Hybrid air-bulk multi-pass cell compressor for high pulse energies with full spatio-temporal characterization.

Multi-pass cell (MPC) compressors have proven to be the method of choice for compression of high average power long-pulse Yb lasers. Yet, generating sub-30 fs pulses at high pulse energy with compact and simple components remains a challenge. This work demonstrates an efficient and cost-effective approach for nonlinear pulse compression at high pulse energy using a hybrid air-bulk MPC. By carefully balancing the relative nonlinear contributions of ambient air and fused silica, we achieve strong spectral broadening without dispersion engineering or pressure-control inside the cell at 400-µJ pulse energy. In this way, we compress pulses from 220 fs to 27 fs at 40.3 W of average power (100 kHz repetition rate), enhancing the peak power from 1.6 GW to 10.2 GW while maintaining 78% of the energy within the main pulse. Our approach combines the strengths of gas-filled and bulk compression schemes and exhibits excellent overall optical transmission (91%) and spectral uniformity. Moreover, we utilize the INSIGHT technique to investigate spatio-temporal couplings and geometrical aberrations of the compressed pulse. Our results demonstrate remarkable temporal homogeneity, with an average Strehl ratio of 0.97 consistently observed throughout the entire spectral profile. Additionally, all spectrally-integrated Zernike coefficients for geometrical aberrations maintain values below 0.02λ.

Revisiting Electronic Topological Transitions in the Silver-Palladium (AgcPd1-c) Solid Solution: An Experimental and Theoretical Investigation.

Multiple thick film samples of the AgcPd1-c solid solution were prepared using physical vapour deposition over a borosilicate glass substrate. This synthesis technique allows continuous variation in stoichiometry, while the distribution of silver or palladium atoms retains the arrangement into an on-average periodic lattice with smoothly varying unit cell parameters. The alloy concentration and geometry were measured over a set of sample points, respectively, via energy-dispersive X-ray spectroscopy and via X-ray diffraction. These results are compared with ab initio total energy and electronic structure calculations based on density functional theory, and using the coherent potential approximation for an effective medium description of disorder. The theoretically acquired lattice parameters appear in qualitative agreement with the measured trends. The numerical study of the Fermi surface also shows a variation in its topological features, which follow the change in silver concentration. These were related to the electrical resistivity of the AgcPd1-c alloy. The theoretically obtained variation exhibits a significant correlation with nonlinear changes in the resistivity as a function of composition. This combined experimental and theoretical study suggests the possibility of using resistivity measurements along concentration gradients as a way to gain some microscopic insight into the electronic structure of an alloy.

The Urine Light Chain/eGFR Quotient as a Tool to Rule out Cast Nephropathy in Myeloma-Associated Kidney Failure.

Kidney involvement with resulting kidney failure leads to increased mortality in patients with multiple myeloma (MM). Cast nephropathy (CN), in particular, if left untreated, quickly leads to kidney failure requiring dialysis and has a very poor prognosis for the affected patient. The gold standard for diagnosing kidney involvement is a kidney biopsy. However, due to bleeding risk, this cannot be done in every patient. We recently reported that a quotient of urine light chain (LCurine) to glomerular filtration rate (eGFR) is a non-invasive diagnostic tool for patients with kidney involvement in MM. But this quotient has not yet been tested in everyday clinical practice. In this study, our LCurine/eGFR ratio was tested on 67 patients in two centers. Enrollment took place between January 2019 and September 2023. A total of 18 of the 67 patients had CN. With the threshold defined in our initial paper, we were able to show a sensitivity of 100% with a specificity of 85.7% for CN in patients with MM. As a result, the LCurine/eGFR quotient recognizes 100% of all CN and can therefore detect this group, which has a very poor prognosis, without the need for a kidney biopsy.

The addition of bortezomib to rituximab, high-dose cytarabine and dexamethasone in relapsed or refractory mantle cell lymphoma-a randomized, open-label phase III trial of the European mantle cell lymphoma network.

The therapy of relapsed or refractory (r/r) mantle cell lymphoma (MCL) patients remains a major clinical challenge to date. We conducted a randomized, open-label, parallel-group phase-III trial hypothesizing superior efficacy of rituximab, high-dose cytarabine and dexamethasone with bortezomib (R-HAD + B) versus without (R-HAD) in r/r MCL ineligible for or relapsed after autologous stem cell transplant (ASCT). Primary endpoint was time to treatment failure (TTF), secondary endpoints included response rates, progression free survival, overall survival, and safety. In total, 128 of 175 planned patients were randomized to R-HAD + B (n = 64) or R-HAD (n = 64). Median TTF was 12 vs. 2.6 months (p = 0.045, MIPI-adjusted HR 0.69; 95%CI 0.47-1.02). Overall and complete response rates were 63 vs. 45% (p = 0.049) and 42 vs. 19% (p = 0.0062). A significant treatment effect was seen in the subgroup of patients >65 years (aHR 0.48, 0.29-0.79) and without previous ASCT (aHR 0.52, 0.28-0.96). Toxicity was mostly hematological and attributable to the chemotherapeutic backbone. Grade ≥3 leukocytopenia and lymphocytopenia were more common in R-HAD + B without differences in severe infections between both arms. Bortezomib in combination with chemotherapy can be effective in r/r MCL and should be evaluated further as a therapeutic option, especially if therapy with BTK inhibitors is not an option. Trial registration: NCT01449344.

Rituximab, gemcitabine and oxaliplatin in relapsed or refractory indolent and mantle cell lymphoma: results of a multicenter phase I/II-study of the German Low Grade Lymphoma Study Group.

Rituximab, gemcitabine and oxaliplatin (R-GemOx) has demonstrated to be effective and safe in lymphoma patients. We aimed to determine the maximum tolerated dose (MTD) of oxaliplatin in combination with rituximab and gemcitabine and to explore the efficacy and safety of R-GemOx in relapsed or refractory (r/r) indolent and mantle cell lymphoma (MCL). In this single-arm, phase I/II trial, we enrolled 55 patients with r/r indolent lymphoma and MCL not suitable for autologous stem-cell transplantation. Patients received 4 cycles of R-GemOx. In the dose escalation group, 70 mg/m2 of oxaliplatin was applied and interindividually increased by 10 mg/m2 until the MTD was reached together with fixed doses of rituximab and gemcitabine. At the oxaliplatin MTD, an extension cohort was opened. Primary aim was to detect an overall response rate (ORR) greater than 65% (α = 0.05). Oxaliplatin 70 mg/m2 (MTD) was chosen for the extension cohort after 3 of 6 patients experienced a DLT at 80 mg/m2. Among 46 patients evaluable for the efficacy analysis ORR was 72% (33/46), missing the primary aim of the study (p = 0.21). After a median follow-up of 7.9 years, median PFS and OS were 1.0 and 2.1 years. Most frequent grade ≥ 3 adverse events were cytopenias. R-GemOx induces decent response rates in r/r indolent lymphoma and MCL, though novel targeted therapies have largely replaced chemotherapy in the relapse setting. Particularly in MCL, R-GemOx might be an alternative option in late relapses or as bridging to CAR-T-cells. This study was registered with ClinicalTrials.gov on Aug 4th, 2009, number NCT00954005.

Highly Selective Tilted Triangular Springs with Constant Force Reaction.

Guiding mechanisms are among the most elementary components of MEMS. Usually, a spring is required to be compliant in only one direction and stiff in all other directions. We introduce triangular springs with a preset tilting angle. The tilting angle lowers the reaction force and implements a constant reaction force. We show the influence of the tilting angle on the reaction force, on the spring stiffness and spring selectivity. Furthermore, we investigate the influence of the different spring geometry parameters on the spring reaction force. We experimentally show tilted triangular springs exhibiting constant force reactions in a large deflection range and a comb-drive actuator guided by tilted triangular springs.

GHz repetition rate, sub-100-fs Ho:CALGO laser at 2.1†µm with watt-level average power.

We report on a GHz fundamental repetition rate Kerr-lens mode-locked Ho:CALGO laser emitting at 2.1 µm. The laser employs a ring cavity to increase the fundamental repetition rate to 1.179 GHz and can be made to oscillate in both directions stably with nearly identical performance: for the counterclockwise oscillation, it generates 93-fs pulses at 1.68 W of average power, whereas 92 fs and 1.69 W were measured for the clockwise operation. Our current results represent the highest average power from a 2-µm GHz oscillator and, to our knowledge, the first sub-100-fs pulse duration from a Ho-based oscillator.

An Innovative Non-Linear Prediction Model for Clinical Benefit in Women with Newly Diagnosed Breast Cancer Using Baseline FDG-PET/CT and Clinical Data.

Objectives: We aimed to develop a novel non-linear statistical model integrating primary tumor features on baseline [18F]-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), molecular subtype, and clinical data for treatment benefit prediction in women with newly diagnosed breast cancer using innovative statistical techniques, as opposed to conventional methodological approaches. Methods: In this single-center retrospective study, we conducted a comprehensive assessment of women newly diagnosed with breast cancer who had undergone a FDG-PET/CT scan for staging prior to treatment. Primary tumor (PT) volume, maximum and mean standardized uptake value (SUVmax and SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured on PET/CT. Clinical data including clinical staging (TNM) but also PT anatomical site, histology, receptor status, proliferation index, and molecular subtype were obtained from the medical records. Overall survival (OS), progression-free survival (PFS), and clinical benefit (CB) were assessed as endpoints. A logistic generalized additive model was chosen as the statistical approach to assess the impact of all listed variables on CB. Results: 70 women with newly diagnosed breast cancer (mean age 63.3 ± 15.4 years) were included. The most common location of breast cancer was the upper outer quadrant (40.0%) in the left breast (52.9%). An invasive ductal adenocarcinoma (88.6%) with a high tumor proliferation index (mean ki-67 expression 35.1 ± 24.5%) and molecular subtype B (51.4%) was by far the most detected breast tumor. Most PTs displayed on hybrid imaging a greater volume (12.8 ± 30.4 cm3) with hypermetabolism (mean ± SD of PT maximum SUVmax, SUVmean, MTV, and TLG, respectively: 8.1 ± 7.2, 4.9 ± 4.4, 12.7 ± 30.4, and 47.4 ± 80.2). Higher PT volume (p < 0.01), SUVmax (p = 0.04), SUVmean (p = 0.03), and MTV (<0.01) significantly compromised CB. A considerable majority of patients survived throughout this period (92.8%), while five women died (7.2%). In fact, the OS was 31.7 ± 14.2 months and PFS was 30.2 ± 14.1 months. A multivariate prediction model for CB with excellent accuracy could be developed using age, body mass index (BMI), T, M, PT TLG, and PT volume as predictive parameters. PT volume and PT TLG demonstrated a significant influence on CB in lower ranges; however, beyond a specific cutoff value (respectively, 29.52 cm3 for PT volume and 161.95 cm3 for PT TLG), their impact on CB only reached negligible levels. Ultimately, the absence of distant metastasis M displayed a strong positive impact on CB far ahead of the tumor size T (standardized average estimate 0.88 vs. 0.4). Conclusions: Our results emphasized the pivotal role played by FDG-PET/CT prior to treatment in forecasting treatment outcomes in women newly diagnosed with breast cancer. Nevertheless, careful consideration is required when selecting the methodological approach, as our innovative statistical techniques unveiled non-linear influences of predictive biomarkers on treatment benefit, highlighting also the importance of early breast cancer diagnosis.

Development of an individual helmet orthosis for infants based on a 3D scan.

An early childhood skull deformity can have long-term health and aesthetic consequences for the growing toddler. Individual helmet therapy aims at a healthy growth of the skull shape, although not every helmet shape guarantees an optimal result. To ensure an optimal fit, a scanning procedure based on a hand-held surface scanner was evaluated.The new helmet orthosis has an inner layer adapted to the shape of the head, which can be exchanged depending on the growth stage without changing the outer layer.In collaboration with surgeons and engineers, a new helmet orthosis concept was developed that is intended to offer improvements in wearing comfort, overall weight, fit and user-friendliness compared to conventional systems. In the course of the development process and in constant exchange with parents, a multi-layer helmet system with generous perforations was created using additive manufacturing processes. The new helmet shape promises easier handling, especially through the closure system.The helmet shape developed in this study is of high quality, especially in terms of fitting accuracy. Unpleasant perspiration is significantly reduced. The integration of the closure as a direct component of the helmet represents a secure closure option.

Ex vivo expansion of lung cancer-derived disseminated cancer cells from lymph nodes identifies cells associated with metastatic progression.

The cellular basis of the apparent aggressiveness in lung cancer is poorly understood but likely associated with functional or molecular features of disseminated cancer cells (DCCs). DCCs from epithelial cancers are mostly detected by antibodies directed against histogenetic markers such as cytokeratin or EpCAM. It has been argued that marker-negative metastatic founder cells might escape detection. We therefore used ex vivo sphere formation for functional detection of candidate metastasis founders. We generated cell suspensions from 199 LN samples of 131 lung cancer patients and placed them into non-adherent cell culture. Sphere formation was associated with detection of DCCs using EpCAM immunocytology and with significantly poorer prognosis. The prognostic impact of sphere formation was strongly associated with high numbers of EpCAM-positive DCCs and aberrant genotypes of expanded spheres. We also noted sphere formation in patients with no evidence of lymphatic spread, however such spheres showed infrequent expression of signature genes associated with spheres from EpCAM-positive samples and displayed neither typical lung cancer mutations (KRAS, TP53, ERBB1) nor copy number variations, but might be linked to disease progression >5 years post curative surgery. We conclude that EpCAM identifies relevant disease-driving DCCs, that such cells can be expanded for model generation and that further research is needed to clarify the functional and prognostic role of rare EpCAM-negative sphere forming cells.

A force-compensated compliant MEMS-amplifier with electrostatic anti-springs.

In this paper, an electrostatic compliant mechanical amplifier intended for force-compensated displacement amplification in MEMS sensor applications is described. Usually, mechanical transformers that enhance a small input displacement into a large output displacement generate large forces at the input of the transformer. The microsystem proposed here allows for the reduction and compensation of the input stiffness of the amplifier and any mechanical components connected to it while providing a constant amplification ratio at the same time. The amplifying mechanism features bidirectional electrostatic anti-springs enabling the control of the stiffness by applying a constant DC voltage. The electrode design of the anti-springs and its influence on the force-displacement characteristic, the side instability and the maximal displacement are studied through analytical approaches and supported by FEA and by experiments. Based on the derived models, a compliant electromechanical amplifier is developed, featuring an amplification ratio of 50. For this amplifier the initial input stiffness of 422 N/m could be reduced to 6.8 N/m by applying a voltage of 100 V. As an additional application, we show how the amplifier can be used as a mechanical force sensor with tuneable sensitivity, where the forces at the input are transformed into large output displacements. Through experiments, we show how the sensitivity can be adjusted and increased by a factor of 25 by applying a voltage at the anti-springs.

Predictive Value of Total Metabolic Tumor Burden Prior to Treatment in NSCLC Patients Treated with Immune Checkpoint Inhibition.

OBJECTIVES: We aimed to assess the predictive value of the total metabolic tumor burden prior to treatment in patients with advanced non-small-cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICIs). METHODS: Pre-treatment 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (PET/CT) scans performed in two consecutive years for staging in adult patients with confirmed NSCLC were considered. Volume, maximum/mean standardized uptake value (SUVmax/SUVmean), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were assessed per delineated malignant lesion (including primary tumor, regional lymph nodes and distant metastases) in addition to the morphology of the primary tumor and clinical data. Total metabolic tumor burden was captured by totalMTV and totalTLG. Overall survival (OS), progression-free survival (PFS) and clinical benefit (CB) were used as endpoints for response to treatment. RESULTS: A total of 125 NSCLC patients were included. Osseous metastases were the most frequent distant metastases (n = 17), followed by thoracal distant metastases (pulmonal = 14 and pleural = 13). Total metabolic tumor burden prior to treatment was significantly higher in patients treated with ICIs (mean totalMTV ± standard deviation (SD) 72.2 ± 78.7; mean totalTLG ± SD 462.2 ± 538.9) compared to those without ICI treatment (mean totalMTV ± SD 58.1 ± 233.8; mean totalTLG ± SD 290.0 ± 784.2). Among the patients who received ICIs, a solid morphology of the primary tumor on imaging prior to treatment was the strongest outcome predictor for OS (Hazard ratio HR 28.04, p < 0.01), PFS (HR 30.89, p < 0.01) and CB (parameter estimation PE 3.46, p < 0.01), followed by the metabolic features of the primary tumor. Interestingly, total metabolic tumor burden prior to immunotherapy showed a negligible impact on OS (p = 0.04) and PFS (p = 0.01) after treatment given the hazard ratios of 1.00, but also on CB (p = 0.01) given the PE < 0.01. Overall, biomarkers on pre-treatment PET/CT scans showed greater predictive power in patients receiving ICIs, compared to patients without ICI treatment. CONCLUSIONS: Morphological and metabolic properties of the primary tumors prior to treatment in advanced NSCLC patients treated with ICI showed great outcome prediction performances, as opposed to the pre-treatment total metabolic tumor burdens, captured by totalMTV and totalTLG, both with negligible impact on OS, PFS and CB. However, the outcome prediction performance of the total metabolic tumor burden might be influenced by the value itself (e.g., poorer prediction performance at very high or very low values of total metabolic tumor burden). Further studies including subgroup analysis with regards to different values of total metabolic tumor burden and their respective outcome prediction performances might be needed.

Low-noise, 2-W average power, 112-fs Kerr-lens mode-locked Ho:CALGO laser at 2.1†µm.

We report on an in-band pumped soft-aperture Kerr-lens mode-locked Ho3+-doped CaGdAlO4 (Ho:CALGO) bulk laser at 2.1 µm, generating 2 W of average power with 112 fs pulses at 91-MHz repetition rate. To the best of our knowledge, this is the highest average power from a 100-fs class mode-locked laser based on a Tm3+ or Ho3+ doped bulk material. We show that the laser has excellent noise properties, with an integrated relative intensity noise of 0.02% and a timing jitter of 950 fs (rms phase noise 0.543 mrad) in the integration interval from 10 Hz to 10 MHz of offset frequency. The demonstrated combination of high average power, short pulses, and low noise makes this an outstanding laser source for many applications at 2.1 µm.

Prediction of Bone Marrow Biopsy Results From MRI in Multiple Myeloma Patients Using Deep Learning and Radiomics.

OBJECTIVES: In multiple myeloma and its precursor stages, plasma cell infiltration (PCI) and cytogenetic aberrations are important for staging, risk stratification, and response assessment. However, invasive bone marrow (BM) biopsies cannot be performed frequently and multifocally to assess the spatially heterogenous tumor tissue. Therefore, the goal of this study was to establish an automated framework to predict local BM biopsy results from magnetic resonance imaging (MRI). MATERIALS AND METHODS: This retrospective multicentric study used data from center 1 for algorithm training and internal testing, and data from center 2 to 8 for external testing. An nnU-Net was trained for automated segmentation of pelvic BM from T1-weighted whole-body MRI. Radiomics features were extracted from these segmentations, and random forest models were trained to predict PCI and the presence or absence of cytogenetic aberrations. Pearson correlation coefficient and the area under the receiver operating characteristic were used to evaluate the prediction performance for PCI and cytogenetic aberrations, respectively. RESULTS: A total of 672 MRIs from 512 patients (median age, 61 years; interquartile range, 53-67 years; 307 men) from 8 centers and 370 corresponding BM biopsies were included. The predicted PCI from the best model was significantly correlated ( P ≤ 0.01) to the actual PCI from biopsy in all internal and external test sets (internal test set: r = 0.71 [0.51, 0.83]; center 2, high-quality test set: r = 0.45 [0.12, 0.69]; center 2, other test set: r = 0.30 [0.07, 0.49]; multicenter test set: r = 0.57 [0.30, 0.76]). The areas under the receiver operating characteristic of the prediction models for the different cytogenetic aberrations ranged from 0.57 to 0.76 for the internal test set, but no model generalized well to all 3 external test sets. CONCLUSIONS: The automated image analysis framework established in this study allows for noninvasive prediction of a surrogate parameter for PCI, which is significantly correlated to the actual PCI from BM biopsy.

Improvement of vertebral body fracture reduction utilizing a posterior reduction tool: a single-center experience.

BACKGROUND: Extensive research regarding instabilities and prevention of kyphotic malalignment in the thoracolumbar spine exists. Keystones of this treatment are posterior instrumentation and anterior vertebral height restoration. Anterior column reduction via a single-stage procedure seems to be advantageous regarding complication, blood loss, and OR-time. Mechanical elevation of the anterior cortex of the vertebra may prevent the necessity of additional anterior stabilization or vertebral body replacement. The purpose of this study was to examine (1) if increased bony reduction in the anterior vertebral cortex could be achieved by utilization of an additional reduction tool, (2) if postoperative loss of vertebral height could be reduced, and (3) if anterior column reduction is related to clinical outcome. METHODS: From one level I trauma center, 173 patients underwent posterior stabilization for fractures of the thoracolumbar region between 2015 and 2020. Reduction in the vertebral body was performed via intraoperative lordotic positioning or by utilization of an additional reduction tool (Nforce, Medtronic). The reduction tool was mounted onto the pedicle screws and removed after tightening of the locking screws. To assess bony reduction, the sagittal index (SI) and vertebral kyphosis angle (VKA) were measured on X-rays and CT images at different time points ((1) preoperative, (2) postoperative, (3) ≥ 3 months postoperative). Clinical outcome was assessed utilizing the Ostwestry Disability Index (ODI). RESULTS: Bisegmental stabilization of AO/OTA type A3/A4 vertebral fractures was performed in 77 patients. Thereof, reduction was performed in 44 patients (females 34%) via intraoperative positioning alone (control group), whereas 33 patients (females 33%) underwent additional reduction utilizing a mechanical reduction tool (instrumentation group). Mean age was 41 ± 13 years in the instrumentation group (IG) and 52 ± 12 years in the control group (CG) (p < 0.001). No differences in terms of gender and comorbidities were found between the two groups. Preoperatively, the sagittal index (SI) was 0.69 in IG compared to 0.74 in CG (p = 0.039), resulting in a vertebral kyphosis angle (VKA) of 15.0° vs. 11.7° (p = 0.004). Intraoperatively, a significantly greater correction of the kyphotic deformity was achieved in the IG (p < 0.001), resulting in a compensation of the initially more severe kyphotic malalignment. The SI was corrected by 0.20-0.88 postoperatively, resulting in an improvement of the VKA by 8.7°-6.3°. In the CG, the SI could be corrected by 0.12-0.86 and the VKA by 5.1°-6.6°. The amount of correction was influenced by the initial deformity (p < 0.001). Postoperatively, both groups showed a loss of correction, resulting in a gain of 0.08 for the SI and 4.1° in IG and 0.03 and 2.0°, respectively. The best results were observed in younger patients with initially severe kyphotic deformity. Considering various influencing factors, clinical outcome determined by the ODI showed no significant differences between both groups. CONCLUSION: Utilization of the investigated reduction tool during posterior stabilization of vertebral body fractures in a suitable collective of young patients with good bone quality and severe fracture deformity may lead to better reduction in the ventral column of the fractured vertebral body and angle correction. Therefore, additional anterior stabilization or vertebral body replacement may be prevented.

Additional Primary Tumors Detected Incidentally on FDG PET/CT at Staging in Patients with First Diagnosis of NSCLC: Frequency, Impact on Patient Management and Survival.

We aimed to assess the frequency of additional primary malignancies detected incidentally on [18F]fluoro-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) at staging in NSCLC patients. Moreover, their impact on patient management and survival was assessed. Consecutive NSCLC patients with available staging FDG-PET/CT between 2020 and 2021 were retrospectively enrolled. We reported whether further investigations of suspicious findings presumably not related to NSCLC were recommended and performed after FDG-PET/CT. Any additional imaging, surgery or multimodal management was considered as an impact on patient management. Patient survival was defined using overall survival OS and progression-free survival PFS. A total of 125 NSCLC patients were included, while 26 findings in 26 different patients were suspicious for an additional malignancy on FDG-PET/CT at staging. The most frequent anatomical site was the colon. A total of 54.2% of all additional suspicious lesions turned out to be malignant. Almost every malignant finding had an impact on patient management. No significant differences were found between NSCLC patients with suspicious findings versus no suspicious findings with regards to their survival. FDG-PET/CT performed for staging might be a valuable tool to identify additional primary tumors in NSCLC patients. Identification of additional primary tumors might have substantial implications for patient management. An early detection together with interdisciplinary patient management could prevent a worsening of survival compared to patients with NSCLC only.

MAD HATTER Correctly Annotates 98% of Small Molecule Tandem Mass Spectra Searching in PubChem.

Metabolites provide a direct functional signature of cellular state. Untargeted metabolomics usually relies on mass spectrometry, a technology capable of detecting thousands of compounds in a biological sample. Metabolite annotation is executed using tandem mass spectrometry. Spectral library search is far from comprehensive, and numerous compounds remain unannotated. So-called in silico methods allow us to overcome the restrictions of spectral libraries, by searching in much larger molecular structure databases. Yet, after more than a decade of method development, in silico methods still do not reach the correct annotation rates that users would wish for. Here, we present a novel computational method called Mad Hatter for this task. Mad Hatter combines CSI:FingerID results with information from the searched structure database via a metascore. Compound information includes the melting point, and the number of words in the compound description starting with the letter 'u'. We then show that Mad Hatter reaches a stunning 97.6% correct annotations when searching PubChem, one of the largest and most comprehensive molecular structure databases. Unfortunately, Mad Hatter is not a real method. Rather, we developed Mad Hatter solely for the purpose of demonstrating common issues in computational method development and evaluation. We explain what evaluation glitches were necessary for Mad Hatter to reach this annotation level, what is wrong with similar metascores in general, and why metascores may screw up not only method evaluations but also the analysis of biological experiments. This paper may serve as an example of problems in the development and evaluation of machine learning models for metabolite annotation.

Spectral broadening of 2-mJ femtosecond pulses in a compact air-filled convex-concave multi-pass cell.

Multi-pass cell (MPC) based temporal pulse compressors have emerged in recent years as a powerful and versatile solution to the intrinsic issue of long pulses from Yb-based high-power ultrafast lasers. The spectral broadening of high-energy (typically more than 100 µJ) pulses has only been realized in gas-filled MPCs due to the significantly lower nonlinear coefficient of gases compared with solid-state media. Whereas these systems reach impressive performance in terms of spectral broadening with very low spatiotemporal couplings, they are typically complex setups, i.e., large and costly pressure-controlled vacuum chambers to avoid strong focusing, ionization, and damage to the mirrors. Here, we present spectral broadening of 2-mJ pulses in a simple and compact (60-cm-long) multi-pass cell operated in ambient air. Instead of the traditional Herriott cell with concave-concave (CC/CC) mirrors, we use a convex-concave (CX/CC) design, where the beam stays large at all times, both minimizing damage and allowing operation in ambient air. We demonstrate spectral broadening of 2.1-mJ pulses at 100 kHz repetition rate (200 W of average power) from 2.1 nm (pulse duration of 670 fs) to a spectral bandwidth of 24.5 nm, supporting 133-fs pulses with 96% transmission efficiency. We show the compressibility of these pulses down to 134 fs and verify that the spectral homogeneity of the beam is similar to previously reported CC/CC designs. To the best of the authors' knowledge, this is the first report of a CX/CC MPC compressor operated at high pulse energies in air. Because of its simplicity, small footprint, and low cost, we believe this demonstration will have significant impact in the ultrafast laser community.

A program of successive gene expression in mouse one-cell embryos.

At the moment of union in fertilization, sperm and oocyte are transcriptionally silent. The ensuing onset of embryonic transcription (embryonic genome activation [EGA]) is critical for development, yet its timing and profile remain elusive in any vertebrate species. We here dissect transcription during EGA by high-resolution single-cell RNA sequencing of precisely synchronized mouse one-cell embryos. This reveals a program of embryonic gene expression (immediate EGA [iEGA]) initiating within 4 h of fertilization. Expression during iEGA produces canonically spliced transcripts, occurs substantially from the maternal genome, and is mostly downregulated at the two-cell stage. Transcribed genes predict regulation by transcription factors (TFs) associated with cancer, including c-Myc. Blocking c-Myc or other predicted regulatory TF activities disrupts iEGA and induces acute developmental arrest. These findings illuminate intracellular mechanisms that regulate the onset of mammalian development and hold promise for the study of cancer.