differences in proteinuria between groups. Cytomegalovirus and BK virus infection were significantly more frequent with MPA/TAC. Thus, everolimus with TAC or CsA showed comparable efficacy to MPA/TAC in de novokidney transplant patients. Non-inferiority of renal function, when pre-specified, was not shown, but the mean increase in eGFR from month 1 to 12 was comparable to MPA/TAC.

Background: Recent data demonstrate potentially protective pre-existing T cells reactive against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in samples of healthy blood donors, collected before the SARS-CoV-2 pandemic. Whether pre-existing immunity is also detectable in immunosuppressed patients is currently not known. Methods: Fifty-seven patients were included in this case–control study. We compared the frequency of SARS-CoV-2-reactive T cells in the samples of 20 renal transplant (RTx) patients to 20 age/gender matched non-immunosuppressed/immune competent healthy individuals collected before the onset of the SARS-CoV-2 pandemic. Seventeen coronavirus disease 2019 (COVID-19) patients were used as positive controls. T cell reactivity against Spike-, Nucleocapsid-, and Membrane- SARS-CoV-2 proteins were analyzed by multi-parameter flow cytometry. Antibodies were analyzed by neutralization assay. Results: Pre-existing SARS-CoV-2-reactive T cells were detected in the majority of unexposed patients and healthy individuals. In RTx patients, 13/20 showed CD4+T cells reactive against at least one SARS-CoV-2 protein. CD8+T cells reactive against at least one SARS-CoV-2 protein were demonstrated in 12/20 of RTx patients. The frequency and Th1 cytokine expression pattern of pre-formed SARS-CoV-2 reactive T cells did not differ between RTx and non-immunosuppressed healthy individuals. Conclusions: This study shows that the magnitude and functionality of pre-existing SARS-CoV-2 reactive T cell in transplant patients is non-inferior compared to the immune competent cohort. Although several pro-inflammatory cytokines were produced by the detected T cells, further studies are required to prove their antiviral protection. Graphic abstract:

Sequential treatment of Fe[N(SiMe3)DIPP]2(2) with Et3NHCl, IAd, and KC8(IAd = 1,3-diadamantyl-imidazolin-2-ylidene, DIPP = 2,6-diisopropylphenyl) results in the formation of two new complexes, (IAd)Fe[N(SiMe3)DIPP]2(3) and {(IAd)Fe[N(SiMe3)DIPP]}2(μ-N2) (4), via disproportionation and N2trapping of the intermediate species (IAd)Fe[N(SiMe3)DIPP] (A), respectively. Independent syntheses of complexes 3and 4were also developed. These results differ from those observed with the IPr-supported analogue (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene); a similar treatment of 2with Et3NHCl, IPr, and KC8results exclusively in the formation of the two-coordinate complex (IPr)Fe[N(SiMe3)DIPP] (1). DFT calculations show that the IAd–Fe[N(SiMe3)DIPP] interaction is weaker than the analogous IPr–Fe[N(SiMe3)DIPP] interaction by 10.6 kJ/mol. This difference appears to stem largely from greater steric repulsion and diminished dispersion stabilization in the IAd-containing transient species Ain comparison to 1.

Organometallic catalysts with strong metal-to-ligand charge-transfer (MLCT) optical transitions and reactive metal–hydride bonds provide opportunities for new excited-state reactivity. Toward this end, we have investigated photoinduced transfer hydrogenation reactions for a series of Cp*IrH complexes with functionalized bipyridyl ligands. Overcoming the baseline reactivity of this class of catalyst toward hydrogen evolution in aqueous media presents a major challenge for focusing this photochemical reactivity into desired transformations of more complex organic substrates. In this work, a photochemically induced aqueous ketone reduction catalyzed by [Cp*Ir(bpy)H][Cl] is reported and benchmarked to the competing hydrogen evolution reaction (HER). A detailed mechanistic study is conducted of the reduction of cyclohexanone with sodium formate delivering the reducing equivalent. Examining the kinetic profile of the cyclohexanone reduction revealed an unexpected induction period, suggesting a more complex underlying reaction mechanism where product selectivity was not simply a function of direct competition from a common excited-state reactive intermediate. The reaction kinetics were analyzed by variable time normalization analysis (VTNA), and the catalyst resting state was interrogated through operandolight-emitting diode (LED) illumination 1H NMR spectroscopy. These and other mechanistic studies provide insight into a photochemical reaction pathway to ketone reduction that is distinct from that previously reported for HER.

Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19.

Abstract:On the North Coast of British Columbia, First Nations face dozens of major industrial development proposals, including both crude oil and liquid natural gas pipelines and associated tanker traffic. In response to this overwhelming industrial expansion, First Nations have expanded their environmental stewardship programs to meaningfully engage in regulatory review, impacts research, and environmental monitoring. The Gitxaała First Nation provides an interesting case study of transforming such processes through integration of Gitxaała values into environmental assessment methodology and the application of Aboriginal rights and title. Protecting their territories against colonial intrusions and environmental change requires Gitxaała and their neighboring Nations to use Indigenous knowledge and collaborative governance institutions to limit and mitigate the impacts of these projects. For Indigenous societies under such extreme pressure, conservation is not only the achievement of higher or newer forms of protection, but simply maintaining the environmental status quo against encroaching industrial development. As other departments and programs engage in the selection of marine protected areas or developing conservancy management plans—recognizable conservation initiatives—in the face of rapid industrial development, the real frontline of Indigenous conservation can be considered engagement in regulatory review, the negotiation of impact benefit agreements, and long-term and cumulative effects monitoring. It is on the environmental assessment battleground that the unstoppable force of industrial development meets the immovable object of First Nations sovereignty and territorial protection, and where invisible but critical conservation wins are achieved.

Preventing the progression to acute respiratory distress syndrome (ARDS) in COVID-19 is an unsolved challenge. The involvement of T cell immunity in this exacerbation remains unclear. To identify predictive markers of COVID-19 progress and outcome, we analyzed peripheral blood of 10 COVID-19-associated ARDS patients and 35 mild/moderate COVID-19 patients, not requiring intensive care. Using multi-parametric flow cytometry, we compared quantitative, phenotypic, and functional characteristics of circulating bulk immune cells, as well as SARS-CoV-2 S-protein-reactive T cells between the two groups. ARDS patients demonstrated significantly higher S-protein-reactive CD4+and CD8+T cells compared to non-ARDS patients. Of interest, comparison of circulating bulk T cells in ARDS patients to non-ARDS patients demonstrated decreased frequencies of CD4+and CD8+T cell subsets, with activated memory/effector T cells expressing tissue migration molecule CD11a++. Importantly, survival from ARDS (4/10) was accompanied by a recovery of the CD11a++T cell subsets in peripheral blood. Conclusively, data on S-protein-reactive polyfunctional T cells indicate the ability of ARDS patients to generate antiviral protection. Furthermore, decreased frequencies of activated memory/effector T cells expressing tissue migratory molecule CD11a++observed in circulation of ARDS patients might suggest their involvement in ARDS development and propose the CD11a-based immune signature as a possible prognostic marker.

Pentacene’s extraordinary photophysical and electronic properties are highly dependent on intermolecular through-space interactions. Macrocyclic arrangements of chromophores have been shown to provide a high level of control over these interactions, but few examples exist for pentacene due to inherent synthetic challenges. In this work, zirconocene-mediated alkyne coupling was used as a dynamic covalent C–C bond forming reaction to synthesize two geometrically distinct, pentacene-containing macrocycles on a gram scale and in four or fewer steps. Both macrocycles undergo singlet fission in solution with rates that differ by an order of magnitude, while the rate of triplet recombination is approximately the same. This independent modulation of singlet and triplet decay rates is highly desirable for the design of efficient singlet fission materials. The dimeric macrocycle adopts a columnar packing motif in the solid state with large void spaces between pentacene units of the crystal lattice.

The new mineral species bohuslavite, Fe 4 3 + (PO4)3(SO4)(OH)(H2O)10·nH2O (5 = n = 14), has been discovered in the Buca della Vena baryte ± iron oxides ± pyrite ore deposit, Apuan Alps, Tuscany (Italy), and in the Horní Mesto deposit, northern Moravia (Czech Republic). It occurs as pinkish to lilac tabular {001} crystals, with a pseudohexagonal outline, up to 0.25 mm in size, forming globular aggregates up to 1 mm across. At both localities, it is associated with gypsum. Optically, bohuslavite is biaxial negative. Indices of refraction and 2V angles, measured with white light, are a = 1.537(2), ß = 1.567(1), ? = 1.568(1), 2V = 16(3)° and a = 1.550(2), ß = 1.579(2), ? = 1.579(1), 2V = 5–10° for the samples from Buca della Vena (BdV) and Horní Mesto (HM), respectively. Dispersion, with r > v, is slight in BdV sample and it was not observed in HM. In both cases, X ˜ c. No pleochroism was observed. Electron microprobe analyses gave (in wt% – mean of 10 spot analyses on each sample): SO3 10.92, P2O5 25.34, Al2O3 0.26, Fe2O3 40.70, H2O 35.96, total 113.18 (BdV), and SO3 9.32, P2O5 24.84, Al2O3 0.30, Fe2O3 36.63, H2O 32.49, total 103.58 (HM). The H2O contents were determined through thermo-gravimetric analyses. Mössbauer spectroscopy indicated that all iron occurs as Fe3+. Thus, the empirical formulae of bohuslavite, based on S(Fe,Al) = 4 atoms per formula unit (apfu), are (Fe3.96Al0.04)(PO4)2.77(SO4)1.06(OH)1.56(H2O)10·7.90H2O (BdV) and (Fe3.95Al0.05)(PO4)3.02(SO4)1.00(OH)0.94(H2O)10·5.08H2O (HM), ideally Fe 4 3 + (PO4)3(SO4)(OH)(H2O)10·nH2O. Bohuslavite is triclinic, space group P 1 ¯ , with a = 13.376(3), b = 13.338(3), c = 10.863(4) Å, a = 92.80(2), ß = 91.03(2), ? = 119.92(2)°, V = 1675.7(9) Å3, Z = 2 (sample BdV). The crystal structure was solved and refined to R 1 = 0.232 on the basis of 2177 unique reflections with F o > 4s (F o) and 208 refined parameters. Its crystal structure is based on {001} heteropolyhedral layers with composition [Fe4(PO4)3O(OH)(H2O)10]. These layers are decorated, on both sides, by SO4 groups. Additional H2O groups are hosted in the interlayers and in the [001] channels. The name bohuslavite honours the Czech mineralogist and geologist Bohuslav Fojt for his contributions to mineralogy and economic geology. A third occurrence of bohuslavite from the Jeremias Glück mine, Garnsdorf near Saalfeld, Thuringia (Germany), is briefly discussed.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by T-cell-dependent B-cell activation and altered T-cell response. Co-stimulatory and co-inhibitory molecules regulate and exert T-cell differentiation, survival and cytokine production. CD134+and PD-1+T-cells in SLE patients are increased in SLE. The aim of this study was to characterize CD134+and PD-1+CD4+T-cells according to their ability to produce IFN-γ, IL-21 and IL-22 in SLE patients. Peripheral blood of 39 SLE patients and 19 healthy controls (HC) was stimulated with phorbol myristate acetate (PMA) calcium ionophore (Ca-Io). The expression of IFN-γ, IL-21 and IL-22 T-cells within the CD134+and PD-1+T-cells was analyzed by flow cytometry. Disease activity was assessed by SLE Disease Activity Index. Peripheral unstimulated CD134+and PD-1+CD4+T-cells were significantly increased in patients with lupus nephritis. Upon stimulation both, CD134+and PD-1+CD4+T-cells, produced significantly less IFN-γ in SLE patients as compared to HC. The percentages of IL-22 within the CD134+CD4+T-cells were also significantly decreased in SLE as compared to HC. CD134+and PD-1+CD4+T-cells have mainly a Th1 effector T-cell signature. A lower proportion produces also IL-21 and IL-22. The impaired capacity to produce IFN-γ and IL-22 in SLE patients may contribute to the pathogenesis of the disease.

TRANSFORM (TRANSplant eFficacy and safety Outcomes with an eveRolimus-based regiMen) was a 24-month, prospective, open-label trial in 2037 de novo renal transplant recipients randomized (1:1) within 24 hours of transplantation to receive everolimus (EVR) with reduced-exposure calcineurin inhibitor (EVR + rCNI) or mycophenolate with standard-exposure CNI. Consistent with previously reported 12-month findings, noninferiority of the EVR + rCNI regimen for the primary endpoint of treated biopsy-proven acute rejection (tBPAR) or estimated glomerular filtration rate (eGFR) <50 mL/min per 1.73 m2was achieved at month 24 (47.9% vs 43.7%; difference = 4.2%; 95% confidence interval = −0.3, 8.7; P =.006). Mean eGFR was stable up to month 24 (52.6 vs 54.9 mL/min per 1.73 m2) in both arms. The incidence of de novo donor-specific antibodies (dnDSA) was lower in the EVR + rCNI arm (12.3% vs 17.6%) among on-treatment patients. Although discontinuation rates due to adverse events were higher with EVR + rCNI (27.2% vs 15.0%), rates of cytomegalovirus (2.8% vs 13.5%) and BK virus (5.8% vs 10.3%) infections were lower. Cytomegalovirus infection rates were significantly lower with EVR + rCNI even in the D+/R− high-risk group (P< .0001). In conclusion, the EVR + rCNI regimen offers comparable efficacy and graft function with low tBPAR and dnDSA rates and significantly lower incidence of viral infections relative to standard-of-care up to 24 months. Clinicaltrials.gov number: NCT01950819.

TRANSFORM(TRANSplant eFficacy and safety Outcomes with an eveRolimus‐based regiMen) was a 24‐month, prospective, open‐label trial in 2037 de novo renal transplant recipients randomized (1:1) within 24 hours of transplantation to receive everolimus (EVR) with reduced‐exposure calcineurin inhibitor (EVR+ rCNI) or mycophenolate with standard‐exposure CNI. Consistent with previously reported 12‐month findings, noninferiority of the EVR+ rCNIregimen for the primary endpoint of treated biopsy‐proven acute rejection (tBPAR) or estimated glomerular filtration rate (eGFR) <50 mL/min per 1.73 m2was achieved at month 24 (47.9% vs 43.7%; difference = 4.2%; 95% confidence interval = −0.3, 8.7; P = .006). Mean eGFRwas stable up to month 24 (52.6 vs 54.9 mL/min per 1.73 m2) in both arms. The incidence of de novo donor‐specific antibodies (dnDSA) was lower in the EVR+ rCNIarm (12.3% vs 17.6%) among on‐treatment patients. Although discontinuation rates due to adverse events were higher with EVR+ rCNI(27.2% vs 15.0%), rates of cytomegalovirus (2.8% vs 13.5%) and BKvirus (5.8% vs 10.3%) infections were lower. Cytomegalovirus infection rates were significantly lower with EVR+ rCNIeven in the D+/R− high‐risk group (P <.0001). In conclusion, the EVR+ rCNIregimen offers comparable efficacy and graft function with low tBPARand dnDSArates and significantly lower incidence of viral infections relative to standard‐of‐care up to 24 months. Clinicaltrials.gov number: NCT01950819. Two‐year follow‐up findings from TRANSFORM, the largest study in de novo renal transplantation to date, demonstrate that everolimus‐facilitated calcineurin inhibitor reduction provides a valid alternative to standard‐of‐care immunosuppression comprising mycophenolate with standard calcineurin inhibitor by offering comparable antirejection efficacy, stable renal function, and significant benefit in protecting from viral infections.

Identifying individual reactive intermediates within the “zoo” of organometallic species that form on catalytic surfaces during reactions is a long-standing challenge in heterogeneous catalysis. Here, we identify distinct reactive intermediates, all of which exist at low coverages, that lead to distinguishable reaction pathways during the hydrogenolysis of 2-methyltetrahydrofuran (MTHF) on Ni, Ni12P5, and Ni2P catalysts by combining advanced spectroscopic methods with quantum chemical calculations. Each of these reactive complexes cleaves specific C–O bonds, gives rise to unique products, and exhibits different apparent activation barriers for ring opening. The spectral features of the reactive intermediates are extracted by collecting in situ infrared spectra while sinusoidally modulating the H2pressure during MTHF hydrogenolysis and applying phase-sensitive detection (PSD), which suppresses the features of inactive surface species. The combined spectra of all reactive species are deconvoluted using singular-value decomposition techniques that yield spectra and changes in surface coverage for each set of kinetically differentiable species. These deconvoluted spectra are consistent with predicted spectral features for the reactive surface intermediates implicated by detailed kinetic measurements and DFT calculations. Notably, these methods give direct evidence for several anticipated differences in the coordination and composition of reactive MTHF-derived species. The compositions of the most abundant reactive intermediate (MARI) on Ni, Ni12P5, and Ni2P nanoparticles during the C–O bond rupture of MTHF are identical; however, MARI changes orientation from Ni3(μ3-C5H10O) to Ni3(η5-C5H10O) (i.e., lies more parallel with the catalyst surface) with increasing phosphorus content. The shift in binding configuration with phosphorus content suggests that the decrease in steric hindrance to rupture the 3C–O bond is the fundamental cause of increased selectivity toward 3C–O bond rupture. Previous kinetic measurements and DFT calculations indicate that C–O bond rupture occurs on Ni ensembles on Ni, Ni12P5, and Ni2P catalysts; however, the addition of more electronegative phosphorus atoms that withdraw a small charge from Ni ensembles results in differences in the binding configuration, activation enthalpy, and selectivity. The results from this in situ spectroscopic methodology support previous proposals that the manipulation of the electronic structure of metal ensembles by the introduction of phosphorus provides strategies for designing catalysts for the selective cleavage of hindered C–X bonds and demonstrate the utility of this approach in identifying individual reactive species within the zoo.

AbstractObjective:This study was done to determine the relationship between pre-procedural anaemia and mortality post transcatheter aortic valve replacement (TAVR).Introduction:TAVR is now a treatment option for patients with severe aortic stenosis (AS) with high surgical risk. Anaemia is a common comorbidity in the TAVR population. Small studies have suggested that anaemia is associated with worse short-term and long-term mortality in patients who underwent TAVR. However, there are no meta-analyses to further assess this association.Method:Studies were systematically searched from electronic databases (EMBASE and MEDLINE). Inclusion criteria were adult population with aortic stenosis who underwent TAVR, and number of patients with pre-procedural anaemia reported. Outcomes were short-term mortality or long-term mortality. Pooled effect size was calculated with a random-effect model, weighted for the inverse of variance. Heterogeneity was assessed with I2.Results:Six studies were included in the final analysis. Of these, pooled analysis of four studies examining association between anaemia and 30-day mortality did not show a statistically significant relationship. A pooled analysis of four studies examining the association of anaemia and long-term mortality after TAVR showed pooled adjusted risk ratio (RR) of 1.43, 95% CI 1.22–1.67 with low heterogeneity (I2 = 33%). Subgroup analysis after exclusion of one smaller study showed that the association remained significant (RR 1.41, 95% CI 1.27–1.56) with decreased heterogeneity (I2 = 0%).Conclusion:This systematic review and meta-analysis found an association between pre-procedural anaemia and increased long-term but not short-term mortality after TAVR. Further study of the pathophysiology underlying this association is needed.

Histopathological differentiation between severe urocystitis with reactive urothelial atypia and carcinoma in situ(CIS) can be difficult, particularly after a treatment that deliberately induces an inflammatory reaction, such as intravesical instillation of Bacillus Calmette-Guèrin. However, precise grading in bladder cancer is critical for therapeutic decision making and thus requires reliable immunohistochemical biomarkers. Herein, an exemplary potential biomarker in bladder cancer was identified by the novel approach of Fourier transform infrared imaging for label-free tissue annotation of tissue thin sections. Identified regions of interest are collected by laser microdissection to provide homogeneous samples for liquid chromatography–tandem mass spectrometry–based proteomic analysis. This approach afforded label-free spatial classification with a high accuracy and without interobserver variability, along with the molecular resolution of the proteomic analysis. Cystitis and invasive high-grade urothelial carcinoma samples were analyzed. Three candidate biomarkers were identified and verified by immunohistochemistry in a small cohort, including low-grade urothelial carcinoma samples. The best-performing candidate AHNAK2 was further evaluated in a much larger independent verification cohort that also included CIS samples. Reactive urothelial atypia and CIS were distinguishable on the basis of the expression of this newly identified and verified immunohistochemical biomarker, with a sensitivity of 97% and a specificity of 69%. AHNAK2 can differentiate between reactive urothelial atypia in the setting of an acute or chronic cystitis and nonmuscle invasive-type CIS.

A general synthetic strategy for the construction of large, nitrogen-containing polycyclic aromatic hydrocarbons (PAHs) is reported. The strategy involves two key steps: (1) a titanocene-mediated reductive cyclization of an oligo(dinitrile) precursor to form a PAH appended with di(aza)titanacyclopentadiene functionality; (2) a divergent titanocene transfer reaction, which allows final-step installation of one or more o-quinone, diazole, or pyrazine units into the PAH framework. The new methodology enables rational, late-stage control of HOMO and LUMO energy levels and thus photophysical and electrochemical properties, as revealed by UV/vis and fluorescence spectroscopy, cyclic voltammetry, and DFT calculations. More generally, this contribution presents the first productive use of di(aza)metallacyclopentadiene intermediates in organic synthesis, including the first formal [2 + 2 + 2] reaction to form a pyrazine ring.