Overall survival and central nervous system activity of crizotinib in ROS1-rearranged lung cancer-final results of the EUCROSS trial.

BACKGROUND: In 2019, we reported the first efficacy and safety analysis of EUCROSS, a phase II trial investigating crizotinib in ROS1 fusion-positive lung cancer. At that time, overall survival (OS) was immature and the effect of crizotinib on intracranial disease control remained unclear. Here, we present the final analysis of OS, systemic and intracranial activity, and the impact of co-occurring aberrations. MATERIALS AND METHODS: EUCROSS was a prospective, single-arm, phase II trial. The primary endpoint was best overall response rate (ORR) using RECIST 1.1. Secondary and exploratory endpoints were progression-free survival (PFS), OS, and efficacy in pre-defined subgroups. RESULTS: Median OS of the intention-to-treat population (N = 34) was 54.8 months [95% confidence interval (CI) 20.3 months-not reached (NR); median follow-up 81.4 months] and median all-cause PFS of the response-evaluable population (N = 30) was 19.4 months (95% CI 10.1-32.2 months). Time on treatment was significantly correlated with OS (R = 0.82; P < 0.0001). Patients with co-occurring TP53 aberrations (28%) had a significantly shorter OS [hazard ratio (HR) 11; 95% CI 2.0-56.0; P = 0.006] and all-cause PFS (HR 4.2; 95% CI 1.2-15; P = 0.025). Patients with central nervous system (CNS) involvement at baseline (N = 6; 20%) had a numerically shorter median OS and all-cause PFS. Median intracranial PFS was 32.2 months (95% CI 23.7 months-NR) and the rate of isolated CNS progression was 24%. CONCLUSIONS: Our final analysis proves the efficacy of crizotinib in ROS1-positive lung cancer, but also highlights the devastating impact of TP53 mutations on survival and treatment efficacy. Additionally, our data show that CNS disease control is durable and the risk of CNS progression while on crizotinib treatment is low.

Implementation and validation of swept density reflectometry for integrated data analysis at ASDEX Upgrade.

In the tokamak ASDEX Upgrade, Integrated Data Analysis (IDA) is used to infer plasma quantities, such as electron density, using heterogeneous data sources. Essential is forward modeling from the parameter space into the data space with physically reasonable models for probabilistic evaluation. This paper presents a new forward model for O-mode profile reflectometry, a necessary prerequisite for Bayesian inference and inclusion in IDA. An efficient forward model based on the analytic solution for a piece-wise linear density description allows IDA to overcome problems associated with the established determination of cut-off locations via Abel inversion and Bottollier-Curtet's method. Instead of using a hard-coded initialization for densities below the first measured cut-off density, other diagnostics, such as the lithium beam, are used to analyze the shape of the initial part of the profile. Error propagation from the measured data, and other uncertain sources, to the uncertainties in the density profile and also its gradient is an intrinsic property of the probabilistic approach, which benefits from the joint analysis. Missing or ambiguous data do not prevent the profile evaluation, but only increase the uncertainty for densities in the affected range. Density profiles together with their uncertainties are determined by the joint analysis of complementary diagnostics, with the newly added reflectometry closing a gap in the outer core region. A stand-alone inversion based on the new forward model, including uncertainty quantification, is introduced, optionally providing an n(R) profile with uncertainties and a gradient. This method is a candidate for real-time analysis, providing error bars.

[Recommendations for the healthcare of patients with FOP]. / Empfehlungen zur Versorgung von Patient:innen mit FOP.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is a very rare, severe genetic disorder triggered by a gain-of-function mutation in the ACVR1 gene that codes for the type I bone morphogenetic protein (BMP) receptor ACVR1 (activin A receptor-type 1), also known as ALK2 (activin receptor-like kinase-2). It leads to the onset and progression of heterotopic ossification (HO) in soft and connective tissue. HO is often preceded by episodes of soft tissue swelling or flare-ups. Flare-ups, characteristic of FOP, may be induced by trauma, infection, vaccination, or other medications, as well as surgical procedures or may occur spontaneously. As patients age, they develop severe mobility limitations due to progressive HO formation, including immobility, causing a shortened life expectancy. FOP's first characteristic clinical sign is the congenital malformation of one or both big toes with valgus axis deviation, which is present in almost all patients. To confirm the diagnosis, molecular genetic analysis of the ACVR1 gene is possible. AIM OF THE RECOMMENDATIONS: This white paper aims to provide an overview of the necessary prerequisites and conditions for the care of patients with FOP and positively contribute to patients with FOP by improving the overall availability of knowledge. To achieve this, relevant aspects of the care of the very rare disease FOP are presented, from the initial diagnosis to the care in regular care based on the authors' knowledge (German FOP network) and the international FOP Treatment Guidelines. The recommendations presented here are addressed to all actors and decision-makers in the health care system and are also intended to inform patients and the public.

Effectiveness of recombinant human follicle-stimulating hormone (r-hFSH): recombinant human luteinizing hormone versus r-hFSH alone in assisted reproductive technology treatment cycles among women aged 35-40 years: A German database study.

This non-interventional study compared the effectiveness of recombinant human follicle-stimulating hormone (r-hFSH) and recombinant human luteinizing hormone (r-hLH) (2:1 ratio) versus r-hFSH alone for ovarian stimulation (OS) during assisted reproductive technology treatment in women aged 35-40 years, using real-world data from the Deutsches IVF-Register (D·I·R). Numerically higher clinical pregnancy (29.8% [95% CI 28.2, 31.6] vs. 27.8% [26.5, 29.2]) and live birth (20.3% [18.7, 21.8] vs. 18.0% [16.6, 19.4]) rates were observed with r-hFSH:r-hLH versus r-hFSH alone. The treatment effect was consistently higher for r-hFSH:r-hLH compared with r-hFSH alone in terms of clinical pregnancy (relative risk [RR] 1.16 [1.05, 1.26]) and live birth (RR 1.16 [1.02, 1.31]) in a post-hoc analysis of women with 5-14 oocytes retrieved (used as a surrogate for normal ovarian reserve), highlighting the potential benefits of r-hFSH:r-hLH for OS in women aged 35-40 years with normal ovarian reserve.

Tau filaments are tethered within brain extracellular vesicles in Alzheimer's disease.

The abnormal assembly of tau protein in neurons is the pathological hallmark of multiple neurodegenerative diseases, including Alzheimer's disease (AD). In addition, assembled tau associates with extracellular vesicles (EVs) in the central nervous system of patients with AD, which is linked to its clearance and prion-like propagation between neurons. However, the identities of the assembled tau species and the EVs, as well as how they associate, are not known. Here, we combined quantitative mass spectrometry, cryo-electron tomography and single-particle cryo-electron microscopy to study brain EVs from AD patients. We found filaments of truncated tau enclosed within EVs enriched in endo-lysosomal proteins. We observed multiple filament interactions, including with molecules that tethered filaments to the EV limiting membrane, suggesting selective packaging. Our findings will guide studies into the molecular mechanisms of EV-mediated secretion of assembled tau and inform the targeting of EV-associated tau as potential therapeutic and biomarker strategies for AD.

Detection of SARS-CoV-2 IgG antibodies and inflammatory cytokines in saliva-a pilot study.

Objective: The pandemic caused by SARS-CoV-2 virus continues to have a profound effect worldwide. However, COVID-19 induced oral facial manifestations have not been fully described. We conducted a prospective study to demonstrate feasibility of anti-SARS-CoV-2 IgG and inflammatory cytokine detection in saliva. Our primary objective was to determine whether COVID-19 PCR positive patients with xerostomia or loss of taste had altered serum or saliva cytokine levels compared to COVID-19 PCR positive patients without those oral symptoms. Our secondary objective was to determine the correlation between serum and saliva COVID-19 antibody levels. Materials and methods: For cytokine analysis, saliva and serum were obtained from 17 participants with PCR-confirmed COVID-19 infection at three sequential time points, yielding 48 saliva samples and 19 paired saliva-serum samples from 14 of the 17 patients. For COVID-19 antibody analyses, an additional 27 paired saliva-serum samples from 22 patients were purchased. Results: The saliva antibody assay had 88.64% sensitivity [95% Confidence Interval (CI) 75.44%, 96.21%] to detect SARS-CoV-2 IgG antibodies compared to serum antibody. Among the inflammatory cytokines assessed - IL-6, TNF-α, IFN-γ, IL-10, IL-12p70, IL-1ß, IL-8, IL-13, IL-2, IL-5, IL-7 and IL-17A, xerostomia correlated with lower levels of saliva IL-2 and TNF-α, and elevated levels of serum IL-12p70 and IL-10 (p < 0.05). Loss of taste was observed in patients with elevated serum IL-8 (p < 0.05). Conclusions: Further studies are needed to construct a robust saliva-based COVID-19 assay to assess antibody and inflammatory cytokine response, which has potential utility as a non-invasive monitoring modality during COVID-19 convalescence.

Merging molecular catalysts and metal-organic frameworks for photocatalytic fuel production.

In the effort to generate sustainable clean energy from abundant resources such as water and carbon dioxide, solar fuel production-the combination of solar-light harvesting and the generation of efficient chemical energy carriers-by artificial molecular photosystems is very attractive. Molecular constituents that display attractive features for chemical energy conversion (such as high product selectivity and atom economy) have been developed, and their interfacing with host materials has enabled recyclability, controlled site positioning, as well as access to fundamental insights into the catalytic mechanism and environment-governed selectivity. Among the wide variety of supports, metal-organic frameworks (MOFs) possess valuable characteristics (such as their porosity and versatility) that can influence the reaction environment and material architecture in a unique fashion. Here we highlight the various existing synthetic strategies to graft molecular complexes such as catalysts and photosensitizers onto MOFs for solar fuel production. The opportunities and limitations of one-pot and stepwise approaches are critically assessed, and the resulting materials are discussed based on their photocatalytic performances and the practical applicability of selected examples.

Quasicontinuous Exhaust Scenario for a Fusion Reactor: The Renaissance of Small Edge Localized Modes.

Tokamak operational regimes with small edge localized modes (ELMs) could be a solution to the problem of large transient heat loads in fusion reactors. A ballooning mode near the last closed flux surface governed by the pressure gradient and the magnetic shear there has been proposed for small ELMs. In this Letter, we experimentally investigate several stabilizing effects near the last closed flux surface and present linear ideal simulations that indeed develop ballooninglike fluctuations there and connect them with nonlinear resistive simulations. The dimensionless parameters of the small ELM regime in the region of interest are very similar to those in a reactor, making this regime the ideal exhaust scenario for a future device.

Effectiveness of the lateral pedicled endonasal flap for prevention of restenosis in frontal sinus drillouts.

BACKGROUND: Frontal sinus median drainage according to Draf is an established procedure for achieving maximum drainage of the frontal sinus. Despite great efforts and several modifications, restenosis of the neo-ostium is still a persistent problem. This study presents an approach by implementing local mucosal flaps to prevent restenosis and compares it with the conventional technique without using the flap. METHODS: Description of endonasal, lateral pedicle mucosal flap. A Draf III procedure was performed on 156 patients between 2012 and 2021. Data for 123 of the included patients were retrospectively analyzed in terms of surgical indication, technique, postoperative aftercare and patency of the drainage pathway. The follow-up observation period was between 3 and 24 months. RESULTS: Treatment with the pedicle mucosal flap took place in 86 cases. 37 patients were treated as a control group without this flap. The analysis showed a significant association to the event "total closure of the drainage pathway" for surgical technique, as well as in the case of the presence of an allergy and the existence of Samter's triad. Furthermore, there was a significant association between the onset of "near total closure of the frontal sinus ostium" and Samter';s triad, CRS and revision surgery was involved. CONCLUSIONS: Use of an endonasal lateral pedicle flap for reconstruction of mucosal defects in frontal sinus surgery improves the long-term chances of a patent drainage pathway. Bone exposed by drilling was covered with a local mucosal flap for a faster epithelialization, healing and less scarring.

Antimicrobial effect of Moringa oleifera seed powder against Vibrio cholerae isolated from the rearing water of shrimp (Penaeus vannamei) postlarvae.

Shrimp farming has experienced rising costs as a result of disease outbreaks associated with Vibrio spp. Suitable strategies for disease prevention and control are therefore urgently needed. This study aimed to evaluate the antimicrobial effect of Moringa oleifera seed powder against Vibrio cholerae in the rearing water of Pacific white shrimp (Penaeus vannamei) postlarvae. In vitro assays included the determination of minimum inhibitory concentration (MIC) of M. oleifera seed powder against V. cholerae, whereas in vivo assays included the effect of M. oleifera seed powder on bacterial load and water quality parameters in the rearing tanks, as well as its effect on shrimp postlarvae survival. M. oleifera seed powder inhibited the growth of V. cholerae with MIC values of 62·5 µg ml-1 . Moreover, seawater pH of treated tanks (8·66) was significantly lower (P < 0·01) than pH of the control tanks (9·02), whereas the visibility of treated tanks (37·08 cm) was significantly higher (P < 0·01) as compared to control tanks (35·37 cm). Likewise, V. cholerae load was significantly reduced (P < 0·01) from 4·7 × 104 to 3·1 × 103  CFU per ml in tanks treated with M. oleifera seed powder. Altogether, this study demonstrates the antimicrobial activity of M. oleifera against V. cholerae in shrimp culture.

TIMolol nasal spray as a treatment for epistaxis in hereditary hemorrhagic telangiectasia (HHT) - Study protocol of the prospective, randomized, double-blind, controlled cross-over TIM-HHT trial.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an inherited orphan disease, in which the absence of capillary beds between arterioles and venules lead to arteriovenous shunts. Epistaxis is the core symptom. Several case reports have described the nonselective beta-adrenergic receptor antagonist timolol as a successful treatment method of nosebleeds due in HHT patients. OBJECTIVE: TIM-HHT is a single-site, prospective, randomized, placebo-controlled, double-blind, cross-over study to investigate whether the efficacy of standard laser treatment of epistaxis in HHT patients can be increased by the additional use of timolol nasal spray (1 mg/d). METHODS: Twenty patients will be randomly allocated to one of two treatment sequences. Primary outcome is the severity of epistaxis determined by the Epistaxis Severity Score (ESS). Secondary outcomes are subjective satisfaction, quality of life, as well as the hemoglobin, ferritin, and transferrin levels of the participating patients. Safety outcome is assessed by means of pulse, blood pressure, and adverse events. CONCLUSION: TIM-HHT will evaluate the efficacy and safety of timolol as an additional treatment of epistaxis in HHT patients in a three-month trial period. Benzalkonium chloride is used as a placebo, which has no documented positive effect on the nasal mucosa and hence on epistaxis in HHT patients (in contrast to saline). TRIAL REGISTRATION: German Clinical Trials Register (DRKS), DRKS00020994. Registered on 10 March 2020.

Diabetic mitochondria are resistant to palmitoyl CoA inhibition of respiration, which is detrimental during ischemia.

The bioactive lipid intermediate palmitoyl CoA (PCoA) can inhibit mitochondrial ADP/ATP transport, though the physiological relevance of this regulation remains unclear. We questioned whether myocardial ischemia provides a pathological setting in which PCoA regulation of ADP/ATP transport would be beneficial, and secondly, whether the chronically elevated lipid content within the diabetic heart could make mitochondria less sensitive to the effects of PCoA. PCoA acutely decreased ADP-stimulated state 3 respiration and increased the apparent Km for ADP twofold. The half maximal inhibitory concentration (IC50 ) of PCoA in control mitochondria was 22 µM. This inhibitory effect of PCoA on respiration was blunted in diabetic mitochondria, with no significant difference in the Km for ADP in the presence of PCoA, and an increase in the IC50 to 32 µM PCoA. The competitive inhibition by PCoA was localised to the phosphorylation apparatus, particularly the ADP/ATP carrier (AAC). During ischemia, the AAC imports ATP into the mitochondria, where it is hydrolysed by reversal of the ATP synthase, regenerating the membrane potential. Addition of PCoA dose-dependently prevented this wasteful ATP hydrolysis for membrane repolarisation during ischemia, however, this beneficial effect was blunted in diabetic mitochondria. Finally, using 31 P-magnetic resonance spectroscopy we demonstrated that diabetic hearts lose ATP more rapidly during ischemia, with a threefold higher ATP decay rate compared with control hearts. In conclusion, PCoA plays a role in protecting mitochondrial energetics during ischemia, by preventing wasteful ATP hydrolysis. However, this beneficial effect is blunted in diabetes, contributing to the impaired energy metabolism seen during myocardial ischemia in the diabetic heart.

Xenograft materials in maxillary sinus floor elevation surgery: a systematic review with network meta-analyses.

A systematic review and network meta-analysis was conducted to compare different commercially available xenograft materials used in maxillary sinus floor elevation surgery (MSFES). Embase, PubMed, the Cochrane Library, Web of Science, Scopus, LILACS, and grey literature were searched up to 13 July 2020. Only randomised controlled trials (RCTs) were included. A frequentist network meta-analysis using a random effects model compared different commercially available xenograft materials. The primary outcomes were the percentage of newly-formed bone and residual bone-substitute rate. Both were measured by histomorphometric analysis from bone biopsies obtained during preparation of the implant site. Of the 659 studies initially identified, 11 involving 242 MSFES were included in the quantitative analyses. A total of six bone-substitute materials were analysed (Bio-Oss® (Geistlich Pharma), InduCera® Dual Coat, Lumina-Bone Porous® (Critéria), Osseous® (SIN - Sistema de Implantes Nacional), THE Graft® (Purgo Biologics), and Osteoplant Osteoxenon® (Bioteck)). The P-score estimation showed that Osteoplant Osteoxenon® produced the most newly-formed bone and reabsorbed faster than other xenograft materials after six months. The combination of Bio-Oss® plus bone marrow aspirate concentrate (BMAC) significantly increased the percentage of newly-formed bone compared with Bio-Oss® alone. In contrast, the addition of Emdogain® (Straumann) and leucocyte and platelet-rich fibrin (L-PRF) to Bio-Oss® did not significantly improve the amount of regenerated bone. Study-level data indicated that the percentage of newly-formed bone differs among commercially available xenograft materials. Osteoplant Osteoxenon® seems to result in the highest amount of new bone in MSFES.

Skeletal muscle fat quantification by dual-energy computed tomography in comparison with 3T MR imaging.

OBJECTIVES: To quantify the proportion of fat within the skeletal muscle as a measure of muscle quality using dual-energy CT (DECT) and to validate this methodology with MRI. METHODS: Twenty-one patients with abdominal contrast-enhanced DECT scans (100 kV/Sn 150 kV) underwent abdominal 3-T MRI. The fat fraction (DECT-FF), determined by material decomposition, and HU values on virtual non-contrast-enhanced (VNC) DECT images were measured in 126 regions of interest (≥ 6 cm2) within the posterior paraspinal muscle. For validation, the MR-based fat fraction (MR-FF) was assessed by chemical shift relaxometry. Patients were categorized into groups of high or low skeletal muscle mean radiation attenuation (SMRA) and classified as either sarcopenic or non-sarcopenic, according to the skeletal muscle index (SMI) and cut-off values from non-contrast-enhanced single-energy CT. Spearman's and intraclass correlation, Bland-Altman analysis, and mixed linear models were employed. RESULTS: The correlation was excellent between DECT-FF and MR-FF (r = 0.91), DECT VNC HU and MR-FF (r = - 0.90), and DECT-FF and DECT VNC HU (r = - 0.98). Intraclass correlation between DECT-FF and MR-FF was good (r = 0.83 [95% CI 0.71-0.90]), with a mean difference of - 0.15% (SD 3.32 [95% CI 6.35 to - 6.66]). Categorization using the SMRA yielded an eightfold difference in DECT VNC HU values between both groups (5 HU [95% CI 23-11], 42 HU [95% CI 33-56], p = 0.05). No significant relationship between DECT-FF and SMI-based classifications was observed. CONCLUSIONS: Fat quantification within the skeletal muscle using DECT is both feasible and reliable. DECT muscle analysis offers a new approach to determine muscle quality, which is important for the diagnosis and therapeutic monitoring of sarcopenia, as a comorbidity associated with poor clinical outcome. KEY POINTS: • Dual-energy CT (DECT) material decomposition and virtual non-contrast-enhanced DECT HU values assess muscle fat reliably. • Virtual non-contrast-enhanced dual-energy CT HU values allow to differentiate between high and low native skeletal muscle mean radiation attenuation in contrast-enhanced DECT scans. • Measuring muscle fat by dual-energy computed tomography is a new approach for the determination of muscle quality, an important parameter for the diagnostic confirmation of sarcopenia as a comorbidity associated with poor clinical outcome.

Metastatic Renal Cell Carcinoma Rapidly Progressive to Sunitinib: What to Do Next?

BACKGROUND: From 10% to 26% of patients with metastatic renal cell carcinoma (mRCC) experience rapidly progressive disease (PD) on treatment with sunitinib. OBJECTIVE: To investigate the benefit of subsequent treatment with another tyrosine kinase inhibitor (TKI) or a mammalian target of rapamycin (mTOR) inhibitor in such primary refractory patients. DESIGN, SETTING, AND PARTICIPANTS: A total of 150 mRCC patients with rapidly PD on first-line sunitinib (within two cycles, n=93, or four cycles, n=57) were identified: median age 59yr; nephrectomy 86%; histological subtypes: clear cell (77.8%), papillary (14%), and sarcomatoid features (18%); according to the Memorial Sloan-Kettering Cancer Center and French classifications: good risk (11% and 7%, respectively), intermediate (68% and 63%, respectively), and poor (21% and 29%, respectively). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Data were retrospectively collected by a questionnaire from 19 European oncology centers between March 2005 and March 2011. Progression-free survival (PFS) and overall survival (OS) were calculated (Kaplan-Meier method). RESULTS AND LIMITATIONS: Median OS from the start of first-line treatment was 7.4mo. Second-line treatment was administered to 86 (57%) patients (44 mTOR inhibitors: 23 everolimus and 21 temsirolimus; 39 TKIs alone or in combination; three chemotherapy). Second-line PFS was not significantly different between TKIs and mTOR inhibitors (2.0 vs 0.9mo; p=0.536). Median OS from the start of second-line treatment was 5.0mo for mTOR inhibitors and 6.6mo for TKIs (p=0.15). CONCLUSIONS: Treatment with further TKIs or mTOR inhibitors for mRCC patients primarily refractory to first-line sunitinib in the observed time period achieved very minimal benefit, suggesting avoiding TKI rechallenge and possibly preferring alternative strategies, such as immune checkpoint inhibitors, after PD to a treatment line including a TKI in this setting. PATIENT SUMMARY: The present work collected data about 150 patients affected by metastatic renal cell carcinoma, who received one of the current standard of care as first-line treatment, namely, the antiangiogenic drug sunitinib, and experienced rapid worsening of the disease. We investigated and described the subsequent outcome of such patients treated with two different types of drug, administered as second-line therapy, to better understand the best strategy to adopt for patients who got no benefit from sunitinib and to describe the current therapeutic approach in such cases.

Value of lipocalin 2 as a potential biomarker for bacterial meningitis.

OBJECTIVES: Central nervous system (CNS) infections are common causes of morbidity and mortality worldwide. We aimed to discover protein biomarkers that could rapidly and accurately identify the likely cause of the infections, essential for clinical management and improving outcome. METHODS: We applied liquid chromatography tandem mass spectrometry on 45 cerebrospinal fluid (CSF) samples from a cohort of adults with and without CNS infections to discover potential diagnostic biomarkers. We then validated the diagnostic performance of a selected biomarker candidate in an independent cohort of 364 consecutively treated adults with CNS infections admitted to a referral hospital in Vietnam. RESULTS: In the discovery cohort, we identified lipocalin 2 (LCN2) as a potential biomarker of bacterial meningitis (BM) other than tuberculous meningitis. The analysis of the validation cohort showed that LCN2 could discriminate BM from other CNS infections (including tuberculous meningitis, cryptococcal meningitis and virus/antibody-mediated encephalitis), with sensitivity of 0.88 (95% confident interval (CI), 0.77-0.94), specificity of 0.91 (95% CI, 0.88-0.94) and diagnostic odds ratio of 73.8 (95% CI, 31.8-171.4). LCN2 outperformed other CSF markers (leukocytes, glucose, protein and lactate) commonly used in routine care worldwide. The combination of LCN2, CSF leukocytes, glucose, protein and lactate resulted in the highest diagnostic performance for BM (area under the receiver operating characteristics curve, 0.96; 95% CI, 0.93-0.99). Data are available via ProteomeXchange with identifier PXD020510. CONCLUSIONS: LCN2 is a sensitive and specific biomarker for discriminating BM from a broad spectrum of other CNS infections. A prospective study is needed to assess the diagnostic utility of LCN2 in the diagnosis and management of CNS infections.

Cultivar × Management Interaction to Reduce Lodging and Improve Grain Yield of Irrigated Spring Wheat: Optimising Plant Growth Regulator Use, N Application Timing, Row Spacing and Sowing Date.

Severe lodging of irrigated spring-wheat in sub-tropical Australia has previously caused yield loss of between 1.7 and 4.6 t ha-1 (20-60% of potential yield). In response, agronomic management options were assessed for their ability to reduce lodging and increase grain yield, namely plant growth regulators (PGRs), timing of nitrogen (N) application, row spacing and sowing date, in combination with long and short duration cultivars across 15 irrigated environments from 2012 to 2016. Our study identified significant interaction between genotype, environment and agronomic management (G × E × M) for grain yield and lodging, although some combinations of agronomic techniques were broadly applicable across cultivars. PGR application improved grain yield of most cultivars in well-irrigated fields that had more than 120 kg ha-1 N (mineral N + fertiliser N) at sowing, with yield gains of up to 0.5 t ha-1 observed in both lodged and non-lodged fields. However, PGRs had little effect on grain yield when soil + fertiliser N at sowing was less than 80 kg ha-1 N. In-crop N application (compared to sowing N application) often improved grain yield of short duration, lodging resistant cultivars, but reduced the yield of long-duration, lodging susceptible cultivars in some environments. Narrow row spacing of 19 cm had the highest grain yield across cultivars in low lodging environments. At a severely lodged environment, narrow rows were the highest yielding for five out of six cultivars when PGRs were used, but was the highest yielding for only half of the tested cultivars when PGRs were not used. Cultivar × sowing date interaction for grain yield was also associated with the occurrence of lodging. Neither early nor late sowing had a consistent yield benefit across a range of cultivars, as lodging severity varied between sowing date depending on the timing of storm-induced lodging events. Lodging resistant long-duration cultivars had more stable grain yield across environments and increased grain yield in response to early sowing. Further research is needed to determine the optimum management strategy for new cultivars, because farmers do not always choose the most lodging resistant cultivars for reasons of cultivar disease resistance, grain quality and seed availability.

Supramolecular attack particles are autonomous killing entities released from cytotoxic T cells.

Cytotoxic T lymphocytes (CTLs) kill infected and cancerous cells. We detected transfer of cytotoxic multiprotein complexes, called supramolecular attack particles (SMAPs), from CTLs to target cells. SMAPs were rapidly released from CTLs and were autonomously cytotoxic. Mass spectrometry, immunochemical analysis, and CRISPR editing identified a carboxyl-terminal fragment of thrombospondin-1 as an unexpected SMAP component that contributed to target killing. Direct stochastic optical reconstruction microscopy resolved a cytotoxic core surrounded by a thrombospondin-1 shell of ~120 nanometer diameter. Cryo-soft x-ray tomography analysis revealed that SMAPs had a carbon-dense shell and were stored in multicore granules. We propose that SMAPs are autonomous extracellular killing entities that deliver cytotoxic cargo targeted by the specificity of shell components.

Histomorphometric evaluation of different grafting materials used for alveolar ridge preservation: a systematic review and network meta-analysis.

In this systematic review and network meta-analysis including only randomized clinical trials (RCTs), different grafting materials used in alveolar ridge preservation after tooth extraction were analysed, focusing on histomorphometric new bone formation (NBF) in core biopsies obtained during implant placement. The PubMed, Embase, Cochrane Library, Web of Science, Scopus, and LILACS databases, as well as the grey literature, were searched for published and unpublished trials (from database inception to January 14, 2019). The primary outcome was the percentage of NBF. The secondary outcomes were the percentage of residual biomaterial and the percentage of soft tissue. An arm-based network meta-analysis was performed. The rank of intervention efficacy was obtained to measure the probability of each biomaterial being ranked first across all interventions. A total of 1526 studies were found, of which 38 were included for quantitative analysis. Three trials were rated as having a high risk of bias and 35 trials as having an unclear risk of bias. The network meta-analysis showed that nine grafting materials decreased NBF and 25 did not decrease NBF. The grafting material with the highest amount of NBF was plasma rich in growth factors. Due to the lack of studies with a low risk of bias, further RCTs are needed for definitive conclusions.

Multi-quantum quadrupole relaxation enhancement effects in 209Bi compounds.

1H spin-lattice nuclear magnetic resonance relaxation experiments have been performed for triphenylbismuth dichloride (C18H15BiCl2) and phenylbismuth dichloride (C6H5BiCl2) in powder. The frequency range of 20-128 MHz has been covered. Due to 1H-209Bi dipole-dipole interactions, a rich set of pronounced Quadrupole Relaxation Enhancement (QRE) peaks (quadrupole peaks) has been observed. The QRE patterns for both compounds have been explained in terms of single- and double-quantum transitions of the participating nuclei. The analysis has revealed a complex, quantum-mechanical mechanism of the QRE effects. The mechanism goes far beyond the simple explanation of the existence of three quadrupole peaks for 14N reported in literature. The analysis has been supported by nuclear quadrupole resonance results that independently provided the 209Bi quadrupole parameters (amplitude of the quadrupole coupling constant and asymmetry parameter).