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Abstract Carbon dioxide removal from the atmosphere and storage over long times scales in terrestrial and marine reservoirs is urgently needed to limit global warming and for sustainable management of the global carbon cycle. Ocean alkalinity enhancement by the artificial addition of carbonate minerals to the seafloor has been proposed as a method to sequester atmospheric CO2 and store it in the ocean as dissolved bicarbonate. Here, a reaction-transport model is used to scrutinize the efficacy of calcite addition and dissolution at a well-studied site in the southwestern Baltic Sea – a brackish coastal water body in northern Europe. We find that most calcite is simply buried without dissolution under moderate addition rates. Applying the model to other sites in the Baltic Sea suggests that dissolution rates and efficiencies are higher in areas with low salinity and undersaturated bottom waters. A simple box model predicts a tentative net CO2 uptake rate from the atmosphere of 3.2 megatonnes of carbon dioxide per year for the wider Baltic Sea after continually adding calcite to muddy sediments for 10 years. More robust estimates now require validation by field studies.

Abstract Urothelial bladder cancer (UC) has a wide tumor biological spectrum with challenging prognostic stratification and relevant therapy-associated morbidity. Most molecular classifications relate only indirectly to the therapeutically relevant protein level. We improve the pre-analytics of clinical samples for proteome analyses and characterize a cohort of 434 samples with 242 tumors and 192 paired normal mucosae covering the full range of UC. We evaluate sample-wise tumor specificity and rank biomarkers by target relevance. We identify robust proteomic subtypes with prognostic information independent from histopathological groups. In silico drug prediction suggests efficacy of several compounds hitherto not in clinical use. Both in silico and in vitro data indicate predictive value of the proteomic clusters for these drugs. We underline that proteomics is relevant for personalized oncology and provide abundance and tumor specificity data for a large part of the UC proteome ( www.cancerproteins.org ).

Abstract Purpose To identify key components and variations in family-centered care practices. Methods A cross-sectional study, conducted across ESICM members. Participating ICUs completed a questionnaire covering general ICU characteristics, visitation policies, team-family interactions, and end-of-life decision-making. The primary outcome, self-rated family-centeredness, was assessed using a visual analog scale. Additionally, respondents completed the Maslach Burnout Inventory and the Ethical Decision Making Climate Questionnaire to capture burnout dimensions and assess the ethical decision-making climate. Results The response rate was 53% (respondents from 359/683 invited ICUs who actually open the email); participating healthcare professionals (HCPs) were from Europe (62%), Asia (9%), South America (6%), North America (5%), Middle East (4%), and Australia/New Zealand (4%). The importance of family-centeredness was ranked high, median 7 (IQR 6–8) of 10 on VAS. Significant differences were observed across quartiles of family centeredness, including in visitation policies availability of a waiting rooms, family rooms, family information leaflet, visiting hours, night visits, sleep in the ICU, and in team-family interactions, including daily information, routine day-3 conference, and willingness to empower nurses and relatives. Higher family centeredness correlated with family involvement in rounds, participation in patient care and end-of-life practices. Burnout symptoms (41% of respondents) were negatively associated with family-centeredness. Ethical climate and willingness to empower nurses were independent predictors of family centeredness. Conclusions This study emphasizes the need to prioritize healthcare providers’ mental health for enhanced family-centered care. Further research is warranted to assess the impact of improving the ethical climate on family-centeredness.

Abstract Background The optimal amount and timing of protein intake in critically ill patients are unknown. REPLENISH (Replacing Protein via Enteral Nutrition in a Stepwise Approach in Critically Ill Patients) trial evaluates whether supplemental enteral protein added to standard enteral nutrition to achieve a high amount of enteral protein given from ICU day five until ICU discharge or ICU day 90 as compared to no supplemental enteral protein to achieve a moderate amount of enteral protein would reduce all-cause 90-day mortality in adult critically ill mechanically ventilated patients. Methods In this multicenter randomized trial, critically ill patients will be randomized to receive supplemental enteral protein (1.2 g/kg/day) added to standard enteral nutrition to achieve a high amount of enteral protein (range of 2–2.4 g/kg/day) or no supplemental enteral protein to achieve a moderate amount of enteral protein (0.8–1.2 g/kg/day). The primary outcome is 90-day all-cause mortality; other outcomes include functional and health-related quality-of-life assessments at 90 days. The study sample size of 2502 patients will have 80% power to detect a 5% absolute risk reduction in 90-day mortality from 30 to 25%. Consistent with international guidelines, this statistical analysis plan specifies the methods for evaluating primary and secondary outcomes and subgroups. Applying this statistical analysis plan to the REPLENISH trial will facilitate unbiased analyses of clinical data. Conclusion Ethics approval was obtained from the institutional review board, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia (RC19/414/R). Approvals were also obtained from the institutional review boards of each participating institution. Our findings will be disseminated in an international peer-reviewed journal and presented at relevant conferences and meetings. Trial registration ClinicalTrials.gov, NCT04475666 . Registered on July 17, 2020.

Ticks are obligate hematophagous arthropods that transmit a wide range of pathogens to humans as well as wild and domestic animals. They also harbor a non-pathogenic microbiota, although our previous study has shown that the diverse bacterial microbiome in the midgut of Ixodes ricinus is quantitatively poor and lacks a core. In artificial infections by capillary feeding of ticks with two model bacteria (Gram-positive Micrococcus luteus and Gram-negative Pantoea sp.), rapid clearance of these microbes from the midgut was observed, indicating the presence of active immune mechanisms in this organ. In the current study, RNA-seq analysis was performed on the midgut of I. ricinus females inoculated with either M. luteus or Pantoea sp. or with sterile water as a control. While no immune-related transcripts were upregulated by microbial inoculation compared to that of the sterile control, capillary feeding itself triggered dramatic transcriptional changes in the tick midgut. Manual curation of the transcriptome from the midgut of unfed I. ricinus females, complemented by the proteomic analysis, revealed the presence of several constitutively expressed putative antimicrobial peptides (AMPs) that are independent of microbial stimulation and are referred to here as ‘guard’ AMPs. These included two types of midgut-specific defensins, two different domesticated amidase effector 2 (Dae2), microplusin/ricinusin-related molecules, two lysozymes, and two gamma interferon-inducible lysosomal thiol reductases (GILTs). The in vitro antimicrobial activity assays of two synthetic mature defensins, defensin 1 and defensin 8, confirmed their specificity against Gram-positive bacteria showing exceptional potency to inhibit the growth of M. luteus at nanomolar concentrations. The antimicrobial activity of midgut defensins is likely part of a multicomponent system responsible for the rapid clearance of bacteria in the tick midgut. Further studies are needed to evaluate the role of other identified ‘guard’ AMPs in controlling microorganisms entering the tick midgut.

In recent years, cold plasma treatment has emerged as a promising method to positively impact early seed growth. This study aimed to investigate the effects of cold plasma treatment on millet seeds with ambient air plasma discharge at pressures of 100 Pa and power ranging from 40 to 250 W. Results indicated that cold plasma treatment significantly increased radicle length by up to 112.5% (250 W) after 48 h and up to 57% (120 W) after 72 h compared to nontreated plants. The study also found that cold plasma treatment influenced electron transport during the primary phase of photosynthesis, with the effect varying with the power of discharge. However, high levels of discharge resulted in a significantly higher chlorophyll synthesis. These results suggest that cold plasma treatment may be used to reduce plant stress and improve growing properties.

Haptoglobin is a plasma protein of mammals that plays a crucial role in vascular homeostasis by binding free haemoglobin released from ruptured red blood cells. Trypanosoma brucei can exploit this by internalising haptoglobin-haemoglobin complex to acquire host haem. Here, we investigated the impact of haptoglobin deficiency (Hp-/-) on T. brucei brucei infection and the parasite´s capacity to internalise haemoglobin in a Hp-/- mouse model. The infected Hp-/- mice exhibited normal disease progression, with minimal weight loss and no apparent organ pathology, similarly to control mice. While the proteomic profile of mouse sera significantly changed in response to T. b. brucei, no differences in the infection response markers of blood plasma between Hp-/- and control Black mice were observed. Similarly, very few quantitative differences were observed between the proteomes of parasites harvested from Hp-/- and Black mice, including both endogenous proteins and internalised host proteins. While haptoglobin was indeed absent from parasites isolated from Hp-/-mice, haemoglobin peptides were unexpectedly detected in parasites from both Hp-/- and Black mice. Combined, the data support the dispensability of haptoglobin for haemoglobin internalisation by T. b. brucei during infection in mice. Since the trypanosomes knock-outs for their haptoglobin-haemoglobin receptor (HpHbR) internalised significantly less haemoglobin from Hp-/- mice compared to those isolated from Black mice, it suggests that T. b. brucei employs also an HpHbR-independent haptoglobin-mediated mode for haemoglobin internalisation. Our study reveals a so-far hidden flexibility of haemoglobin acquisition by T. b. brucei and offers novel insights into alternative haemoglobin uptake pathways.

Background: Oxygen supplementation is ubiquitous in intensive care unit (ICU) patients with chronic obstructive pulmonary disease (COPD) and acute hypoxaemia, but the optimal oxygenation target has not been established. Methods: This was a pre-planned subgroup analysis of the Handling Oxygenation Targets in the ICU (HOT-ICU) trial, which allocated patients with acute hypoxaemia to a lower oxygenation target (partial pressure of arterial oxygen [Pao2] of 8 kPa) vs a higher target (Pao2 of 12 kPa) during ICU admission, for up to 90 days; the allocation was stratified for presence or absence of COPD. Here, we report key outcomes for patients with COPD. Results: The HOT-ICU trial enrolled 2928 patients of whom 563 had COPD; 277 were allocated to the lower and 286 to the higher oxygenation group. After allocation, the median Pao2 was 9.1 kPa (inter-quartile range 8.7–9.9) in the lower group vs 12.1 kPa (11.2–12.9) in the higher group. Data for arterial carbon dioxide (Paco2) were available for 497 patients (88%) with no between-group difference in time-weighted average; median Paco2 6.0 kPa (5.2–7.2) in the lower group vs 6.2 kPa (5.4–7.3) in the higher group. At 90 days, 122/277 patients (44%) in the lower oxygenation group had died vs 132/285 patients (46%) in the higher (relative risk 0.98; 95% confidence interval 0.82–1.17; P=0.67). No statistically significant differences were found in any secondary outcome. Conclusions: In ICU patients with COPD and acute hypoxaemia, a lower vs a higher oxygenation target did not reduce mortality. There were no between-group differences in Paco2 or in secondary outcomes. Clinical trial registration: NCT 03174002, EudraCT number 2017-000632-34.

Despite the significant health risks associated with Dermanyssus gallinae infestations in humans, they are often overlooked. This study investigated a household case of D. gallinae infestation and explored the resulting clinical manifestations and risk of infection in family members. Microfluidic PCR was employed for high-throughput screening of pathogens in collected mites and blood samples from both chickens and family members. Morphological and molecular examinations confirmed the identity of the mites as D. gallinae sensu stricto (s.s.), with evidence indicating recent blood feeding. Results indicated that the mites exclusively harbored various pathogens, including Bartonella spp., Ehrlichia spp., Apicomplexa, and Theileria spp. Blood samples from family members and poultry tested negative for these pathogens, suggesting a potential reservoir role for D. gallinae. The study further identified haplotypes of D. gallinae, classifying them into D. gallinae s.s., cosmopolitan haplogroup A. Serological analysis revealed elevated IgE seroreactivity against mite proteins in the family member with bite lesions. Antibodies against Bartonella spp. were detected in this individual, indicating exposure to the pathogen. In summary, this study sheds light on the clinical manifestations, pathogen detection, and genetic characterization of D. gallinae infestations, underscoring the necessity of adopting comprehensive approaches to manage such infestations effectively.

[english] From January to May 2012, 1,860 hospitals throughout Germany received a questionnaire encompassing 77 items. Additionally, 300 outpatient care services and 310 nursing homes for elderly in Berlin also received a 10-item questionnaire asking on their implemented infection control practices. All questionnaires were anonymous. A total of 229 completed questionnaires from hospitals, 14 questionnaires from outpatient care services, and 16 questionnaires from nursing homes were eligible for further analysis.The lack of Infection Control physicians was identified as the largest issue. In hospitals sized 400–999 beds a gap of 71%, and in hospitals sized ≥1,000 beds a gap of 17% was reported. Depending on the number of hospital beds, 13–29% of hospitals sized ≥100 beds reported not havening one infection control nurse. Since based on the number of beds in larger institutions or in facilities caring for high-risk patients several infection control nurses may be required, the deficiency in infection control nurses may even be higher, particularly in secondary and tertiary care facilities. Furthermore, the analysis revealed that the legal requirements for surveillance and reporting of notifiable infectious diseases have not yet been implemented in 11% of the facilities. The implementation of antibiotic strategies did show significant gaps. However, deficiencies in the implemented measures for the prevention of surgical site infections were less frequent. Yet 12% of the participants did not have a dedicated infection control concept for their surgical services. Eight percent of hospitals were not prepared for an outbreak management and 10% did not have established regulations for wearing surgical scrubs. Deficiencies in waste disposal and the control of air-conditioning systems were also noted. Based on the results of this survey, conclusions on the optimal resource allocation for further improvement of patient safety may be drawn.While all participating nursing homes had some sort of infection control consultation, this only applied to 12 out of 16 outpatient nursing services. However, all 16 nursing services worked on the basis of an implemented infection control plan. Though legally binding hygiene recommendations have not yet been implemented for nursing homes, the necessity of infection control to assure patient safety has obviously been recognised throughout these services.

Abstract Pharmacologic targeting of chromatin-associated protein complexes has shown significant responses in KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) but resistance frequently develops to single agents. This points to a need for therapeutic combinations that target multiple mechanisms. To enhance our understanding of functional dependencies in KMT2A-r AML, we have used a proteomic approach to identify the catalytic immunoproteasome subunit PSMB8 as a specific vulnerability. Genetic and pharmacologic inactivation of PSMB8 results in impaired proliferation of murine and human leukemic cells while normal hematopoietic cells remain unaffected. Disruption of immunoproteasome function drives an increase in transcription factor BASP1 which in turn represses KMT2A-fusion protein target genes. Pharmacologic targeting of PSMB8 improves efficacy of Menin-inhibitors, synergistically reduces leukemia in human xenografts and shows preserved activity against Menin-inhibitor resistance mutations. This identifies and validates a cell-intrinsic mechanism whereby selective disruption of proteostasis results in altered transcription factor abundance and repression of oncogene-specific transcriptional networks. These data demonstrate that the immunoproteasome is a relevant therapeutic target in AML and that targeting the immunoproteasome in combination with Menin-inhibition could be a novel approach for treatment of KMT2A-r AML.

Abstract For trace gas sensing and precision spectroscopy, optical cavities incorporating low-loss mirrors are indispensable for path length and optical intensity enhancement. Optical interference coatings in the visible and near-infrared (NIR) spectral regions have achieved total optical losses below 2 parts per million (ppm), enabling a cavity finesse in excess of 1 million. However, such advancements have been lacking in the mid-infrared (MIR), despite substantial scientific interest. Here, we demonstrate a significant breakthrough in high-performance MIR mirrors, reporting substrate-transferred single-crystal interference coatings capable of cavity finesse values from 200 000 to 400 000 near 4.5 µm, with excess optical losses (scatter and absorption) below 5 ppm. In a first proof-of-concept demonstration, we achieve the lowest noise-equivalent absorption in a linear cavity ring-down spectrometer normalized by cavity length. This substantial improvement in performance will unlock a rich variety of MIR applications for atmospheric transport and environmental sciences, detection of fugitive emissions, process gas monitoring, breath-gas analysis, and verification of biogenic fuels and plastics.