Electron Glass Phase with Resilient Zhang-Rice Singlets in LiCu_{3}O_{3}.

LiCu_{3}O_{3} is an antiferromagnetic mixed valence cuprate where trilayers of edge-sharing Cu(II)O (3d^{9}) are sandwiched in between planes of Cu(I) (3d^{10}) ions, with Li stochastically substituting Cu(II). Angle-resolved photoemission spectroscopy (ARPES) and density functional theory reveal two insulating electronic subsystems that are segregated in spite of sharing common oxygen atoms: a Cu d_{z^{2}}/O p_{z} derived valence band (VB) dispersing on the Cu(I) plane, and a Cu 3d_{x^{2}-y^{2}}/O 2p_{x,y} derived Zhang-Rice singlet (ZRS) band dispersing on the Cu(II)O planes. First-principle analysis shows the Li substitution to stabilize the insulating ground state, but only if antiferromagnetic correlations are present. Li further induces substitutional disorder and a 2D electron glass behavior in charge transport, reflected in a large 530 meV Coulomb gap and a linear suppression of VB spectral weight at E_{F} that is observed by ARPES. Surprisingly, the disorder leaves the Cu(II)-derived ZRS largely unaffected. This indicates a local segregation of Li and Cu atoms onto the two separate corner-sharing Cu(II)O_{2} sub-lattices of the edge-sharing Cu(II)O planes, and highlights the ubiquitous resilience of the entangled two hole ZRS entity against impurity scattering.

Considerations for the development of guidance on dose level selection for developmental and reproductive toxicity studies.

In 2022, the European Chemicals Agency issued advice on the selection of high dose levels for developmental and reproductive toxicity (DART) studies indicating that the highest dose tested should aim to induce clear evidence of reproductive toxicity without excessive toxicity and severe suffering in parental animals. In addition, a recent publication advocated that a 10% decrease in body weight gain should be replaced with a 10% decrease in bodyweight as a criterion for dose adequacy. Experts from the European Centre for Ecotoxicology and Toxicology of Chemicals evaluated these recent developments and their potential impact on study outcomes and interpretation and identified that the advice was not aligned with OECD test guidelines or with humane endpoints guidance. Furthermore, data analysis from DART studies indicated that a 10% decrease in maternal body weight during gestation equates to a 25% decrease in body weight gain, which differs from the consensus of experts at a 2010 ILSI/HESI workshop. Dose selection should be based on a biological approach that considers a range of other factors. Excessive dose levels that cause frank toxicity and overwhelm homeostasis should be avoided as they can give rise to effects that are not relevant to human health assessments.

Clofazimine Inhalation Suspension Demonstrates Promising Toxicokinetics in Canines for Treating Pulmonary Nontuberculous Mycobacteria Infection.

Pulmonary nontuberculous mycobacteria (NTM) infection is recognized as a major global health concern due to its rising prevalence worldwide. As an opportunistic pathogen with increasing antibiotics resistance, prolonged systemic dosing with multiple antibiotics remains the primary treatment paradigm. These prolonged treatments, administered predominantly by oral or parenteral routes, often lead to systemic toxicity. A novel inhaled formulation of clofazimine may finally resolve issues of toxicity, thereby providing for improved NTM therapy. Clofazimine inhalation suspension was evaluated in canines to determine toxicity over 28 days of once-a-day dosing. The good laboratory practice (GLP) repeat dosing study evaluated low, mid, and high dosing (2.72 mg/kg and 2.95 mg/kg; 5.45 mg/kg and 5.91 mg/kg; and 10.87 mg/kg and 10.07 mg/kg, average male versus female dosing) of nebulized clofazimine over 30, 60, and 120 min using a jet nebulizer. Toxicokinetic analyses were performed on study days 29, 56, and 84. All three dose levels showed significant residual drug in lung tissue, demonstrating impressive lung loading and long lung residence. Drug concentrations in the lung remained well above the average NTM MIC at all time points, with measurable clofazimine levels at 28 and 56 days postdosing. In contrast, plasma levels of clofazimine were consistently measurable only through 14 days postdosing, with measurements below the limit of quantitation at 56 days postdosing. Clofazimine inhalation suspension may provide an effective therapy for the treatment of NTM infections through direct delivery of antibiotic to the lungs, overcoming the systemic toxicity seen in oral clofazimine treatment for NTM.

Terahertz-frequency dielectric anisotropy in three-dimensional polymethacrylates fabricated by stereolithography.

The anisotropic optical dielectric functions of slanted columnar layers fabricated using polymethacrylate based stereolithography are reported for the terahertz-frequency domain using generalized spectroscopic ellipsometry. The slanted columnar layers are composed of spatially coherent columnar structures with a diameter of 100 µm and a length of 700 µm that are tilted by 45° with respect to the surface normal of the substrates. A simple biaxial (orthorhombic) layer homogenization approach is used to analyze the terahertz ellipsometric data obtained at three different sample azimuthal orientations. The permittivity along the major polarizability directions varies by almost 25%. Our results demonstrate that stereolithography allows tailoring of the polarizability and anisotropy of the host material, and provides a flexible alternative metamaterials fabrication method for the terahertz spectral range.

Lactifluus (Russulaceae) diversity in Central America and the Caribbean: melting pot between realms.

Species of the ectomycorrhizal genus Lactifluus, and often entire sections, are typically unique to a single continent. Given these biogeographic patterns, an interesting region to study their diversity is Central America and the Caribbean, since the region is closely connected to and often considered a part of the North American continent, but biogeographically belong to the Neotropical realm, and comprises several regions with different geologic histories. Based on a multi-gene phylogeny and morphological study, this study shows that Central America, Mexico and the Caribbean harbour at least 35 Lactifluus species, of which 33 were never reported outside of this region. It was found that species from the Caribbean generally show affinities to South American taxa, while species from the Central American mainland generally show affinities to Northern hemispheric taxa. We hypothesise that host specificity and/or climate play a crucial role in these different origins of diversity. Because of these different affinities, Caribbean islands harbour a completely different Lactifluus diversity than the Central American mainland. The majority of species occurring on the islands can be considered endemic to certain islands or island groups. In this paper, detailed morphological descriptions are given, with a focus on the unique diversity of the islands, and identification keys to all hitherto described Lactifluus species occurring in Central America and the Caribbean are provided. One new section, Lactifluus sect. Nebulosi, and three new species, Lactifluus guadeloupensis, Lactifluus lepus and Lactifluus marmoratus are described.

Comparison of adjustable male slings and artificial urinary sphincter in the treatment of male urinary incontinence: a retrospective analysis of patient selection and postoperative continence status.

PURPOSE: To analyze and compare preoperative patient characteristics and postoperative results in men with stress urinary incontinence (SUI) selected for an adjustable male sling system or an artificial urinary sphincter (AUS) in a large, contemporary, multi-institutional patient cohort. METHODS: 658 male patients who underwent implantation between 2010 and 2012 in 13 participating institutions were included in this study (n = 176 adjustable male sling; n = 482 AUS). Preoperative patient characteristics and postoperative outcomes were analyzed. For statistical analysis, the independent T test and Mann-Whitney U test were used. RESULTS: Patients undergoing adjustable male sling implantation were less likely to have a neurological disease (4.5% vs. 8.9%, p = 0.021), a history of urethral stricture (21.6% vs. 33.8%, p = 0.024) or a radiation therapy (22.7% vs. 29.9%, p = 0.020) compared to patients that underwent AUS implantation. Mean pad usage per day (6.87 vs. 5.82; p < 0.00) and the ratio of patients with a prior incontinence surgery were higher in patients selected for an AUS implantation (36.7% vs. 22.7%; p < 0.001). At maximum follow-up, patients that underwent an AUS implantation had a significantly lower mean pad usage during daytime (p < 0.001) and nighttime (p = 0.018). Furthermore, the patients' perception of their continence status was better with a subjective complete dry rate of 57.3% vs. 22.0% (p < 0.001). CONCLUSIONS: Patients selected for an AUS implantation showed a more complex prior history and pathogenesis of urinary incontinence as well as a more severe grade of SUI. Postoperative results reflect a better continence status after AUS implantation, favoring the AUS despite the more complicated patient cohort.

Identification of responders to immune checkpoint therapy: which biomarkers have the highest value?

Evasion of immune recognition by the innate and acquired immune system is a major principle of tumour cells and belongs to the hallmarks of cancer. Immune checkpoint inhibitor-based cancer therapies targeting the co-inhibitory receptors CTLA-4 or PD-1 have received enormous scientific and clinical attention during the last few years, because of promising clinical results observed in the treatment of different cancer entities including melanoma and cutaneous squamous cell carcinoma. However, the enthusiasm about the effects of the immune checkpoint inhibitors is muted as only a subfraction of patients shows a stable clinical response. To predefine the patient cohorts that may benefit from immune checkpoint therapy, rigorous biomarker analyses, which predict the response to these novel therapies, need to be performed. In addition, combination of immune checkpoint therapy with classical DNA-damaging chemotherapy or radiotherapy, which positively affects tumour neo-antigen presentation, appears to be a promising approach in optimizing patients' response. In this review, we briefly summarize important biomarkers for patient stratification and discuss the current limitations of these biomarkers in defining responders vs. non-responders to immune checkpoint therapy.

High-contrast infrared polymer photonic crystals fabricated by direct laser writing.

One-dimensional (1D) photonic crystals (PCs) were fabricated by three-dimensional (3D) direct laser writing using a single polymer to obtain reflectance values approaching that of a gold reference in the near-infrared (near-IR) spectral range. The PCs are composed of alternating compact and low-density polymer layers that provide the necessary periodic variation of the refractive index. The low-density polymer layers are composed of subwavelength-sized pillars which simultaneously serve as a scaffold while also providing refractive index contrast to the adjacent compact polymer layers. The Bruggemann effective medium theory and stratified-layer optical-model calculated reflectivity profiles were employed to optimize the PC's design to operate at a desired wavelength of 1.55 µm. After the fabrication, the PC's structure was compared to the nominal geometry using complementary scanning electron microscopy and optical microscopy micrographs identifying a true-to-form fabrication. The performance of the PCs was investigated experimentally using FTIR reflection and transmission measurements. A good agreement between stratified-layer optical-model calculated and measured data is observed. Therefore, we demonstrate the ease of predictive design and fabrication of highly efficient 1D PCs for the IR spectral range using 3D direct laser writing of a single polymer.

Broadband near-infrared antireflection coatings fabricated by three-dimensional direct laser writing.

Three-dimensional direct laser writing via two-photon polymerization is used to fabricate anti-reflective structured surfaces (ARSSs) composed of subwavelength conicoid features optimized to operate over a wide bandwidth in the near-infrared range from 3700 cm-1 to 6600 cm-1 (2.7-1.52 µm). Analytic Bruggemann effective medium calculations are used to predict nominal geometric parameters such as the fill factor of the constitutive conicoid features of the anti-reflective structured surfaces (ARSSs) presented here. The performance of the ARSSs was investigated experimentally using infrared reflection and transmission measurements. An enhancement of the transmittance by 1.35%-2.14% over a broadband spectral range from 3700 cm-1 to 6600 cm-1 (2.7-1.52 µm) was achieved. We further report on finite-element-based reflection and transmission data using three-dimensional (3D) model geometries for comparison. A good agreement between experimental results and the finite-element-based numerical analysis is observed once as-fabricated deviations from the nominal conicoid forms are included in the model. 3D direct laser writing is demonstrated here as an efficient method for the fabrication and optimization of ARSSs designed for the infrared spectral range.

The type of loose seton for complex anal fistula is essential to improve perianal comfort and quality of life.

AIM: The use of a loose seton for complex anal fistulae can cause perianal discomfort and reduced quality of life. The aim of this study was to assess the impact of the novel knot-free Comfort Drain on quality of life, perianal comfort and faecal continence compared to conventional loose setons. METHOD: Forty-four patients treated for complex anal fistula at a single institution between July 2013 and September 2014 were included in the study. A matched-pair analysis was performed to compare patients with a knot-free Comfort Drain and controls who were managed by conventional knotted setons. The 12-item Short Form survey (SF-12) questionnaire was used to assess quality of life. Additionally, patients reported perianal comfort and faecal incontinence using a Visual Analog Scale (VAS) and the St Mark's Incontinence Score. RESULTS: The Comfort Drain was associated with improved quality of life with significant higher median physical (P = 0.001) and mental (P = 0.04) health scores compared with a conventional loose seton. According to the VAS, patients with a Comfort Drain in situ reported greater perianal comfort with significantly less burning sensation (P < 0.001) and pruritus (P < 0.001). Faecal continence was similar in each group. CONCLUSION: The Comfort Drain offers improved perianal comfort and better quality of life compared with a conventional loose seton and therefore facilitates long-term therapy in patients with complex fistula-in-ano.

Cavity-enhanced optical Hall effect in two-dimensional free charge carrier gases detected at terahertz frequencies.

The effect of a tunable, externally coupled Fabry-Perot cavity to resonantly enhance the optical Hall effect signatures at terahertz frequencies produced by a traditional Drude-like two-dimensional electron gas is shown and discussed in this Letter. As a result, the detection of optical Hall effect signatures at conveniently obtainable magnetic fields, for example, by neodymium permanent magnets, is demonstrated. An AlInN/GaN-based high-electron mobility transistor structure grown on a sapphire substrate is used for the experiment. The optical Hall effect signatures and their dispersions, which are governed by the frequency and the reflectance minima and maxima of the externally coupled Fabry-Perot cavity, are presented and discussed. Tuning the externally coupled Fabry-Perot cavity strongly modifies the optical Hall effect signatures, which provides a new degree of freedom for optical Hall effect experiments in addition to frequency, angle of incidence, and magnetic field direction and strength.

Consumption of a dark roast coffee decreases the level of spontaneous DNA strand breaks: a randomized controlled trial.

PURPOSE: Coffee consumption has been reported to decrease oxidative damage in peripheral white blood cells (WBC). However, effects on the level of spontaneous DNA strand breaks, a well established marker of health risk, have not been specifically reported yet. We analyzed the impact of consuming a dark roast coffee blend on the level of spontaneous DNA strand breaks. METHODS: Healthy men (n = 84) were randomized to consume daily for 4 weeks either 750 ml of fresh coffee brew or 750 ml of water, subsequent to a run in washout phase of 4 weeks. The study coffee was a blend providing high amounts of both caffeoylquinic acids (10.18 ± 0.33 mg/g) and the roast product N-methylpyridinium (1.10 ± 0.05 mg/g). Before and after the coffee/water consumption phase, spontaneous strand breaks were determined by comet assay. RESULTS: At baseline, both groups exhibited a similar level of spontaneous DNA strand breaks. In the intervention phase, spontaneous DNA strand breaks slightly increased in the control (water only) group whereas they significantly decreased in the coffee group, leading to a 27% difference within both arms (p = 0.0002). Food frequency questionnaires indicated no differences in the overall diet between groups, and mean body weight during the intervention phases remained stable. The consumption of the study coffee substantially lowered the level of spontaneous DNA strand breaks in WBC. CONCLUSION: We conclude that regular coffee consumption contributes to DNA integrity.

Inhalation of macrolides: a novel approach to treatment of pulmonary infections.

Systemic antibiotic treatment is established for many pulmonary diseases, e.g., cystic fibrosis (CF), bronchiectasis and chronic obstructive pulmonary disease (COPD) where recurrent bacterial infections cause a progressive decline in lung function. In the last decades inhalative administration of antibiotics was introduced into clinical routine, especially tobramycin, colistin, and aztreonam for treatment of CF and bronchiectasis. Even though they are important in systemic treatment of these diseases due to their antimicrobial spectrum and anti-inflammatory and immunomodulatory properties, macrolides (e.g., azithromycin, clarithromycin, erythromycin, and telithromycin) up to now are not administered by inhalation. The number of in vitro aerosol studies and in vivo inhalation studies is also sparse. We analyzed publications on preparation and administration of macrolide aerosols available in PUBMED focusing on recent publications. Studies with solutions and dry powder aerosols were published. Publications investigating physicochemical properties of aerosols demonstrated that macrolide aerosols may serve for inhalation and will achieve sufficient lung deposition and that the bitter taste can be masked. In vivo studies in rats demonstrated high concentrations and areas under the curve sufficient for antimicrobial treatment in alveolar macrophages and epithelial lining fluid without lung toxicity. The obtained data demonstrate the feasibility of macrolide inhalation which should be further investigated.

[Is the decrease in corneal endothelial cell density in relation to age linear?]. / Ist die Abnahme der Hornhaut-Endothelzellzahl mit dem Alter wirklich linear?

BACKGROUND: Corneal endothelial cell density is an important factor in maintaining corneal transparency. It is generally assumed that corneal endothelial cell density continuously decreases from birth. MATERIAL AND METHODS: On healthy eyes of 191 subjects, images of the endothelium were taken using a specular endothelial microscope. Statistical analyses were done on corneal endothelial cell density, polymegatism and proportion of hexagonal cells in relation to age. RESULTS: Extrapolated endothelial cell density at birth was 2957 cells/mm2. Using linear regression, the calculated annual cell loss was 7.58 cells/mm2. With age, polymegatism is increasing and the proportion of hexagonal cells is decreasing. Based on our data, the decrease in corneal endothelial cell density can be described in two different time periods: from birth until 35 years of age, endothelial cell density is considerably and continuously decreasing; after this corneal endothelial cell density is decreasing at a much slower rate. CONCLUSIONS: Our data suggest that changes in the structure of the corneal endothelium are different in the first three decades of life compared to later decades. Reasons for this could be mechanical and physical influences, changing biochemical properties of the cornea and aqueous humor, or the embryological origin of the endothelium. This observation shows that age generally is not a deciding factor for intraocular surgeries.

Activation of TRPM7 channels by small molecules under physiological conditions.

Transient receptor potential cation channel, subfamily M, member 7 (TRPM7) is a cation channel covalently linked to a protein kinase domain. TRPM7 is ubiquitously expressed and regulates key cellular processes such as Mg(2+) homeostasis, motility, and proliferation. TRPM7 is involved in anoxic neuronal death, cardiac fibrosis, and tumor growth. The goal of this work was to identify small molecule activators of the TRPM7 channel and investigate their mechanism of action. We used an aequorin bioluminescence-based assay to screen for activators of the TRPM7 channel. Valid candidates were further characterized using patch clamp electrophysiology. We identified 20 drug-like compounds with various structural backbones that can activate the TRPM7 channel. Among them, the δ opioid antagonist naltriben was studied in greater detail. Naltriben's action was selective among the TRP channels tested. Naltriben activates TRPM7 currents without prior depletion of intracellular Mg(2+) even under conditions of low PIP2. Moreover, naltriben interfered with the effect of the TRPM7 inhibitor NS8593. Finally, our experiments with TRPM7 variants carrying mutations in the pore, TRP, and kinase domains indicate that the site of TRPM7 activation by this small-molecule ligand is most likely located in or near the TRP domain. In conclusion, we identified the first organic small-molecule activators of TRPM7 channels, thus providing new experimental tools to study TRPM7 function in native cellular environments.

Growth of highly oriented deuterium crystals in silicon nanochannels.

The structure of solid deuterium confined in 9 nm wide tubular silicon nanochannels has been studied by means of elastic neutron scattering techniques. As a result we report the formation of fcc D(2) as the stable solid phase in confinement in contrast to the hcp bulk structure. Further, a preferred alignment of D(2) nanocrystals with respect to the surrounding crystalline silicon matrix is discussed in terms of heteroepitaxial growth of solid D(2) on crystalline pore walls.

Polarization selection rules for inter-Landau-level transitions in epitaxial graphene revealed by the infrared optical Hall effect.

We report on the polarization selection rules of inter-Landau-level transitions using reflection-type optical Hall effect measurements from 600 to 4000 cm(-1) on epitaxial graphene grown by thermal decomposition of silicon carbide. We observe symmetric and antisymmetric signatures in our data due to polarization preserving and polarization mixing inter-Landau-level transitions, respectively. From field-dependent measurements, we identify that transitions in coupled graphene monolayers are governed by polarization mixing selection rules, whereas transitions in decoupled graphene monolayers are governed by polarization preserving selection rules. The selection rules may find explanation by different coupling mechanisms of inter-Landau-level transitions with free charge carrier magneto-optic plasma oscillations.

Maternal and foetal effects of remifentanil for general anaesthesia in parturients undergoing caesarean section: a systematic review and meta-analysis.

BACKGROUND: Remifentanil has been suggested for the induction of general anaesthesia for caesarean section. We aimed to define remifentanil effects on maternal stress response as well as neonatal effects. METHODS: Relevant articles were retrieved by a systematic literature search. Randomized, controlled trials comparing remifentanil use before delivery with placebo were selected. Maternal outcome parameters were blood pressure and heart rate; neonatal effects included the need for mask ventilation and intubation, base excess, pH values, Apgar < 7 at 1 and 5 min. The random effects model was used for meta-analysis; risk ratio or weighted mean difference (WMD) and 95% confidence interval (95% CI) were calculated. RESULTS: Five articles including 186 patients were identified. Highest and lowest systolic blood pressure were significantly lower in the remifentanil group (WMD: -29.98, -50.90 to -9.07 mmHg, 95% CI; P = 0.005; and WMD: -12.46, -18.21 to -6.71 mmHg, 95% CI; P < 0.0001), the lowest heart rate was significantly lower after remifentanil treatment (WMD: -8.22, -11.67 to -4.78, 95% CI; P < 0.00001). Base excess was significantly higher in infants of remifentanil-treated mothers (WMD: 1.15, -0.27 to 2.03, 95% CI; P = 0.01); pH was also higher in the remifentanil group, but significance was missed (P = 0.07). No differences were observed for Apgar values or the need of airway assist. CONCLUSION: Remifentanil was found to attenuate the maternal circulatory response to intubation and surgery. Higher base excess and pH suggest a beneficial effect on the neonatal acid-base status. A trial with adequate power is warranted that addresses neonatal side-effects of remifentanil.

Vasopressors for the management of hypotension after spinal anesthesia for elective caesarean section. Systematic review and cumulative meta-analysis.

BACKGROUND: Phenylephrine use has been recommended over ephedrine for the management of hypotension after spinal anesthesia for elective caesarean section. The evidence for this is rather limited because in previous trials, pH was significantly lower after ephedrine, but absolute values were still within normal range. We pooled the available data to define maternal and neonatal effects of the two vasopressors. METHODS: Literature was identified by a systematic search. Hypotension, hypertension, and bradycardia of the mothers, fetal acidosis defined as a pH < 7.20, and the continuous variables base excess (BE) and arterial pCO(2) of the neonates were recorded. Meta-analysis using the random effects model was performed, and the weighted mean difference (WMD) or risk ratio (RR), and 95% confidence interval (95% CI) were calculated. RESULTS: The criteria for eligibility were fulfilled by 20 trials including 1069 patients. The RR of true fetal acidosis was 5.29 (95%CI 1.62-17.25, ) for ephedrine vs. phenylephrine (P = 0.006). BE values after ephedrine use were significantly lower than after phenylephrine (WMD -1.17; 95% CI -2.01 - -0.33). Umbilical artery pCO(2) did not differ. Mothers treated with ephedrine had a lower risk for bradycardia (RR 0.17; 95%CI 0.07-0.43; P = 0.004). No differences between vasopressors were observed for hypotension and hypertension. CONCLUSIONS: Our analysis could clearly demonstrate a decreased risk of fetal acidosis associated with phenylephrine use. In addition with our findings for BE, this suggests a favorable effect of phenylephrine on fetal outcome parameters. The mechanism of pH depression is not related to pCO(2) .

[Chronic musculoskeletal pain syndrome in primary hyperparathyroidism]. / Chronisches muskuloskelettales Schmerzsyndrom bei primärem Hyperparathyreoidismus.

Chronic somatic pain disorders with somatic and mental factors (ICD-10: F45.41) are common among psychosomatic patients. In the present case, due to the close temporal association with a trauma and the subsequent development of symptoms including depressive symptoms, a chronic pain disorder with a relevant somatoform component was suspected. However, after a period of several months without significant somatic findings, targeted diagnostic approaches resulted in the diagnoses of primary hyperparathyroidism and a papillary thyroid carcinoma. Surgical therapy resulted in an almost complete decline of symptoms within a short period of time.