Detection efficiency and bandwidth optimized electro-optic sampling of mid-infrared waves

Electro-optic sampling (EOS) is a powerful method for the characterization of electric fields with frequencies in the range of ~ 1-300 THz. For mid-infrared (MIR) radiation (2-20 µm), it can be understood as a two-step process: first, a sub-MIR-cycle visible/infrared gate pulse generates sum and/or difference frequency radiation with the light field under investigation in a nonlinear medium. Second, the newly generated frequencies are detected in a heterodyne scheme with the transmitted gate pulse serving as the local oscillator. Scanning the delay of the gate pulse with respect to the MIR waveform results in a signal proportional to the incident MIR field, with the spectral response depending on the gate pulse duration and phasematching in the detection crystal. The nonlinear frequency conversion on the one hand transfers the detection to the near-infrared spectral range, affording the use of low-noise photodetectors. On the other hand, it limits the detection efficiency and subjects it to a trade-off against bandwidth. Our research group develops high-power ultrashort-pulsed laser sources for field-resolved infrared spectroscopy. Explicitly, nonlinearly post-compressed femtosecond lasers are used both to drive the generation of waveform-stable MIR light for molecular-sample excitation, as well as for obtaining gate pulses for EOS of the full macroscopic sample response. To maximize the sensitivity of our field-resolved spectrometers, this thesis studied the photon detection efficiency of EOS for MIR radiation with wavelengths in the 6-18-μm range in experiment and theory. Three different types of gate pulses were investigated experimentally: first, the EOS detection efficiency was characterized for gate pulses with 1030-nm central wavelength, generated by an Yb-thin-disk oscillator. Limited by multi-photon-absorption-caused damage of the GaSe crystal, with an average gate-pulse power of 450mW, a conversion efficiency of 2% from the MIR into sum-frequency photons was achieved in a 500-μm-thick detection crystal. Accounting for Fresnel reflections at the crystal and losses in the heterodyne detection, up to 0.76% of the incident MIR photons arrived at the balanced diodes. Together with mW-level MIR average powers, this resulted in 13 orders of magnitude frequency-domain intensity dynamic range at 9-μm wavelength for a measurement time of 16 s and a scan range of 3.3 ps. However, phase-mismatch limited the −20 dB spectral width to 1.2 µm. Using a 85-μm-thick GaSe crystal, the full MIR spectrum of the source, spanning from 6.6 to 10.7 µm at −20 dB, was detected, while trading in two orders of magnitude in peak dynamic range. In our research group, the prototype field-sensitive spectrometer with this record detection efficiency and dynamic range is currently being used for fingerprinting real-world biomedical samples, with up to 40 times higher molecular detection sensitivity than commercial Fourier-transform infrared spectrometers. Due to the dispersion of GaSe, the trade-off between detection efficiency and spectral coverage is mitigated for longer-wavelength gate pulses. Using gate pulses centered at 1550 nm wavelength from an Er-fiber laser and a 300-μm-thick crystal, a comparable detection dynamic range and bandwidth as with the 85-μm-thick crystal at 1030 nm was achieved, despite the lower gate pulse power of 120mW. This performance enables high sensitivity spectroscopic measurements, when employing the Er-laser in a dual-oscillator fast-scanning mode (~ 1 kHz scan rate), avoiding low-frequency noise sources. In addition to the broader phasematching bandwidth, choosing a longer gate-pulse wavelength also increases the detection-crystal damage threshold due to reduced multi-photon absorption, allowing for the use of higher gate pulse powers and, consequently, enhancing the nonlinear interaction. This benefit was harnessed in the investigation of limitations to the detection efficiency with 1.9-W gate pulses from a Tm-fiber laser at 1965 nm central wavelength, comparing several EOS crystal thicknesses with respect to detection efficiency and spectral coverage. Traces measured with 100 to 300-μm-thin crystals closely resemble the incident field, spanning from 8.1 µm to 14.2 µm at −10 dB, with a conversion efficiency from the MIR into sum-frequency photons of up to ~ 10%. Using a 500-μm-thick GaSe crystal, more than 20% of the MIR photons from a 3-μm spectral band around 9.3 µm were upconverted. Further increasing the crystal thickness resulted in saturation of the depletion, explained by temporal walk-off and reduced peak powers due to dispersion. The overall number of detectable MIR photons of ~ 6.4% from within the detection crystal an interaction time window, together with mW-level MIR powers, lead to a peak intensity dynamic range > 10^14, with twice the detection bandwidth as for the 1030-nm gate pulses in the efficiency-optimized configuration, thus spanning ~ 5 μm at −20 dB. Despite the MIR depletion upon detection, the EOS signal scaled linearly with the field strength for average photon numbers between 10^3 and 10^17 per second within our measurement accuracy, because enough MIR photons stay available for nonlinear interaction. The multi-percent-level conversion efficiency allows for characterization of waveforms with an average of 22 photons inside the detection crystal in a 2.2-ms-long integration time window per temporal element. The combination of sensitivity, dynamic range and spectral coverage finds application e.g., in broadband vibrational spectroscopy, where the minimum detectable concentration is only a factor of ~ 4 higher than what would be possible when detecting all incident MIR photons. Furthermore, the detection bandwidth allows for the simultaneous measurement of multiple molecular species with spectrally wide-spread absorption lines. Employing the high detection dynamic range, a further study in the frame of this thesis concerned the use of EOS as a highly sensitive characterization technique for the stability and reproducibility of the MIR waveform and, therefore, for the control over optical fields. These capabilities were demonstrated by measuring the temporal fluctuations of the EOS trace, resulting in a record-low timing jitter of < 10 as over billions of pulses. A theoretical model simulating the chain of nonlinear processes from the laser frontend to EOS detection confirmed the measured values, identifying intensity noise of the modelocked oscillator front-end as the main source of the remaining MIR waveform instabilities. These jitter values were 3 orders of magnitude above the field fluctuations expected from a shot noise- limited driving pulse train

Intravenous versus epidural analgesia to reduce the incidence of gastrointestinal complications after elective pancreatoduodenectomy (the PAKMAN trial, DRKS 00007784): study protocol for a randomized controlled trial

Background: Despite substantial improvements in surgical and anesthesiological practices leading to decreased mortality of less than 5 % at high-volume centers, pancreatic surgery is still associated with high morbidity rates of up to 50 %. Attention is increasingly directed toward the optimization of perioperative management to reduce complications and enhance postoperative recovery. Currently, two different strategies for postoperative pain management after pancreatoduodenectomy are being routinely used: patient-controlled intravenous analgesia and thoracic epidural analgesia. Evidence is lacking to assess which strategy entails fewer postoperative complications. Methods/design: The PAKMAN trial is designed as an adaptive, pragmatic, randomized, controlled, multicenter, open-label, superiority trial with two parallel study groups. A total of 370 patients scheduled for elective pancreatoduodenectomy will be randomized after giving written informed consent, and 278 patients are needed for analysis. Patients with chronic pancreatitis, severe chronic obstructive pulmonary disease (COPD), American Society of Anesthesiologists (ASA) physical status classification ≥ IV, or chronic pain syndrome will be excluded. The group A intervention includes intraoperative general anesthesia and postoperative patient-controlled intravenous analgesia; the group B intervention comprises combined intraoperative general anesthesia and epidural analgesia with postoperative epidural analgesia. The primary endpoint of this trial is a composite of the gastrointestinal complications (delayed gastric emptying, pancreatic fistula, biliary leak, gastrointestinal bleeding, and postoperative ileus) up to postoperative day 30. The aim is to investigate whether the frequency of gastrointestinal complications following pancreatoduodenectomy can be reduced by 15 % using postoperative, patient-controlled intravenous analgesia compared with epidural analgesia. Discussion: Several previous studies investigating the two different strategies for postoperative pain management have mainly focused on their effectiveness in pain control. However, the PAKMAN trial is the first to compare them with regard to their impact on the surgical endpoint “postoperative gastrointestinal complications” after pancreatoduodenectomy. Trial registration: German Clinical Trials Register, DRKS0000778

Glioblastoma in the oldest old: Clinical characteristics, therapy, and outcome in patients aged 80 years and older

Background: Incidence rates of glioblastoma in very old patients are rising. The standard of care for this cohort is only partially defined and survival remains poor. The aims of this study were to reveal current practice of tumor-specific therapy and supportive care, and to identify predictors for survival in this cohort. Methods: Patients aged 80 years or older at the time of glioblastoma diagnosis were retrospectively identified in 6 clinical centers in Switzerland and France. Demographics, clinical parameters, and survival outcomes were annotated from patient charts. Cox proportional hazards modeling was performed to identify parameters associated with survival. Results: Of 107 patients, 45 were diagnosed by biopsy, 30 underwent subtotal resection, and 25 had gross total resection. In 7 patients, the extent of resection was not specified. Postoperatively, 34 patients did not receive further tumor-specific treatment. Twelve patients received radiotherapy with concomitant temozolomide, but only 2 patients had maintenance temozolomide therapy. Fourteen patients received temozolomide alone, 35 patients received radiotherapy alone, 1 patient received bevacizumab, and 1 took part in a clinical trial. Median progression-free survival (PFS) was 3.3 months and median overall survival (OS) was 4.2 months. Among patients who received any postoperative treatment, median PFS was 3.9 months and median OS was 7.2 months. Karnofsky performance status (KPS) ≥70%, gross total resection, and combination therapy were associated with better outcomes. The median time spent hospitalized was 30 days, accounting for 23% of the median OS. End-of-life care was mostly provided by nursing homes (n = 20; 32%) and palliative care wards (n = 16; 26%). Conclusions: In this cohort of very old patients diagnosed with glioblastoma, a large proportion was treated with best supportive care. Treatment beyond surgery and, in particular, combined modality treatment were associated with longer OS and may be considered for selected patients even at higher ages

Antithrombin deficiency is associated with mortality and impaired organ function in septic pediatric patients: a retrospective study

Background Sepsis remains a major problem in intensive care medicine. It is often accompanied by coagulopathies, leading to thrombotic occlusion of small vessels with subsequent organ damage and even fatal multi-organ failure. Prediction of the clinical course and outcome—especially in the heterogeneous group of pediatric patients—is difficult. Antithrombin, as an endogenous anticoagulant enzyme with anti-inflammatory properties, plays a central role in controling coagulation and infections. We investigated the relationship between antithrombin levels and organ failure as well as mortality in pediatric patients with sepsis. Methods Data from 164 patients under the age of 18, diagnosed with sepsis, were retrospectively reviewed. Antithrombin levels were recorded three days before to three days after peak C-reactive protein to correlate antithrombin levels with inflammatory activity. Using the concept of developmental haemostasis, patients were divided into groups <1 yr and ≥1 yr of age. Results In both age groups, survivors had significantly higher levels of antithrombin than did deceased patients. An optimal threshold level for antithrombin was calculated by ROC analysis for survival: 41.5% (<1 yr) and 67.5% (≥1 yr). The mortality rate above this level was 3.3% (<1 yr) and 9.5% (≥1 yr), and below this level 41.7% (<1 yr) and 32.2% (≥1 yr); OR 18.8 (1.74 to 1005.02), p = 0.0047, and OR 4.46 (1.54 to 14.89), p = 0.003. In children <1 yr with antithrombin levels <41.5% the rate of respiratory failure (66.7%) was significantly higher than in patients with antithrombin levels above this threshold level (23.3%), OR 6.23 (1.23 to 37.81), p = 0.0132. In children ≥1 yr, both liver failure (20.3% vs 1.6%, OR 15.55 (2.16 to 685.01), p = 0.0008) and a dysfunctional intestinal tract (16.9% vs 4.8%, OR 4.04 (0.97 to 24.08), p = 0.0395) occurred more frequently above the antithrombin threshold level of 67.5%. Conclusion In pediatric septic patients, significantly increased mortality and levels of organ failure were found below an age-dependent antithrombin threshold level. Antithrombin could be useful as a prognostic marker for survival and occurrence of organ failure in pediatric sepsis

Chromium-based bcc-superalloys strengthened by iron supplements

Chromium alloys are being considered for next-generation concentrated solar power applications operating &gt; 800 °C. Cr offers advantages in melting point, cost, and oxidation resistance. However, improvements in mechanical performance are needed. Here, Cr-based body-centred-cubic (bcc) alloys of the type Cr(Fe)-NiAl are investigated, leading to ‘bcc-superalloys’ comprising a bcc-Cr(Fe) matrix (β) strengthened by ordered-bcc NiAl intermetallic precipitates (β’), with iron additions to tailor the precipitate volume fraction and mechanical properties at high temperatures. Computational design using CALculation of PHAse Diagram (CALPHAD) predicts that Fe increases the solubility of Ni and Al, increasing precipitate volume fraction, which is validated experimentally. Nano-scale, highly-coherent B2-NiAl precipitates with lattice misfit ∼ 0.1% are formed in the Cr(Fe) matrix. The Cr(Fe)-NiAl A2-B2 alloys show remarkably low coarsening rate (∼102 nm3/h at 1000 °C), outperforming ferritic-superalloys, cobalt- and nickel-based superalloys. Low interfacial energies of ∼ 40/20 mJ/m2 at 1000/1200 °C are determined based on the coarsening kinetics. The low coarsening rates are principally attributed to the low solubility of Ni and Al in the Cr matrix. The alloys show high compressive yield strength of ∼320 MPa at 1000 °C. The Fe-modified alloy exhibits resistance to age softening, related to the low coarsening rate as well as the relatively stable Orowan strengthening as a function of precipitate radius. Microstructure tailoring with Fe additions offers a new design route to improve the balance of properties in “Cr-superalloys”, accelerating their development as a new class of high-temperature materials

Diffuse alveolar hemorrhage in children with interstitial lung disease: Determine etiologies!

OBJECTIVE: Diffuse alveolar hemorrhage (DAH) in children is a rare condition resulting from different underlying diseases. This study aimed at describing characteristics and diagnostic measures in children with ILD (children\u27s interstitial lung disease, chILD) and DAH to improve the diagnostic approach by increasing clinician\u27s awareness of diagnostic shortcomings. PATIENTS AND METHODS: A retrospective data analysis of patients with ILD and DAH treated in our own or collaborating centers between 01/07/1997 and 31/12/2020 was performed. Data on clinical courses and diagnostic measures were systematically retrieved as case-vignettes and investigated. To assess suitability of diagnostic software-algorithms, the Human Phenotype Ontology (HPO) was revised and expanded to optimize conditions of its associated tool the Phenomizer. RESULTS: For 97 (74%) of 131 patients, etiology of pulmonary hemorrhage was clarified. For 34 patients (26%), no underlying condition was found (termed as idiopathic pulmonary hemorrhage, IPH). Based on laboratory findings or clinical phenotype/comorbidities, 20 of these patients were assigned to descriptive clusters: IPH associated with autoimmune features (9), eosinophilia (5), renal disease (3) or multiorgan involvement (3). For 14 patients, no further differentiation was possible. CONCLUSION: Complete and sometimes repeated diagnostics are essential for establishing the correct diagnosis in children with DAH. We suggest assignment of patients with IPH to descriptive clusters, which may also guide further research. Digital tools such as the Phenomizer/HPO are promising, but need to be extended to increase diagnostic accuracy