Modelling human rostro-caudal neural patterning with a microfluidic morphogenic gradient

The study of biological mechanisms involved in human fetal brain development requires suitable models. To date, most findings have been acquired from animal models that fail to account for human-specific developmental traits. To counteract this limitation, a novel in vitro model is proposed where human pluripotent stem cells are differentiated into a coherent fetal brain tissue in a gradient forming microfluidic system. Stainings show that the model can be used to investigate the patterning, an important developmental event, of stem cells into forebrain, midbrain and hindbrain. In conclusion, this model could provide a new platform for studying human-specific brain development

MSLibrarian: Optimized Predicted Spectral Libraries for Data-Independent Acquisition Proteomics

Data-independent acquisition-mass spectrometry (DIA-MS) is the method of choice for deep, consistent, and accurate single-shot profiling in bottom-up proteomics. While classic workflows for targeted quantification from DIA-MS data require auxiliary data-dependent acquisition (DDA) MS analysis of subject samples to derive prior-knowledge spectral libraries, library-free approaches based on in silico prediction promise deep DIA-MS profiling with reduced experimental effort and cost. Coverage and sensitivity in such analyses are however limited, in part, by the large library size and persistent deviations from the experimental data. We present MSLibrarian, a new workflow and tool to obtain optimized predicted spectral libraries by the integrated usage of spectrum-centric DIA data interpretation via the DIA-Umpire approach to inform and calibrate the in silico predicted library and analysis approach. Predicted-vs-observed comparisons enabled optimization of intensity prediction parameters, calibration of retention time prediction for deviating chromatographic setups, and optimization of the library scope and sample representativeness. Benchmarking via a dedicated ground-truth-embedded experiment of species-mixed proteins and quantitative ratio-validation confirmed gains of up to 13% on peptide and 8% on protein level at equivalent FDR control and validation criteria. MSLibrarian is made available as an open-source R software package, including step-by-step user instructions, at https://github.com/MarcIsak/MSLibrarian

Modeling neural tube development by differentiation of human embryonic stem cells in a microfluidic WNT gradient

The study of brain development in humans is limited by the lack of tissue samples and suitable in vitro models. Here, we model early human neural tube development using human embryonic stem cells cultured in a microfluidic device. The approach, named microfluidic-controlled stem cell regionalization (MiSTR), exposes pluripotent stem cells to signaling gradients that mimic developmental patterning. Using a WNT-activating gradient, we generated a neural tissue exhibiting progressive caudalization from forebrain to midbrain to hindbrain, including formation of isthmic organizer characteristics. Single-cell transcriptomics revealed that rostro-caudal organization was already established at 24 h of differentiation, and that the first markers of a neural-specific transcription program emerged in the rostral cells at 48 h. The transcriptomic hallmarks of rostro-caudal organization recapitulated gene expression patterns of the early rostro-caudal neural plate in mouse embryos. Thus, MiSTR will facilitate research on the factors and processes underlying rostro-caudal neural tube patterning

Effect of vaccination on household transmission of SARS-CoV-2 Delta variant of concern

Effective vaccines protect individuals by not only reducing the susceptibility to infection, but also reducing the infectiousness of breakthrough infections in vaccinated cases. To disentangle the vaccine effectiveness against susceptibility to infection (VE(S)) and vaccine effectiveness against infectiousness (VE(I)), we took advantage of Danish national data comprising 24,693 households with a primary case of SARS-CoV-2 infection (Delta Variant of Concern, 2021) including 53,584 household contacts. In this setting, we estimated VE(S) as 61% (95%-CI: 59-63), when the primary case was unvaccinated, and VE(I) as 31% (95%-CI: 26-36), when the household contact was unvaccinated. Furthermore, unvaccinated secondary cases with an infection exhibited a three-fold higher viral load compared to fully vaccinated secondary cases with a breakthrough infection. Our results demonstrate that vaccinations reduce susceptibility to infection as well as infectiousness, which should be considered by policy makers when seeking to understand the public health impact of vaccination against transmission of SARS-CoV-2

Postoperative Pulmonary Complications After Cardiac Surgery: The VENICE International Cohort Study.

Postoperative pulmonary complications (PPC) remain a main issue after cardiac surgery. The objective was to report the incidence and identify risk factors of PPC after cardiac surgery. An international multicenter prospective study (42 international centers in 9 countries). A total of 707 adult patients who underwent cardiac surgery under cardiopulmonary bypass. None MEASUREMENTS AND MAIN RESULTS: During a study period of 2 weeks, the investigators included all patients in their respective centers and screened for PPCs. PPC was defined as the occurrence of at least 1 pulmonary complication among the following: atelectasis, pleural effusion, respiratory failure, respiratory infection, pneumothorax, bronchospasm, or aspiration pneumonitis. Among 676 analyzed patients, 373 patients presented with a PPC (55%). The presence of PPC was significantly associated with a longer intensive care length of stay and hospital length of stay. One hundred ninety (64%) patients were not intraoperatively ventilated during cardiopulmonary bypass. Ventilation settings were similar regarding tidal volume, respiratory rate, inspired oxygen. In the regression model, age, the Euroscore II, chronic obstructive pulmonary disease, preoxygenation modality, intraoperative positive end-expiratory pressure, the absence of pre- cardiopulmonary bypass ventilation, the absence of lung recruitment, and the neuromuscular blockade were associated with PPC occurrence. Both individual risk factors and ventilatory settings were shown to explain the high level of PPCs. These findings require further investigations to assess a bundle strategy for optimal ventilation strategy to decrease PPC incidence

Household transmission of SARS-CoV-2 Omicron variant of concern subvariants BA.1 and BA.2 in Denmark

SARS coronavirus 2 (SARS-CoV-2) continues to evolve and new variants emerge. Using nationwide Danish data, we estimate the transmission dynamics of SARS-CoV-2 Omicron subvariants BA.1 and BA.2 within households. Among 22,678 primary cases, we identified 17,319 secondary infections among 50,588 household contacts during a 1–7 day follow-up. The secondary attack rate (SAR) was 29% and 39% in households infected with Omicron BA.1 and BA.2, respectively. BA.2 was associated with increased susceptibility of infection for unvaccinated household contacts (Odds Ratio (OR) 1.99; 95%–CI 1.72-2.31), fully vaccinated contacts (OR 2.26; 95%–CI 1.95–2.62) and booster-vaccinated contacts (OR 2.65; 95%–CI 2.29–3.08), compared to BA.1. We also found increased infectiousness from unvaccinated primary cases infected with BA.2 compared to BA.1 (OR 2.47; 95%–CI 2.15–2.84), but not for fully vaccinated (OR 0.66; 95%–CI 0.57–0.78) or booster-vaccinated primary cases (OR 0.69; 95%–CI 0.59–0.82). Omicron BA.2 is inherently more transmissible than BA.1. Its immune-evasive properties also reduce the protective effect of vaccination against infection, but do not increase infectiousness of breakthrough infections from vaccinated individuals

Household transmission of the SARS-CoV-2 Omicron variant in Denmark

In late 2021, the Omicron SARS-CoV-2 variant overtook the previously dominant Delta variant, but the extent to which this transition was driven by immune evasion or a change in the inherent transmissibility is currently unclear. We estimate SARS-CoV-2 transmission within Danish households during December 2021. Among 26,675 households (8,568 with the Omicron VOC), we identified 14,140 secondary infections within a 1–7-day follow-up period. The secondary attack rate was 29% and 21% in households infected with Omicron and Delta, respectively. For Omicron, the odds of infection were 1.10 (95%-CI: 1.00-1.21) times higher for unvaccinated, 2.38 (95%-CI: 2.23-2.54) times higher for fully vaccinated and 3.20 (95%-CI: 2.67-3.83) times higher for booster-vaccinated contacts compared to Delta. We conclude that the transition from Delta to Omicron VOC was primarily driven by immune evasiveness and to a lesser extent an inherent increase in the basic transmissibility of the Omicron variant