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Abstract To prepare very-long-chain fatty acids and alkenes (VLCFAs and VLC alkenes) that are known pollinator attractants for sexually deceptive orchids, and biosynthetic precursors thereof, we applied a methodology allowing us to prepare monounsaturated VLCFAs with chain lengths up to 28 carbons and VLC alkenes up to 31 carbons. We implemented a coupling reaction between commercially available terminal alkynes and bromoalkanoic acids to prepare VLCFAs, allowing the products to be formed in two steps. For VLC alkenes, with many alkyltriphenylphosphonium bromides commercially available, we applied a Wittig reaction approach to prepare (Z)-configured monoenes in a single step. Using practical methods not requiring special reagents or equipment, we obtained 11 VLCFAs in > 90% isomeric purity, and 17 VLC alkenes in > 97% isomeric purity. Such general and accessible synthetic methods are essential for chemical ecology and biochemistry research to aid researchers in unambiguously identifying isolated semiochemicals and their precursors.

Abstract Aims This study aims to assess the applicability of the mitral regurgitation (MR) proportionality concept in patients with atrial functional mitral regurgitation (aFMR) treated with transcatheter edge‐to‐edge repair (M‐TEER). We hypothesized that patients with disproportionate MR (higher MR relative to left ventricular size) would exhibit different outcomes compared to those with proportionate MR, despite undergoing M‐TEER. Methods and results We retrospectively analysed 98 patients with aFMR from the EuroSMR registry who underwent M‐TEER between 2008 and 2019. Patients met criteria for aFMR (normal indexed left ventricular end‐diastolic volume [LVEDV], preserved left ventricular ejection fraction [LVEF] ≥ 50% without regional wall motion abnormalities, and structurally normal mitral valves). We excluded patients with missing effective regurgitant orifice area (EROA) or LVEDV data. The primary endpoint was 2‐year mortality, with an EROA/LVEDV ratio employed to differentiate disproportionate from proportionate MR. Procedural success and baseline characteristics were analysed, and multivariate Cox proportional hazards models were used to identify mortality predictors. The mean patient age was 79 ± 7.3 years, with 68.8% female, and 79% had a history of atrial fibrillation. The mean EROA was 0.27 ± 0.14 cm2, and LVEDV was 95.6 ± 33.7 mL. Disproportionate MR was identified with an EROA/LVEDV ratio >0.339 cm2/100 mL. While procedural success was similar in both groups, disproportionate MR was associated with a numerically higher estimate of systolic pulmonary artery pressures (sPAP) and rates of NYHA ≥III and TR ≥ 3+. Disproportionate MR had a significant association with increased 2‐year mortality (P

Abstract Pollinator-driven evolution of floral traits is thought to be a major driver of angiosperm speciation and diversification. Ophrys orchids mimic female insects to lure male pollinators into pseudocopulation. This strategy, called sexual deception, is species-specific, thereby providing strong premating reproductive isolation. Identifying the genomic architecture underlying pollinator adaptation and speciation may shed light on the mechanisms of angiosperm diversification. Here, we report the 5.2 Gb chromosome-scale genome sequence of Ophrys sphegodes. We find evidence for transposable element expansion that preceded the radiation of the O. sphegodes group, and for gene duplication having contributed to the evolution of chemical mimicry. We report a highly differentiated genomic candidate region for pollinator-mediated evolution on chromosome 2. The Ophrys genome will prove useful for investigations into the repeated evolution of sexual deception, pollinator adaptation and the genomic architectures that facilitate evolutionary radiations.

Transcatheter tricuspid valve replacement (TTVR) is an increasingly used treatment technique for patients with severe tricuspid regurgitation (TR). Currently, available data from international registries and randomized controlled trials provide outcome data until a maximum follow-up of 2 years after the procedure. This case report presents 4-year follow-up data for an 84-year-old woman who underwent TTVR for torrential TR in 2019. The patient experienced durable TR reduction, symptomatic improvement, right ventricular reverse remodeling, and substantial improvement in liver and kidney function.

Abstract Objectives The implementation of the Lung Allocation Score (LAS) in the Eurotransplant international collaborative framework decreased waiting list mortality, but organ shortage remains a significant problem. Transplantation of two single lungs from one donor into two recipients (lung twinning) may decrease waiting list mortality. We sought to analyze if this strategy can lead to an acceptable intermediate-term outcome. Methods Since the LAS-implementation we performed 32 paired single-lung transplantations from 16 postmortal donors. Data and outcome were analyzed retrospectively comparing recipients receiving the first lung (first twins) with recipients receiving the second lung (second twins), left versus right transplantation and restrictive versus obstructive disease. Results Survival at one year was 81% and 54% at five years. Veno-venous ECMO had been successfully used as bridge-to-transplant in three patients with ECMO-explantation immediately after surgery. Bronchial anastomotic complications were not observed in any patient. First twins and second twins exhibited similar survival (p = 0.82) despite higher LAS in first twins (median 45 versus 34, p

Abstract Background Because physical activity (PA) has many benefits for children’s and adolescents’ mental health, it has been suggested that PA may be an effective strategy to physically and mentally recover from the COVID-19 pandemic. This study tested the reciprocal relationship between PA and mental health during the easing of COVID-19 restrictions. It was hypothesized that mental health during the pandemic would determine how much children and adolescents re-engage in PA after easing the restrictions. Furthermore, it was hypothesized that PA engagement would predict mental health improvement after the pandemic. Methods This was a prospective study with two measurement occasions. Pretest data collection was undertaken in February 2022, shortly before German authorities eased and lifted the COVID-19 restrictions. The follow-up (posttest) occurred six weeks later (April 2022). Both times, a sample of elementary and grammar school students aged 6 to 18 years (N = 170) reported their mental health problems and health-related quality of life. Mental health problems were assessed with the Strengths and Difficulties Questionnaire and health-related quality of life was assessed with the KIDSCREEN-52 questionnaire. PA was measured continuously during the study period using smart electronic devices with a built-in pedometer. Results PA gradually increased after the easing of COVID-19 restrictions (p

The orchid genus Dipodium R.Br. (Epidendroideae) comprises leafy autotrophic and leafless mycoheterotrophic species, with the latter confined to sect. Dipodium. This study examined plastome degeneration in Dipodium in a phylogenomic and temporal context. Whole plastomes were reconstructed and annotated for 24 Dipodium samples representing 14 species and two putatively new species, encompassing over 80% of species diversity in sect. Dipodium. Phylogenomic analysis based on 68 plastid loci including a broad outgroup sampling across Orchidaceae found that sect. Leopardanthus is the sister lineage to sect. Dipodium. Dipodium ensifolium, the only leafy autotrophic species in sect. Dipodium, was found to be a sister to all leafless, mycoheterotrophic species, supporting a single evolutionary origin of mycoheterotrophy in the genus. Divergence-time estimations found that Dipodium arose ca. 33.3 Ma near the lower boundary of the Oligocene and that crown diversification commenced in the late Miocene, ca. 11.3 Ma. Mycoheterotrophy in the genus was estimated to have evolved in the late Miocene, ca. 7.3 Ma, in sect. Dipodium. The comparative assessment of plastome structure and gene degradation in Dipodium revealed that plastid ndh genes were pseudogenised or physically lost in all Dipodium species, including in leafy autotrophic species of both Dipodium sections. Levels of plastid ndh gene degradation were found to vary among species as well as within species, providing evidence of relaxed selection for retention of the NADH dehydrogenase complex within the genus. Dipodium exhibits an early stage of plastid genome degradation, as all species were found to have retained a full set of functional photosynthesis-related genes and housekeeping genes. This study provides important insights into plastid genome degradation along the transition from autotrophy to mycoheterotrophy in a phylogenomic and temporal context.

Eastern Africa and Arabia were major hominin hotspots and critical crossroads for migrating towards Asia during the late Pleistocene. To decipher the role of spatiotemporal environmental change on human occupation and migration patterns, we remeasured the marine core from Meteor Site KL 15 in the Gulf of Aden and reanalyzed its data together with the aridity index from ICDP Site Chew Bahir in eastern Africa and the wet-dry index from ODP Site 967 in the eastern Mediterranean Sea using linear and nonlinear time series analysis. These analyses show major changes in the spatiotemporal paleoclimate dynamics at 400 and 150 ka BP (thousand years before 1950), presumably driven by changes in the amplitude of the orbital eccentricity. From 400 to 150 ka BP, eastern Africa and Arabia show synchronized wet-dry shifts, which changed drastically at 150 ka BP. After 150 ka BP, an overall trend to dry climate states is observable, and the hydroclimate dynamics between eastern Africa and Arabia are negatively correlated. Those spatio-temporal variations and interrelationships of climate potentially influenced the availability of spatial links for human expansion along those vertices. We observe positively correlated network links during the supposed out-of-Africa migration phases of H. sapiens. Furthermore, our data do not suggest hominin occupation phases during specific time intervals of humid or stable climates but provide evidence of the so far underestimated potential role of climate predictability as an important factor of hominin ecological competitiveness.

Abstract The naked mole rat (NMR), Heterocephalus glaber, the longest-living rodent, provides a unique opportunity to explore how evolution has shaped adult stem cell (ASC) activity and tissue function with increasing lifespan. Using cumulative BrdU labelling and a quantitative imaging approach to track intestinal ASCs (Lgr5 + ) in their native in vivo state, we find an expanded pool of Lgr5 + cells in NMRs, and these cells specifically at the crypt base (Lgr5 +CBC ) exhibit slower division rates compared to those in short-lived mice but have a similar turnover as human LGR5 +CBC cells. Instead of entering quiescence (G0), NMR Lgr5 +CBC cells reduce their division rates by prolonging arrest in the G1 and/or G2 phases of the cell cycle. Moreover, we also observe a higher proportion of differentiated cells in NMRs that confer enhanced protection and function to the intestinal mucosa which is able to detect any chemical imbalance in the luminal environment efficiently, triggering a robust pro-apoptotic, anti-proliferative response within the stem/progenitor cell zone.

Abstract Transmission electron microscopy (TEM) is essential for determining atomic scale structures in structural biology and materials science. In structural biology, three-dimensional structures of proteins are routinely determined from thousands of identical particles using phase-contrast TEM. In materials science, three-dimensional atomic structures of complex nanomaterials have been determined using atomic electron tomography (AET). However, neither of these methods can determine the three-dimensional atomic structure of heterogeneous nanomaterials containing light elements. Here, we perform ptychographic electron tomography from 34.5 million diffraction patterns to reconstruct an atomic resolution tilt series of a double wall-carbon nanotube (DW-CNT) encapsulating a complex ZrTe sandwich structure. Class averaging the resulting tilt series images and subpixel localization of the atomic peaks reveals a Zr11Te50 structure containing a previously unobserved ZrTe2 phase in the core. The experimental realization of atomic resolution ptychographic electron tomography will allow for the structural determination of a wide range of beam-sensitive nanomaterials containing light elements.

Abstract Background Mechanical thrombectomy has been shown to reduce thrombus burden and pulmonary artery pressure (PAP) and to improve right ventricular (RV) function in patients with high-risk or intermediate-high-risk pulmonary embolism (PE). As hemodynamic data after mechanical thrombectomy for PE are scarce, we aimed to assess the hemodynamic effects of mechanical thrombectomy in acute PE with right heart overload. Methods In this prospective, open-label study, patients with acute symptomatic, computed tomography-documented PE with signs of right heart overload underwent mechanical thrombectomy using the FlowTriever System. Right heart catheterization was performed immediately before and after thrombectomy and after three months. Transthoracic echocardiography was performed before thrombectomy, discharge, and at three months. This analysis was done after 20 patients completed three months of follow-up. Results Twenty-nine patients (34% female) underwent mechanical thrombectomy, of which 20 completed three months follow-up with right heart catheterization. Most patients were at high (17%) or intermediate-high (76%) risk and had bilateral PE (79%). Before thrombectomy, systolic PAP (sPAP) was severely elevated (mean 51.3 ± 11.6 mmHg). Mean sPAP dropped by -15.0 mmHg (95% confidence interval [CI]: -18.9 to -11.0; p

Abstract Background Antimicrobial materials or surfaces are advertised as part of infection prevention bundles. However, the efficacy of such antimicrobial surfaces has not been sufficiently investigated in hospitals. In this study, the antimicrobial activity of examination gloves with light-activated antimicrobial properties against Gram-positive microorganisms was investigated modelling real live conditions. Method In a standardized experimental set-up with dry and realistic contamination, the antimicrobial properties of gloves claiming light dependent antimicrobial activity against Gram-positive organisms were tested in comparison with conventional examination gloves. All gloves were contaminated through a standardized activity of the test persons for construction with contaminated building blocks. For contamination suspensions of Enterococcus faecium ATCC 6057, Acinetobacter baumannii (outbreak strain), methicillin resistant Staphylococcus aureus ATCC 43300 or E. faecium (VRE) patient isolate were dried on the surfaces. After the standardized activity, the gloves were held for 10 min in the light present in the room (bright conditions) and the grade of contamination was determined subsequently by quantitative culture. In one experimental series gloves were held in a dark box after contamination as a control (dark conditions). Results The light intensity in all experiments under bright conditions was significantly above the limit value specified by the manufacturer for the activation of antimicrobial properties (> 500 lx). The mean values for experiments with antimicrobial active and non-active gloves were 955 and 935 lx, respectively. As claimed by the manufacture, the gloves showed no sufficient efficacy against A. baumannii under bright conditions. Against Gram-positive microorganisms such as E. faecium, E. faecium (VRE) and methicillin resistant S. aureus the gloves showed only very low antimicrobial activity with a reduction factor 4 log10 within 5 min for Gram-positive microorganisms claimed for the product using a standard test procedure (ASTM D7907) could not be confirmed in a realistic experimental test set-up even after 10 min of light exposure. The effectiveness against Gram-positive microorganisms should be further investigated under realistic (dry) conditions, including patient care. At this stage, the use of supposedly antimicrobial gloves should not be recommended, as the belief in their efficacy may encourage the misuse of gloves.

Abstract Background Current COVID-19 guidelines recommend the early use of systemic corticoids for COVID-19 acute respiratory distress syndrome (ARDS). It remains unknown if high-dose methylprednisolone pulse therapy (MPT) ameliorates refractory COVID-19 ARDS after many days of mechanical ventilation or rapid deterioration with or without extracorporeal membrane oxygenation (ECMO). Methods This is a retrospective observational study. Consecutive patients with COVID-19 ARDS treated with a parenteral high-dose methylprednisolone pulse therapy at the intensive care units (ICU) of two University Hospitals between January 1st 2021 and November 30st 2022 were included. Clinical data collection was at ICU admission, start of MPT, 3-, 10- and 14-days post MPT. Results Thirty-seven patients (mean age 55 ± 12 years) were included in the study. MPT started at a mean of 17 ± 12 days after mechanical ventilation. Nineteen patients (54%) received ECMO support when commencing MPT. Mean paO2/FiO2 significantly improved 3- (p = 0.034) and 10 days (p = 0.0313) post MPT. The same applied to the necessary FiO2 10 days after MPT (p = 0.0240). There were no serious infectious complications. Twenty-four patients (65%) survived to ICU discharge, including 13 out of 20 (65%) needing ECMO support. Conclusions Late administration of high-dose MPT in a critical subset of refractory COVID-19 ARDS patients improved respiratory function and was associated with a higher-than-expected survival of 65%. These data suggest that high-dose MPT may be a viable salvage therapy in refractory COVID-19 ARDS.

In the modern world, plastics have become indispensable. Due to their properties, they are used for a wide variety of applications ranging from packaging materials to textiles and medical technology. The vast majority of these plastics are made from finite fossil feedstocks that will need to be replaced in the long term to meet consumer demands in the future. Intensive research is being conducted into alternative bio‐based feedstocks to replace petroleum‐based plastics with more environmentally friendly variants. This includes polylactide, a polyester derived from lactic acid, which is mainly used as packaging material. In this work, star‐shaped copolymers consisting of polylactide and OrganoCat lignin with varying lignin loadings are synthesized using a “grafting‐from” approach directly from the lactide melt using a zinc‐based guanidine catalyst. This method proves to be efficient and copolymers can be produced after 30 min to three hours with high lactide conversions. Kinetic studies are performed to investigate the influence of different lignin loadings on the polymerization rate and 31P NMR experiments are used to analyze the functionalization of the lignin. Thermal analysis reveals an increase of the glass transition temperature and a higher thermal decomposition temperature with increasing lignin content.

Abstract Background Pseudoprogression (PsPD) is a rare response pattern to immune checkpoint inhibitor (ICI) therapy in oncology. This study aims to reveal imaging features of PsPD, and their association to other relevant findings. Methods Patients with PsPD who had at least three consecutive cross-sectional imaging studies at our comprehensive cancer center were retrospectively analyzed. Treatment response was assessed according to immune Response Evaluation Criteria in Solid Tumors (iRECIST). PsPD was defined as the occurrence of immune unconfirmed progressive disease (iUPD) without follow-up confirmation. Target lesions (TL), non-target lesions (NTL), new lesions (NL) were analyzed over time. Tumor markers and immune-related adverse events (irAE) were correlated. Results Thirty-two patients were included (mean age: 66.7 ± 13.6 years, 21.9% female) with mean baseline STL of 69.7 mm ± 55.6 mm. PsPD was observed in twenty-six patients (81.3%) at FU1, and no cases occurred after FU4. Patients with iUPD exhibited the following: TL increase in twelve patients, (37.5%), NTL increase in seven patients (21.9%), NL appearance in six patients (18.8%), and combinations thereof in four patients (12.5%). The mean and maximum increase for first iUPD in sum of TL was 19.8 and 96.8 mm (+ 700.8%). The mean and maximum decrease in sum of TL between iUPD and consecutive follow-up was − 19.1 mm and − 114.8 mm (-60.9%) respectively. The mean and maximum sum of new TL at first iUPD timepoint were 7.6 and 82.0 mm respectively. In two patients (10.5%), tumor-specific serologic markers were elevated at first iUPD, while the rest were stable or decreased among the other PsPD cases (89.5%). In fourteen patients (43.8%), irAE were observed. Conclusions PsPD occurred most frequently at FU1 after initiation of ICI treatment. The two most prevalent reasons for PsPD were TL und NTL progression, with an increase in TL diameter commonly below + 100%. In few cases, PsPD was observed even if tumor markers were rising compared to baseline. Our findings also suggest a correlation between PsPD and irAE. These findings may guide decision-making of ICI continuation in suspected PsPD.

Introduction: This prospective cohort study assessed the effects of chronic hypoxaemia due to high-altitude residency on the cerebral tissue oxygenation (CTO) and cerebrovascular reactivity.Methods: Highlanders, born, raised, and currently living above 2,500 m, without cardiopulmonary disease, participated in a prospective cohort study from 2012 until 2017. The measurements were performed at 3,250 m. After 20 min of rest in supine position while breathing ambient air (FiO2 0.21) or oxygen (FiO2 1.0) in random order, guided hyperventilation followed under the corresponding gas mixture. Finger pulse oximetry (SpO2) and cerebral near-infrared spectroscopy assessing CTO and change in cerebral haemoglobin concentration (cHb), a surrogate of cerebral blood volume changes and cerebrovascular reactivity, were applied. Arterial blood gases were obtained during ambient air breathing.Results: Fifty three highlanders, aged 50 ± 2 years, participated in 2017 and 2012. While breathing air in 2017 vs. 2012, PaO2 was reduced, mean ± SE, 7.40 ± 0.13 vs. 7.84 ± 0.13 kPa; heart rate was increased 77 ± 1 vs. 70 ± 1 bpm (p < 0.05) but CTO remained unchanged, 67.2% ± 0.7% vs. 67.4% ± 0.7%. With oxygen, SpO2 and CTO increased similarly in 2017 and 2012, by a mean (95% CI) of 8.3% (7.5–9.1) vs. 8.5% (7.7–9.3) in SpO2, and 5.5% (4.1–7.0) vs. 4.5% (3.0–6.0) in CTO, respectively. Hyperventilation resulted in less reduction of cHb in 2017 vs. 2012, mean difference (95% CI) in change with air 2.0 U/L (0.3–3.6); with oxygen, 2.1 U/L (0.5–3.7).Conclusion: Within 5 years, CTO in highlanders was preserved despite a decreased PaO2. As this was associated with a reduced response of cerebral blood volume to hypocapnia, adaptation of cerebrovascular reactivity might have occurred.

Abstract Background Currently, there are several studies showing that wearable inertial sensors are highly sensitive in the detection of gait disturbances in people with multiple sclerosis (PwMS), showing excellent reliability within one or 7–14 days. However, it is not known how stable these gait parameters remain over a longer period of time. This is surprising, because many treatments last longer than two weeks. Thus, the purpose of the current study was to examine gait parameters obtained by means of wearable inertial sensors during a 6-min walk and to reassess these parameters after a period of one year. Methods Fifty PwMS (without a relapse or a recent change in the Expanded Disability Status Scale (EDSS) or treatment) and 20 healthy participants were examined at two assessment points (interval between assessments: 14.4 ± 6.6 months). At each assessment point, all participants had to complete a 6-min walking test, an observer-rater test (Berg Balance Scale, BBS) and a Timed-up and Go Test (TUG). To measure mean gait parameters (i.e. walking speed, stride length, stride time, the duration of the stance and swing phase and minimum toe-to-floor distance), as well as the intraindividual standard deviation of each mean gait parameter, wearable inertial sensors were utilized. Results We found that even after one year all mean gait parameters showed excellent Intraclass Correlation Coefficients (ICC between 0.75 and 0.95) in PwMS. Looking at MS subgroups, the ICCs were slightly higher in MS subgroup 2 (EDSS 2.0–5.0) than those in MS subgroup 1 (EDSS 0.0–1.5) and healthy controls. Compared to the mean gait parameters, parameters of gait variability showed only good-to-fair ICC values in PwMS. Concerning BBS and TUG, the ICC values after one year were close to the ICC values of the measured mean gait parameters. Conclusions Due to the excellent stability of mean gait parameters after one year, these sensor-based gait parameters can be identified as clinically relevant markers to evaluate treatment effects over a longer (several months) period of time in MS.

Abstract Background Besides other factors, complication rate of transarterial interventions depends on the size of the vascular access. Therefore, the vascular access is mostly chosen as small as possible while still allowing all planned parts of the intervention. This retrospective analysis is to evaluate the safety and feasibility of sheathless arterial interventions for a broad spectrum of interventions in daily practice. Methods All sheathless interventions using a 4 F main catheter between May 2018 and September 2021 were included in the evaluation. Additionally, intervention parameters such as type of catheter, use of microcatheter and required change of main catheters were assessed. Information about the use about sheathless approach and catheters were obtained from the material registration system. All catheters were braided. Results 503 sheathless interventions with 4 F catheters from the groin were documented. The spectrum comprised bleeding embolization, diagnostic angiographies, arterial DOTA-TATE-therapy, uterine fibroid embolization, transarterial chemotherapy, transarterial radioembolization and others. In 31 cases (6 %) a change of the main catheter was required. In 381 cases (76 %) a microcatheter was utilized. No clinically relevant adverse events were observed (grade 2 or higher [CIRSE AE-classification]). None of the cases later required conversion to a sheath-based intervention. Conclusions Sheathless interventions with a 4 F braided catheter from the groin are safe and feasible. It allows for a broad spectrum of interventions in daily practice.

Mitral valve transcatheter edge-to-edge repair (M-TEER) and replacement (TMVR) have evolved as guideline-recommended treatment approaches for mitral regurgitation (MR). Even though they are supported by a growing body of evidence from either randomized trials or large registries, there are still several unsolved challenges in the field of interventional MR treatment. In the present review, we discuss the ten most important open questions regarding M-TEER and TMVR.

Be X-ray binaries (Be-XRBs) are one of the largest subclasses of high-mass X-ray binaries, comprised of a rapidly rotating Be star and neutron star companion in an eccentric orbit, intermittently accreting material from a decretion disk around the donor. Originating from binary stellar evolution, Be-XRBs are of significant interest to binary population synthesis (BPS) studies, encapsulating the physics of supernovae, common envelope, and mass transfer (MT). Using the state-of-the-art BPS code, POSYDON , which relies on precomputed grids of detailed binary stellar evolution models, we investigate the Galactic Be-XRB population. POSYDON incorporates stellar rotation self-consistently during MT phases, enabling detailed examination of the rotational distribution of Be stars in multiple phases of evolution. Our fiducial BPS and Be-XRB model aligns well with the orbital properties of Galactic Be-XRBs, emphasizing the role of rotational constraints. Our modeling reveals a rapidly rotating population ( ω / ω _crit ≳ 0.3) of Be-XRB-like systems with a strong peak at intermediate rotation rates ( ω / ω _crit ≃ 0.6) in close alignment with observations. All Be-XRBs undergo an MT phase before the first compact object forms, with over half experiencing a second MT phase from a stripped helium companion (Case BB). Computing rotationally limited MT efficiencies and applying them to our population, we derive a physically motivated MT efficiency distribution, finding that most Be-XRBs have undergone highly nonconservative MT ( ${\bar{\beta }}_{\mathrm{rot}}\simeq 0.15$ ). Our study underscores the importance of detailed angular momentum modeling during MT in interpreting Be-XRB populations, emphasizing this population as a key probe for the stability and efficiency of MT in interacting binaries.

Abstract The Oman upwelling zone (OUZ) creates an unfavorable environment and a major biogeographic barrier for many coral reef species, such as giant clams, thus promoting and maintaining faunal differences among reefs on the east and west side of the Arabian Peninsula. We record the former existence of Tridacna in the Gulf of Oman and review its stratigraphic distribution in the Persian Gulf to provide new insights on the connectivity of coral reef habitats around southern Arabia under changing climate and ocean conditions. Fossil shells were carbon-14 dated and employed as sclerochronological proxy archives. This reveals that the Omani population represents a last glacial colonization event during the Marine Isotope Stage 3 interstadial under colder-than-present temperatures and variable upwelling intensity linked to Dansgaard-Oeschger climate oscillations. It was favored by temperatures just above the lower threshold for the habitat-forming reef coral communities and instability of the upwelling barrier. We conclude that the distribution of Tridacna in the northern Arabian Sea is generally limited by either strong upwelling or cool sea surface temperature under gradually changing climate conditions at the interglacial-glacial scale. Opportunities for dispersal and temporary colonization existed only when there was a simultaneous attenuation of both limiting factors due to high-frequency climate variability. The OUZ will unlikely become a future climate change refuge for giant clams because they will be exposed either to thermal stress by rapid anthropogenic Indian Ocean warming or to unfavorable upwelling conditions.

ABSTRACT: Background: Early prognostication of COVID-19 severity will potentially improve patient care. Biomarkers, such as TNF-related apoptosis-inducing ligand (TRAIL), interferon gamma-induced protein 10 (IP-10), and C-reactive protein (CRP), might represent possible tools for point-of-care testing and severity prediction. Methods: In this prospective cohort study, we analyzed serum levels of TRAIL, IP-10, and CRP in patients with COVID-19, compared them with control subjects, and investigated the association with disease severity. Results: A total of 899 measurements were performed in 132 patients (mean age 64 years, 40.2% females). Among patients with COVID-19, TRAIL levels were lower (49.5 vs 87 pg/ml, P = 0.0142), whereas IP-10 and CRP showed higher levels (667.5 vs 127 pg/ml, P

Obtaining information about the structure of metal-organic layers (MOLs) using standard electron microscopy methods is challenging due to damage under electron beam irradiation. Here, the authors reveal a multistep formation process of MOLs and identify missing clusters, dislocations, loop and flat surface terminations and ligand connector of MOLs via complementary electron microscopy techniques.

Rod-shaped bacteria typically elongate and divide by transverse fission, but a few species are known to divide longitudinally. Here, the authors use genomic, phylogenetic and microscopy techniques to shed light on the evolution of cell shape, multicellularity and division mode within the family Neisseriaceae.

Chronic lymphocytic leukemia (CLL) cells are highly dependent on interactions with the immunosuppressive tumor microenvironment (TME) for survival and proliferation. In the search for novel treatments, pro-inflammatory cytokines have emerged as candidates to reactivate the immune system. Among those, interleukin 27 (IL-27) has recently gained attention, but its effects differ among malignancies. Here, we utilized the Eμ-TCL1 and EBI3 knock-out mouse models as well as clinical samples from patients to investigate the role of IL-27 in CLL. Characterization of murine leukemic spleens revealed that the absence of IL-27 leads to enhanced CLL development and a more immunosuppressive TME in transgenic mice. Gene-profiling of T-cell subsets from EBI3 knock-out highlighted transcriptional changes in the CD8+ T-cell population associated with T-cell activation, proliferation, and cytotoxicity. We also observed an increased anti-tumor activity of CD8+ T cells in the presence of IL-27 ex vivo with murine and clinical samples. Notably, IL-27 treatment led to the reactivation of autologous T cells from CLL patients. Finally, we detected a decrease in IL-27 serum levels during CLL development in both pre-clinical and patient samples. Altogether, we demonstrated that IL-27 has a strong anti-tumorigenic role in CLL and postulate this cytokine as a promising treatment or adjuvant for this malignancy.

Due to its ample production of lignocellulosic biomass, Sida hermaphrodita (Sida), a perennial forb, is considered a valuable raw material for biorefinery processes. The recalcitrant nature of Sida lignocellulosic biomass towards pretreatment and fractionation processes has previously been studied. However, Sida is a non-domesticated species and here we aimed at expanding the potential of such plants in terms of their processability for downstream processes by making use of the natural variety of Sida. To achieve this goal, we established a collection comprising 16 different Sida accessions obtained from North America and Europe. First, we asked whether their cell wall characteristics are reflected in genetic distance or geographical distribution, respectively. A genotyping-by-sequencing (GBS) analysis resulting in a phylogenic tree based on 751 Single Nucleotide Polymorphisms (SNPs), revealed a high genetic diversity and a clear separation between accessions collected in North America and Europe. Further, all three North American accessions were separated from each other. Of the eleven European accessions, five form individual groups and six others belong to a single group. Clonal plants of seven selected accessions of American and European origin were produced and cultivated under greenhouse conditions and the resulting plant material was used for in-depth wet-chemical and spectroscopic cell wall characterization. Two accessions with contrasting cell wall characteristics were then selected and processed using the OrganoCat technology. Results of the different product yields and chemical compositions are reported. Overall, cell wall analyses revealed contrasting clusters regarding these main components between the accessions that can be related to genetic and, partly, geographical distance. Phenotypically, the accessions clustered into two groups that are not entirely overlapping with geographical origin. These results can be the basis for a targeted selection or cultivation of Sida accessions for biorefinery approaches.

Background COPD may predispose to symptomatic pulmonary hypertension at high altitude. We investigated haemodynamic changes in lowlanders with COPD ascending to 3100 m and evaluated whether preventive acetazolamide treatment would attenuate the altitude-induced increase in pulmonary artery pressure (PAP). Methods In this randomised, placebo-controlled, double-blind, parallel-group trial, patients with COPD Global Initiative for Chronic Obstructive Lung Disease grades 2–3 who were living 92% and arterial carbon dioxide tension

Introduction In clear cell renal cell carcinoma (ccRCC), tumor-associated macrophage (TAM) induction of CD8+T cells into a terminally exhausted state has been implicated as a major mechanism of immunotherapy resistance, but a deeper biological understanding is necessary.Methods Primary ccRCC tumor samples were obtained from 97 patients between 2004 and 2018. Multiplex immunofluorescence using lymphoid and myeloid markers was performed in seven regions of interest per patient across three predefined zones, and geospatial analysis was performed using Ripley’s K analysis, a methodology adapted from ecology.Results Clustering of CD163+M2 like TAMs into the stromal compartment at the tumor–stroma interface was associated with worse clinical stage (tumor/CD163+nK(75): stage I/II: 4.4 (IQR −0.5 to 5.1); stage III: 1.4 (IQR −0.3 to 3.5); stage IV: 0.6 (IQR −2.1 to 2.1); p=0.04 between stage I/II and stage IV), and worse overall survival (OS) and cancer-specific survival (CSS) (tumor/CD163+nK(75): median OS–hi=149 months, lo=86 months, false-discovery rate (FDR)-adj. Cox p

Abstract Background Severe COVID-19 induced acute respiratory distress syndrome (ARDS) often requires extracorporeal membrane oxygenation (ECMO). Recent German health insurance data revealed low ICU survival rates. Patient characteristics and experience of the ECMO center may determine intensive care unit (ICU) survival. The current study aimed to identify factors affecting ICU survival of COVID-19 ECMO patients. Methods 673 COVID-19 ARDS ECMO patients treated in 26 centers between January 1st 2020 and March 22nd 2021 were included. Data on clinical characteristics, adjunct therapies, complications, and outcome were documented. Block wise logistic regression analysis was applied to identify variables associated with ICU-survival. Results Most patients were between 50 and 70 years of age. PaO2/FiO2 ratio prior to ECMO was 72 mmHg (IQR: 58–99). ICU survival was 31.4%. Survival was significantly lower during the 2nd wave of the COVID-19 pandemic. A subgroup of 284 (42%) patients fulfilling modified EOLIA criteria had a higher survival (38%) (p = 0.0014, OR 0.64 (CI 0.41–0.99)). Survival differed between low, intermediate, and high-volume centers with 20%, 30%, and 38%, respectively (p = 0.0024). Treatment in high volume centers resulted in an odds ratio of 0.55 (CI 0.28–1.02) compared to low volume centers. Additional factors associated with survival were younger age, shorter time between intubation and ECMO initiation, BMI > 35 (compared to

Abstract Salt marshes exist along the gradient of the marine mudflat to the terrestrial dunes, with a gradient of shore height and associated plant zonation. The lower salt marsh (LSM) extends from the mean high tidal level to 35 cm above that level and is followed by the upper salt marsh (USM). Despite changes in the amount of allochthonous marine input and in abiotic conditions, little is known about changes in the trophic structure and used of basal resources by the soil macrofauna along marine—terrestrial boundaries. Natural variations in carbon stable isotope ratios (δ13C signatures) allow insight into basal resources of consumers such as marine algae, terrestrial C3 and C4 photosynthesising plants. Furthermore, variations in nitrogen stable isotope ratios (δ15N signatures) allow insight into the trophic position of consumers. We investigated spatial and temporal changes in stable isotope signatures in salt marsh soil macrofauna of the island of Spiekeroog, German Wadden Sea. The range of δ15N signatures indicated no changes in food chain length across salt marsh zones with consumers in both zones comprising primary decomposers, secondary decomposers and first order predators. However, the trophic position of individual species changed between zones, but in particular with season. Contrasting δ15N signatures, the range in δ13C signatures in the LSM was twice that in the USM indicating a wider range of resources consumed. Bayesian mixing models indicated predominant autochthonous resource use in both the LSM and USM, with the use of marine allochthonous resources never exceeding 29.6%. However, the models also indicate an increase in the use of marine resources in certain species in the LSM with no use in the USM. Overall, the results indicate that the resource use of salt marsh macrofauna varies more in space than in time, with the food web being generally based on autochthonous rather than allochthonous resources. However, there also is trophic plasticity in certain species across both temporal and spatial scales including variations in the use of allochthonous resources. Generally, however, marine input contributes little to the nutrition of salt marsh soil macroinvertebrates.

Chronic lymphocytic leukemia (CLL) is a common and incurable B-cell malignancy. Recent therapeutic approaches that target the B-cell receptor signaling pathway include inhibition of phosphatidylinositol-3-kinase (PI3K). The PI3K isoform delta is constitutively active in CLL, making it an attractive therapeutic target. However, the expression of PI3K isoforms is not exclusive to leukemic cells, as other immune cells in the tumor microenvironment also rely on PI3K activity. Subsequently, therapeutic inhibition of PI3K causes immune-related adverse events (irAEs). Here, we analyzed the impact of the clinically approved PI3Kδ inhibitors idelalisib and umbralisib, the PI3Kγ inhibitor eganelisib, and the dual-γ and -δ inhibitor duvelisib on the functional capacity of T cells. All investigated inhibitors reduced T-cell activation and proliferation in vitro, which is in line with PI3K being a crucial signaling component of the T-cell receptor signaling. Further, dual inhibition of PI3Kγ and PI3Kδ showed strong additive effects suggesting a role also for PI3Kγ in T cells. Extrapolation of this data to a clinical setting could provide an explanation for the observed irAEs in CLL patients undergoing treatment with PI3K inhibitors. Consequently, this highlights the need for a close monitoring of patients treated with PI3K inhibitors, and particularly duvelisib, due to their potentially increased risk of T-cell deficiencies and associated infections.

When a compact object is formed in a binary, any mass lost during core collapse will impart a kick on the binary’s center of mass. Asymmetries in this mass loss or neutrino emission would impart an additional natal kick on the remnant black hole or neutron star, whether it was formed in a binary or in isolation. While it is well established that neutron stars receive natal kicks upon formation, it is unclear whether black holes do as well. Here, we consider the low-mass X-ray binary MAXI J1305-704, which has been reported to have a space velocity ≳200 km s ^−1 . In addition to integrating its trajectory to infer its velocity upon formation of its black hole, we account for recent estimates of its period, black hole mass, mass ratio, and donor effective temperature from photometric and spectroscopic observations. We find that if MAXI J1305-704 formed via isolated binary evolution in the thick Galactic disk, then the supernova that formed its black hole imparted a natal kick of at least 70 km s ^−1 while ejecting less than ≃1 M _⊙ with 95% confidence assuming uninformative priors on mass loss and natal kick velocity.

The phenotypic efficacy of somatic copy number alterations (SCNAs) stems from their incidence per base pair of the genome, which is orders of magnitudes greater than that of point mutations. One mitotic event stands out in its potential to significantly change a cell's SCNA burden-a chromosome missegregation. A stochastic model of chromosome mis-segregations has been previously developed to describe the evolution of SCNAs of a single chromosome type. Building upon this work, we derive a general deterministic framework for modeling missegregations of multiple chromosome types. The framework offers flexibility to model intra-tumor heterogeneity in the SCNAs of all chromosomes, as well as in missegregation- and turnover rates. The model can be used to test how selection acts upon coexisting karyotypes over hundreds of generations. We use the model to calculate missegregation-induced population extinction (MIE) curves, that separate viable from non-viable populations as a function of their turnover- and missegregation rates. Turnover- and missegregation rates estimated from scRNA-seq data are then compared to theoretical predictions. We find convergence of theoretical and empirical results in both the location of MIE curves and the necessary conditions for MIE. When a dependency of missegregation rate on karyotype is introduced, karyotypes associated with low missegregation rates act as a stabilizing refuge, rendering MIE impossible unless turnover rates are exceedingly high. Intra-tumor heterogeneity, including heterogeneity in missegregation rates, increases as tumors progress, rendering MIE unlikely.

Abstract Background Diagnostics of Alzheimer’s Disease (AD) require a multimodal approach. Neuropsychologists examine the degree and etiology of dementia syndromes and results are combined with those of cerebrospinal fluid markers and imaging data. In the diagnostic process, neuropsychologists often rely on anamnestic and clinical information, as well as cognitive tests, prior to the availability of exhaustive etiological information. The congruency of this phenomenological approach with results from FDG-PET/CT examinations remains to be explored. The latter yield highly accurate diagnostic information. Method A mixed sample of N = 127 hospitalized neurological patients suspected of displaying a dementia syndrome underwent extensive neuropsychological and FDG-PET/CT examinations. Neuropsychological examinations included an anamnestic and clinical interview, and the CERAD cognitive test battery. Two decisional approaches were considered: First, routine diagnostic results were obtained, i.e. the final clinical decision of the examining neuropsychologist (ADClinical vs. non-ADClinical). Secondly, a logistic regression model was implemented, relying on CERAD profiles alone. CERAD subscales that best predicted AD based on FDG-PET/CT were identified and a nominal categorization obtained (ADTest vs. non-ADTest). Congruency of results from both approaches with those of the FDG-PET/CT (ADPET vs. non-ADPET) were estimated with Cohen’s Kappa (κ) and Yule’s Y coefficient of colligation. Descriptive estimates of accuracy, sensitivity and specificity of CERAD relative to FDG-PET/CT diagnostics were derived. Results ADPET patients constituted N = 33/127 (26%) of the sample. The clinical decision approach (ADClinical vs. non-ADClinical) showed substantial agreement with the FDG-PET/CT classification (κ = .69, Y = .72) involving good accuracy (84.2%), moderate sensitivity (75.8%) and excellent specificity (92.6%). In contrast, the decisional approach that relied on CERAD data alone (ADTest vs. non-ADTest) involved only moderate agreement with the FDG-PET/CT (κ = .54, Y = .62) with lower accuracy (74.8%), attributable to decreased sensitivity (56.3%) and comparable specificity (93.3%). Conclusions It is feasible to identify AD through a comprehensive neuropsychological examination in a mixed sample of neurological patients. However, within the boundaries of methods applied here, decisions based on cognitive test results alone appear limited. One may conclude that the clinical impression based on anamnestic and clinical information obtained by the neuropsychological examiner plays a crucial role in the identification of AD patients in routine clinical practice.

Abstract Introduction Individuals with proopiomelanocortin (POMC) or leptin receptor (LEPR) deficiency are young and experience severe obesity, hyperphagia, and comorbidities, which can impair quality of life (QOL). Methods Two pivotal Phase 3 trials explored the effect of setmelanotide on body weight and hunger in individuals with obesity due to POMC (NCT02896192) or LEPR (NCT03287960) deficiency. QOL and depression were investigated in parallel using the disease-specific, age-appropriate Impact of Weight on Quality of Life-Lite (IWQOL-Lite), Pediatric Quality of Life Inventory (PedsQL), and Patient Health Questionnaire-9 (PHQ-9). Results In total, the POMC and LEPR trials enrolled 21 patients. Adults (≥ 18 years old; n = 7) had moderate-to-severe impairment in QOL at baseline, with mean (standard deviation [SD]) IWQOL-Lite total score 60.3 (13.2; maximum IWQOL-Lite total score = 100). The effect of setmelanotide on IWQOL-Lite total score was observed as soon as Week 5. Among those with scores at Week 52, 5 of 6 adults experienced a clinically meaningful improvement, with mean (SD) total scores increased from baseline by 24.2 (12.1) points. Children (6–12 years old; n = 2) and adolescents (13–17 years old; n = 4) had impaired QOL at baseline, with mean (SD) self-reported PedsQL total scores 53.3 (6.2) and 63.3 (29.1), respectively (maximum PedsQL total score = 100). Three of 5 patients experienced clinically meaningful improvement in PedsQL, with 2 children whose PedsQL total score increased by 28.3 and 3.3 points and 3 adolescents whose mean (SD) total score increased from baseline by 5.8 (18.3) points. Baseline mean (SD) PHQ-9 score (in those ≥ 12 years old) was 5.3 (3.8) and was generally maintained through Week 52. Conclusions Patients with POMC or LEPR deficiency had impaired, and in some cases severely impaired, QOL before setmelanotide treatment. Setmelanotide improved QOL in patients as early as Week 5, with some patients no longer experiencing impaired QOL at Week 52. Improvements in QOL may be related to a reduction in hunger and body weight associated with setmelanotide. Because of the highly complex psychological consequences of rare genetic diseases of obesity, some patients may require a long period of treatment to improve QOL and benefit from interdisciplinary care.

Extracorporeal membrane oxygenation (ECMO) is an important rescue therapy method for the treatment of severe hypoxic lung injury. In some cases, oxygen saturation and oxygen partial pressure in the arterial blood are low despite ECMO therapy. There are case reports in which patients with such instances of refractory hypoxemia received a second membrane lung, either in series or in parallel, to overcome the hypoxemia. It remains unclear whether the parallel or serial connection is more effective. Therefore, we used an improved version of our full-flow ECMO mock circuit to test this. The measurements were performed under conditions in which the membrane lungs were unable to completely oxygenate the blood. As a result, only the photometric pre- and post-oxygenator saturations, blood flow and hemoglobin concentration were required for the calculation of oxygen transfer rates. The results showed that for a pre-oxygenator saturation of 45% and a total blood flow of 10 L/min, the serial connection of two identical 5 L rated oxygenators is 17% more effective in terms of oxygen transfer than the parallel connection. Although the idea of using a second membrane lung if refractory hypoxia occurs is intriguing from a physiological point of view, due to the invasiveness of the solution, further investigations are needed before this should be used in a wider clinical setting.

The unsymmetrical diborane(4) derivative [(d(CH2P(iPr)2)abB)–Bpin] (1) proved to be a versatile PBP boryl pincer ligand precursor for Co(I) (2a, 4a), Rh(I) (2–3b) and Ir(I/III) (2–3c, 5–6c) complexes, in particular of the types [(d(CH2P(iPr)2)abB)M(PMe3)2] (2a–c) and [(d(CH2P(iPr)2)abB)M–PMe3] (2b–c). Whilst similar complexes have been obtained before, for the first time, the coordination chemistry of a homologous series of PBP pincer complexes, in particular the interconversion of the five- and four-coordinate complexes 2a–c/3a–c, was studied in detail. For Co, instead of the mono phosphine complex 2a, the dinitrogen complex [(d(CH2P(iPr)2)abB)Co(N2)(PMe3)] (4a) is formed spontaneously upon PMe3 abstraction from 2a in the presence of N2. All complexes were comprehensively characterised spectroscopically in solution via multinuclear (VT-)NMR spectroscopy and structurally in the solid state through single-crystal X-ray diffraction. The unique properties of the PBP ligand with respect to its coordination chemical properties are addressed.

Multiparametric magnetic resonance imaging (mpMRI) has emerged as a new cornerstone in the diagnostic pathway of prostate cancer. However, mpMRI is not devoid of factors influencing its detection rate of clinically significant prostate cancer (csPCa). Amongst others, prostate volume has been demonstrated to influence the detection rates of csPCa. Particularly, increasing volume has been linked to a reduced cancer detection rate. However, information about the linkage between PI-RADS, prostate volume and detection rate is relatively sparse. Therefore, the current study aims to assess the association between prostate volume, PI-RADS score and detection rate of csP-Ca, representing daily practice and contemporary mpMRI expertise. Thus, 1039 consecutive patients with 1151 PI-RADS targets, who underwent mpMRI-guided prostate biopsy at our tertiary referral center, were included. Prior mpMRI had been assessed by a plethora of 111 radiology offices, including academic centers and private practices. mpMRI was not secondarily reviewed in house before biopsy. mpMRI-targeted biopsy was performed by a small group of a total of ten urologists, who had performed at least 100 previous biopsies. Using ROC analysis, we defined cut-off values of prostate volume for each PI-RADS score, where the detection rate drops significantly. For PI-RADS 4 lesions, we found a volume > 61.5 ccm significantly reduced the cancer detection rate (OR 0.24; 95% CI 0.16–0.38; p < 0.001). For PI-RADS 5 lesions, we found a volume > 51.5 ccm to significantly reduce the cancer detection rate (OR 0.39; 95% CI 0.25–0.62; p < 0.001). For PI-RADS 3 lesions, none of the evaluated clinical parameters had a significant impact on the detection rate of csPCa. In conclusion, we show that enlarged prostate volume represents a major limitation in the daily practice of mpMRI-targeted biopsy. This study is the first to define exact cut-off values of prostate volume to significantly impair the validity of PI-RADS assessed in a real-world setting. Therefore, the results of mpMRI-targeted biopsy should be interpreted carefully, especially in patients with prostate volumes above our defined thresholds.

Syntheses of anilines occur through a variety of methods, most requiring transition metals or multiple steps. Here the authors disclose a protocol to form anilines from benzyl alcohols via an aza-Hock rearrangement that uses only a sulfonyl hydroxylamine and solvent.

Abstract Objectives Persons with MS (PwMS) are frequently affected by fatigue and depression. Mindfulness-based interventions may reduce these symptoms in PwMS and consequently their application has been extended to various settings. Only few efforts have been made to explore effects of short-term mindfulness training during brief periods of hospitalization. In the current study, the feasibility and potential effects of short-term mindfulness training on depression, fatigue, rumination and cognition were explored in PwMS in an acute-care hospital setting. Based on previous work, it was further examined whether the relation between trait mindfulness and fatigue prior to and following the intervention was mediated by depression and whether a mediation effect was also observable throughout the intervention. Methods A short-term mindfulness training protocol was developed, tailored to the requirements of the acute-care setting. Subsequently, 30 PwMS were recruited sequentially and received mindfulness training during the routine clinical process (median duration in hospital: eight days, number of sessions: four). Participants completed relevant self-report measures (depression, fatigue, rumination) and a neuropsychological assessment before and after training. Results Participants reported significantly increased trait mindfulness and decreased depression and fatigue following the intervention. Respective change scores were highly correlated so that increased trait mindfulness was associated with decreased symptoms. In the rumination domain, patients reported a tendency for an increased adaptive ability to engage in distractive behavior during arising negative mood. Other measures of trait rumination and cognition remained relatively stable. Results of the mediation analyses indicated that depression mediated the negative relationship between trait mindfulness and fatigue symptoms at pre and post assessments. With regards to the change scores, an association between mindfulness and cognitive fatigue ceased to be significant when depression was controlled, albeit in this case, the mediation effect did not reach significance. Conclusion Results of the current study indicate that short-term mindfulness training during brief periods of hospitalization may be beneficial for PwMS. They further complement previous work by identifying depression as a potential mediator of the antagonistic relationship between mindfulness and fatigue. Based on the current exploratory study, future trials are warranted to address this mechanism of mindfulness training in more detail.

Abstract This trial evaluates whether nocturnal oxygen therapy (NOT) during a stay at 2048 m improves altitude-induced exercise intolerance in lowlanders with chronic obstructive pulmonary disease (COPD). 32 lowlanders with moderate to severe COPD, mean ± SD forced expiratory volume in the first second of expiration (FEV1) 54 ± 13% predicted, stayed for 2 days at 2048 m twice, once with NOT, once with placebo according to a randomized, crossover trial with a 2-week washout period at

BACKGROUND Results of many randomized trials on COVID-19 convalescent plasma (CCP) have been reported, but information on long-term outcome after CCP treatment is limited. The objectives of this extended observation of the randomized CAPSID trial are to assess long-term outcome and disease burden in patients initially treated with or without CCP.METHODS Of 105 randomized patients, 50 participated in the extended observation. Quality of life (QoL) was assessed by questionnaires and a structured interview. CCP donors (n = 113) with asymptomatic to moderate COVID-19 were included as a reference group.RESULTS The median follow-up of patients was 396 days, and the estimated 1-year survival was 78.7% in the CCP group and 60.2% in the control (P = 0.08). The subgroup treated with a higher cumulative amount of neutralizing antibodies showed a better 1-year survival compared with the control group (91.5% versus 60.2%, P = 0.01). Medical events and QoL assessments showed a consistent trend for better results in the CCP group without reaching statistical significance. There was no difference in the increase in neutralizing antibodies after vaccination between the CCP and control groups.CONCLUSION The trial demonstrated a trend toward better outcome in the CCP group without reaching statistical significance. A predefined subgroup analysis showed a significantly better outcome (long-term survival, time to discharge from ICU, and time to hospital discharge) among those who received a higher amount of neutralizing antibodies compared with the control group. A substantial long-term disease burden remains after severe COVID-19.Trial registration EudraCT 2020-001310-38 and ClinicalTrials.gov NCT04433910.Funding Bundesministerium für Gesundheit (German Federal Ministry of Health).

As a consequence of the continued Covid-19 lockdown in Germany, in-hospital teaching for medical students was impossible. While lectures and other theoretical training were relatively easily converted into online sessions using platforms such as Moodle, Zoom and Microsoft Teams, this was not the case for practical skills and clinical interventions, such as bronchoscopy or colonoscopy. This study describes a workaround that was implemented at the Saarland University Hospital utilizing virtual reality equipment to convey the impressions of shadowing clinical procedures to the students without physical presence. To achieve this, 3D 180° videos of key clinical interventions of various internal medicine specialities were recorded, cut, and censored. The videos were uploaded to the e-learning YouTube channel of our institution and shared with the students via the private share function. The students could choose whether to use a VR-viewer to watch the videos immersively or to watch them without a viewer on a screen non-immersively. At the end of the course after 1 week, the students completed a questionnaire anonymously focusing on learning-success regarding the presented topics, a self-assessment, and an evaluation of the course. A total of 27 students watched the videos with a VR-Viewer and 74 watched non-immersively. Although the VR-viewer group self-assessed their expertise higher, there was no significant difference between the two groups in the learning-success test score. However, students in the VR-viewer group rated the learning atmosphere, comprehensibility, and overall recommendation of the course significantly higher. They also agreed significantly more to the statement, that they gained a better conception of the presented procedures, and that virtual reality might be an appropriate tool for online teaching. Video-assisted teaching facilitates learning and might be a valuable add-on to conventional teaching.Abbreviations: Covid-19: severe acute respiratory syndrome coronavirus 2; 3D: three-dimensional; 2D: Two-dimensional; VR: virtual reality

Since transcatheter edge-to-edge repair (TEER) has become a valuable therapy in the treatment of both, mitral (MR) and tricuspid regurgitation (TR), the question of optimized patient selection has gained growing importance. After years of attributing rather little attention to the right ventricle (RV) and its function in the setting of valvular heart failure, this neglect has recently changed. The present review sought to summarize anatomy and function of the RV in a clinical context and aimed at presenting the current knowledge on how the RV influences outcomes after TEER for atrioventricular regurgitation. The anatomy of the RV is determined by its unique shape, which necessitates to use three-dimensional imaging methods for detailed and comprehensive characterization. Complex parameters such as RV to pulmonary artery coupling (RVPAc) have been developed to combine information of RV function and afterload which is primary determined by the pulmonary vasculature and LV filling pressure. Beyond that, TR, which is closely related to RV function also plays an important role in the setting of TEER. While mitral valve transcatheter edge-to-edge repair (M-TEER) leads to reduction of concomitant TR in some patients, the prognostic value of TR in the setting of M-TEER remains unclear. Overall, this review summarizes the current state of knowledge of the outstanding role of RV function and associated TR in the setting of TEER and outlines the unsolved questions associated with right-sided heart failure.

ObjectivesTo determine the profile of cytokines in patients with severe COVID-19 who were enrolled in a trial of COVID-19 convalescent plasma (CCP).MethodsPatients were randomized to receive standard treatment and 3 CCP units or standard treatment alone (CAPSID trial, ClinicalTrials.gov NCT04433910). The primary outcome was a dichotomous composite outcome (survival and no longer severe COVID-19 on day 21). Time to clinical improvement was a key secondary endpoint. The concentrations of 27 cytokines were measured (baseline, day 7). We analyzed the change and the correlation between serum cytokine levels over time in different subgroups and the prediction of outcome in receiver operating characteristics (ROC) analyses and in multivariate models.ResultsThe majority of cytokines showed significant changes from baseline to day 7. Some were strongly correlated amongst each other (at baseline the cluster IL-1ß, IL-2, IL-6, IL-8, G-CSF, MIP-1α, the cluster PDGF-BB, RANTES or the cluster IL-4, IL-17, Eotaxin, bFGF, TNF-α). The correlation matrix substantially changed from baseline to day 7. The heatmaps of the absolute values of the correlation matrix indicated an association of CCP treatment and clinical outcome with the cytokine pattern. Low levels of IP-10, IFN-γ, MCP-1 and IL-1ß on day 0 were predictive of treatment success in a ROC analysis. In multivariate models, low levels of IL-1ß, IFN-γ and MCP-1 on day 0 were significantly associated with both treatment success and shorter time to clinical improvement. Low levels of IP-10, IL-1RA, IL-6, MCP-1 and IFN-γ on day 7 and high levels of IL-9, PDGF and RANTES on day 7 were predictive of treatment success in ROC analyses. Low levels of IP-10, MCP-1 and high levels of RANTES, on day 7 were associated with both treatment success and shorter time to clinical improvement in multivariate models.ConclusionThis analysis demonstrates a considerable dynamic of cytokines over time, which is influenced by both treatment and clinical course of COVID-19. Levels of IL-1ß and MCP-1 at baseline and MCP-1, IP-10 and RANTES on day 7 were associated with a favorable outcome across several endpoints. These cytokines should be included in future trials for further evaluation as predictive factors.

Abstract Background The aim of the current study was to examine multiple gait parameters obtained by wearable inertial sensors and their sensitivity to clinical status in early multiple sclerosis (MS). Further, a potential correlation between gait parameters and subjective fatigue was explored. Methods Automated gait analyses were carried out on 88 MS patients and 31 healthy participants. To measure gait parameters (i.e. walking speed, stride length, stride duration, duration of stance and swing phase, minimal toe-to-floor distance), wearable inertial sensors were utilized throughout a 6-min 25-ft walk. Additionally, self-reported subjective fatigue was assessed. Results Mean gait parameters consistently revealed significant differences between healthy participants and MS patients from as early as an Expanded Disability Status Scale (EDSS) value of 1.5 onwards. Further, MS patients showed a significant linear trend in all parameters, reflecting continuously deteriorating gait performance throughout the test. This linear deterioration trend showed significant correlations with fatigue. Conclusions Wearable inertial sensors are highly sensitive in the detection of gait disturbances, even in early MS, where global scales such as the EDSS do not provide any clinical information about deviations in gait behavior. Moreover, these measures provide a linear trend parameter of gait deterioration that may serve as a surrogate marker of fatigue. In sum, these results suggest that classic timed walking tests in routine clinical practice should be replaced by readily and automatically applicable gait assessments, as provided by inertial sensors.

Abstract Background Despite numerous advances in the identification of risk factors for the development of severe coronavirus disease 2019 (COVID-19), factors that promote recovery from COVID-19 remain unknown. Natural killer (NK) cells provide innate immune defense against viral infections and are known to be activated during moderate and severe COVID-19. Killer immunoglobulin-like receptors (KIR) mediate NK cell cytotoxicity through recognition of an altered MHC-I expression on infected target cells. However, the influence of KIR genotype on outcome of patients with COVID-19 has not been investigated so far. We retrospectively analyzed the outcome associations of NK cell count and KIR genotype of patients with COVID-19 related severe ARDS treated on our tertiary intensive care unit (ICU) between February and June 2020 and validated our findings in an independent validation cohort of patients with moderate COVID-19 admitted to our tertiary medical center. Results Median age of all patients in the discovery cohort (n = 16) was 61 years (range 50–71 years). All patients received invasive mechanical ventilation; 11 patients (68%) required extracorporeal membrane oxygenation (ECMO). Patients who recovered from COVID-19 had significantly higher median NK cell counts during the whole observational period compared to patients who died (121 cells/µL, range 16–602 cells/µL vs 81 cells/µL, range 6–227 cells/µL, p-value = 0.01). KIR2DS5 positivity was significantly associated with shorter time to recovery (21.6 ± 2.8 days vs. 44.6 ± 2.2 days, p-value = 0.01). KIR2DS5 positivity was significantly associated with freedom from transfer to ICU (0% vs 9%, p-value = 0.04) in the validation cohort which consisted of 65 patients with moderate COVID-19. Conclusion NK cells and KIR genotype might have an impact on recovery from COVID-19.

Abstract COVID-19 impacts the daily lives of millions of people. This radical change in our daily activities affected many aspects of life, but acted as well as a natural experiment for research into the spatial distribution of 911 calls. We analyse the impact of the COVID-19 measures on the spatial pattern of police interventions. Crime is not uniformly distributed across street segments, but how does COVID-19 affect these spatial patterns? To this end, Gini coefficients are calculated and a proportion differences spatial point pattern test is applied to compare the similarity of the patterns of incidents before, during, and after the first lockdown in Antwerp, Belgium. With only essential mobility being allowed, the emergency call pattern has not significantly changed before, during or after this lockdown, however, a qualitative shift in police officer’s daily work may have had an effect on the daily operation of the Antwerp police force.