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.

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.

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.

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.

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.

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.

Disseminated cancer cells detected by immunocytology in lymph nodes of NSCLC patients are highly prognostic and undergo parallel molecular evolution.

In melanoma, immunocytology (IC) after sentinel lymph node disaggregation not only enables better quantification of disseminated cancer cells (DCCs) than routine histopathology (HP) but also provides a unique opportunity to detect, isolate, and analyse these earliest harbingers of metachronous metastasis. Here, we explored lymph node IC in non-small cell lung cancer (NSCLC). For 122 NSCLC patients, 220 lymph nodes (LNs) were split in half and prepared for IC and HP. When both methods were compared, IC identified 22% positive patients as opposed to 4.5% by HP, revealing a much higher sensitivity of IC (p < 0.001). Assessment of all available 2,952 LNs of the same patients by HP uncovered additional patients escaping detection of lymphatic tumour spread by IC alone, consistent with the concept of skip metastasis. A combined lymph node status of IC and complete HP on a larger cohort of patients outperformed all risk factors in multivariable analysis for prognosis (p < 0.001; RR = 2.290; CI 1.407-3.728). Moreover, isolation of DCCs and single-cell molecular characterization revealed that (1) LN-DCCs differ from primary tumours in terms of copy number alterations and selected mutations and (2) critical alterations are acquired during colony formation within LNs. We conclude that LN-IC in NSCLC patients when combined with HP improves diagnostic precision, has the potential to reduce total workload, and facilitates molecular characterization of lymphatically spread cancer cells, which may become key for the selection and development of novel systemic therapies. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

50-W average power Ho:YAG SESAM-modelocked thin-disk oscillator at 2.1†µm.

Ultrafast laser systems operating with high-average power in the wavelength range from 1.9 µm to 3 µm are of interest for a wide range of applications for example in spectroscopy, material processing and as drivers for secondary sources in the XUV spectral region. In this area, laser systems based on holmium-doped gain materials directly emitting at 2.1 µm have made significant progress over the past years, however so far only very few results were demonstrated in power-scalable high-power laser geometries. In particular, the thin-disk geometry is promising for directly modelocked oscillators with high average power levels that are comparable to amplifier systems at MHz repetition rate. In this paper, we demonstrate semiconductor saturable absorber mirror (SESAM) modelocked Ho:YAG thin-disk lasers (TDLs) emitting at 2.1-µm wavelength with record-holding performance levels. In our highest average power configuration, we reach 50 W of average power, with 1.13-ps pulses, 2.11 µJ of pulse energy and ∼1.9 MW of peak power. To the best of our knowledge, this represents the highest average power, as well as the highest output pulse energy so far demonstrated from a modelocked laser in the 2-µm wavelength region. This record performance level was enabled by the recent development of high-power GaSb-based SESAMs with low loss, adapted for high intracavity power and pulse energy. We also explore the limitations in terms of reaching shorter pulse durations at high power with this gain material in the disk geometry and using SESAM modelocking, and present first steps in this direction, with the demonstration of 30 W of output power, with 692-fs pulses in another laser configuration. In the near future, with the development of a next generation of SESAM samples for this wavelength region, we believe higher pulse energy approaching the 10-µJ regime, and sub-500-fs pulses should be straightforward to reach using SESAM modelocking.

8.7-W average power, in-band pumped femtosecond Ho:CALGO laser at 2.1 µm.

We report on an in-band pumped SESAM mode-locked Ho:CALGO bulk laser with a record-high average power of 8.7 W and an optical-to-optical efficiency of 38.2% at a central wavelength of 2.1 µm. At this power level, the bulk laser generates pulses with a duration of 369 fs at an 84.4-MHz repetition rate, corresponding to a pulse energy of 103 nJ and a peak power of 246 kW. To the best of our knowledge, this is the highest average power and pulse energy directly generated from a mode-locked bulk laser in the 2-3 µm wavelength region. Our current results indicate that Ho:CALGO is a competitive candidate for average power scaling of 2-µm femtosecond lasers.

Early dissemination seeds metastasis in breast cancer.

Accumulating data suggest that metastatic dissemination often occurs early during tumour formation, but the mechanisms of early metastatic spread have not yet been addressed. Here, by studying metastasis in a HER2-driven mouse breast cancer model, we show that progesterone-induced signalling triggers migration of cancer cells from early lesions shortly after HER2 activation, but promotes proliferation in advanced primary tumour cells. The switch from migration to proliferation was regulated by increased HER2 expression and tumour-cell density involving microRNA-mediated progesterone receptor downregulation, and was reversible. Cells from early, low-density lesions displayed more stemness features, migrated more and founded more metastases than cells from dense, advanced tumours. Notably, we found that at least 80% of metastases were derived from early disseminated cancer cells. Karyotypic and phenotypic analysis of human disseminated cancer cells and primary tumours corroborated the relevance of these findings for human metastatic dissemination.

Persistent acute cholecystitis after cholecystostomy - increased mortality due to treatment approach?

BACKGROUND: Percutaneous cholecystostomy (PC) is a treatment option for acute cholecystitis (AC) in cases where cholecystectomy (CCY) is not feasible due to limited health conditions. The use of PC remains questionable. The aim was to retrospectively analyse the outcome of patients after PC. METHODS: All patients who underwent PC for AC at a tertiary referral hospital over 10 years were included. Descriptive statistics, analysed mortality with and without CCY after PC, and a multivariable logistic regression for potential confounder and a landmark sensitivity analysis for immortal time bias were used. RESULTS: Of 158 patients, 79 were treated with PC alone and 79 had PC with subsequent CCY. Without CCY, 48% (38 patients) died compared to 9% with CCY. In the multivariable analysis CCY was associated with 85% lower risk of mortality. The landmark analysis was compatible with the main analyses. Direct PC-complications occurred in 17% patients. Histologically, 22/75 (29%) specimens showed chronic cholecystitis, and 76% AC. CONCLUSION: Due to the high mortality rate of PC alone, performing up-front CCY is proposed. PC represents no definitive treatment for AC and should remain a short-term solution because of the persistent inflammatory focus. According to these findings, almost all specimens showed persistent inflammation.

Analysis of THz generation using the tilted-pulse-front geometry in the limit of small pulse energies and beam sizes.

Optical rectification in lithium niobate using the tilted-pulse-front geometry is one of the most commonly used techniques for efficient generation of energetic single-cycle THz pulses and the details of this generation scheme are well understood for high pulse energy driving lasers, such as mJ-class, kHz-repetition rate Ti:Sa amplifier systems. However, as modern Yb-based laser systems with ever increasing repetition rate become available, other excitation regimes become relevant. In particular, the use of more moderate pulse energies (in the few µJ to multi-10 µJ regime), available nowadays by laser systems with MHz repetition rates, have never been thoroughly explored. As increasing the repetition rate of THz sources for spectroscopy becomes more relevant in the community, we present a thorough numerical analysis of this regime using a 2+1-D numerical model. Our work allows us to confirm experimental trends observed in this unusual excitation regime and shows that the conversion efficiency is naturally limited by the small pump beam sizes as a consequence of spatial walk-off between the pump and THz beams. Based on our findings, we discuss strategies to overcome the current limitations, which will pave the way for powerful THz sources approaching the watt level with multi-MHz repetition rates.

The urine light chain/glomerular filtration rate (GFR) quotient shows a high sensitivity and specificity to detect cast nephropathy in monoclonal light chain disease.

BACKGROUND: Cast nephropathy (CN) is associated with a unfavourable outcome in monoclonal light chain (mLC) disease, but also more possible LC-related renal diseases as well as non-LC-related disease can occur. Thus, it is crucial to understand the underlying renal disease. On the other hand, LC can interfere with coagulation preventing kidney biopsy as the gold standard. We sought to develop a non-invasive algorithm to diagnose CN with a good sensitivity and specificity. METHOD: We analysed data from patients with mLC disease who underwent kidney biopsy. The patients were classified in 4 groups according the renal histology: CN, AL amyloidosis, light chain deposition disease, and other renal disease. Afterwards, different algorithms were calculated for their sensitivity and specificity. RESULTS: CN showed a significant higher concentration of serum-free LC and urine LC (LCu), but there was a wide and overlapping range with the other groups. The best accuracy was achieved for a LCu/GFR ratio >2 in patients with lambda LC and either a LCu/GFR > 1 and proteinuria <8 g/24 h or a LCu/GFR > 5 in patients with proteinuria >8 g/24 h in patients with kappa LC. In lambda LC, the sensitivity and specificity for CN was 94% and 90%, respectively; in kappa LC 87% and 81%, respectively. DISCUSSION: In patients with coagulation disturbances due to LC, a non-invasive algorithm can separate patients with CN from other renal disease in mLC disease.

Developing Industrial CPS: A Multi-Disciplinary Challenge.

Industrial Cyber-Physical System (CPS) is an emerging approach towards value creation in modern industrial production. The development and implementation of industrial CPS in real-life production are rewarding yet challenging. This paper aims to present a concept to develop, commercialize, operate, and maintain industrial CPS which can motivate the advance of the research and the industrial practice of industrial CPS in the future. We start with defining our understanding of an industrial CPS, specifying the components and key technological aspects of the industrial CPS, as well as explaining the alignment with existing work such as Industrie 4.0 concepts, followed by several use cases of industrial CPS in practice. The roles of each component and key technological aspect are described and the differences between traditional industrial systems and industrial CPS are elaborated. The multidisciplinary nature of industrial CPS leads to challenges when developing such systems, and we present a detailed description of several major sub-challenges that are key to the long-term sustainability of industrial CPS design. Since the research of industrial CPS is still emerging, we also discuss existing approaches and novel solutions to overcome these sub-challenges. These insights will help researchers and industrial practitioners to develop and commercialize industrial CPS.

Terahertz Beam Steering Concept Based on a MEMS-Reconfigurable Reflection Grating.

With an increasing number of applications of terahertz systems in industrial fields and communications, terahertz beamforming and beam steering techniques are required for high-speed, large-area scanning. As a promising means for beam steering, micro-electro-mechanical system (MEMS)-based reflection gratings have been successfully implemented for terahertz beam control. So far, the diffraction grating efficiency is relatively low due to the limited vertical displacement range of the reflectors. In this paper, we propose a design for a reconfigurable MEMS-based reflection grating consisting of multiple subwavelength reflectors which are driven by 5-bit, high-throw electrostatic actuators. We vary the number of the reflectors per grating period and configure the throw of individual reflectors so that the reflection grating is shaped as a blazed grating to steer the terahertz beam with maximum diffraction grating efficiency. Furthermore, we provide a mathematical model for calculating the radiation pattern of the terahertz wave reflected by general reflection gratings consisting of subwavelength reflectors. The calculated and simulated radiation patterns of the designed grating show that we can steer the angle of the terahertz waves in a range of up to ± 56.4 ∘ with a maximum sidelobe level of -10 dB at frequencies from 0.3 THz to 1 THz.

Integration of Novel Sensors and Machine Learning for Predictive Maintenance in Medium Voltage Switchgear to Enable the Energy and Mobility Revolutions.

The development of renewable energies and smart mobility has profoundly impacted the future of the distribution grid. An increasing bidirectional energy flow stresses the assets of the distribution grid, especially medium voltage switchgear. This calls for improved maintenance strategies to prevent critical failures. Predictive maintenance, a maintenance strategy relying on current condition data of assets, serves as a guideline. Novel sensors covering thermal, mechanical, and partial discharge aspects of switchgear, enable continuous condition monitoring of some of the most critical assets of the distribution grid. Combined with machine learning algorithms, the demands put on the distribution grid by the energy and mobility revolutions can be handled. In this paper, we review the current state-of-the-art of all aspects of condition monitoring for medium voltage switchgear. Furthermore, we present an approach to develop a predictive maintenance system based on novel sensors and machine learning. We show how the existing medium voltage grid infrastructure can adapt these new needs on an economic scale.

Efficient nonlinear compression of a mode-locked thin-disk oscillator to 27 fs at 98 W average power.

We demonstrate efficient pulse compression of a 13.4 MHz, 534 fs, 123 W, Yb:YAG thin-disk oscillator down to 27 fs at 98 W average power, resulting in a record-high 166 MW peak power from an amplifier-free oscillator-driven setup. Our compressor is based on two stages: one multipass cell allowing us to reduce the pulse duration to sub-90 fs and, subsequently, a multiple-plate compressor, allowing us to reach 27 fs. The overall average power compression efficiency is 80%, and the beam has excellent beam quality and homogeneity. In addition, we demonstrate further spectral broadening that supports a transform limit of 5 fs in a second multiple-plate stage, demonstrating the potential for reaching a 100 W class, amplifier-free, few-cycle source in the near future. The performance of this unique source is very promising for applications previously restricted to amplified sources, such as efficient generation of extreme ultraviolet light at high repetition rate, and the generation of high-power broadband THz radiation.

Stabilizing the magnetic moment of single holmium atoms by symmetry.

Single magnetic atoms, and assemblies of such atoms, on non-magnetic surfaces have recently attracted attention owing to their potential use in high-density magnetic data storage and as a platform for quantum computing. A fundamental problem resulting from their quantum mechanical nature is that the localized magnetic moments of these atoms are easily destabilized by interactions with electrons, nuclear spins and lattice vibrations of the substrate. Even when large magnetic fields are applied to stabilize the magnetic moment, the observed lifetimes remain rather short (less than a microsecond). Several routes for stabilizing the magnetic moment against fluctuations have been suggested, such as using thin insulating layers between the magnetic atom and the substrate to suppress the interactions with the substrate's conduction electrons, or coupling several magnetic moments together to reduce their quantum mechanical fluctuations. Here we show that the magnetic moments of single holmium atoms on a highly conductive metallic substrate can reach lifetimes of the order of minutes. The necessary decoupling from the thermal bath of electrons, nuclear spins and lattice vibrations is achieved by a remarkable combination of several symmetries intrinsic to the system: time reversal symmetry, the internal symmetries of the total angular momentum and the point symmetry of the local environment of the magnetic atom.