On Chemical Bonding in ht-Ga3Rh and Its Effect on Structural Organization and Thermoelectric Behavior.

In the course of systematic studies of intermetallic compounds Ga3TM (TM─transition metal), the compound Ga3Rh is synthesized by direct reaction of the elements at 700 °C. The material obtained is characterized as a high-temperature modification of Ga3Rh. Powder and single-crystal X-ray diffraction analyses reveal tetragonal symmetry (space group P42/mnm, No. 146) with a = 6.4808(2) Å and c = 6.5267(2) Å. Large values and strong anisotropy of the atomic displacement parameters of Ga atoms indicate essential disorder in the crystal structure. A split-position technique is applied to describe the real crystal structure of ht-Ga3Rh. Bonding analysis in ht-Ga3Rh performed on ordered models with the space groups P1̅, P42nm, and P42212 shows, besides the omnipresent heteroatomic Ga-Rh bonds in the rhombic prisms ∞3[Ga8/2Rh2], the formation of homoatomic Ga-Ga bonds bridging the Rh-Rh contacts and the absence of significant Rh-Rh bonding. These features are essential reasons for the experimentally observed disorder in the lattice. In agreement with the calculated electronic density of states, ht-Ga3Rh shows temperature-dependent electrical resistivity of a "bad metal". The very low lattice thermal conductivity of less than 0.5 W m-1 K-1 at 300 K, being lower than those for most other Ga3TM compounds, correlates with the enhanced bonding complexity.

Safety, tolerability, and pharmacokinetics of single- and multiple-ascending doses of olamkicept: Results from randomized, placebo-controlled, first-in-human phase I trials.

Olamkicept selectively inhibits the cytokine interleukin-6 (IL-6) trans-signaling pathway without blocking the classic pathway and is a promising immunoregulatory therapy for inflammatory bowel disease (IBD). These first-in-human, randomized, placebo-controlled, single- (SAD) and multiple-ascending dose (MAD) trials evaluated olamkicept safety, tolerability, pharmacokinetic, and pharmacodynamic characteristics. Doses tested in the SAD trial included seven single intravenous doses (0.75, 7.5, 75, 150, 300, 600, and 750 mg) and one subcutaneous (SC) dose (60 mg) given to healthy subjects (N = 64), and three intravenous doses (75 mg, 300 mg, and 750 mg) given to patients with Crohn's disease (CD; N = 24). Doses tested in the MAD trial included multiple intravenous doses (75, 300, and 600 mg once weekly for 4 weeks) given to healthy subjects (N = 24). No severe or serious treatment-emergent adverse events (TEAEs) were recorded. The most common TEAEs were headache, nasopharyngitis, and myalgia in the SAD trial, and diarrhea, headache, and cough in the MAD trial. Infusion-related reactions occurred in one and two subjects in the SAD and MAD trial, respectively, leading to treatment discontinuation in the MAD trial. Olamkicept showed dose-independent pharmacokinetics after single and multiple administrations, and there was no major difference in systemic exposure between healthy subjects and patients with CD. Complete target engagement (inhibition of phosphorylation of signal transducer and activator of transcription-3) was achieved in blood around or above olamkicept serum concentrations of 1-5 µg/mL. Overall, these results suggest that olamkicept is safe and well-tolerated in healthy subjects and patients with CD after single intravenous/SC and multiple intravenous administrations.

The Effect of Various Degrees of Renal or Hepatic Impairment on the Pharmacokinetic Properties of Once-Weekly Insulin Icodec.

BACKGROUND AND OBJECTIVE: Icodec is a once-weekly insulin being developed to provide basal insulin coverage in diabetes mellitus. This study evaluated the effects of renal or hepatic impairment on icodec pharmacokinetics. METHODS: Two open-label, parallel-group, single-dose (1.5 U/kg subcutaneously) trials were conducted. In a renal impairment trial, 58 individuals were allocated to normal renal function (measured glomerular filtration rate ≥ 90 mL/min), mild (60 to < 90 mL/min), moderate (30 to < 60 mL/min) or severe (< 30 mL/min) renal impairment or end-stage renal disease. In a hepatic impairment trial, 25 individuals were allocated to normal hepatic function or mild (Child-Pugh Classification grade A), moderate (grade B) or severe (grade C) hepatic impairment. Blood was sampled frequently for a pharmacokinetic analysis until 35 days post-dose. RESULTS: The shape of the icodec pharmacokinetic profile was not affected by renal or hepatic impairment. Total icodec exposure was greater for mild (estimated ratio [95% confidence interval]: 1.12 [1.01; 1.24]), moderate (1.24 [1.12; 1.37]) and severe (1.28 [1.16; 1.42]) renal impairment, and for end-stage renal disease (1.14 [1.03; 1.28]), compared with normal renal function. It was also greater for mild (1.13 [1.00; 1.28]) and moderate (1.15 [1.02; 1.29]) hepatic impairment versus normal hepatic function. There was no statistically significant difference between severe hepatic impairment and normal hepatic function. Serum albumin levels (range 2.7-5.1 g/dL) did not statistically significantly influence icodec exposure. CONCLUSIONS: The clinical relevance of the slightly higher icodec exposure with renal or hepatic impairment is limited as icodec should be dosed according to individual need. No specific icodec dose adjustment is required in renal or hepatic impairment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT03723785 and NCT04597697.

IA-PACS-CFS: a double-blinded, randomized, sham-controlled, exploratory trial of immunoadsorption in patients with chronic fatigue syndrome (CFS) including patients with post-acute COVID-19 CFS (PACS-CFS).

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severely debilitating condition which markedly restricts activity and function of affected people. Since the beginning of the COVID-19 pandemic ME/CFS related to post-acute COVID-19 syndrome (PACS) can be diagnosed in a subset of patients presenting with persistent fatigue 6 months after a mostly mild SARS-CoV-2 infection by fulfillment of the Canadian Consensus Criteria (CCC 2003). Induction of autoimmunity after viral infection is a mechanism under intensive investigation. In patients with ME/CFS, autoantibodies against thyreoperoxidase (TPO), beta-adrenergic receptors (ß2AR), and muscarinic acetylcholine receptors (MAR) are frequently found, and there is evidence for effectiveness of immunomodulation with B cell depleting therapy, cyclophosphamide, or intravenous immunoglobulins (IVIG). Preliminary studies on the treatment of ME/CFS patients with immunoadsorption (IA), an apheresis that removes antibodies from plasma, suggest clinical improvement. However, evidence from placebo-controlled trials is currently missing. METHODS: In this double-blinded, randomized, sham-controlled, exploratory trial the therapeutic effect of five cycles of IA every other day in patients with ME/CFS, including patients with post-acute COVID-19 chronic fatigue syndrome (PACS-CFS), will be evaluated using the validated Chalder Fatigue Scale, a patient-reported outcome measurement. A total of 66 patients will be randomized at a 2:1 ratio: 44 patients will receive IA (active treatment group) and 22 patients will receive a sham apheresis (control group). Moreover, safety, tolerability, and the effect of IA on patient-reported outcome parameters, biomarker-related objectives, cognitive outcome measurements, and physical parameters will be assessed. Patients will be hospitalized at the clinical site from day 1 to day 10 to receive five IA treatments and medical visits. Four follow-up visits (including two visits at site and two visits via telephone call) at month 1 (day 30), 2 (day 60), 4 (day 120), and 6 (day 180; EOS, end of study visit) will take place. DISCUSSION: Although ME/CFS including PACS-CFS causes an immense individual, social, and economic burden, we lack efficient therapeutic options. The present study aims to investigate the efficacy of immunoadsorption and to contribute to the etiological understanding and establishment of diagnostic tools for ME/CFS. TRIAL REGISTRATION: Registration Number: NCT05710770 . Registered on 02 February 2023.

Ordering by cation replacement in the system Na2-xLixGa7.

Samples of the pseudo-binary system Na2-xLixGa7 (x ≤ 1) were synthesized from the elements at 300 °C in sealed Ta ampoules or by the reaction of Na2Ga7 with LiCl. The peritectic formation temperature decreases with increasing Li content from 501(2) °C (x = 0) to 489(2) °C (x = 1). The boundary compositions Na2Ga7 and Na1Li1Ga7 crystallize with different structure types related by a group-subgroup relation. While the Na-rich compositions (x ≤ 0.5) represent a substitutional solid solution (space group Pnma), the Li-rich compositions feature an unconventional replacement mechanism in which Li atoms occupying interstitial positions induce vancancies at the Na positions (space group Cmce). The crystal structure of Na1Li1Ga7 (a = 8.562(1) Å, b = 14.822(2) Å, c = 11.454(2) Å; Z = 8) was determined from X-ray single-crystal diffraction data, and reveals an anionic framework comprising 12-bonded Ga12 icosahedra and 4-bonded Ga atoms, with alkali-metal atoms occupying channels and cavities. The arrangement of cations makes NaLiGa7 a new structure type within the MgB12Si2 structure family. Band structure calculations for the composition NaLiGa7 predict semiconducting behavior consistent with the balance [Na+]2[Li+]2[(Ga12)2-][Ga-]2, considering closo Wade clusters [(12b)Ga12]2- and Zintl anions [(4b)Ga]-. Susceptibility measurements indicate temperature-independent diamagnetic behavior.

Polarity-extended 8 - Neff rule for semiconducting main-group compounds with the TiNiSi-type of crystal structure.

Application of chemical bonding analysis in position-space techniques based on combined topological analysis of the electron density and electron-localizability indicator distributions has recently led to the formulation of a polarity-extended 8 - Neff rule for consistent inclusion of quantum chemically obtained polar-covalent bonding data into the classical 8 - N scheme for main-group compounds. Previous application of this scheme to semiconducting main-group compounds of the cubic MgAgAs type of structure with 8 valence electrons per formula unit (8 ve per f.u.) has shown a covalent bonding tendency preferring one zinc blende type partial structure over the other one, which seems to corroborate the classical Lewis picture of maximally four covalent bonds per main-group element. In contrast to the MgAgAs type, the orthorhombic TiNiSi type of structure displays a much higher geometrical flexibility to incorporate different kinds of metal atoms. The analysis of polar-covalent bonding in semiconducting 8 ve per f.u. containing main-group compounds AA'E of this structure type reveals a transition to non-Lewis type bonding scenarios of species E with up to ten polar-covalently bonded metal atoms. This kind of situation is consistently included into the extended 8 - Neff type bonding scheme. A systematic increase of partially covalent bonding from chalcogenides E16 to the tetrelides E14 is found, summing up to as much as 2 covalent bonds E14-A and E14-A', and correspondingly remaining 4 lone pair type electrons on species E14. The familiar notion of this structure type consisting of a '[NiSi]'-type framework with 'Ti'-type atoms filling the voids cannot be supported for the compounds investigated.

Fourier-synthesis approach for static charge-density reconstruction from theoretical structure factors of CaB6.

In a pilot study, electron-density (ED) and ED Laplacian distributions were reconstructed for the challenging case of CaB6 (Pearson symbol cP7) with conceptually fractional B-B bonds from quantum-chemically calculated structure-factor sets with resolutions 0.5 Å-1 ≤ [sin(θ)/λ]max ≤ 5.0 Å-1 by means of Fourier-synthesis techniques. Convergence of norm deviations of the distributions obtained with respect to the reference ones was obtained in the valence region of the unit cell. The QTAIM (quantum theory of atoms in molecules) atomic charges, and the ED and ED Laplacian values at the characteristic critical points of the Fourier-synthesized distributions have been analysed for each resolution and found to display a convergent behaviour with increasing resolution. The presented method(exponent) (ME) type of Fourier-synthesis approach can qualitatively reconstruct all characteristic chemical bonding features of the ED from valence-electron structure-factor sets with resolutions of about 1.2 Å-1 and beyond, and from all-electron structure-factor sets with resolutions of about 2.0 Å-1 and beyond. Application of the ME type of Fourier-synthesis approach for reconstruction of ED and ED Laplacian distributions at experimental resolution is proposed to complement the usual extrapolation to infinite resolution in Hansen-Coppens multipole model derived static ED distributions.

Dose escalation randomised study of efmarodocokin alfa in healthy volunteers and patients with ulcerative colitis.

BACKGROUND: The interleukin-22 cytokine (IL-22) has demonstrated efficacy in preclinical colitis models with non-immunosuppressive mechanism of action. Efmarodocokin alfa (UTTR1147A) is a fusion protein agonist that links IL-22 to the crystallisable fragment (Fc) of human IgG4 for improved pharmacokinetic characteristics, but with a mutation to minimise Fc effector functions. METHODS: This randomised, phase 1b study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of repeat intravenous dosing of efmarodocokin alfa in healthy volunteers (HVs; n=32) and patients with ulcerative colitis (n=24) at 30-90 µg/kg doses given once every 2 weeks or monthly (every 4 weeks) for 12 weeks (6:2 active:placebo per cohort). RESULTS: The most common adverse events (AEs) were on-target, reversible, dermatological effects (dry skin, erythema and pruritus). Dose-limiting non-serious dermatological AEs (severe dry skin, erythema, exfoliation and discomfort) were seen at 90 µg/kg once every 2 weeks (HVs, n=2; patients, n=1). Pharmacokinetics were generally dose-proportional across the dose levels, but patients demonstrated lower drug exposures relative to HVs at the same dose. IL-22 serum biomarkers and IL-22-responsive genes in colon biopsies were induced with active treatment, and microbiota composition changed consistent with a reversal in baseline dysbiosis. As a phase 1b study, efficacy endpoints were exploratory only. Clinical response was observed in 7/18 active-treated and 1/6 placebo-treated patients; clinical remission was observed in 5/18 active-treated and 0/6 placebo-treated patients. CONCLUSION: Efmarodocokin alfa had an adequate safety and pharmacokinetic profile in HVs and patients. Biomarker data confirmed IL-22R pathway activation in the colonic epithelium. Results support further investigation of this non-immunosuppressive potential inflammatory bowel disease therapeutic. TRIAL REGISTRATION NUMBER: NCT02749630.

Polycation-Polyanion Architecture of the Intermetallic Compound Mg3-xGa1+xIr.

Mg3-xGa1+xIr (x = 0.05) was synthesized by direct reaction of the elements in welded tantalum containers at 1200 °C and subsequent annealing at 500 °C for 30 days. Its crystal structure represents a new prototype and was determined by single-crystal technique as follows: space group P63/mcm, Pearson symbol hP90, Z = 18, a = 14.4970(3) Å, c = 8.8638(3) Å. The composition and atomic arrangement in Mg3GaIr do not follow the 8-N rule due to the lack of valence electrons. Based on chemical bonding analysis in positional space, it was shown that the title compound has a polycationic-polyanionic organization. In comparison with other known intermetallic substances with this kind of bonding pattern, both the polyanion and the polyanion are remarkably complex. Mg3-xGa1+xIr is an example of how the general organization of intermetallic substances (e.g., formation of polyanions and polycations) can be understood by extending the principles of 8-N compounds to electron-deficient materials with multi-atomic bonding.

Interacting Quantum Atoms Method for Crystalline Solids.

An implementation of the Interacting Quantum Atoms method for crystals is presented. It provides a real space energy decomposition of the energy of crystals in which all energy components are physically meaningful. The new package ChemInt enables one to compute intra-atomic and inter-atomic energies, as well as electron population measures used for quantitative description of chemical bonds in crystals. The implementation is tested and applied to characteristic molecular and crystalline systems with different types of bonding.

Beam-size effects on the measurement of sub-picosecond intrinsic laser induced damage threshold of dielectric oxide coatings.

Laser-induced damage experiments on HfO2 and Nb2O5 thin films were performed with 500 fs pulse duration at 1030 nm wavelength. Threshold fluences as a function of beam size have been determined for effective beam diameters ranging from 40 to 220 µm, in a single shot regime. The results suggest no beam-size effect related to material properties in the investigated range, but size effects related to the metrology. The results indicate the importance of appropriate focusing conditions and beam measurement to qualify the optics for use in lasers with large beam sizes.

A Randomised, Controlled Trial: Effect of a Multi-Strain Fermented Milk on the Gut Microbiota Recovery after Helicobacter pylori Therapy.

Helicobacter pylori (Hp) eradication therapy alters gut microbiota, provoking gastrointestinal (GI) symptoms that could be improved by probiotics. The study aim was to assess the effect in Hp patients of a Test fermented milk containing yogurt and Lacticaseibacillus (L. paracasei CNCM I-1518 and I-3689, L. rhamnosus CNCM I-3690) strains on antibiotic associated diarrhea (AAD) (primary aim), GI-symptoms, gut microbiota, and metabolites. A randomised, double-blind, controlled trial was performed on 136 adults under 14-day Hp treatment, receiving the Test or Control product for 28 days. AAD and GI-symptoms were reported and feces analysed for relative and quantitative gut microbiome composition, short chain fatty acids (SCFA), and calprotectin concentrations, and viability of ingested strains. No effect of Test product was observed on AAD or GI-symptoms. Hp treatment induced a significant alteration in bacterial and fungal composition, a decrease of bacterial count and alpha-diversity, an increase of Candida and calprotectin, and a decrease of SCFA concentrations. Following Hp treatment, in the Test as compared to Control group, intra-subject beta-diversity distance from baseline was lower (padj = 0.02), some Enterobacteriaceae, including Escherichia-Shigella (padj = 0.0082) and Klebsiella (padj = 0.013), were less abundant, and concentrations of major SCFA (p = 0.035) and valerate (p = 0.045) were higher. Viable Lacticaseibacillus strains were detected during product consumption in feces. Results suggest that, in patients under Hp treatment, the consumption of a multi-strain fermented milk can induce a modest but significant faster recovery of the microbiota composition (beta-diversity) and of SCFA production and limit the increase of potentially pathogenic bacteria.

Licogliflozin versus placebo in women with polycystic ovary syndrome: A randomized, double-blind, phase 2 trial.

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and insulin resistance. The dual sodium-glucose co-transporter 1/2 inhibitor (SGLT1/2i) licogliflozin (LIK066) ameliorates hyperinsulinism in patients with diabetes and obesity. This study examines the effect of licogliflozin on androgens in women with PCOS. In a multicentre, randomized, placebo-controlled, double-blind, 2-week trial, patients with PCOS received licogliflozin 50 mg or placebo three times a day (TID). Changes in free testosterone (FT), other androgens and variables of insulin resistance were analysed. Concentration of FT did not change (TRLIK066 :TRPCB [FT]: 0.88; 90% CI: 0.70-1.11; P = .353). Licogliflozin reduced androstendione (A4) by 19% (TRLIK066 :TRPCB [A4]: 0.81; 90% CI: 0.68-0.99; P = .089) and dehydroepiandrosteron sulphate (DHEAS) by 24% (TRLIK066 :TRPCB [DHEAS]: 0.76; 90% CI: 0.65-0.89; P = .008). Hyperinsulinaemia was reduced by 70% by licogliflozin (highest insulin concentration [MAXI]; TRLIK066 :TRPCB [MAXI]: 0·26; 90% CI:0.20-0.34; P < .001 and area under the curve insulin [AUCI]; TRLIK066 :TRPCB [AUCI]: 0.32; 90% CI: 0.25-0.41; P < .001). Diarrhoea and nausea occurred as common adverse events. Dual inhibition of SGLT1/2 ameliorates hyperinsulinaemia and hyperandrogenaemia in women with PCOS. Licogliflozin may represent a promising novel treatment option for PCOS.

Beam quality and efficiency of ns-pulsed high-power mid-IR ZGP OPOs compared in linear and non-planar ring resonators.

We compare the performance of ns-pulsed mid-infrared optical parametric oscillators (OPOs) based on ZGP crystals in a simple linear cavity and two non-planar image-rotating resonators. Our 2 µm pump source is a 68 W 10 kHz diffraction limited Ho:LLF MOPA system. In a linear cavity, it allows us to generate up to 38 W of the total average power with M2<2.2 from the ZGP OPO in the 3-5 µm range. Beam quality and stability are significantly improved in both types of non-planar ring resonators (M2<1.8 in RISTRA and M2<1.4 in FIRE), while the total average power is above 21 W. Factors influencing the beam quality such as average power and pump repetition rate are studied in detail.

Tricyanidoferrates(-IV) and Ruthenates(-IV) with Non-Innocent Cyanido Ligands.

Exceptionally electron-rich, nearly trigonal-planar tricyanidometalate anions [Fe(CN)3 ]7- and [Ru(CN)3 ]7- were stabilized in LiSr3 [Fe(CN)3 ] and AE3.5 [M(CN)3 ] (AE=Sr, Ba; M=Fe, Ru). They are the first examples of group 8 elements with the oxidation state of -IV. Microcrystalline powders were obtained by a solid-state route, single crystals from alkali metal flux. While LiSr3 [Fe(CN)3 ] crystallizes in P63 /m, the polar space group P63 with three-fold cell volume for AE3.5 [M(CN)3 ] is confirmed by second harmonic generation. X-ray diffraction, IR and Raman spectroscopy reveal longer C-N distances (124-128 pm) and much lower stretching frequencies (1484-1634 cm-1 ) than in classical cyanidometalates. Weak C-N bonds in combination with strong M-C π-bonding is a scheme also known for carbonylmetalates. Instead of the formal notation [Fe-IV (CN- )3 ]7- , quantum chemical calculations reveal non-innocent intermediate-valent CN1.67- ligands and a closed-shell d10 configuration for Fe, that is, Fe2- .

Resumé of the challenges and burden of living with transplanted hearts for >31 years.

Heart transplantation has extended the lives of many patients with end-stage heart failure. Although beset with the arduous aftermaths of immunosuppression, those who survived live meaningful lives similar to that of the general population. In this series, heart transplantation has led to a considerable extension of life span of >31-34 years. Development of cardiac allograft vasculopathy is a major concern in the long-term follow-up of transplant patients. Immunosuppressive drugs have a major impact on the development and progression of cardiac allograft vasculopathy and the main cause of cardiac allograft loss after the first post-transplantation year. Post-transplant neoplasia remains a challenging long-term problem for patients after orthotopic heart transplantation. Post-transplant lymphoproliferative disease appears to be largely the result of the effectiveness of current agents used for long-term immunosuppression, and the neoplasms typically harbor the Epstein Barr virus genome, which is presumed to play a major role in neoplastic transformation. Post-transplantation, new diseases may occur or there may be worsening of pre-existing diseases. By the end of the 5th year, all suffered from hypertension. Renal insufficiency developed within 5 years after transplantation, and 10% have a creatinine value of >2.5 mg/dL. Hyperlipidemia, mostly hypercholesterolemia occurs especially in patients on tacrolimus or everolimus. Quality of life is not impaired despite somatic problems. In this period >31 years post-post-orthotopic heart transplantation, they even reported a surprising increase in their emotional well-being. The 10 patients are active and satisfied with their daily lives. They regard their own life as meaningful, have good families and active social relations. Nonetheless, it is burdened by chronic allograft vasculopathy and immunosuppression sequelae, the main limiting factors for survival, which needed to be constantly addressed throughout their lifetime. This brief report provides an insight into the challenges and burden patients living >31 years with transplanted hearts are confronted with.

Organ-saving surgical alternatives to treatment of heart failure.

Over time, various surgical treatment strategies have evolved to manage advanced heart failure (HF). Scientific and technological breakthroughs through the last 50 years have put forward various surgical alternatives to patients with advanced HF encompassing surgical ventricular restoration to surgical gene therapy and stem cell replacement of the diseased ventricles. Organ-saving surgical options which used to be promising included dynamic cardiomyoplasty, partial resection of ventricle and cardiac wrapping with Acorn CorCap cardiac support device. These procedures were eventually abandoned due to negative outcomes and without proven disadvantages. Another organ-saving surgical option currently being considered but still make little sense is cardiac regeneration by stem cell therapy, i.e., cardiomyocyte restoration and replacement. Presently, the organ-saving surgical alternatives to treat end-stage HF are revascularization for ischemic cardiomyopathy, mitral valve surgery (repair or replacement) for ischemic mitral incompetence (IMI), left ventricular (LV) aneurysmectomy (surgical ventricular restoration) and mitral valve repair for IMI. These aforementioned procedures have become quite established approaches and with increasing experience are continuously being modified to improve outcome. Various mechanical circulatory support systems have emerged over time to improve functional status of patients with advanced HF, either as a bridge to heart transplantation or as a bridge to myocardial recovery. Likewise offered in those with contraindications to transplantation. Ventricular assist devices (VAD) can keep patients alive until an eventual transplantation. This article reviews the variety of the myriad of alternative organ-saving surgical alternatives that have been available or are currently available provided to patients with end-stage HF, their advantages and deficiencies, as well as prospects in HF therapy.

Efficacy and safety of single- and repeated-selurampanel dosing for 2 weeks in patients with chronic subjective tinnitus: Results of a randomized, double-blind, placebo-controlled, cross-over, proof-of-concept phase IIa study.

To evaluate efficacy and safety of BGG492 (selurampanel; an orally active, competitive AMPA glutamate receptor antagonist) in patients with moderate-to-catastrophic chronic subjective tinnitus. Study (NCT01302873) enrolled patients with subjective tinnitus based on THI severity grade 3, 4 or 5 (moderate, severe or catastrophic), and those with chronic (>6 and <36 months) tinnitus. Primary endpoints were clinical status of tinnitus using TBF-12 and tinnitus loudness using VAS after multiple dose 2-week BGG492 treatment. Safety was assessed by recording all adverse events (AEs). After a single dose of BGG492 VAS scores for tinnitus loudness (P=0.012) and tinnitus annoyance (P=0.004) were significantly reduced vs placebo. After 2 weeks treatment a significantly greater proportion of patients showed improvement of ≥4 points from baseline in TBF-12 (stringent responder definition) with BGG492 vs placebo (26.7% [n=23] vs 14% [n=12], respectively; odds ratio [OR] (90% CI):2.30 (1.10, 4.83); P=0.064), fulfilling proof-of-concept achievement criteria. No notable difference in proportion of responders to BGG492 vs placebo was observed as assessed using VAS (26.7% [n=23] vs 27.6% [n=24], respectively; OR (90% CI):0.94 (0.52, 1.67); P=0.848). Dizziness was the most frequently reported AE in 50% [n=21] and 31.5% [n=17] patients on BGG492 100 and 50mg TID, respectively vs 9.6% [n=9] on placebo. In conclusion, BGG492 showed reduction of both tinnitus loudness and annoyance after a single dose and reduction of tinnitus handicap after 2 weeks of treatment in patients with chronic subjective tinnitus, thereby supporting further clinical investigation of AMPA receptor antagonists with an improved benefit/risk ratio. A dose of 100mg TID BGG492 showed higher efficacy but somewhat lower tolerability compared to 50mg TID.

"Excess" electrons in LuGe.

The monogermanide LuGe is obtained via high-pressure high-temperature synthesis (5-15 GPa, 1023-1423 K). The crystal structure is solved from single-crystal X-ray diffraction data (structure type FeB, space group Pnma, a=7.660(2) Å, b=3.875(1) Å, and c=5.715(2) Å, RF =0.036 for 206 symmetry independent reflections). The analysis of chemical bonding applying quantum-chemical techniques in position space was performed. It revealed-beside the expected 2c-Ge-Ge bonds in the germanium polyanion-rather unexpected four-atomic bonds between lutetium atoms indicating the formation of a polycation by the excess electrons in the system Lu3+ (2b)Ge2- ×1 e- . Despite the reduced VEC of 3.5, lutetium monogermanide is following the extended 8-N rule with the trend to form lutetium-lutetium bonds utilizing the electrons left after satisfying the bonding needs in the anionic Ge-Ge zigzag chain.

Ianalumab (VAY736) in primary Sjögren's syndrome: assessing disease activity using multi-modal ultrasound.

OBJECTIVES: To apply serial ultrasound (US) assessments to show effects of ianalumab (anti-BAFF-R monoclonal antibody) on inflamed salivary glands of patients with primary Sjögren's syndrome (pSS). METHODS: In a single-centre, 24-week double-blind study (NCT02149420), 27 pSS patients of moderate-to-severe activity were randomly assigned to receive a single i.v. dose of either 3 mg/kg or 10 mg/kg ianalumab, or placebo. Concurrent with clinical and laboratory outcomes, multi-modal US images were acquired of bilateral parotid glands (PG) and submandibular glands (SMG) at weeks 0, 6, 12, and 24. Applied US modalities included 1) B-mode echostructure scored by de Vita classification, 2) macrovascular blood flow by power Doppler, and in PG only 3) microvascularisation using contrast-enhanced US (area under the curve, time to peak or TTP) and 4) gland stiffness by sonoelastography. RESULTS: Clinical study results were previously published. US data for PG differed from SMG but were comparable between respective left and right sides of these glands. Numerical improvements in salivary gland quality and declining tissue inflammation were observed in treated versus placebo groups, including more patients achieving ≥1-point reduction from baseline in De Vita score, together with trends towards decreased perfusion and stiffness. Correlations between clinical endpoints and US parameters were largely restricted to microvascular perfusion TTP and at the 12-week timepoint when ianalumab effects were predicted at maximal. CONCLUSIONS: Early in vivo signs of salivary gland improvement in response to an effective intervention can be shown without need of biopsy by using a non-invasive, comprehensive, ultrasound-based approach over multiple time points.