Phase noise of an electro-optic terahertz comb.

Photonic millimeter wave and terahertz frequency generation and detection benefit from a large tunability of several octaves as opposed to electronic frequency generation and multiplication. However, reaching multiple 100 GHz continuous tuning range while simultaneously featuring a 3-dB linewidth in the Hz range and low phase noise is still very challenging. We present an electro-optical comb driving a photomixer with potential usability as an extension module based on side-band generation by an electro-optical phase modulator. This enables a Hz-level 3-dB linewidth from microwaves to terahertz frequencies. We discuss the working principle of the mentioned electro-optical comb, characterize the phase noise of the optical subsystem up to frequencies of 40 GHz where electronic phase noise analyzers are available and draw conclusions on the phase noise at higher frequencies in the THz domain.

Broadband high-contrast-grating-type waveplates for the terahertz range.

The high-contrast-grating waveplates utilizing high contrast between silicon and air refractive indexes were developed in order to perform as a quarter wave and a half wave plate in the selected THz frequency range. The waveplates possessed anti-reflective properties due to the specific inclination of the walls both in parallel and in perpendicular direction to grating axis, efficiently suppressing the reflection losses caused by air-dielectric interface for both transverse magnetic and transverse electric polarizations. Moreover, significant reduction of the transmittance gap was achieved between both polarizations while mitigating overall Fabry-Perot effect. Validation of the concepts was carried out by measuring transmission amplitude and phase spectra of the fabricated samples in a broadband of THz time-domain spectroscopy and vector-network-analysis systems considering also some real applications.

High saturation photocurrent THz waveguide-type MUTC-photodiodes reaching mW output power within the WR3.4 band.

In this paper, we report on waveguide-type modified uni-traveling-carrier photodiodes (MUTC-PDs) providing a record high output power level for non-resonant photodiodes in the WR3.4 band. Indium phosphide (InP) based waveguide-type 1.55 µm MUTC-PDs have been fabricated and characterized thoroughly. Maximum output powers of -0.6 dBm and -2.7 dBm were achieved at 240 GHz and 280 GHz, respectively. This has been accomplished by an optimized layer structure and doping profile design that takes transient carrier dynamics into account. An energy-balance model has been developed to study and optimize carrier transport at high optical input intensities. The advantageous THz capabilities of the optimized MUTC layer structure are confirmed by experiments revealing a transit time limited cutoff frequency of 249 GHz and a saturation photocurrent beyond 20 mA in the WR3.4 band. The responsivity for a 16 µm long waveguide-type THz MUTC-PD is found to be 0.25 A/W. In addition, bow-tie antenna integrated waveguide-type MUTC-PDs are fabricated and reported to operate up to 0.7 THz above a received power of -40 dBm.

Terahertz photodiode integration with multi-octave-bandwidth dielectric rod waveguide probe.

Photonic integrated circuits play a vital role in enabling terahertz (THz) applications that require multi-octave bandwidth. Prior research has been limited in bandwidth due to rectangular waveguide (WRs) interconnects, which can only support single octave at low loss. To overcome this fundamental limitation, we exploit the ultra-wideband (UWB) near-field coupling between planar waveguides and silicon (Si)-based subwavelength dielectric rod waveguides (DRWs) to interconnect THz bandwidth uni-traveling-carrier photodiodes (UTC-PDs) at 0.08-1.03 THz. In a proof-of-concept experiment, the on-chip integrated UTC-PDs demonstrate a UWB operation from 0.1 THz to 0.4 THz. Furthermore, by employing Si DRWs as probes, multi-octave device-under-test characterization of UTC-PDs integrated with UWB transition is enabled with only one DRW probe. The proposed UWB interconnect technology is distinct from previously used WR-based ground-signal-ground probes or quasi-optical free-space coupling since it can provide multi-octave bandwidth and enable on-chip THz circuit integration.

High-power UTC-photodiodes for an optically pumped subharmonic terahertz receiver.

In this work, we present an optically subharmonic pumped WR3-mixer for enabling photonic coherent frequency-domain terahertz (THz) imaging and spectroscopy systems in the future. The studied mixer operates within the upper range of the WR3-band from 270 GHz to 320 GHz. High-power uni-travelling carrier photodiodes (UTC-PDs) are developed for providing the subharmonic local oscillator (LO) signal within the corresponding WR6-band in the range between 135 GHz and 160 GHz. The proposed THz mixer module consists of a gallium arsenide (GaAs)-based low barrier Schottky diodes (LBSDs) chip and an indium phosphide (InP)-based UTC-PD chip. For integrating the UTC-PD with the WR6 at the mixer's LO input, an E-plane transition and a stepped-impedance microstrip line low pass filter (MSL-LPF) are developed and monolithically integrated with the UTC-PD chip on a 100 µm thick InP substrate. The E-plane transition converts the quasi-TEM mode of the grounded coplanar waveguide (GCPW) to the dominant TE10 mode of the WR6 and matches the GCPW's impedance with the WR6's impedance. According to full-wave EM simulations, the transition exhibits a 1 dB bandwidth (BW) of more than 30 GHz (138.8-172.1 GHz) with a corresponding return loss (RL) better than 10 dB, whereas the minimum insertion loss (IL) is 0.65 dB at a frequency of 150 GHz. Experimentally, the 1 dB BW of the fabricated transition is found to be between 140 GHz and 170 GHz, which confirms the numerical results. The minimum measured IL is 2.94 dB, i.e., about 2 dB larger than the simulated value. In order to achieve the required LO power for successfully pumping the mixer in a direct approach (i.e., without an additional LO amplifier), the design of the epitaxial system of the UTC-PD is optimized to provide a high output power within the WR6-band (110-170 GHz). Experimentally, at 150 GHz, the output power of the fabricated UTC-PD chip is measured to be +3.38 dBm at a photocurrent of 21 mA. To our knowledge, this is the highest output power ever achieved from a UTC-PD at 150 GHz. Finally, the developed high-power UTC-PDs are used as LO source to pump the subharmonic WR3-mixer. Experimentally, the conversion loss (CL) is determined in dependency of the LO power levels within the RF frequency range between 271 GHz and 321 GHz for a fixed IF at 1 GHz. The achieved results have revealed an inverse relation between the CL and LO power level, where the average minimum CL of 16.8 dB is achieved at the highest applied LO power level, corresponding to a photocurrent of 10 mA. This CL figure is promising and is expected to reach the CL of electronically pumped and commercially available THz mixers (∼12 dB) after packaging the LO source with the mixer. Furthermore, an average CL of 17.2 dB is measured at a fixed LO frequency of 150 GHz and a tuned RF frequency between 301 GHz and 310 GHz, i.e., IF between 1 GHz and 10 GHz.

Photonic-assisted 2-D terahertz beam steering enabled by a LWA array monolithically integrated with a BFN.

A novel photonic-assisted 2-D Terahertz beam steering chip using only two tuning elements is presented. The chip is based on an array of three leaky wave antennas (LWAs) with a monolithically integrated beamforming network (BFN) on a 50 µm-thick indium phosphide substrate. The THz beam angle in elevation (E-plane) is controlled via optical frequency tuning using a tunable dual-wavelength laser. An optical delay line is used for azimuth (H-plane) beam control. The simulated beam scanning range is 92° in elevation for a frequency sweep from 0.23 THz to 0.33 THz and 69.18° in azimuth for a time delay of 3.6 ps. For the frequency range from 0.26 THz to 0.32 THz, it is confirmed experimentally that the THz beam scans from -12° to +33°, which is in good agreement with the numerical simulations. The beam direction in azimuth scans with a total angle of 39° when applying a delay difference of 1.68 ps. A good agreement is found between theoretically predicted and experimentally determined THz beam angles with a maximum angle deviation below 5°. The experimental scanning angles are limited due to the mechanical constraints of the on-wafer probes, the on-chip integrated transition and the bandwidth of the THz receiver LNA. The mechanical limitation will be overcome when using a packaged chip.

Mobile THz communications using photonic assisted beam steering leaky-wave antennas.

THz communications is envisaged for wide bandwidth mobile communications eventually reaching data capacities exceeding 100 Gbit/s. The technology enabling compact chip-integrated transceivers with highly directive, steerable antennas is the key challenge at THz frequencies to overcome the very high free-space path losses and to support user mobility. In this article, we report on mobile and multi-user THz communications using a photonic THz transmitter chip featuring 1D beam steering for the first time. In the proposed approach, 1D THz beam steering is achieved by using a photodiode excited leaky-wave antenna (LWA) in the transmitter chip. The on-chip LWA allows to steer the directive THz beam from 6° to 39° within the upper WR3-band (0.28-0.33 THz). The antenna's directivity is 14 dBi which is further increased to 23 dBi using an additional hemicylindrical Teflon lens. The 3-dB beam width and coherence bandwidth of the fabricated THz transmitter chips with lens are 9° and 12 GHz, respectively. The proposed approach allows steering the THz beam via the beat frequency of an optical heterodyne system at a speed up to 28°/s. Without using a THz amplifier in the transmitter chip, a data rate of 24 Gbit/s is achieved for a single user for all beam directions and at short wireless distances up to 6 cm. The wireless distance is successfully increased to 32 cm for a lower data rate of 4 Gbit/s, still without using a transmitter amplifier. Also, multi-user THz communications and the overall capacity of the developed THz transmitter chip is studied revealing that up to 12 users could be supported together with a total wireless data capacity of 48 Gbit/s. Fully integrated 2D transmitter chips are expected to reach wireless distances of several meters without additional amplifiers.

Ultra-low phase-noise photonic terahertz imaging system based on two-tone square-law detection.

In this paper, we demonstrate a phase-sensitive photonic terahertz imaging system, based on two-tone square-law detection with a record-low phase noise. The system comprises a high-frequency photodiode (PD) for THz generation and a square-law detector (SLD) for THz detection. Two terahertz of approximately 300 GHz tones, separated by an intermediate frequency (IF) (7 GHz-15 GHz), are generated in the PD by optical heterodyning and radiated into free-space. After transmission through a device-under-test, the two-tones are self-mixed inside the SLD. The mixing results in an IF-signal, which still contains the phase information of the terahertz tones. To achieve ultra-low phase-noise, we developed a new mixing scheme using a reference PD and a low-frequency electrical local oscillator (LO) to get rid of additional phase-noise terms. In combination with a second reference PD, the output signal of the SLD can be down-converted to the kHz region to realize lock-in detection with ultra-low phase noise. The evaluation of the phase-noise shows the to-date lowest reported value of phase deviation in a frequency domain photonic terahertz imaging and spectroscopy system of 0.034°. Consequently, we also attain a low minimum detectable path difference of 2 µm for a terahertz difference frequency of 15 GHz. This is in the same range as in coherent single-tone THz systems. At the same time, it lacks their complexity and restrictions caused by the necessary optical LOs, photoconductive antennas, temperature control and delay lines.

[Prehospital Strategies to Stop the Bleeding]. / Prähospitale Strategien zur Minimierung des Blutverlustes.

Seriously injured patients represent only a small group of patients in the emergency medical service with 0.5% (ground based) to 5% (HEMS), but they are associated with a high mortality rate. Among people younger than 45, trauma is the most common cause of death, mostly as a result of severe traumatic brain injury (TBI) and/or extreme hemorrhage. As the outcome of severe TBI prehospitally can only be influenced to a very limited extent, a majority of preventable deaths in prehospital setting are caused by "critical" bleeding. The "critical" bleeding is defined by its life-threatening dimension. Anticoagulation medication can have a reinforcing effect. Adequate prehospital therapy strategies exist for external bleeding. In contrast, internal bleeding regularly evades a causal prehospital care, so that in such cases, transport prioritization and rapid definitive surgical intervention remain the only option. In the civilian environment the tested and evaluated "ABCDE" scheme must be preceded by the (for "critical bleeding") in order to react time-critically to compressible external bleeding, possibly even prior to airway management. These findings have found their way into the current version of the S3 guideline on treatment of multi system trauma by the German Society for Trauma Surgery (DGU). According to this "severely bleeding injuries that can impair vital functions should be treated with priority". Thus, this publication focuses on prehospital bleeding control.

Spectral efficient 64-QAM-OFDM terahertz communication link.

We report on a record spectral efficient terahertz communication system using a coherent radio-over-fiber (CRoF) approach. High spectral efficient back-to-back and wireless THz transmission around 325 GHz is experimentally demonstrated using a 64-QAM-OFDM modulation format and a 10 GHz wide wireless channel resulting in a data rate of 59 Gbit/s.

A Stepwise Psychotherapy Intervention for Reducing Risk in Coronary Artery Disease (SPIRR-CAD): Results of an Observer-Blinded, Multicenter, Randomized Trial in Depressed Patients With Coronary Artery Disease.

BACKGROUND: Depression predicts adverse prognosis in patients with coronary artery disease (CAD), but previous treatment trials yielded mixed results. We tested the hypothesis that stepwise psychotherapy improves depressive symptoms more than simple information. METHODS: In a multicenter trial, we randomized 570 CAD patients scoring higher than 7 on the Hospital Anxiety and Depression Scale-depression subscale to usual care plus either one information session (UC-IS) or stepwise psychotherapy (UC-PT). UC-PT patients received three individual psychotherapy sessions. Those still depressed were offered group psychotherapy (25 sessions). The primary outcome was changed in the Hospital Anxiety and Depression Scale-depression scores from baseline to 18 months. Preplanned subgroup analyses examined whether treatment responses differed by patients' sex and personality factors (Type D). RESULTS: The mean (standard deviation) depression scores declined from 10.4 (2.5) to 8.7 (4.1) at 18 months in UC-PT and from 10.4 (2.5) to 8.9 (3.9) in UC-IS (both p < .001). There was no significant group difference in change of depressive symptoms (group-by-time effect, p = .90). Preplanned subgroup analyses revealed no differences in treatment effects between men versus women (ptreatment-by-sex interaction = .799) but a significant treatment-by-Type D interaction on change in depressive symptoms (p = .026) with a trend for stronger improvement with UC-PT than UC-IS in Type D patients (n = 341, p = .057) and no such difference in improvement in patients without Type D (n = 227, p = .54). CONCLUSIONS: Stepwise psychotherapy failed to improve depressive symptoms in CAD patients more than UC-IS. The intervention might be beneficial for depressed CAD patients with Type D personality. However, this finding requires further study. TRIAL REGISTRATION: www.clinicaltrials.gov NCT00705965; www.isrctn.com ISRCTN76240576.

Triple transit region photodiodes (TTR-PDs) providing high millimeter wave output power.

We report on a novel triple transit region (TTR) layer structure for 1.55 µm waveguide photodiodes (PDs) providing high output power in the millimeter wave (mmW) regime. Basically, the TTR-PD layer structure consists of three transit layers, in which electrons drift at saturation velocity or even at overshoot velocity. Sufficiently strong electric fields (>3000 V/cm) are achieved in all three transit layers even in the undepleted absorber layer and even at very high optical input power levels. This is achieved by incorporating three 10 nm thick p-doped electric field clamp layers. Numerical simulations using the drift-diffusion model (DDM) indicate that for optical intensities up to ~500 kW/cm(2), no saturation effects occur, i.e. the electric field exceeds the critical electric field in all three transit layers. This fact in conjunction with a high-frequency double-mushroom cross-section of the waveguide TTR-PD ensures high output power levels at mmW frequencies. Fabricated 1.55 µm InGaAs(P)/InP waveguide TTR-PDs exhibit output power levels exceeding 0 dBm (1 mW) and a return loss (RL) up to ~24 dB. Broadband operation with a 3 dB bandwidth beyond 110 GHz is achieved.

Prognostic markers for the clinical course in the blood of patients with SARS-CoV-2 infection.

BACKGROUND: The presentation of peptides and the subsequent immune response depend on the MHC characteristics and influence the specificity of the immune response. Several studies have found an association between HLA variants and differential COVID-19 outcomes and have shown that HLA genotypes are associated with differential immune responses against SARS-CoV-2, particularly in severely ill patients. Information, whether HLA haplotypes are associated with the severity or length of the disease in moderately diseased individuals is absent. METHODS: Next-generation sequencing-based HLA typing was performed in 303 female and 231 male non-hospitalized North Rhine Westphalian patients infected with SARS-CoV2 during the first and second wave. For HLA-Class I, we obtained results from 528 patients, and for HLA-Class II from 531. In those patients, who became ill between March 2020 and January 2021, the 22 most common HLA-Class I (HLA-A, -B, -C) or HLA-Class II (HLA -DRB1/3/4, -DQA1, -DQB1) haplotypes were determined. The identified HLA haplotypes as well as the presence of a CCR5Δ32 mutation and number of O and A blood group alleles were associated to disease severity and duration of the disease. RESULTS: The influence of the HLA haplotypes on disease severity and duration was more pronounced than the influence of age, sex, or ABO blood group. These associations were sex dependent. The presence of mutated CCR5 resulted in a longer recovery period in males. CONCLUSION: The existence of certain HLA haplotypes is associated with more severe disease.

Reconvalescent plasma/camostat mesylate in early SARS-CoV-2 Q-PCR positive high-risk individuals (RES-Q-HR): a structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: Currently, there are no approved treatments for early disease stages of COVID-19 and few strategies to prevent disease progression after infection with SARS-CoV-2. The objective of this study is to evaluate the safety and efficacy of convalescent plasma (CP) or camostat mesylate administered within 72 h of diagnosis of SARS-CoV-2 infection in adult individuals with pre-existing risk factors at higher risk of getting seriously ill with COVID-19. Camostat mesylate acts as an inhibitor of the host cell serine protease TMPRSS2 and prevents the virus from entering the cell. CP represents another antiviral strategy in terms of passive immunization. The working hypothesis to be tested in the RES-Q-HR study is that the early use of CP or camostat mesylate reduces the likelihood of disease progression to (modified) WHO stages 4b-8 in SARS-CoV-2-positive adult patients at high risk of moderate or severe COVID-19 progression. TRIAL DESIGN: This study is a 4-arm (parallel group), multicenter, randomized (2:2:1:1 ratio), partly double-blind, controlled trial to evaluate the safety and efficacy of convalescent plasma (CP) or camostat mesylate with control or placebo in adult patients diagnosed with SARS-CoV-2 infection and high risk for progression to moderate/severe COVID-19. Superiority of the intervention arms will be tested. PARTICIPANTS: The trial is conducted at 10-15 tertiary care centers in Germany. Individuals aged 18 years or above with ability to provide written informed consent with SARS-CoV-2 infection, confirmed by PCR within 3 days or less before enrolment and the presence of at least one SARS-CoV-2 symptom (such as fever, cough, shortness of breath, sore throat, headache, fatigue, smell/and or taste disorder, diarrhea, abdominal symptoms, exanthema) and symptom duration of not more than 3 days. Further inclusion criteria comprise: Presence of at least one of the following criteria indicating increased risk for severe COVID-19: Age > 75 years Chronic obstructive pulmonary disease (COPD) and/or pulmonary fibrosis BMI > 40 kg/m2 Age > 65 years with at least one other risk factor (BMI > 35 kg/m2, coronary artery disease (CAD), chronic kidney disease (CKD) with GFR < 60 ml/min but ≥ 30 ml/min, diabetes mellitus, active tumor disease) BMI > 35 kg/m2 with at least one other risk factor (CAD, CKD with GFR < 60 ml/min but ≥ 30 ml/min, diabetes mellitus, active tumor disease) Exclusion criteria: 1. Age < 18 years 2. Unable to give informed consent 3. Pregnant women or breastfeeding mothers 4. Previous transfusion reaction or other contraindication to a plasma transfusion 5. Known hypersensitivity to camostat mesylate and/or severe pancreatitis 6. Volume stress due to CP administration would be intolerable 7. Known IgA deficiency 8. Life expectancy < 6 months 9. Duration SARS-CoV-2 typical symptoms > 3 days 10. SARS-CoV-2 PCR detection older than 3 days 11. SARS-CoV-2 associated clinical condition ≥ WHO stage 3 (patients hospitalized for other reasons than COVID-19 may be included if they fulfill all inclusion and none of the exclusion criteria) 12. Previously or currently hospitalized due to SARS-CoV-2 13. Previous antiviral therapy for SARS-CoV-2 14. ALT or AST > 5 x ULN at screening 15. Liver cirrhosis > Child A (patients with Child B/C cirrhosis are excluded from the trial) 16. Chronic kidney disease with GFR < 30 ml/min 17. Concurrent or planned anticancer treatment during trial period 18. Accommodation in an institution due to legal orders (§40(4) AMG). 19. Any psycho-social condition hampering compliance with the study protocol. 20. Evidence of current drug or alcohol abuse 21. Use of other investigational treatment within 5 half-lives of enrolment is prohibited 22. Previous use of convalescent plasma for COVID-19 23. Concomitant proven influenza A infection 24. Patients with organ or bone marrow transplant in the three months prior to screening visit INTERVENTION AND COMPARATOR: Participants will be randomized to the following 4 groups: 1) Convalescent plasma (CP), 2 units at screening/baseline visit (day 0) or day 1; CP is defined by the presence of neutralizing anti-SARS-CoV-2 antibodies with titers ≥ 1:160; individuals with body weight ≥ 150 kg will receive a third unit of plasma on day 3 2) Camostat mesylate (200 mg per capsule, one capsule taken each in the morning, afternoon and evening on days 1-7) 3) Standard of care (SOC, control for CP) 4) Placebo (identical in appearance to camostat mesylate capsules, one capsule taken each morning, afternoon and evening on days 1-7; for camostat mesylate control group) Participants will be monitored after screening/baseline on day 3, day 5, day 8, and day 14. On day 28 and day 56, telephone visits and on day 90, another outpatient visit are scheduled. Adverse events and serious adverse events will be monitored and reported until the end of the study. An independent data safety monitoring committee will review trial progression and safety. MAIN OUTCOMES: The primary endpoint of the study is the cumulative number of individuals who progress to or beyond category 4b on the modified WHO COVID-19 ordinal scale (defined as hospitalization with COVID-19 pneumonia and additional oxygen demand via nasal cannula or mask) within 28 days after randomization. RANDOMIZATION: Participants will be randomized using the Alea-Tool ( aleaclinical.com ) in a 2:2:1:1 ratio to the treatment arms (1) CP, (2) camostat mesylate, (3) standard of care (SoC), and (4) placebo matching camostat mesylate. Randomization will be stratified by study center. BLINDING (MASKING): The camostat mesylate treatment arm and the respective placebo will be blinded for participants, caregivers, and those assessing outcomes. The treatment arms convalescent plasma and standard of care will not be blinded and thus are open-labeled, unblinded. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): Overall, n = 994 participants will be randomized to the following groups: n = 331 to convalescent plasma (CP), n = 331 to camostat mesylate, n = 166 to standard of care (SoC), and n = 166 to placebo matching camostat mesylate. TRIAL STATUS: The RES-Q-HR protocol (V04F) was approved on the 18 December 2020 by the local ethics committee and by the regulatory institutions PEI/BfARM on the 2 December 2020. The trial was opened for recruitment on 26 December 2020; the first patient was enrolled on 7 January 2021 and randomized on 8 January 2021. Recruitment shall be completed by June 2021. The current protocol version RES-Q HR V05F is from 4 January 2021, which was approved on the 18 January 2021. TRIAL REGISTRATION: EudraCT Number 2020-004695-18 . Registered on September 29, 2020. ClinicalTrial.gov NCT04681430 . Registered on December 23, 2020, prior to the start of the enrollment (which was opened on December 26, 2020). FULL PROTOCOL: The full protocol (V05F) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Association of HLA genotypes, AB0 blood type and chemokine receptor 5 mutant CD195 with the clinical course of COVID-19.

BACKGROUND: COVID-19, the pandemic disease caused by infection with SARS-CoV-2, may take highly variable clinical courses, ranging from symptom-free and pauci-symptomatic to fatal disease. The goal of the current study was to assess the association of COVID-19 clinical courses controlled by patients' adaptive immune responses without progression to severe disease with patients' Human Leukocyte Antigen (HLA) genetics, AB0 blood group antigens, and the presence or absence of near-loss-of-function delta 32 deletion mutant of the C-C chemokine receptor type 5 (CCR5). PATIENT AND METHODS: An exploratory observational study including 157 adult COVID-19 convalescent patients was performed with a median follow-up of 250 days. The impact of different HLA genotypes, AB0 blood group antigens, and the CCR5 mutant CD195 were investigated for their role in the clinical course of COVID-19. In addition, this study addressed levels of severity and morbidity of COVID-19. The association of the immunogenetic background parameters were further related to patients' humoral antiviral immune response patterns by longitudinal observation. RESULTS: Univariate HLA analyses identified putatively protective HLA alleles (HLA class II DRB1*01:01 and HLA class I B*35:01, with a trend for DRB1*03:01). They were associated with reduced durations of disease instead decreased (rather than increased) total anti-S IgG levels. They had a higher virus neutralizing capacity compared to non-carriers. Conversely, analyses also identified HLA alleles (HLA class II DQB1*03:02 und HLA class I B*15:01) not associated with such benefit in the patient cohort of this study. Hierarchical testing by Cox regression analyses confirmed the significance of the protective effect of the HLA alleles identified (when assessed in composite) in terms of disease duration, whereas AB0 blood group antigen heterozygosity was found to be significantly associated with disease severity (rather than duration) in our cohort. A suggestive association of a heterozygous CCR5 delta 32 mutation status with prolonged disease duration was implied by univariate analyses but could not be confirmed by hierarchical multivariate testing. CONCLUSION: The current study shows that the presence of HLA class II DRB1*01:01 and HLA class I B*35:01 is of even stronger association with reduced disease duration in mild and moderate COVID-19 than age or any other potential risk factor assessed. Prospective studies in larger patient populations also including novel SARS-CoV-2 variants will be required to assess the impact of HLA genetics on the capacity of mounting protective vaccination responses in the future.

Nonintubated Surfactant Application vs Conventional Therapy in Extremely Preterm Infants: A Randomized Clinical Trial.

IMPORTANCE: Treatment of respiratory distress syndrome in premature infants with continuous positive airway pressure (CPAP) preserves surfactant and keeps the lung open but is insufficient in severe surfactant deficiency. Traditional surfactant administration is related to short periods of positive pressure ventilation and implies the risk of lung injury. CPAP with surfactant but without any positive pressure ventilation may work synergistically. This randomized trial investigated a less invasive surfactant application protocol (LISA). OBJECTIVE: To test the hypothesis that LISA increases survival without bronchopulmonary dysplasia (BPD) at 36 weeks' gestational age in extremely preterm infants. DESIGN, SETTING, AND PARTICIPANTS: The Nonintubated Surfactant Application trial was a multicenter, randomized, clinical, parallel-group study conducted between April 15, 2009, and March 25, 2012, in 13 level III neonatal intensive care units in Germany. The final follow-up date was June 21, 2012. Participants included 211 of 558 eligible (37.8%) spontaneously breathing preterm infants born between 23.0 and 26.8 weeks' gestational age with signs of respiratory distress syndrome. In an intention-to-treat design, infants were randomly assigned to receive surfactant either via a thin endotracheal catheter during CPAP-assisted spontaneous breathing (intervention group) or after conventional endotracheal intubation during mechanical ventilation (control group). Analysis was conducted from September 6, 2012, to June 20, 2013. INTERVENTION: LISA via a thin catheter. MAIN OUTCOMES AND MEASURES: Survival without BPD at 36 weeks' gestational age. RESULTS: Of 211 infants who were randomized, 104 were randomized to the control group and 107 to the LISA group. Of the infants who received LISA, 72 (67.3%) survived without BPD compared with 61 (58.7%) of those in the control group. The reduction in absolute risk was 8.6% (95% CI, -5.0% to 21.9%; P = .20). Intervention group infants were less frequently intubated (80 infants [74.8%] vs 103 [99.0%]; P < .001) and required fewer days of mechanical ventilation. Significant reductions were seen in pneumothorax (5 of 105 intervention group infants [4.8%] vs 13 of 103 12.6%]; P = .04) and severe intraventricular hemorrhage (11 infants [10.3%] vs 23 [22.1%]; P = .02), and the combined survival without severe adverse events was increased in the intervention group (54 infants [50.5%] vs 37 [35.6%]; P = .02; absolute risk reduction, 14.9; 95% CI, 1.4 to 28.2). CONCLUSIONS AND RELEVANCE: LISA did not increase survival without BPD but was associated with increased survival without major complications. Because major complications are related to lifelong disabilities, LISA may be a promising therapy for extremely preterm infants. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN64011614.

Xylem sap flow and drought stress of Fraxinus excelsior saplings.

We report on diurnal and seasonal variations in sap flow rate and stem water potential of Fraxinus excelsior L. saplings growing at the edge of a Fraxino-Aceretum forest in western Germany. Because of shallow soil, the trees were subjected to drought in summer. When soil water availability was not limiting, sap flow rate was related to changes in solar radiation and vapor pressure deficit. Maximum transpiration rates per leaf area were 3.5-7.4 mmol m-2 s-1, and maximum daily totals were 1.7-3.3 kg m-2 day-1. Under drought conditions, stem water potential dropped to midday minima of -2.6 to -3.5 MPa and sap flow rate was strongly related to this parameter. After the drought period, reduced apparent (whole-plant) hydraulic conductance was observed, which was attributed to a continued reduction in stomatal conductance after the drought stress had ceased. A model was developed that linked sap flow rate directly to climatic variables and stem water potential. Good correlation between measured and simulated sap flow rates allowed the model to be used for data interpretation.