A local subset of mesenchymal cells expressing the transcription factor Osr1 orchestrates lymph node initiation.

During development, lymph node (LN) initiation is coordinated by lymphoid tissue organizer (LTo) cells that attract lymphoid tissue inducer (LTi) cells at strategic positions within the embryo. The identity and function of LTo cells during the initial attraction of LTi cells remain poorly understood. Using lineage tracing, we demonstrated that a subset of Osr1-expressing cells was mesenchymal LTo progenitors. By investigating the heterogeneity of Osr1+ cells, we uncovered distinct mesenchymal LTo signatures at diverse anatomical locations, identifying a common progenitor of mesenchymal LTos and LN-associated adipose tissue. Osr1 was essential for LN initiation, driving the commitment of mesenchymal LTo cells independent of neural retinoic acid, and for LN-associated lymphatic vasculature assembly. The combined action of chemokines CXCL13 and CCL21 was required for LN initiation. Our results redefine the role and identity of mesenchymal organizer cells and unify current views by proposing a model of cooperative cell function in LN initiation.

The little skate genome and the evolutionary emergence of wing-like fins.

Skates are cartilaginous fish whose body plan features enlarged wing-like pectoral fins, enabling them to thrive in benthic environments1,2. However, the molecular underpinnings of this unique trait remain unclear. Here we investigate the origin of this phenotypic innovation by developing the little skate Leucoraja erinacea as a genomically enabled model. Analysis of a high-quality chromosome-scale genome sequence for the little skate shows that it preserves many ancestral jawed vertebrate features compared with other sequenced genomes, including numerous ancient microchromosomes. Combining genome comparisons with extensive regulatory datasets in developing fins-including gene expression, chromatin occupancy and three-dimensional conformation-we find skate-specific genomic rearrangements that alter the three-dimensional regulatory landscape of genes that are involved in the planar cell polarity pathway. Functional inhibition of planar cell polarity signalling resulted in a reduction in anterior fin size, confirming that this pathway is a major contributor to batoid fin morphology. We also identified a fin-specific enhancer that interacts with several hoxa genes, consistent with the redeployment of hox gene expression in anterior pectoral fins, and confirmed its potential to activate transcription in the anterior fin using zebrafish reporter assays. Our findings underscore the central role of genome reorganization and regulatory variation in the evolution of phenotypes, shedding light on the molecular origin of an enigmatic trait.

Chromosome-level genome assemblies of 2 hemichordates provide new insights into deuterostome origin and chromosome evolution.

Deuterostomes are a monophyletic group of animals that includes Hemichordata, Echinodermata (together called Ambulacraria), and Chordata. The diversity of deuterostome body plans has made it challenging to reconstruct their ancestral condition and to decipher the genetic changes that drove the diversification of deuterostome lineages. Here, we generate chromosome-level genome assemblies of 2 hemichordate species, Ptychodera flava and Schizocardium californicum, and use comparative genomic approaches to infer the chromosomal architecture of the deuterostome common ancestor and delineate lineage-specific chromosomal modifications. We show that hemichordate chromosomes (1N = 23) exhibit remarkable chromosome-scale macrosynteny when compared to other deuterostomes and can be derived from 24 deuterostome ancestral linkage groups (ALGs). These deuterostome ALGs in turn match previously inferred bilaterian ALGs, consistent with a relatively short transition from the last common bilaterian ancestor to the origin of deuterostomes. Based on this deuterostome ALG complement, we deduced chromosomal rearrangement events that occurred in different lineages. For example, a fusion-with-mixing event produced an Ambulacraria-specific ALG that subsequently split into 2 chromosomes in extant hemichordates, while this homologous ALG further fused with another chromosome in sea urchins. Orthologous genes distributed in these rearranged chromosomes are enriched for functions in various developmental processes. We found that the deeply conserved Hox clusters are located in highly rearranged chromosomes and that maintenance of the clusters are likely due to lower densities of transposable elements within the clusters. We also provide evidence that the deuterostome-specific pharyngeal gene cluster was established via the combination of 3 pre-assembled microsyntenic blocks. We suggest that since chromosomal rearrangement events and formation of new gene clusters may change the regulatory controls of developmental genes, these events may have contributed to the evolution of diverse body plans among deuterostomes.

Rewiring of the epigenome and chromatin architecture by exogenously induced retinoic acid signaling during zebrafish embryonic development.

Retinoic acid (RA) is the ligand of RA receptors (RARs), transcription factors that bind to RA response elements. RA signaling is required for multiple processes during embryonic development, including body axis extension, hindbrain antero-posterior patterning and forelimb bud initiation. Although some RA target genes have been identified, little is known about the genome-wide effects of RA signaling during in vivo embryonic development. Here, we stimulate the RA pathway by treating zebrafish embryos with all-trans-RA (atRA) and use a combination of RNA-seq, ATAC-seq, ChIP-seq and HiChIP to gain insight into the molecular mechanisms by which exogenously induced RA signaling controls gene expression. We find that RA signaling is involved in anterior/posterior patterning, central nervous system development, and the transition from pluripotency to differentiation. AtRA treatment also alters chromatin accessibility during early development and promotes chromatin binding of RARαa and the RA targets Hoxb1b, Meis2b and Sox3, which cooperate in central nervous system development. Finally, we show that exogenous RA induces a rewiring of chromatin architecture, with alterations in chromatin 3D interactions involving target genes. Altogether, our findings identify genome-wide targets of RA signaling and provide a molecular mechanism by which developmental signaling pathways regulate target gene expression by altering chromatin topology.

Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest.

BACKGROUND: Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty. METHODS: In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33°C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, ≥37.8°C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device. RESULTS: A total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P = 0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score ≥4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, P<0.001). The incidence of other adverse events did not differ significantly between the two groups. CONCLUSIONS: In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, NCT02908308.).

Hyperinflammatory environment drives dysfunctional myeloid cell effector response to bacterial challenge in COVID-19.

COVID-19 displays diverse disease severities and symptoms including acute systemic inflammation and hypercytokinemia, with subsequent dysregulation of immune cells. Bacterial superinfections in COVID-19 can further complicate the disease course and are associated with increased mortality. However, there is limited understanding of how SARS-CoV-2 pathogenesis and hypercytokinemia impede the innate immune function against bacterial superinfections. We assessed the influence of COVID-19 plasma hypercytokinemia on the functional responses of myeloid immune cells upon bacterial challenges from acute-phase COVID-19 patients and their corresponding recovery-phase. We show that a severe hypercytokinemia status in COVID-19 patients correlates with the development of bacterial superinfections. Neutrophils and monocytes derived from COVID-19 patients in their acute-phase showed an impaired intracellular microbicidal capacity upon bacterial challenges. The impaired microbicidal capacity was reflected by abrogated MPO and reduced NETs production in neutrophils along with reduced ROS production in both neutrophils and monocytes. Moreover, we observed a distinct pattern of cell surface receptor expression on both neutrophils and monocytes, in line with suppressed autocrine and paracrine cytokine signaling. This phenotype was characterized by a high expression of CD66b, CXCR4 and low expression of CXCR1, CXCR2 and CD15 in neutrophils and low expression of HLA-DR, CD86 and high expression of CD163 and CD11b in monocytes. Furthermore, the impaired antibacterial effector function was mediated by synergistic effect of the cytokines TNF-α, IFN-γ and IL-4. COVID-19 patients receiving dexamethasone showed a significant reduction of overall inflammatory markers in the plasma as well as exhibited an enhanced immune response towards bacterial challenge ex vivo. Finally, broad anti-inflammatory treatment was associated with a reduction in CRP, IL-6 levels as well as length of ICU stay and ventilation-days in critically ill COVID-19 patients. Our data provides insights into the transient functional dysregulation of myeloid immune cells against subsequent bacterial infections in COVID-19 patients and describe a beneficial role for the use of dexamethasone in these patients.

Coexistence of a fluid responsive state and venous congestion signals in critically ill patients: a multicenter observational proof-of-concept study.

BACKGROUND: Current recommendations support guiding fluid resuscitation through the assessment of fluid responsiveness. Recently, the concept of fluid tolerance and the prevention of venous congestion (VC) have emerged as relevant aspects to be considered to avoid potentially deleterious side effects of fluid resuscitation. However, there is paucity of data on the relationship of fluid responsiveness and VC. This study aims to compare the prevalence of venous congestion in fluid responsive and fluid unresponsive critically ill patients after intensive care (ICU) admission. METHODS: Multicenter, prospective cross-sectional observational study conducted in three medical-surgical ICUs in Chile. Consecutive mechanically ventilated patients that required vasopressors and admitted < 24 h to ICU were included between November 2022 and June 2023. Patients were assessed simultaneously for fluid responsiveness and VC at a single timepoint. Fluid responsiveness status, VC signals such as central venous pressure, estimation of left ventricular filling pressures, lung, and abdominal ultrasound congestion indexes and relevant clinical data were collected. RESULTS: Ninety patients were included. Median age was 63 [45-71] years old, and median SOFA score was 9 [7-11]. Thirty-eight percent of the patients were fluid responsive (FR+), while 62% were fluid unresponsive (FR-). The most prevalent diagnosis was sepsis (41%) followed by respiratory failure (22%). The prevalence of at least one VC signal was not significantly different between FR+ and FR- groups (53% vs. 57%, p = 0.69), as well as the proportion of patients with 2 or 3 VC signals (15% vs. 21%, p = 0.4). We found no association between fluid balance, CRT status, or diagnostic group and the presence of VC signals. CONCLUSIONS: Venous congestion signals were prevalent in both fluid responsive and unresponsive critically ill patients. The presence of venous congestion was not associated with fluid balance or diagnostic group. Further studies should assess the clinical relevance of these results and their potential impact on resuscitation and monitoring practices.

Incidence of adverse respiratory events after adjustment of clear fluid fasting recommendations to 1 h: a prospective, observational, multi-institutional cohort study.

BACKGROUND: Preoperative fasting reduces the risk of pulmonary aspiration during anaesthesia, and 2-h fasting for clear fluids has commonly been recommended. Based on recent evidence of shorter fasting times being safe, the Swiss Society of Paediatric Anaesthesia began recommending 1-h fasting for clear fluids in 2018. This prospective, observational, multi-institutional cohort study aimed to investigate the incidence of adverse respiratory events after implementing the new national recommendation. METHODS: Eleven Swiss anaesthesia institutions joined this cohort study and included patients aged 0-15 yr undergoing anaesthesia for elective procedures after implementation of the 1-h fasting instruction. The primary outcome was the perioperative (defined as the time from anaesthesia induction to emergence) incidence of pulmonary aspiration, gastric regurgitation, and vomiting. Data are presented as median (inter-quartile range; minimum-maximum) or count (percentage). RESULTS: From June 2019 to July 2021, 22 766 anaesthetics were recorded with pulmonary aspiration occurring in 25 (0.11%), gastric regurgitation in 34 (0.15%), and vomiting in 85 (0.37%) cases. No major morbidity or mortality was associated with pulmonary aspiration. Subgroup analysis by effective fasting times (<2 h [n=7306] vs ≥2 h [n=14 660]) showed no significant difference for pulmonary aspiration between these two groups (9 [0.12%] vs 16 [0.11%], P=0.678). Median effective fasting time for clear fluids was 157 [104-314; 2-2385] min. CONCLUSIONS: Implementing a national recommendation of 1-h clear fluid fasting was not associated with a higher incidence of pulmonary aspiration compared with previously reported data.

Polysensitization in the Spanish Contact Dermatitis Registry (REIDAC): A 2019-2022 prospective study with cluster and network analysis.

BACKGROUND: There is still limited clinical-practice data on specific clinical and patch test features, as well as on allergen clusters in polysensitization (PS). OBJECTIVES: To determine the frequency, relevance, symptoms duration and risk factors in polysensitized patients and to assess possible allergen aggregation. METHODS: Prospective multicentric study (January 2019-December 2022) conducted in setting of the Spanish Contact Dermatitis Register (REIDAC). Clinical and patch test data of polysensitized and oligosensitized patients were compared, and risk factors of PS were investigated with logistic multivariate regression. Unsupervised hierarchical clustering and network analysis were used to study allergen aggregation in PS. RESULTS: A total of 10,176 patients were analysed. PS was found in 844 (8.3%). Current relevance was significantly higher in polysensitized patients (p < 0.01). Risk factors for PS were atopic dermatitis (OR: 1.58, 95% CI: 1.24-2.02), age (≥60 years vs. ≤24 years, OR: 1.75, 95% CI: 1.25-2.44) and some special locations (legs vs. face OR: 1.54, 95% CI: 1.05-2.25, hands vs. face OR: 1.46, 95% CI:1.15-1.85, arms vs. face OR: 1.49, 95% CI:1.01-2.20, trunk vs. face OR: 1.40, 95% CI:1.06-1.85). Cluster and network analyses revealed specific-allergen clusters and significant associations, including allergens belonging to metals group, fragrances and botanicals group, topical drugs group, rubber allergens and biocides. CONCLUSIONS: This study confirms that PS is structured by discernible patterns of specific-allergen clusters and reinforces significant allergen associations in PS. Cross-reactivity and/or concomitant sensitization could explain the formation of allergen clusters in PS.

Cosmetovigilance for infrequent allergens in Spain using a national online registry: The example of allergic contact dermatitis caused by phenylethyl resorcinol.

BACKGROUND: Monitoring of adverse events induced by cosmetics performed by health authorities, known as cosmetovigilance, has been relied on the collection of case notifications. OBJECTIVES: We aimed to show how a contact dermatitis registry can contribute to the cosmetovigilance of emerging allergens. We used the example of phenylethyl resorcinol, an infrequent allergen with only 6 previous cases reported in Europe and Japan since 2013. METHODS: A systematic search in the Spanish Registry of Contact Dermatitis and Cutaneous Allergy (REIDAC) database was performed to identify patients with positive patch test to phenylethyl resorcinol or cosmetics that contains it between June 2018 and January 2023. We collected the main clinical features of these patients and compared them with those of patients recorded in the registry with similar epidemiological features. RESULTS: Thirteen patients with positive patch test to phenylethyl resorcinol were identified. All the patients were women with a mean age of 42 years (range 32-59) and their lesions were mainly in the face. CONCLUSION: Assessing the importance of infrequent allergens based solely on a case series is difficult. Multicentre registries facilitate the collection of cases and provide appropriate background information for new allergens.

Sensitization to textile dyes in Spain: Epidemiological situation (2019-2022).

BACKGROUND: Current frequency and features for positivity to textile dye mix (TDM) in Spain are unknown. OBJECTIVES: To study the frequency, clinical features and simultaneous positivity between TDM, para-phenylenediamine (PPD) and specific disperse dyes. MATERIALS AND METHODS: We analysed all consecutive patients patch-tested with TDM from the Spanish Contact Dermatitis Registry (REIDAC), from 1 January 2019 to 31 December 2022. Within this group, we studied all selected patients patch-tested with a textile dye series. RESULTS: Out of 6128 patients analysed, 3.3% were positive to the TDM and in 34% of them, the sensitization was considered currently relevant. TDM positivity was associated with working as a hairdresser/beautician and scalp, neck/trunk and arm/forearm dermatitis. From TDM-positive patients, 57% were positive to PPD. One hundred and sixty-four patients were patch-tested with the textile dye series. Disperse Orange 3 was the most frequent positive dye (16%). One of every six cases positive to any dye from the textile dye series would have been missed if patch-tested with the TDM alone. CONCLUSIONS: Positivity to TDM is common in Spain and often associated with PPD sensitization. TDM is a valuable marker of disperse dyes allergy that should be part of the Spanish and European standard series.

2-Hydroxyethyl methacrylate (2-HEMA) sensitization, a global epidemic at its peak in Spain?

BACKGROUND: A global epidemic of allergic contact dermatitis to (meth)acrylates has been described in relation to the widespread use of manicure products. OBJECTIVES: To evaluate the frequency of sensitization to 2-hydroxyethyl methacrylate (2-HEMA) among consecutively patch tested patients with eczema in Spain; the percentage of current relevance; the MOAHLFA index; and, the potential sources of exposure to (meth)acrylates. METHODS: From January 2019 to December 2022, 2-HEMA 2% pet. was prospectively patch tested in 24 REIDAC (Spanish Allergic Contact Dermatitis Registry) centres. RESULTS: Six thousand one hundred thirty-four patients were consecutively patch tested with 2-HEMA 2% pet. 265/6134 (4.3%) were positive. Positive reactions of current relevance were identified to involve 184/265 (69%). The efficiency (number of patch tests needed to detect relevant positive patch test reactions) was 34 (6134/184). The variable 'occupational' was found to be significantly associated with a higher risk for relevant positive reactions to 2-HEMA (OR: 10.9; 95% CI: 8.1-14.9). CONCLUSION: (Meth)acrylate sensitization is a prevalent health issue in Spain. 2-HEMA 2% pet. has been identified to be a highly effective (meth)acrylate allergy marker in the GEIDAC baseline series. The responsible authorities should implement policies guaranteeing accurate labelling of industrial, medical, and consumer materials while ensuring the enforcement of said labelling through appropriate legal means.

Impact of sex and gender on post-COVID-19 syndrome, Switzerland, 2020.

BackgroundWomen are overrepresented among individuals with post-acute sequelae of SARS-CoV-2 infection (PASC). Biological (sex) as well as sociocultural (gender) differences between women and men might account for this imbalance, yet their impact on PASC is unknown.AimWe assessed the impact of sex and gender on PASC in a Swiss population.MethodOur multicentre prospective cohort study included 2,856 (46% women, mean age 44.2 ± 16.8 years) outpatients and hospitalised patients with PCR-confirmed SARS-CoV-2 infection.ResultsAmong those who remained outpatients during their first infection, women reported persisting symptoms more often than men (40.5% vs 25.5% of men; p < 0.001). This sex difference was absent in hospitalised patients. In a crude analysis, both female biological sex (RR = 1.59; 95% CI: 1.41-1.79; p < 0.001) and a score summarising gendered sociocultural variables (RR = 1.05; 95% CI: 1.03-1.07; p < 0.001) were significantly associated with PASC. Following multivariable adjustment, biological female sex (RR = 0.96; 95% CI: 0.74-1.25; p = 0.763) was outperformed by feminine gender-related factors such as a higher stress level (RR = 1.04; 95% CI: 1.01-1.06; p = 0.003), lower education (RR = 1.16; 95% CI: 1.03-1.30; p = 0.011), being female and living alone (RR = 1.91; 95% CI: 1.29-2.83; p = 0.001) or being male and earning the highest income in the household (RR = 0.76; 95% CI: 0.60-0.97; p = 0.030).ConclusionSpecific sociocultural parameters that differ in prevalence between women and men, or imply a unique risk for women, are predictors of PASC and may explain, at least in part, the higher incidence of PASC in women. Once patients are hospitalised during acute infection, sex differences in PASC are no longer evident.

Evaluation of the venting principle to reduce start-up delays in syringe infusion pumps used for microinfusions.

Start-up delays of syringe pump assemblies can impede the timely commencement of an effective drug therapy when using microinfusions in hemodynamically unstable patients. The application of the venting principle has been proposed to eliminate start-up delays in syringe pump assemblies. However, effectively delivered infusion volumes using this strategy have so far not been measured. This invitro study used two experimental setups to measure the effect of the venting principle compared to a standard non-venting approach on delivered start-up infusion volumes at various timepoints, backflow volumes, flow inversion and zero drug delivery times by means of liquid flow measurements at flow rates of 0.5, 1.0 and 2.0 mL/h. Measured delivered initial start-up volumes were negative with all flow rates in the vented and non-vented setup. Maximum backflow volumes were 1.8 [95% CI 1.6 to 2.3] times larger in the vented setup compared to the non-vented setup (p < 0.0001). Conversely, times until flow inversion were 1.5 [95% CI 1.1 to 2.9] times shorter in the vented setup (p < 0.002). This led to comparable zero drug delivery times between the two setups (p = 0.294). Start-up times as defined by the achievement of at least 90% of steady state flow rate were achieved faster with the vented setup (p < 0.0001), but this was counteracted by the increased backflow volumes. The application of the venting principle to the start-up of microinfusions does not improve the timely delivery of drugs to the patient since the faster start-up times are counteracted by higher backflow volumes when opening the three-way stopcock.

Effect of vertical stopcock position on start-up fluid delivery in syringe pumps used for microinfusions.

The purpose of this in vitro study was to evaluate the impact of the vertical level of the stopcock connecting the infusion line to the central venous catheter on start-up fluid delivery in microinfusions. Start-up fluid delivery was measured under standardized conditions with the syringe outlet and liquid flow sensors positioned at heart level (0 cm) and exposed to a simulated CVP of 10 mmHg at a set flow rate of 1 ml/h. Flow and intraluminal pressures were measured with the infusion line connected to the stopcock primarily placed at vertical levels of 0 cm, + 30 cm and - 30 cm or primarily placed at 0 cm and secondarily, after connecting the infusion line, displaced to + 30 cm and - 30 cm. Start-up fluid delivery 10 s after opening the stopcock placed at zero level and after opening the stopcock primarily connected at zero level and secondary displaced to vertical levels of + 30 cm and - 30 cm were similar (- 10.52 [- 13.85 to - 7.19] µL; - 8.84 [- 12.34 to - 5.33] µL and - 11.19 [- 13.71 to - 8.67] µL (p = 0.469)). Fluid delivered at 360 s related to 65% (zero level), 71% (+ 30 cm) and 67% (- 30 cm) of calculated infusion volume (p = 0.395). Start-up fluid delivery with the stopcock primarily placed at + 30 cm and - 30 cm resulted in large anterograde and retrograde fluid volumes of 34.39 [33.43 to 35.34] µL and - 24.90 [- 27.79 to - 22.01] µL at 10 s, respectively (p < 0.0001). Fluid delivered with the stopcock primarily placed at + 30 cm and - 30 cm resulted in 140% and 35% of calculated volume at 360 s, respectively (p < 0.0001). Syringe infusion pumps should ideally be connected to the stopcock positioned at heart level in order to minimize the amounts of anterograde and retrograde fluid volumes after opening of the stopcock.

Pressure-adjusted venting eliminates start-up delays and compensates for vertical position of syringe infusion pumps used for microinfusion.

Microinfusions are commonly used for the administration of catecholamines, but start-up delays pose a problem for reliable and timely drug delivery. Recent findings show that venting of the syringe infusion pump with draining of fluid to ambient pressure before directing the flow towards the central venous catheter does not counteract start-up delays. With the aim to reduce start-up delays, this study compared fluid delivery during start-up of syringe infusion pumps without venting, with ambient pressure venting, and with central venous pressure (CVP)-adjusted venting. Start-up fluid delivery from syringe pumps using a microinfusion of 1 mL/h was assessed by means of liquid flow measurement at 10, 60, 180 and 360 s after opening the stopcock and starting the pump. Assessments were performed using no venting, ambient pressure venting or CVP-adjusted venting, with the pump placed either at zero, - 43 cm or + 43 cm level and exposed to a simulated CVP of 10 mmHg. Measured fluid delivery was closest to the calculated fluid delivery for CVP-adjusted venting (87% to 100% at the different timepoints). The largest deviations were found for ambient pressure venting (- 1151% to + 82%). At 360 s after start-up 72% to 92% of expected fluid volumes were delivered without venting, 46% to 82% with ambient pressure venting and 96% to 99% with CVP-adjusted venting. CVP-adjusted venting demonstrated consistent results across vertical pump placements (p = 0.485), whereas the other methods had significant variances (p < 0.001 for both). In conclusion, CVP-adjusted venting effectively eliminates imprecise drug delivery and start-up delays when using microinfusions.

Antiphospholipid antibodies are enriched post-acute COVID-19 but do not modulate the thrombotic risk.

BACKGROUND AND OBJECTIVES: COVID-19-associated coagulopathy, shown to increase the risk for the occurrence of thromboses and microthromboses, displays phenotypic features of the antiphospholipid syndrome (APS), a prototype antibody-mediated autoimmune disease. Several groups have reported elevated levels of criteria and non-criteria antiphospholipid antibodies (aPL), assumed to cause APS, during acute or post-acute COVID-19. However, disease heterogeneity of COVID-19 is accompanied by heterogeneity in molecular signatures, including aberrant cytokine profiles and an increased occurrence of autoantibodies. Moreover, little is known about the association between autoantibodies and the clinical events. Here, we first aim to characterise the antiphospholipid antibody, anti-SARS-CoV-2 antibody, and the cytokine profiles in a diverse collective of COVID-19 patients (disease severity: asymptomatic to intensive care), using vaccinated individuals and influenza patients as comparisons. We then aim to assess whether the presence of aPL in COVID-19 is associated with an increased incidence of thrombotic events in COVID-19. METHODS AND RESULTS: We conducted anti-SARS-CoV-2 IgG and IgA microELISA and IgG, IgA, and IgM antiphospholipid line immunoassay (LIA) against 10 criteria and non-criteria antigens in 155 plasma samples of 124 individuals, and we measured 16 cytokines and chemokines in 112 plasma samples. We additionally employed clinical and demographic parameters to conduct multivariable regression analyses within multiple paradigms. In line with recent results, we find that IgM autoantibodies against annexin V (AnV), ß2-glycoprotein I (ß2GPI), and prothrombin (PT) are enriched upon infection with SARS-CoV-2. There was no evidence for seroconversion from IgM to IgG or IgA. PT, ß2GPI, and AnV IgM as well as cardiolipin (CL) IgG antiphospholipid levels were significantly elevated in the COVID-19 but not in the influenza or control groups. They were associated predominantly with the strength of the anti-SARS-CoV-2 antibody titres and the major correlate for thromboses was SARS-CoV-2 disease severity. CONCLUSION: While we have recapitulated previous findings, we conclude that the presence of the aPL, most notably PT, ß2GPI, AnV IgM, and CL IgG in COVID-19 are not associated with a higher incidence of thrombotic events.

Tuning the emission properties of electrically pumped semiconductor random lasers via controlled pulsed laser ablation.

Electrically pumped random lasers with distributed feedback can be obtained by introducing random defects into the device active layer, modifying the epitaxial growth process and losing the ease of fabrication potentially offered by disordered structures. We recently demonstrated an alternative and more practical approach in which random lasing emission is obtained from a modified Fabry-Perot laser diode after pulsed laser ablation of its output mirror. Here, we improve our fabrication technique by sweeping the ablating laser beam along the output mirror at different speeds and with different pulse energies, obtaining control over the total energy delivered at each point. We optimize the ablation parameters by evaluating the device performances in terms of lasing threshold and output power and we present the device emission characteristics. The proposed technique is tunable, fast and reliable, allowing the fabrication of devices with different properties by proper selection of the ablation parameters.

The Angiopoietin-2/Angiopoietin-1 ratio increases early in burn patients and predicts mortality.

BACKGROUND: Angiopoietin-2 (Angpt-2) is involved in the pathogenesis of the capillary leak syndrome in sepsis and has been shown to be associated with worse outcomes in diverse critical illnesses. It is however unclear whether Angpt-2 plays a similar role in severely burned patients during the early phase characterized by massive capillary leakage. Our aim was to analyze the Angiopoietin-2/Angiopoietin-1 ratio (Angpt-2/Angpt-1 ratio) over the first two days in critically ill burn patients and examine its association with survival and further clinical parameters. METHODS: Adult burn patients with a total burn surface area (TBSA) ≥ 20% treated in the burn intensive care unit (ICU) of the University Hospital of Zurich, Switzerland, were included. Serum samples were collected prospectively and serum Angpt-1 and Angpt-2 were measured by enzyme-linked immunosorbent assay (ELISA) over the first two days after burn insult and stratified according to survival status, TBSA and the abbreviated burn severity index (ABSI). Due to hemodilution in the initial resuscitation phase, the Angpt-2/Angpt-1 ratio was normalized to albumin. RESULTS: Fifty-six patients were included with a median age of 51.5 years. Overall mortality was 14.3% (8/56 patients). The total amount of infused crystalloids was 12́902 ml (IQR 9́362-16́770 ml) at 24 h and 18́461 ml (IQR 13́024-23́766 ml) at 48 h. The amount of substituted albumin was 20 g (IQR 10-50 g) at 24 h and 50 g (IQR 20-60 g) at 48 h. The albumin-corrected Angpt-2/Angpt-1 ratios increased over the first 48 h after the burn insult (d0: 0.5 pg*l/ml*g [IQR 0.24 - 0.80 pg*l/ml*g]; d1: 0.83 pg*l/ml*g [IQR 0.29 - 1.98 pg*l/ml*g]; d2: 1.76 pg*l/ml*g [IQR 0.70 - 3.23 pg*l/ml*g]; p < 0.001) and were significantly higher in eventual ICU non-survivors (p = 0.005), in patients with a higher TBSA (p = 0.001) and in patients with a higher ABSI (p = 0.001). CONCLUSIONS: In analogy to the pathological host response in sepsis, the Angpt-2/Angpt-1 ratio steadily increases in the first two days in critically ill burn patients, suggesting a putative involvement in the pathogenesis of capillary leakage in burns. A higher Angpt-2/Angpt-1 ratio is associated with mortality, total burn surface area and burn scores.

Optomechanical Generation of Coherent GHz Vibrations in a Phononic Waveguide.

Nanophononics has the potential for information transfer, in an analogous manner to its photonic and electronic counterparts. The adoption of phononic systems has been limited, due to difficulties associated with the generation, manipulation, and detection of phonons, especially at GHz frequencies. Existing techniques often require piezoelectric materials with an external radiofrequency excitation that are not readily integrated into existing CMOS infrastructures, while nonpiezoelectric demonstrations have been inefficient. In this Letter, we explore the optomechanical generation of coherent phonons in a suspended 2D silicon phononic crystal cavity with a guided mode around 6.8 GHz. By incorporating an air-slot into this cavity, we turn the phononic waveguide into an optomechanical platform that exploits localized photonic modes resulting from inherent fabrication imperfections for the transduction of mechanics. Such a platform exhibits very fine control of phonons using light, and is capable of coherent self-sustained phonon generation around 6.8 GHz, operating at room temperature. The ability to generate high frequency coherent mechanical vibrations within such a simple 2D CMOS-compatible system could be a first step towards the development of sources in phononic circuitry and the coherent manipulation of other solid-state properties.