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.

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.

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.

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.

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.

Fetal dynamic phase-contrast MR angiography using ultrasound gating and comparison with Doppler ultrasound measurements.

OBJECTIVES: To investigate the feasibility of fetal phase-contrast (PC)-MR angiography of the descending aorta (AoD) using an MR-compatible Doppler ultrasound sensor (DUS) for fetal cardiac gating and to compare velocimetry with Doppler ultrasound measurements. METHODS: In this prospective study, 2D PC-MR angiography was performed in 12 human fetuses (mean gestational age 32.8 weeks) using an MR-compatible DUS for gating of the fetal heart at 1.5 T. Peak flow velocities in the fetal AoD were compared with Doppler ultrasound measurements performed on the same day. Reproducibility of PC-MR measurements was tested by repeated PC-MR in five fetuses. RESULTS: Dynamic PC-MR angiography in the AoD was successfully performed in all fetuses using the DUS, with an average fetal heart rate of 140 bpm (range 129-163). Time-velocity curves revealed typical arterial blood flow patterns. PC-MR mean flow velocity and mean flux were 21.2 cm/s (range 8.6-36.8) and 8.4 ml/s (range 3.2-14.6), respectively. A positive association between PC-MR mean flux and stroke volume with gestational age was obtained (r = 0.66, p = 0.02 and r = 0.63, p = 0.03). PC-MR and Doppler ultrasound peak velocities revealed a highly significant correlation (r = 0.8, p < 0.002). Peak velocities were lower for PC-MR with 69.1 cm/s (range 39-125) compared with 96.7 cm/s (range 60-142) for Doppler ultrasound (p < 0.001). Reproducibility of PC-MR was high (p > 0.05). CONCLUSION: The MR-compatible DUS for fetal cardiac gating allows for PC-MR angiography in the fetal AoD. Comparison with Doppler ultrasound revealed a highly significant correlation of peak velocities with underestimation of PC-MR velocities. This new technique for direct fetal cardiac gating indicates the potential of PC-MR angiography for assessing fetal hemodynamics. KEY POINTS: • The developed MR-compatible Doppler ultrasound sensor allows direct fetal cardiac gating and can be used for prenatal dynamic cardiovascular MRI. • The MR-compatible Doppler ultrasound sensor was successfully applied to perform intrauterine phase-contrast MR angiography of the fetal aorta, which revealed a highly significant correlation with Doppler ultrasound measurements. • As fetal flow hemodynamics is an important parameter in the diagnosis and management of fetal pathologies, fetal phase-contrast MR angiography may offer an alternative imaging method in addition to Doppler ultrasound and develop as a second line tool in the evaluation of fetal flow hemodynamics.

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).

Influence of 3 calcium channel blockers on gingival overgrowth in a population of severe refractory hypertensive patients.

OBJECTIVE: The aim of the current study was to assess the association between 3 different calcium channel blockers (CCBs) (nifedipine, amlodipine and felodipine) and gingival overgrowth in patients with a diagnosis of severe refractory hypertension. METHODS: One hundred and sixty-two patients with severe refractory hypertension, taking CCBs, were selected. Gingival overgrowth was graded and periodontal measurements were recorded (probing pocket depth, clinical attachment level, plaque index and bleeding on probing). Unconditional multivariable binary logistic regression analyses were performed to assess the association between CCB intake and gingival overgrowth after adjusting for potential confounders. RESULTS: Of the 162 patients, 26 (16.0%) were current smokers and 101 (62.3%) were females. The mean age (SD) was 54.1 (8.5) years and the median age (range) 52.5 (39-78) years. Gingival overgrowth was observed in 55 patients (34.0%). Nifedipine was the most common medication (35.2%; 57 of 162). The results of multiple binary logistic regression showed statistically significant associations between CCB intake (exposure) and gingival overgrowth (outcome) after adjusting for the variables treatment time with antihypertensive and plaque index. Patients with gingival overgrowth were 2.5 (odds ratio = 2.46; 95% confidence interval: 1.04-5.82) and 4.0 (odds ratio = 3.90; 95% confidence interval: 1.47-10.35) times more likely to be taking nifedipine and amlodipine, respectively, than patients without gingival overgrowth. On the other hand, this significant association was not observed for felodipine. CONCLUSION: Nifedipine and amlodipine, but not felodipine, were associated with gingival overgrowth in patients with severe refractory hypertension.

209Bi quadrupole relaxation enhancement in solids as a step towards new contrast mechanisms in magnetic resonance imaging.

Motivated by the possibility of exploiting species containing high spin quantum number nuclei (referred to as quadrupole nuclei) as novel contrast agents for Magnetic Resonance Imaging, based on Quadrupole Relaxation Enhancement (QRE) effects, 1H spin-lattice relaxation has been investigated for tris(2-methoxyphenyl)bismuthane and tris(2,6-dimethoxyphenyl)bismuthane in powder. The relaxation experiment has been performed in the magnetic field range of 0.5 T to 3 T (the upper limit corresponds to the field used in many medical scanners). A very rich QRE pattern (several frequency specific 1H spin-lattice relaxation rate maxima) has been observed for both compounds. Complementary Nuclear Quadrupole Resonance experiments have been performed in order to determine the quadrupole parameters (quadrupole coupling constant and asymmetry parameters) for 209Bi. Knowing the parameters, the QRE pattern has been explained on the basis of a quantum-mechanical picture of the system including single and double-quantum coherences for the participating nuclei (1H and 209Bi). In this way the quantum-mechanical origin of the spin transitions leading to the QRE effects has been explained.

[CF Lung Disease - a German S3 Guideline: Module 2: Diagnostics and Treatment in Chronic Infection with Pseudomonas aeruginosa]. / S3-Leitlinie: Lungenerkrankung bei Mukoviszidose ­ Modul 2: Diagnostik und Therapie bei der chronischen Infektion mit Pseudomonas aeruginosa.

Cystic Fibrosis (CF) is the most common autosomal-recessive genetic disease affecting approximately 8000 people in Germany. The disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leading to dysfunction of CFTR, a transmembrane chloride channel. This defect causes insufficient hydration of the epithelial lining fluid which leads to chronic inflammation of the airways. Recurrent infections of the airways as well as pulmonary exacerbations aggravate chronic inflammation, lead to pulmonary fibrosis and tissue destruction up to global respiratory insufficiency, which is responsible for the mortality in over 90 % of patients. The main aim of pulmonary treatment in CF is to reduce pulmonary inflammation and chronic infection. Pseudomonas aeruginosa (Pa) is the most relevant pathogen in the course of CF lung disease. Colonization and chronic infection are leading to additional loss of pulmonary function. There are many possibilities to treat Pa-infection. This is a S3-clinical guideline which implements a definition for chronic Pa-infection and demonstrates evidence-based diagnostic methods and medical treatment for Pa-infection in order to give guidance for individual treatment options.

Memory and multitasking performance during acute allergic inflammation in seasonal allergic rhinitis.

BACKGROUND: In previous research, patients with seasonal allergic rhinitis (SAR) showed poorer school and work performance during periods of acute allergic inflammation, supporting the idea of an impact of SAR on cognitive functions. However, the specific cognitive domains particularly vulnerable to inflammatory processes are unclear. OBJECTIVE: In this study, the influence of SAR on memory and multitasking performance, as two potentially vulnerable cognitive domains essential in everyday life functioning, was investigated in patients with SAR. METHODS: Non-medicated patients with SAR (n = 41) and healthy non-allergic controls (n = 42) performed a dual-task paradigm and a verbal learning and memory test during and out of symptomatic allergy periods (pollen vs. non-pollen season). Disease-related factors (e.g. symptom severity, duration of symptoms, duration of disease) and allergy-related quality of life were evaluated as potential influences of cognitive performance. RESULTS: During the symptomatic allergy period, patients showed (1) poorer performance in word list-based learning (P = 0.028) and (2) a general slowing in processing speed (P < 0.001) and a shift in processing strategy (P < 0.001) in multitasking. Yet, typical parameters indicating specific multitasking costs were not affected. A significant negative association was found between learning performance and duration of disease (r = -0.451, P = 0.004), whereas symptom severity (r = 0.326; P = 0.037) and quality of life (r = 0.379; P = 0.015) were positively associated with multitasking strategy. CONCLUSIONS: Our findings suggest that SAR has a differentiated and complex impact on cognitive functions, which should be considered in the management of SAR symptoms. They also call attention to the importance of selecting sensitive measures and carefully interpreting cognitive outcomes.

Activity of inflammatory bowel disease influences the expression of cytokines in gingival tissue.

This study assessed the cytokine expression in gingival and intestinal tissues from periodontitis patients with inflammatory bowel disease (IBD) and evaluated if IBD activity is a covariate to the amount of gingival cytokines. Paired gingival and intestinal tissues were collected from 21 patients and homogenised using a cell disruptor. Cytokine expression (IL-1ß, IL-4, IL-6, IL-10, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IL-17A, IL-17F, IFN-γ, sCD40L, and TNF-α) was evaluated using bead-based multiplex technology. An inflammation score was developed using the intestinal cytokines that showed good accuracy to discriminate IBD active patients from those in remission and then a similar score was applied to gingival tissue. IL-4, IL-10 and IL-21 expressions were significantly increased in gingival tissue from patients with an active disease as compared to those with a disease in remission. The inflammation score (mean value of IL-1ß, IL-6, IL-21, and sCD40L) was significantly higher in gingival tissue from patients with IBD activity. There was a significant correlation between gingival and intestinal inflammation scores (rho=0.548; P=0.01). Significantly higher IL-23 and IFN-γ levels and lower IL-31 and TNF-α levels were observed in gingival tissues than in intestinal ones. Activity of inflammatory bowel disease influenced the cytokine expression in gingival tissue.

Laser beam self-focusing in turbulent dissipative media.

A high-power laser beam propagating through a dielectric in the presence of fluctuations is subject to diffraction, dissipation, and optical Kerr nonlinearity. A method of moments was applied to a stochastic, nonlinear enveloped wave equation to analyze the evolution of the long-term spot radius. For propagation in atmospheric turbulence described by a Kolmogorov-von Kármán spectral density, the analysis was benchmarked against field experiments in the low-power limit and compared with simulation results in the high-power regime. Dissipation reduced the effect of self-focusing and led to chromatic aberration.

Identification of a plasma miRNA biomarker signature for allergic asthma: A translational approach.

BACKGROUND: Asthma is a heterogeneous chronic disease with different phenotypes and treatment responses. Thus, there is a high clinical need for molecular disease biomarkers to aid in differentiating these distinct phenotypes. As MicroRNAs (miRNAs), that regulate gene expression at the post-transcriptional level, are altered in experimental and human asthma, circulating miRNAs are attractive candidates for the identification of novel biomarkers. This study aimed to identify plasmatic miRNA-based biomarkers of asthma, through a translational approach. METHODS: We prescreened miRNAs in plasma samples from two different murine models of experimental asthma (ovalbumin and house dust mite); miRNAs deregulated in both models were further tested in a human training cohort of 20 asthma patients and 9 healthy controls. Candidate miRNAs were then validated in a second, independent group of 26 asthma patients and 12 healthy controls. RESULTS: Ten miRNA ratios consisting of 13 miRNAs were differentially regulated in both murine models. Measuring these miRNAs in the training cohort identified a biomarker signature consisting of five miRNA ratios (7 miRNAs). This signature showed a good sensitivity and specificity in the test cohort with an area under the receiver operating characteristic curve (AUC) of 0.92. Correlation of miRNA ratios with clinical characteristics further revealed associations with FVC % predicted, and oral corticosteroid or antileukotriene use. CONCLUSION: Distinct plasma miRNAs are differentially regulated both in murine and in human allergic asthma and were associated with clinical characteristics of patients. Thus, we suggest that miRNA levels in plasma might have future potential to subphenotype patients with asthma.

Periodontal treatment in patients with chronic kidney disease: a pilot study.

BACKGROUND AND OBJECTIVE: This pilot cohort study evaluated the effect of periodontal treatment on renal function, metabolic markers and asymmetric dimethylarginine (ADMA) in patients with pre-dialysis chronic kidney disease (CKD) presenting chronic periodontitis. MATERIAL AND METHODS: Twenty-six patients with CKD and severe chronic periodontitis were selected. Periodontal parameters included plaque index, bleeding on probing, probing pocket depth and clinical attachment level. Estimated glomerular filtration rate (eGFR), triglycerides, total cholesterol, albumin and ADMA levels were evaluated at baseline, 90 and 180 d after periodontal therapy. eGFR was evaluated by the Modification of Diet in Renal Disease equation. RESULTS: All periodontal clinical parameters significantly improved (p < 0.05) 180 d after periodontal therapy. There was a significant improvement on the median values (25%; 75% percentiles) of eGFR from 34.6 (27; 44.7) mL/min/1.73 m2 on baseline to 37.6 (29.7; 57) mL/min/1.73 m2 on day 90, and to 37.6 (28.6; 56) mL/min/1.73 m2 (p < 0.05) on day 180. ADMA levels significantly reduced 180 d after periodontal treatment. No significant differences were observed at the median values of metabolic markers comparing baseline and 180 d after periodontal treatment. CONCLUSIONS: The results point to a link of kidney disease with endothelium dysfunction and periodontitis, suggesting that periodontal treatment may be beneficial to the course of CKD.

High-power lasers for directed-energy applications: reply.

The comment by Vorontsov and Weyrauch [Appl. Opt.55, 9950 (2016)APOPAI0003-693510.1364/AO.55.009950] is aimed at rebutting the critiques in Sprangle et al. [Appl. Opt.54, F201 (2015)APOPAI0003-693510.1364/AO.54.00F201] and Nelson et al. [Appl. Opt.55, 1757 (2016)APOPAI0003-693510.1364/AO.55.001757]. In the comment, Vorontsov and colleagues describe their experiments aimed at demonstrating the feasibility of coherent combining of lasers on a distant target, using relatively low-power lasers and a cooperative retro-reflective target. The Naval Research Laboratory has demonstrated the capability to project high power on a distant target by making use of an incoherent combining architecture. The proof-of-concept experiments were performed in a realistic environment without employing cooperative targets and without sophisticated adaptive optics instrumentation.

Elevated ST2 Distinguishes Incidences of Pediatric Heart and Small Bowel Transplant Rejection.

Elevated serum soluble (s) suppressor of tumorigenicity-2 is observed during cardiovascular and inflammatory bowel diseases. To ascertain whether modulated ST2 levels signify heart (HTx) or small bowel transplant (SBTx) rejection, we quantified sST2 in serially obtained pediatric HTx (n = 41) and SBTx recipient (n = 18) sera. At times of biopsy-diagnosed HTx rejection (cellular and/or antibody-mediated), serum sST2 was elevated compared to rejection-free time points (1714 ± 329 vs. 546.5 ± 141.6 pg/mL; p = 0.0002). SBTx recipients also displayed increased serum sST2 during incidences of rejection (7536 ± 1561 vs. 2662 ± 543.8 pg/mL; p = 0.0347). Receiver operator characteristic (ROC) analysis showed that serum sST2 > 600 pg/mL could discriminate time points of HTx rejection and nonrejection (area under the curve [AUC] = 0.724 ± 0.053; p = 0.0003). ROC analysis of SBTx measures revealed a similar discriminative capacity (AUC = 0.6921 ± 0.0820; p = 0.0349). Quantitative evaluation of both HTx and SBTx biopsies revealed that rejection significantly increased allograft ST2 expression. Pathway and Network Analysis of biopsy data pinpointed ST2 in the dominant pathway modulated by rejection and predicted tumor necrosis factor-α and IL-1ß as upstream activators. In total, our data indicate that alloimmune-associated pro-inflammatory cytokines increase ST2 during rejection. They also demonstrate that routine serum sST2 quantification, potentially combined with other biomarkers, should be investigated further to aid in the noninvasive diagnosis of rejection.

Probing Quantum Capacitance in a 3D Topological Insulator.

We measure the quantum capacitance and probe thus directly the electronic density of states of the high mobility, Dirac type two-dimensional electron system, which forms on the surface of strained HgTe. Here we show that observed magnetocapacitance oscillations probe-in contrast to magnetotransport-primarily the top surface. Capacitance measurements constitute thus a powerful tool to probe only one topological surface and to reconstruct its Landau level spectrum for different positions of the Fermi energy.

Micro-dose hCG as luteal phase support without exogenous progesterone administration: mathematical modelling of the hCG concentration in circulation and initial clinical experience.

For the last two decades, exogenous progesterone administration has been used as luteal phase support (LPS) in connection with controlled ovarian stimulation combined with use of the human chorionic gonadotropin (hCG) trigger for the final maturation of follicles. The introduction of the GnRHa trigger to induce ovulation showed that exogenous progesterone administration without hCG supplementation was insufficient to obtain satisfactory pregnancy rates. This has prompted development of alternative strategies for LPS. Augmenting the local endogenous production of progesterone by the multiple corpora lutea has been one focus with emphasis on one hand to avoid development of ovarian hyper-stimulation syndrome and, on the other hand, to provide adequate levels of progesterone to sustain implantation. The present study evaluates the use of micro-dose hCG for LPS support and examines the potential advances and disadvantages. Based on the pharmacokinetic characteristics of hCG, the mathematical modelling of the concentration profiles of hCG during the luteal phase has been evaluated in connection with several different approaches for hCG administration as LPS. It is suggested that the currently employed LPS provided in connection with the GnRHa trigger (i.e. 1.500 IU) is too strong, and that daily micro-dose hCG administration is likely to provide an optimised LPS with the current available drugs. Initial clinical results with the micro-dose hCG approach are presented.

[Predictive PD-L1 immunohistochemistry for non-small cell lung cancer : Current state of the art and experiences of the first German harmonization study]. / Prädiktive PD-L1-Immunhistochemie beim nichtkleinzelligen Bronchialkarzinom : Aktueller Stand und Erfahrungen der ersten deutschen Harmonisierungsstudie.

BACKGROUND: Antibodies against PD-1 and PD-L1 can cause strong and durable anti-tumor immune responses in non-small cell lung cancer (NSCLC). Immunohistochemistry for PD-L1 (PD-L1 IHC) was tested as a predictive biomarker. Several IHC assays and interpretation criteria were developed in parallel. AIM: The clinical significance of PD-L1 IHC in NSCLC and the optimum method for staining and interpretation of the results are the subject of ongoing studies. The diagnostic application of immunotherapy in NSCLC necessitates harmonization of PD-L1 IHC to obtain evidence for guidelines; therefore, a consensus opinion on a well-founded diagnostic mode of testing should be defined based on published studies and the results of the first German PD-L1 IHC harmonization study. METHODS: 1. Summary of the current data situation. 2. Evaluation of the first German PD-L1 IHC harmonization study (centralized, staining with PD-L1 IHC analogous to studies, 15 cases of NSCLC, 4 IHC study assays [28­8, 22C3, SP142 and SP263] and scoring by 9 pathologists). RESULTS: The use of PD-L1 IHC in NSCLC is suitable for identification of patients with an increased probability of a clinical benefit from immunotherapy. The various proportional cut-offs used to interpret the staining results can be summarized in a total score, which can be reproducibly assessed. The staining patterns of the four assays investigated were, however, not congruent in all situations. DISCUSSION: In principle, the use of PD-L1 IHC for assessment of the expression in tumor cells is a reliably determinable biomarker. Evaluation algorithms should be based on published clinical trials. For NSCLC approvals with obligatory PD-L1 IHC are to be expected but it remains to be seen to what extent PD-L1 IHC will be implemented in the clinical routine.