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Abstract Background Pulmonary oedema is a feared and difficult to predict complication of severe malaria that can emerge after start of antimalarial treatment. Proinflammatory mediators are thought to play a central role in its pathogenesis. Methods An exploratory study was conducted to evaluate the predictive capacity of biomarkers for development of clinical pulmonary oedema in patients with severe falciparum malaria at two hospitals in Bangladesh. Plasma concentrations of interleukin-6 (IL-6), IL-8, tumour necrosis factor (TNF), soluble Receptor of Advanced Glycation End-products (sRAGE), surfactant protein-D (SP-D), club cell secretory protein (CC16), and Krebs von den Lungen-6 (KL-6) on admission were compared with healthy controls. Correlations between these biomarker and plasma lactate and Plasmodium falciparum histidine-rich protein 2 (PfHRP2) levels were evaluated. Receiver Operating Characteristic (ROC) curves were constructed to assess the predictive capacity for clinical pulmonary oedema of the biomarkers of interest. Results Of 106 screened patients with falciparum malaria, 56 were classified as having severe malaria with a mortality rate of 29%. Nine (16%) patients developed clinical pulmonary oedema after admission. Plasma levels of the biomarkers of interest were higher in patients compared to healthy controls. IL-6, IL-8, TNF, sRAGE, and CC16 levels correlated well with plasma PfHRP2 levels (r s = 0.39; P = 0.004, r s = 0.43; P = 0.001, r s = 0.54; P

Abstract Background The COVID-19 pandemic disrupted routine health care and antenatal and birth services globally. The Shoklo Malaria Research Unit (SMRU) based at the Thailand-Myanmar border provides cross border antenatal care (ANC) and birth services to marginalised pregnant women. The border between the countries entered lockdown in March 2020 preventing cross-border access for women from Myanmar to Thailand. SMRU adapted by opening a new clinic during the COVID-19 pandemic in Myanmar. This study explored the impact of the COVID-19 pandemic and response on access to ANC and pregnancy outcomes for marginalised pregnant women in the border regions between Thailand and Myanmar. Methods A retrospective review of medical records of all pregnancies delivered or followed at antenatal clinics of the SMRU from 2017 to the end of 2022. Logistic regression was done to compare the odds of maternal and neonatal outcomes between women who delivered pre-COVID (2017–2019) and women who delivered in the COVID-19 pandemic (2020–2022), grouped by reported country of residence: Thailand or Myanmar. Results Between 2017 and the end of 2022, there were 13,865 (5,576 resident in Thailand and 8,276 in Myanmar) marginalised pregnant women who followed ANC or gave birth at SMRU clinics. Outcomes of pregnancy were known for 9,748 women with an EGA ≥ 28 weeks. Unknown outcome of pregnancy among women living in Thailand did not increase during the pandemic. However, there was a high (60%) but transient increase in unknown outcome of pregnancy for women with Myanmar residence in March 2020 following border closure and decreasing back to the baseline of 20–30% after establishment of a new clinic. Non-literate women were more likely to have an unknown outcome during the pandemic. There was no statistically significant increase in known stillbirths or maternal deaths during the COVID pandemic in this population but homebirth was over represented in maternal and perinatal mortality. Conclusion Decreasing barriers to healthcare for marginalised pregnant women on the Thailand-Myanmar border by establishment of a new clinic was possible in response to sudden border closure during the COVID-19 pandemic and most likely preventing an increase in maternal and perinatal mortality.

Abstract Background Ventilation management may differ between COVID–19 ARDS (COVID–ARDS) patients and patients with pre–COVID ARDS (CLASSIC–ARDS); it is uncertain whether associations of ventilation management with outcomes for CLASSIC–ARDS also exist in COVID–ARDS. Methods Individual patient data analysis of COVID–ARDS and CLASSIC–ARDS patients in six observational studies of ventilation, four in the COVID–19 pandemic and two pre–pandemic. Descriptive statistics were used to compare epidemiology and ventilation characteristics. The primary endpoint were key ventilation parameters; other outcomes included mortality and ventilator–free days and alive (VFD–60) at day 60. Results This analysis included 6702 COVID–ARDS patients and 1415 CLASSIC–ARDS patients. COVID–ARDS patients received lower median VT (6.6 [6.0 to 7.4] vs 7.3 [6.4 to 8.5] ml/kg PBW; p

Abstract Background Lung ultrasound (LUS) in an emerging technique used in the intensive care unit (ICU). The derivative LUS aeration score has been shown to have associations with mortality in invasively ventilated patients. This study assessed the predictive value of baseline and early changes in LUS aeration scores in critically ill invasively ventilated patients with and without ARDS (Acute Respiratory Distress Syndrome) on 30- and 90-day mortality. Methods This is a post hoc analysis of a multicenter prospective observational cohort study, which included patients admitted to the ICU with an expected duration of ventilation for at least 24 h. We restricted participation to patients who underwent a 12-region LUS exam at baseline and had the primary endpoint (30-day mortality) available. Logistic regression was used to analyze the primary and secondary endpoints. The analysis was performed for the complete patient cohort and for predefined subgroups (ARDS and no ARDS). Results A total of 442 patients were included, of whom 245 had a second LUS exam. The baseline LUS aeration score was not associated with mortality (1.02 (95% CI: 0.99 – 1.06), p = 0.143). This finding was not different in patients with and in patients without ARDS. Early deterioration of the LUS score was associated with mortality (2.09 (95% CI: 1.01 – 4.3), p = 0.046) in patients without ARDS, but not in patients with ARDS or in the complete patient cohort. Conclusion In this cohort of critically ill invasively ventilated patients, the baseline LUS aeration score was not associated with 30- and 90-day mortality. An early change in the LUS aeration score was associated with mortality, but only in patients without ARDS. Trial registration ClinicalTrials.gov, ID NCT04482621.

Abstract Background One single-center randomized clinical trial showed that INTELLiVENT-adaptive support ventilation (ASV) is superior to conventional ventilation with respect to the quality of ventilation in post-cardiac surgery patients. Other studies showed that this automated ventilation mode reduces the number of manual interventions at the ventilator in various types of critically ill patients. In this multicenter study in patients post-cardiac surgery, we test the hypothesis that INTELLiVENT-ASV is superior to conventional ventilation with respect to the quality of ventilation. Methods “POStoperative INTELLiVENT-adaptive support VEntilation in cardiac surgery patients II (POSITiVE II)” is an international, multicenter, two-group randomized clinical superiority trial. In total, 328 cardiac surgery patients will be randomized. Investigators screen patients aged > 18 years of age, scheduled for elective cardiac surgery, and expected to receive postoperative ventilation in the ICU for longer than 2 h. Patients either receive automated ventilation by means of INTELLiVENT-ASV or ventilation that is not automated by means of a conventional ventilation mode. The primary endpoint is quality of ventilation, defined as the proportion of postoperative ventilation time characterized by exposure to predefined optimal, acceptable, and critical (injurious) ventilatory parameters in the first two postoperative hours. One major secondary endpoint is ICU team staff workload, captured by the ventilator software collecting manual settings on alarms. Patient-centered endpoints include duration of postoperative ventilation and length of stay in ICU. Discussion POSITiVE II is the first international, multicenter, randomized clinical trial designed to confirm that POStoperative INTELLiVENT-ASV is superior to non-automated conventional ventilation and secondary to determine if this closed-loop ventilation mode reduces ICU team staff workload. The results of POSITiVE II will support intensive care teams in their choices regarding the use of automated ventilation in postoperative care of uncomplicated cardiac surgery patients. Trial registration Clinicaltrials.gov NCT06178510 . Registered on December 4, 2023.

ABSTRACT In the global efforts to combat antimicrobial resistance and reduce antimicrobial use in pig production, there is a continuous search for methods to prevent and/or treat infections. Within this scope, we explored the relationship between the developing piglet nasal microbiome and (zoonotic) bacterial pathogens from birth until 10 weeks of life. The nasal microbiome of 54 pigs was longitudinally studied over 16 timepoints on 9 farms in 3 European countries (Germany, Ireland, and the Netherlands) using amplicon sequencing targeting the V3-V4 16S rRNA region as well as the tuf gene for its staphylococcal discrimination power. The piglets’ age, the farm, and the litter affected the nasal microbiome, with piglets’ age explaining 19% of the variation in microbial composition between samples. Stabilization of the microbiome occurred around 2 weeks post-weaning. Notably, while opportunistic pathogens were ubiquitously present, they did not cause disease. The piglet nasal microbiome often carried species associated with gut, skin, or vagina, which suggests that contact with the vaginal and fecal microbiomes shapes the piglet nasal microbiome. We identified bacterial co-abundance groups of species that were present in the nasal microbiomes in all three countries over time. Anti-correlation between these species and known bacterial pathogens identified species that might be exploited for pathogen reduction. Further experimental evidence is required to confirm these findings. Overall, this study advances our understanding of the piglet nasal microbiome, the factors influencing it, and its longitudinal development, providing insights into its role in health and disease.IMPORTANCEOur study on the nasal microbiota development in piglets across farms in three European countries found that the microbiomes developed similarly in all locations. Additionally, we observed that the colonization of porcine pathogens was either positively or negatively associated with the presence of other bacterial species. These findings enhance our knowledge of co-colonizing species in the nasal cavity and the identified microbial interactions that can be explored for the development of interventions to control pathogens in porcine husbandry.

BackgroundDespite being essential in patients with acute respiratory distress syndrome (ARDS), mechanical ventilation (MV) may cause lung injury and hemodynamic instability. Mechanical power (MP) may describe the net injurious effects of MV, but whether it reflects the hemodynamic effects of MV is currently unclear. We hypothesized that MP is also associated with cardiac output (CO) and pulmonary blood flow (PBF).Methods24 anesthetized pigs with experimental acute lung injury were ventilated for 18 h according to one of three strategies: 1) Open lung approach (OLA), 2) ARDS Network high-PEEP/FIO2 strategy (HighPEEP), or 3) low-PEEP/FIO2 strategy (LowPEEP). Total MP was assessed as the sum of energy dissipated to overcome airway resistance and energy temporarily stored in the elastic lung tissue per minute. The distribution of pulmonary perfusion was determined by positron emission tomography. Regional PBF and MP, assessed in three iso-gravitational regions of interest (ROI) with equal lung mass (ventral, middle, and dorsal ROI), were compared between groups.ResultsMP was higher in the LowPEEP than in the OLA group, while CO did not differ between groups. After 18 h, regional PBF did not differ between groups. During LowPEEP, regional MP was higher in the ventral ROI compared to OLA and HighPEEP groups (2.5 ± 0.3 vs. 1.4 ± 0.4 and 1.6 ± 0.3 J/min, respectively, P < 0.001 each), and higher in the middle ROI compared to the OLA group (2.5 ± 0.4 vs. 1.6 ± 0.5 J/min, P = 0.04). MP in the dorsal ROI did not differ between groups (1.4 ± 0.9 vs. 1.4 ± 0.5 vs. 1.3 ± 0.8 J/min, P = 0.916). Total MP was independently associated with CO [0.34 (0.09, 0.59), P = 0.020]. Regional MP was positively associated with PBF irrespective of the regions [0.52 (0.14, 0.76), P = 0.01; 0.49 (0.10, 0.74), P = 0.016; 0.64 (0.32, 0.83), P = 0.001 for ventral, middle, and dorsal ROI, respectively]. Subgroup analysis revealed a significant association of MP and CO only in the OLA group as well as a significant association between MP with regional PBF only in the HighPEEP group.ConclusionIn this model of acute lung injury in pigs ventilated with either open lung approach, high, or low PEEP tables recommended by the ARDS network, MP correlated positively with CO and regional PBF, whereby these clinically relevant lung-protective ventilation strategies influenced the associations.

Abstract Radial Reaction–Diffusion–Advection (RDA) fronts for A + B → C reactions find wide applications in many natural and technological processes. In liquid solutions, their dynamics can be perturbed by buoyancy-driven convection due to concentration gradients across the front. In this context, we conducted microgravity experiments aboard a sounding rocket, in order to disentangle dispersion and buoyancy effects in such fronts. We studied experimentally the dynamics due to the radial injection of A in B at a constant flow rate, in absence of gravity. We compared the obtained results with numerical simulations using either radial one– (1D) or two–dimensional (2D) models. We showed that gravitational acceleration significantly distorts the RDA dynamics on ground, even if the vertical dimension of the reactor and density gradients are small. We further quantified the importance of such buoyant phenomena. Finally, we showed that 1D numerical models with radial symmetry fail to predict the dynamics of RDA fronts in thicker geometries, while 2D radial models are necessary to accurately describe RDA dynamics where Taylor–Aris dispersion is significant.

Abstract Background Acute respiratory distress syndrome (ARDS) is a frequent cause of hypoxemic respiratory failure with a mortality rate of approximately 30%. Identifying ARDS subphenotypes based on “focal” or “non-focal” lung morphology has the potential to better target mechanical ventilation strategies of individual patients. However, classifying morphology through chest radiography or computed tomography is either inaccurate or impractical. Lung ultrasound (LUS) is a non-invasive bedside tool that can accurately distinguish “focal” from “non-focal” lung morphology. We hypothesize that LUS-guided personalized mechanical ventilation in ARDS patients leads to a reduction in 90-day mortality compared to conventional mechanical ventilation. Methods The Personalized Mechanical Ventilation Guided by UltraSound in Patients with Acute Respiratory Distress Syndrome (PEGASUS) study is an investigator-initiated, international, randomized clinical trial (RCT) that plans to enroll 538 invasively ventilated adult intensive care unit (ICU) patients with moderate to severe ARDS. Eligible patients will receive a LUS exam to classify lung morphology as “focal” or “non-focal”. Thereafter, patients will be randomized within 12 h after ARDS diagnosis to receive standard care or personalized ventilation where the ventilation strategy is adjusted to the morphology subphenotype, i.e., higher positive end-expiratory pressure (PEEP) and recruitment maneuvers for “non-focal” ARDS and lower PEEP and prone positioning for “focal” ARDS. The primary endpoint is all-cause mortality at day 90. Secondary outcomes are mortality at day 28, ventilator-free days at day 28, ICU length of stay, ICU mortality, hospital length of stay, hospital mortality, and number of complications (ventilator-associated pneumonia, pneumothorax, and need for rescue therapy). After a pilot phase of 80 patients, the correct interpretation of LUS images and correct application of the intervention within the safe limits of mechanical ventilation will be evaluated. Discussion PEGASUS is the first RCT that compares LUS-guided personalized mechanical ventilation with conventional ventilation in invasively ventilated patients with moderate and severe ARDS. If this study demonstrates that personalized ventilation guided by LUS can improve the outcomes of ARDS patients, it has the potential to shift the existing one-size-fits-all ventilation strategy towards a more individualized approach. Trial registration The PEGASUS trial was registered before the inclusion of the first patient, https://clinicaltrials.gov/ (ID: NCT05492344).

Abstract Despite decades of research, the influence of climate on the export of dissolved organic carbon (DOC) from soil remains poorly constrained, adding uncertainty to global carbon models. The limited temporal range of contemporary monitoring data, ongoing climate reorganisation and confounding anthropogenic activities muddy the waters further. Here, we reconstruct DOC leaching over the last ~14,000 years using alpine environmental archives (two speleothems and one lake sediment core) across 4° of latitude from Te Waipounamu/South Island of Aotearoa New Zealand. We selected broadly comparable palaeoenvironmental archives in mountainous catchments, free of anthropogenically-induced landscape changes prior to ~1200 C.E. We show that warmer temperatures resulted in increased allochthonous DOC export through the Holocene, most notably during the Holocene Climatic Optimum (HCO), which was some 1.5–2.5 °C warmer than the late pre-industrial period—then decreased during the cooler mid-Holocene. We propose that temperature exerted the key control on the observed doubling to tripling of soil DOC export during the HCO, presumably via temperature-mediated changes in vegetative soil C inputs and microbial degradation rates. Future warming may accelerate DOC export from mountainous catchments, with implications for the global carbon cycle and water quality.

Abstract Introduction Influenza is a common, seasonal infectious disease with broad medical, economic, and social consequences. Real-world evidence on the effect of influenza treatment on household transmission and healthcare resource utilization is limited in outpatient settings in the USA. This study examined the real-world effectiveness of baloxavir vs oseltamivir in reducing influenza household transmission and healthcare resource utilization. Methods This prospective electronic survey on patient-reported outcomes was conducted between October 2022 and May 2023 via CVS Pharmacy in the USA. Adult participants (≥ 18 years old) were eligible if they filled a prescription for baloxavir or oseltamivir at a CVS Pharmacy within 2 days of influenza symptom onset. Participant demographics, household transmission, and all-cause healthcare resource utilization were collected. Transmission and utilization outcomes were assessed using χ 2 and Fisher exact tests. Results Of 87,871 unique patients contacted, 1346 (1.5%) consented. Of 374 eligible patients, 286 (90 baloxavir- and 196 oseltamivir-treated patients) completed the survey and were included in the analysis. Mean age of participants was 45.4 years, 65.6% were female, and 86.7% were White. Lower household transmission was observed with baloxavir compared with oseltamivir therapy (17.8% vs 26.5%; relative risk = 0.67; 95% CI 0.41–1.11). Healthcare resource utilization, particularly emergency department visits (0.0% vs 4.6%), was also numerically lower in the baloxavir-treated group; no hospitalizations were reported in either cohort. Conclusions The findings from this real-world study suggest that antiviral treatment of influenza with baloxavir may decrease household transmission and reduce healthcare resource utilization compared with oseltamivir.

Abstract Background Dissemination of medical practice and scientific information through social media (SoMe) by clinicians and researchers is increasing. Broad exposure of information can promote connectivity within the scientific community, overcome barriers to access to sources, increase debate, and reveal layperson perspectives and preferences. On the other hand, practices lacking scientific evidence may also be promoted, laypeople may misunderstand the professional message, and clinician may suffer erosion of professional status. The aim of this project was to enhance awareness and advise the anesthesia community and clinicians at large about the potential risks advocate for responsible use of SoMe to disseminate information related to medical practices and knowledge. Methods A modified Delphi process with prespecified consensus criteria was conducted among a multidisciplinary panel of experts, including anesthesiologists-intensivists, clinical psychologists, and forensic medicine specialists. Six items were identified: Ethics and deontological principles, the practice of sharing information via social media, legal aspects, psychological aspects, self-promotion, and criteria for appropriate dissemination. Statements and rationales were produced and subjected to blinded panelists’ votes. After reaching consensus, a document was written which then underwent external review by experts uninvolved in the consensus process. The project was promoted by the Italian Society of Anesthesia Analgesia Resuscitation and Intensive Care (SIAARTI). Results Twelve statements were produced, and consensus was achieved for all. The panel concluded that the general principles guiding dissemination of professional information via SoMe must remain in line with the general principles of ethics, deontology, and scientific validity that guide the medical profession and science in general. Professional equity must be maintained while communicating via SoMe. Medical practices lacking support by scientific evidence should not be disseminated. Patients’ informed consent must be obtained before dissemination of information, images, or data. Self-promotion must not be prioritized over any of these principles. Conclusions When sharing medical practices and scientific information on SoMe, healthcare professionals are advised to act conscientiously and ethically. Local regulations should be adhered to. Institutional training on the potential risks and proper of SoMe for such purpose may contribute to preservation of professional integrity.

Aim:: ATP signalling is involved in urinary bladder motor and sensory pathways, including stimulation-mediated release from parasympathetic varicosities to detrusor muscle and from urothelial cells when mechanically stressed. Both modalities are present in humans and other mammals but are especially prominent in overactive bladder syndromes. There is therefore an unmet need to understand how to regulate such release. This study tested the hypothesis that the nitric oxide (NO•)/ soluble guanylate cyclase (sGC)/ cyclic GMP/ protein kinase-G (PKG) pathway has a central role. Methods:: In vitro nerve-mediated contractions and ATP/acetylcholine (ACh) release were measured from bladder wall strips, as was ATP release from urothelial cell suspensions subject to mechanical stresses. Enhanced spontaneous contractile activity was also measured in bladder wall preparations of spinal cord-injured mice. Interventions were designed to increase cellular cGMP levels (a cell-permeable cGMP analogue, a NO• donor, a phosphodiesterase inhibitor (PDEI), a sGC activator), or agents to reduce activity of pathway enzymes (sCG or PKG). Results:: ATP-dependent contractions were reduced by the above interventions, as was ATP release; but ACh-dependent contractions and ACh release were unaffected. Spontaneous contractile activity was also reduced by the cGMP analogue and by a PDEI. ATP release from urothelial cell suspensions was also reduced by similar interventions. Conclusions:: ATP release from efferent nerves and from urothelial cells were selectively reduced by upregulating the NO•/sGC/cGMP/PKG pathway. Translational aspects are discussed with respect to purinergic pathways and overactive bladder pathologies.

Objectives To describe the effect of multimorbidity on adverse patient centred outcomes in people attending emergency department.Design Population based cohort study.Setting Emergency departments in NHS Lothian in Scotland, from 1 January 2012 to 31 December 2019.Participants Adults (≥18 years) attending emergency departments.Data sources Linked data from emergency departments, hospital discharges, and cancer registries, and national mortality data.Main outcome measures Multimorbidity was defined as at least two conditions from the Elixhauser comorbidity index. Multivariable logistic or linear regression was used to assess associations of multimorbidity with 30 day mortality (primary outcome), hospital admission, reattendance at the emergency department within seven days, and time spent in emergency department (secondary outcomes). Primary analysis was stratified by age (

Summary: Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

Summary: Fragile X syndrome (FXS) is associated with disrupted cognition and sleep abnormalities. Sleep loss negatively impacts cognitive function, and one untested possibility is that disrupted cognition in FXS is exacerbated by abnormal sleep. We tested whether ML297, a hypnotic acting on G-protein-activated inward-rectifying potassium (GIRK) channels, could reverse sleep phenotypes and disrupted memory in Fmr1−/y mice. Fmr1−/y mice exhibit reduced non-rapid eye movement (NREM) sleep and fragmented NREM architecture, altered sleep electroencephalogram (EEG) oscillations, and reduced EEG coherence between cortical areas; these are partially reversed following ML297 administration. Treatment following contextual fear or spatial learning restores disrupted memory consolidation in Fmr1−/y mice. During memory recall, Fmr1−/y mice show an altered balance of activity among hippocampal principal neurons vs. parvalbumin-expressing interneurons; this is partially reversed by ML297. Because sleep disruption could impact neurophysiological phenotypes in FXS, augmenting sleep may improve disrupted cognition in this disorder.

Abstract Isolated indigenous societies who actively avoid sustained peaceful contact with the outside world are critically endangered. Last year, “Tanaru”, the lone surviving man of his tribe for at least 35 years, died in Southwest Amazonia, marking the latest cultural extinction event in a long history of massacres, enslavement, and epidemics. Yet in the upper reaches of the Amazon Basin, dozens of resilient isolated tribes still manage to survive. Remote sensing is a reliable method of monitoring the population dynamics of uncontacted populations by quantifying the area cleared for gardens and villages, along with the fire detections associated with the burning of those clearings. Remote sensing also provides a method to document the number of residential structures and village fissioning. Only with these longitudinal assessments can we better evaluate the current no-contact policies by the United Nations and governments, along with the prospects for the long-term survival of isolated tribes. While the world’s largest isolated indigenous metapopulation, Pano speakers in Acre, Brazil, appears to be thriving, other smaller isolated populations disconnected from metapopulations continue to be extremely vulnerable to external threats. Our applied anthropological conservation approach is to provide analyses of publicly available remote sensing datasets to help inform policies that enhance the survival and well-being of isolated cultural groups.

Introduced trout can induce trophic cascades, however, a lack of pre-introduction data limits knowledge on their impact in many lakes. Traditional paleolimnological approaches have been used to study historic species changes, but until recently these have been restricted to taxa with preservable body-parts. To explore the ecosystem effects of Salmo trutta (brown trout) introduction on an oligotrophic lake in Aotearoa-New Zealand, we used a multi-marker sedimentary environmental DNA (sedDNA) approach coupled with pigments to detect changes across multiple trophic levels. DNA was extracted from core depths capturing approximately 100 years before and after the expected arrival of S. trutta, and metabarcoding was undertaken with four primer sets targeting the 12S rRNA (fish), 18S rRNA (eukaryotes) and cytochrome c oxidase (COI; eukaryotes) genes. The earliest detection of S. trutta eDNA was 1906 (1892–1919 CE with 95% high probability density function) suggesting their introduction was shortly before this. Native fish diversity (12S and 18S rRNA) decreased after the detection of S. trutta, albeit the data was patchy. A shift in overall eukaryotic and algal communities (18S rRNA and COI) was observed around 1856 (1841–1871 CE) to 1891 (1877–1904 CE), which aligns with the expected S. trutta introduction. However, taxonomy could not be assigned to many of the 18S rRNA and COI sequences. Pigment concentrations did not change markedly after S. trutta introduction. SedDNA provides a new tool for understanding the impact of disturbances such as the introduction of non-native species; however, there are still several methodological challenges to overcome.

Introduction Acute respiratory distress syndrome (ARDS), marked by acute hypoxemia and bilateral pulmonary infiltrates, has been defined in multiple ways since its first description. This Delphi study aims to collect global opinions on the conceptual framework of ARDS, assess the usefulness of components within current and past definitions and investigate the role of subphenotyping. The varied expertise of the panel will provide valuable insights for refining future ARDS definitions and improving clinical management.Methods A diverse panel of 35–40 experts will be selected based on predefined criteria. Multiple choice questions (MCQs) or 7-point Likert-scale statements will be used in the iterative Delphi rounds to achieve consensus on key aspects related to the utility of definitions and subphenotyping. The Delphi rounds will be continued until a stable agreement or disagreement is achieved for all statements.Analysis Consensus will be considered as reached when a choice in MCQs or Likert-scale statement achieved ≥80% of votes for agreement or disagreement. The stability will be checked by non-parametric χ2 tests or Kruskal Wallis test starting from the second round of Delphi process. A p-value ≥0.05 will be used to define stability.Ethics and dissemination The study will be conducted in full concordance with the principles of the Declaration of Helsinki and will be reported according to CREDES guidance. This study has been granted an ethical approval waiver by the NMC Healthcare Regional Research Ethics Committee, Dubai (NMCHC/CR/DXB/REC/APP/002), owing to the nature of the research. Informed consent will be obtained from all panellists before the start of the Delphi process. The study will be published in a peer-review journal with the authorship agreed as per ICMJE requirements.Trial registration number NCT06159465.

Background Conservative therapies are recommended as initial treatment for male lower urinary tract symptoms. However, there is a lack of evidence on effectiveness and uncertainty regarding approaches to delivery. Objective The objective was to determine whether or not a standardised and manualised care intervention delivered in primary care achieves superior symptomatic outcome for lower urinary tract symptoms to usual care. Design This was a two-arm cluster randomised controlled trial. Setting The trial was set in 30 NHS general practice sites in England. Participants Participants were adult men (aged ≥ 18 years) with bothersome lower urinary tract symptoms. Interventions Sites were randomised 1 : 1 to deliver the TReatIng Urinary symptoms in Men in Primary Health care using non-pharmacological and non-surgical interventions trial intervention or usual care to all participants. The TReatIng Urinary symptoms in Men in Primary Health care using non-pharmacological and non-surgical interventions intervention comprised a standardised advice booklet developed for the trial from the British Association of Urological Surgeons’ patient information sheets, with patient and expert input. Patients were directed to relevant sections by general practice or research nurses/healthcare assistants following urinary symptom assessment, providing the manualised element. The healthcare professional provided follow-up contacts over 12 weeks to support adherence to the intervention. Main outcome measures The primary outcome was the validated patient-reported International Prostate Symptom Score 12 months post consent. Rather than the minimal clinically important difference of 3.0 points for overall International Prostate Symptom Score, the sample size aimed to detect a difference of 2.0 points, owing to the recognised clinical impact of individual symptoms. Results A total of 1077 men consented to the study: 524 in sites randomised to the intervention arm (n = 17) and 553 in sites randomised to the control arm (n = 13). A difference in mean International Prostate Symptom Score at 12 months was found (adjusted mean difference of –1.81 points, 95% confidence interval –2.66 to –0.95 points), with a lower score in the intervention arm, indicating less severe symptoms. Secondary outcomes of patient-reported urinary symptoms, quality of life specific to lower urinary tract symptoms and perception of lower urinary tract symptoms all showed evidence of a difference between the arms favouring the intervention. No difference was seen between the arms in the proportion of urology referrals or adverse events. In qualitative interviews, participants welcomed the intervention, describing positive effects on their symptoms, as well as on their understanding of conservative care and their attitude towards the experience of lower urinary tract symptoms. The interviews highlighted that structured, in-depth self-management is insufficiently embedded within general practitioner consultations. From an NHS perspective, mean costs and quality-adjusted life-years were similar between trial arms. The intervention arm had slightly lower mean costs (adjusted mean difference of –£29.99, 95% confidence interval –£109.84 to £22.63) than the usual-care arm, and a small gain in quality-adjusted life-years (adjusted mean difference of 0.001, 95% confidence interval –0.011 to 0.014). Conclusions The intervention showed a small, sustained benefit for men’s lower urinary tract symptoms and quality of life across a range of outcome measures in a UK primary care setting. Qualitative data showed that men highly valued the intervention. Intervention costs were marginally lower than usual-care costs. Limitations of the study included that trial participants were unmasked, with limited diversity in ethnicity and deprivation level. Additional research is needed to assess the applicability of the intervention for a more ethnically diverse population.. Trial registration This trial is registered as ISRCTN11669964. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/90/03) and is published in full in Health Technology Assessment; Vol. 28, No. 13. See the NIHR Funding and Awards website for further award information. Plain language summary Urinary problems among men become more common with age. Nearly one-third of all men aged > 65 years experience some urinary symptoms, which can have a substantial effect on their daily lives. Symptoms include needing to pass urine more often, urgently or during the night, and difficulties in passing urine. Men are usually diagnosed and treated by their general practitioner, and should be offered advice on controlling their symptoms themselves (e.g. lifestyle changes and exercises) before trying tablets or surgery. However, it is not known how helpful such advice is, and how general practices can effectively provide it. Thirty general practices in the West of England and Wessex took part in the study. Practices were split into two groups, with each practice providing either the TReatIng Urinary symptoms in Men in Primary Health care using non-pharmacological and non-surgical interventions care package or the practice’s usual care to all of its patients in the trial. The TReatIng Urinary symptoms in Men in Primary Healthcare using nonpharmacological and non-surgical interventions care package included a booklet of advice to help control urinary symptoms, with a nurse or healthcare assistant directing men to relevant sections according to their symptoms, and providing follow-up contacts. We mainly assessed the benefits of the TReatIng Urinary symptoms in Men in Primary Healthcare using nonpharmacological and non-surgical interventions care package, compared with usual care, by using a questionnaire on urinary symptoms completed by participants. A total of 1077 men with urinary symptoms that bothered them joined the study. The main result was that men reported greater improvement in urinary symptoms with the TRIUMPH care package than with usual care, 12 months after joining the study. We also found that men receiving the TRIUMPH care package had a slight improvement in quality of life and outlook on their urinary symptoms. There was no difference between the two groups in the number of patients referred to hospital for treatment, the type, number and severity of side effects or cost to the NHS. Overall, the TRIUMPH care package was more effective in treating men with urinary symptoms than usual care by their general practice. Scientific summary Background Lower urinary tract symptoms (LUTS) can relate to urinary storage or voiding. Among men, the prevalence and severity of symptoms increase with age, with a substantial impact on quality of life. The majority of men presenting with urinary symptoms are assessed and managed by their general practitioner (GP) in the first instance, with conservative therapies recommended as initial treatment. However, there is a lack of evidence on the effectiveness of conservative therapies, and uncertainty regarding approaches to delivery. Provision in primary care is variable and can be time and resource limited, and GPs require practical resources to enhance patient engagement with such interventions. The TReatIng Urinary symptoms in Men in Primary Health care using non-pharmacological and non-surgical interventions (TRIUMPH) trial aimed to address this need in primary care. Objectives The key aim of this research was to determine whether or not a standardised and manualised care intervention achieves superior symptomatic outcome, compared with usual care, for male LUTS, with a primary outcome of overall International Prostate Symptom Score (IPSS) measured 12 months after consent, in a primary care setting. Secondary objectives were to compare the two trial arms with regard to: disease-specific quality of life symptomatic outcomes cost effectiveness relative harms use of NHS resources overall quality of life and general health acceptability of assessment and provision of care patients’ perception of their LUTS. Design This was a pragmatic two-arm cluster randomised controlled trial randomising general practice sites 1 : 1 between a care pathway based on a standardised and manualised care intervention (intervention arm) and one based on usual care (comparator arm) for men with LUTS. The trial design included an internal pilot recruitment phase of 4 months’ duration, primarily to verify feasibility of recruitment before progression to the main phase of the trial. Setting Thirty general practice sites were recruited within nine Clinical Commissioning Groups across the West of England and Wessex Clinical Research Network (CRN) regions in the UK. Participants were identified and recruited from these sites. Participants General Practice Recruitment The CRNs invited general practices to express an interest in taking part in the study. To achieve a balanced range of practices, the following factors were considered in practice selection: number of potentially eligible patients, on conduct of a preliminary database search patient list size deprivation score (calculated using a general practice’s postcode) preference for method of intervention delivery (by practice staff or trial research nurses) treatment room space available for intervention delivery. Participating sites underwent site initiation training. An internal pilot phase was conducted with eight initial sites over a period of 4 months before the main phase of the trial. Participant recruitment This was a pragmatic trial in adult men who considered themselves to have bothersome LUTS and who had presented to primary care within the preceding 5 years with at least one symptom of LUTS. Only men already known to have LUTS (prevalent cases) were screened for inclusion in the trial. Screening was undertaken once by each site pre randomisation, so men newly presenting with LUTS (incident cases) after site randomisation were not included. Interventions Practices were randomised 1 : 1 to deliver the TRIUMPH intervention or a usual-care pathway. The TRIUMPH intervention comprises a LUTS advice booklet developed for the trial from the British Association of Urological Surgeons’ patient information sheets, with patient and expert input, providing the standardised element. Practices in the intervention arm could choose whether the intervention was delivered by central study research nurses or general practice nurses/healthcare assistants (HCAs), who received a 1-hour training session. Patients were directed to relevant sections by the nurses/HCA following symptom assessment, providing the manualised element. The healthcare professional (HCP) provided follow-up contacts over 12 weeks to encourage adherence. Usual care (the comparator arm for the TRIUMPH trial) in this study requested that sites continue to follow their standard local practice for trial patients in terms of delivery and follow-up. Main outcome measures The primary outcome measure was the patient-reported IPSS at 12 months after consent. Key secondary outcomes included quality of life, patient-reported urinary symptoms, adverse events, referrals to secondary care, patient perception of their LUTS, cost effectiveness, number of GP consultations and a qualitative evaluation of patients’ experiences of the intervention. Patient-reported outcomes were collected by questionnaire at baseline and at 6 and 12 months. Other clinical outcomes and NHS resource use were extracted from primary care electronic medical records a minimum of 1 month after the final participant at each site had completed the 12-month follow-up. Qualitative interviews were conducted throughout the trial. Results The trial was successful in meeting general practice site recruitment targets, and participant recruitment exceeded that anticipated. In total, 1077 men consented to the study: 524 in sites randomised to the intervention arm (n = 17) and 553 in sites randomised to the control arm (n = 13). A total of 887 patients (82%) were included in the primary analysis at 12 months post consent. The treatment groups were broadly balanced on baseline characteristics, but the primary outcome measure (IPSS) was slightly lower in the intervention arm than in the usual-care arm (intervention: 13.62 points; usual care: 14.59 points). The intervention was successfully delivered: 98% of men received their intervention booklet and 90% had all three contacts forming the intervention. The primary outcome analysis found that, although there was a reduction in IPSS between baseline and 12 months in both arms, suggesting improved symptoms, symptom improvement was greater in the intervention arm [–1.81, 95% confidence interval (CI) –2.66 to –0.95]. The difference was smaller than the difference we sought to detect in the sample size calculation of 2 points in overall IPSS, and the minimal clinically important difference of 3 points. The improvement in IPSS, however, was mirrored by improvements in the secondary outcomes of incontinence (measured using the International Consultation on Incontinence Questionnaire-Urinary Incontinence-Short Form), IPSS quality-of-life measures and patients’ perception of their LUTS (measured using the Brief Illness Perception Questionnaire). The primary analysis estimates were robust to ways of accounting for clustering and multiple imputation of missing data. High levels of adherence to intervention delivery meant that per-protocol analyses largely reflected the primary analysis. Although there was no strong evidence that the treatment effect was modified by the nature of LUTS at baseline, by who delivered the intervention or by how contact was delivered in the intervention, a post hoc analysis suggests that the treatment effect may have been stronger in the pre-COVID period. No difference was seen between the arms in the proportion of urology referrals or adverse events. In terms of the health economic analysis, from an NHS perspective, costs and quality-adjusted life-years (QALYs) were similar across both trial arms. Compared with the usual-care arm, the intervention arm had slightly lower mean costs (adjusted mean difference of –£29.99, 95% CI –£109.84 to £22.63) and a small gain in QALYs (adjusted mean difference of 0.001, 95% CI –0.011 to 0.014). Two sensitivity analyses adjusting for missing data reversed this finding, reflecting the similar costs and outcomes between the two arms. Overall, the results of the economic evaluation indicate that the costs should not be seen as a limiting factor for the roll-out of the TRIUMPH intervention. Qualitative interviews indicated that many men in both intervention and usual-care arms lived with distressing LUTS for long periods without seeking help. Men tolerated symptoms they portrayed as mundane and inevitable parts of ageing, unworthy of clinical attention, unless severe enough to warrant often unpalatable medication or surgery. Mostly men were unaware that a range of self-management techniques existed and might offer support. In this context, men in the intervention arm strongly welcomed the guidance offered. Men appreciated the accessibility of the booklet, the targeted self-management techniques offered, the interest in their neglected LUTS, the HCP meeting and follow-up contact. Men in the intervention arm reported not only symptom improvement, but also better understanding and a renewed sense of self-efficacy in relation to their symptom management, and an accompanying erosion of the stigma that entangled notions of age, LUTS and inevitable irredeemable bodily decline. Men reported feeling both better able to take action to redress symptoms and more cheerful about their LUTS (and, more broadly, about ageing). Men in the usual-care arm continued to live with distressing symptoms with resigned tolerance. Interviews with both trial participants and GPs in participating practices indicated that self-management guidance for LUTS is currently insufficiently embedded within primary care consultations. Despite describing their contact with primary care positively, men rarely recalled being offered in-depth, structured self-help guidance; men in the usual-care arm remained unfamiliar with the guidance, despite enduring LUTS. Men tended to visit their GP when symptoms were alarming or severe, which may explain why GP encounters often focused on prostate cancer concerns, or moved quickly to medication, forgoing detailed self-management discussions. Most men, and also some GPs, associated pelvic floor exercises with women’s, but not men’s, LUTS. As a result, interviews provided strong grounds for making the intervention guidance routinely available within primary care, to better meet clinical recommendations promoting conservative care for men with LUTS and to better support men’s knowledge and understanding both of their symptoms and of self-management approaches, and to alleviate distressing and neglected symptoms. The strengths of the trial include recruitment to target and excellent follow-up rates, with a clustered trial design to reduce contamination, resulting in informative and robust conclusions. The primary outcome was also intentionally timed to allow the longer-term benefit of the TRIUMPH intervention to be captured, at 12 months post consent, following a 12-week intervention delivery. Sustained benefit was identified, which can be an issue in the longer-term effectiveness of lifestyle and conservative interventions. The limitations of the trial include the necessity of the trial participants being unmasked. In addition, the trial population had only a small number of non-white men, and included only those who had previously sought help from their GP for their LUTS, so may not apply to all men with LUTS. A potential limitation is that sites recruiting to the usual-care arm would potentially have developed renewed awareness of the condition and the current approaches to management as a result of participating in the study. Potentially, this would decrease the observed differences between randomised groups, given that there was some improvement in the usual-care arm in the primary outcome. Conclusions The TRIUMPH intervention showed a sustained benefit for men’s LUTS and quality of life across a range of outcome measures in a UK primary care setting. Although the effect sizes were small, qualitative data showed that men highly valued the intervention. Intervention costs were marginally lower than usual-care costs. The findings show the potential for a short training process to enable nurses or HCA to assess patients and direct them towards appropriate conservative measures in a standardised information booklet. This delivers improved symptoms at low cost, with minimal adverse events. The potential for the same intervention to achieve symptom improvement in incident patients, or for GPs to screen for LUTS to offer the intervention, should be considered. The implications of outcomes in a more diverse population of men need to be evaluated. Trial registration The trial is registered as ISRCTN11669964. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/90/03) and is published in full in Health Technology Assessment; Vol. 28, No. 13. See the NIHR Funding and Awards website for further award information.

Abstract Introduction Awake prone positioning has the potential to improve oxygenation and decrease respiratory rate, potentially reducing the need for intubation in patients with acute hypoxemic respiratory failure. We investigated awake prone positioning-induced changes in oxygenation and respiratory rate, and the prognostic capacity for intubation in patients with COVID-19 pneumonia. Methods International multicenter prospective observation study in critically ill adult patients with COVID-19 receiving supplemental oxygen. We collected data on oxygenation and respiratory rate at baseline, and at 1 h after being placed in prone positioning. The combined primary outcome was oxygenation and respiratory rate at 1 h. The secondary endpoint was treatment failure, defined as need for intubation within 24 h of start of awake prone positioning. Results Between March 27th and November 2020, 101 patients were enrolled of which 99 were fully analyzable. Awake prone positioning lasted mean of 3 [2–4] h. In 77 patients (77.7%), awake prone positioning improved oxygenation, and in 37 patients (54.4%) it decreased respiratory rate. Twenty-nine patients (29.3%) were intubated within 24 h. An increase in SpO2/FiO2 of 116 mmHg (OR 3.6, 95% CI 1.2–10.8, P = 0.02), and a decrease in respiratory rate of

Abstract Background Lung ultrasound (LUS) can detect pulmonary edema and it is under consideration to be added to updated acute respiratory distress syndrome (ARDS) criteria. However, it remains uncertain whether different LUS scores can be used to quantify pulmonary edema in patient with ARDS. Objectives This study examined the diagnostic accuracy of four LUS scores with the extravascular lung water index (EVLWi) assessed by transpulmonary thermodilution in patients with moderate-to-severe COVID-19 ARDS. Methods In this predefined secondary analysis of a multicenter randomized-controlled trial (InventCOVID), patients were enrolled within 48 hours after intubation and underwent LUS and EVLWi measurement on the first and fourth day after enrolment. EVLWi and ∆EVLWi were used as reference standards. Two 12-region scores (global LUS and LUS–ARDS), an 8-region anterior–lateral score and a 4-region B-line score were used as index tests. Pearson correlation was performed and the area under the receiver operating characteristics curve (AUROCC) for severe pulmonary edema (EVLWi > 15 mL/kg) was calculated. Results 26 out of 30 patients (87%) had complete LUS and EVLWi measurements at time point 1 and 24 out of 29 patients (83%) at time point 2. The global LUS (r = 0.54), LUS–ARDS (r = 0.58) and anterior–lateral score (r = 0.54) correlated significantly with EVLWi, while the B-line score did not (r = 0.32). ∆global LUS (r = 0.49) and ∆anterior–lateral LUS (r = 0.52) correlated significantly with ∆EVLWi. AUROCC for EVLWi > 15 ml/kg was 0.73 for the global LUS, 0.79 for the anterior–lateral and 0.85 for the LUS–ARDS score. Conclusions Overall, LUS demonstrated an acceptable diagnostic accuracy for detection of pulmonary edema in moderate–to–severe COVID-19 ARDS when compared with PICCO. For identifying patients at risk of severe pulmonary edema, an extended score considering pleural morphology may be of added value. Trial registration: ClinicalTrials.gov identifier NCT04794088, registered on 11 March 2021. European Clinical Trials Database number 2020–005447-23.

Abstract This study presents novel insight into the mechanisms of Atlantic Meridional Overturning Circulation (AMOC) reduction and its recovery under a warmer climate scenario. An one-thousand-year-long numerical simulation of a global coupled ocean–ice–atmosphere climate model, subjected to a stationary atmospheric radiative forcing, depict a coherent picture of the Arctic sea ice melting as a trigger for the initial AMOC reduction, along with decreases in the northward fluxes of salt and heat. Further atmospheric-driven ocean processes contribute to an erosion of the stable stratification of the fresher, yet colder waters in the surface layers of the North Atlantic, contributing to the recovery of a permanently altered AMOC.

Abstract High-resolution ice core records from coastal Antarctica are particularly useful to inform our understanding of environmental changes and their drivers. Here, we present a decadally resolved record of sea-salt sodium (a proxy for open-ocean area) and non-sea salt calcium (a proxy for continental dust) from the well-dated Roosevelt Island Climate Evolution (RICE) core, focusing on the time period between 40–26 ka BP. The RICE dust record exhibits an abrupt shift towards a higher mean dust concentration at 32 ka BP. Investigating existing ice-core records, we find this shift is a prominent feature across Antarctica. We propose that this shift is linked to an equatorward displacement of Southern Hemisphere westerly winds. Subsequent to the wind shift, data suggest a weakening of Southern Ocean upwelling and a decline of atmospheric CO2 to lower glacial values, hence making this shift an important glacial climate event with potentially important insights for future projections.

Abstract Background Severe malaria in pregnancy causes maternal mortality, morbidity, and adverse foetal outcomes. The factors contributing to adverse maternal and foetal outcomes are not well defined. We aimed to identify the factors predicting higher maternal mortality and to describe the foetal mortality and morbidity associated with severe falciparum malaria in pregnancy. Methods A retrospective cohort study was conducted of severe falciparum malaria in pregnancy, as defined by the World Health Organization severe malaria criteria. The patients were managed prospectively by the Shoklo Malaria Research Unit (SMRU) on the Thailand-Myanmar border or were included in hospital-based clinical trials in six Southeast Asian countries. Fixed-effects multivariable penalised logistic regression was used for analysing maternal mortality. Results We included 213 (123 SMRU and 90 hospital-based) episodes of severe falciparum malaria in pregnancy managed between 1980 and 2020. The mean maternal age was 25.7 (SD 6.8) years, and the mean gestational age was 25.6 (SD 8.9) weeks. The overall maternal mortality was 12.2% (26/213). Coma (adjusted odds ratio [aOR], 7.18, 95% CI 2.01–25.57, p = 0.0002), hypotension (aOR 11.21, 95%CI 1.27–98.92, p = 0.03) and respiratory failure (aOR 4.98, 95%CI 1.13–22.01, p = 0.03) were associated with maternal mortality. Pregnant women with one or more of these three criteria had a mortality of 29.1% (25/86) (95%CI 19.5 to 38.7%) whereas there were no deaths in 88 pregnant women with hyperparasitaemia (> 10% parasitised erythrocytes) only or severe anaemia (haematocrit

Abstract It has been established that the human gut microbiota is central to health, and, consequently, there has been a growing desire to positively modulate its composition and/or function through, for example, the use of fermented foods, prebiotics or probiotics. Here, we compare the relative impact of the daily consumption of an inulin-enriched diet (n = 10), a commercial probiotic-containing fermented milk product (FMP) (n = 10), or a traditional kefir FMP (n = 9), over a 28-day period on the gut microbiome and urine metabolome of healthy human adults. None of the treatments resulted in significant changes to clinical parameters or biomarkers tested. However, shotgun metagenomic analysis revealed that kefir consumption resulted in a significant change in taxonomy, in the form of an increased abundance of the sub-dominant FMP-associated species Lactococcus raffinolactis, which further corresponded to shifts in the urine metabolome. Overall, our results indicated that daily consumption of a single portion of kefir alone resulted in detectable changes to the gut microbiota and metabolome of consumers.

Abstract Introduction The driving pressure (ΔP) has an independent association with outcome in patients with acute respiratory distress syndrome (ARDS). INTELLiVENT-Adaptive Support Ventilation (ASV) is a closed-loop mode of ventilation that targets the lowest work and force of breathing. Aim To compare transpulmonary and respiratory system ΔP between closed-loop ventilation and conventional pressure controlled ventilation in patients with moderate-to-severe ARDS. Methods Single-center randomized cross-over clinical trial in patients in the early phase of ARDS. Patients were randomly assigned to start with a 4-h period of closed-loop ventilation or conventional ventilation, after which the alternate ventilation mode was selected. The primary outcome was the transpulmonary ΔP; secondary outcomes included respiratory system ΔP, and other key parameters of ventilation. Results Thirteen patients were included, and all had fully analyzable data sets. Compared to conventional ventilation, with closed-loop ventilation the median transpulmonary ΔP with was lower (7.0 [5.0–10.0] vs. 10.0 [8.0–11.0] cmH2O, mean difference − 2.5 [95% CI − 2.6 to − 2.1] cmH2O; P = 0.0001). Inspiratory transpulmonary pressure and the respiratory rate were also lower. Tidal volume, however, was higher with closed-loop ventilation, but stayed below generally accepted safety cutoffs in the majority of patients. Conclusions In this small physiological study, when compared to conventional pressure controlled ventilation INTELLiVENT-ASV reduced the transpulmonary ΔP in patients in the early phase of moderate-to-severe ARDS. This closed-loop ventilation mode also led to a lower inspiratory transpulmonary pressure and a lower respiratory rate, thereby reducing the intensity of ventilation. Trial registration Clinicaltrials.gov, NCT03211494, July 7, 2017. https://clinicaltrials.gov/ct2/show/NCT03211494?term=airdrop&draw=2&rank=1 .

Abstract Background High-flow nasal oxygen (HFNO) is increasingly used in patients with acute hypoxemic respiratory failure. It is uncertain whether a broadened Berlin definition of acute respiratory distress syndrome (ARDS), in which ARDS can be diagnosed in patients who are not receiving ventilation, results in similar groups of patients receiving HFNO as in patients receiving ventilation. Methods We applied a broadened definition of ARDS in a multicenter, observational study in adult critically ill patients with acute hypoxemic respiratory failure due to coronavirus disease 2019 (COVID-19), wherein the requirement for a minimal level of 5 cm H2O PEEP with ventilation is replaced by a minimal level of airflow rate with HFNO, and compared baseline characteristics and outcomes between patients receiving HFNO and patients receiving ventilation. The primary endpoint was ICU mortality. We also compared outcomes in risk for death groups using the PaO2/FiO2 cutoffs as used successfully in the original definition of ARDS. Secondary endpoints were hospital mortality; mortality on days 28 and 90; need for ventilation within 7 days in patients that started with HFNO; the number of days free from HFNO or ventilation; and ICU and hospital length of stay. Results Of 728 included patients, 229 patients started with HFNO and 499 patients with ventilation. All patients fulfilled the broadened Berlin definition of ARDS. Patients receiving HFNO had lower disease severity scores and lower PaO2/FiO2 than patients receiving ventilation. ICU mortality was lower in receiving HFNO (22.7 vs 35.6%; p = 0.001). Using PaO2/FiO2 cutoffs for mild, moderate and severe arterial hypoxemia created groups with an ICU mortality of 16.7%, 22.0%, and 23.5% (p = 0.906) versus 19.1%, 37.9% and 41.4% (p = 0.002), in patients receiving HFNO versus patients receiving ventilation, respectively. Conclusions Using a broadened definition of ARDS may facilitate an earlier diagnosis of ARDS in patients receiving HFNO; however, ARDS patients receiving HFNO and ARDS patients receiving ventilation have distinct baseline characteristics and mortality rates. Trial registration: The study is registered at ClinicalTrials.gov (identifier NCT04719182).

Abstract Background Interpreting point-of-care lung ultrasound (LUS) images from intensive care unit (ICU) patients can be challenging, especially in low- and middle- income countries (LMICs) where there is limited training available. Despite recent advances in the use of Artificial Intelligence (AI) to automate many ultrasound imaging analysis tasks, no AI-enabled LUS solutions have been proven to be clinically useful in ICUs, and specifically in LMICs. Therefore, we developed an AI solution that assists LUS practitioners and assessed its usefulness in a low resource ICU. Methods This was a three-phase prospective study. In the first phase, the performance of four different clinical user groups in interpreting LUS clips was assessed. In the second phase, the performance of 57 non-expert clinicians with and without the aid of a bespoke AI tool for LUS interpretation was assessed in retrospective offline clips. In the third phase, we conducted a prospective study in the ICU where 14 clinicians were asked to carry out LUS examinations in 7 patients with and without our AI tool and we interviewed the clinicians regarding the usability of the AI tool. Results The average accuracy of beginners’ LUS interpretation was 68.7% [95% CI 66.8–70.7%] compared to 72.2% [95% CI 70.0–75.6%] in intermediate, and 73.4% [95% CI 62.2–87.8%] in advanced users. Experts had an average accuracy of 95.0% [95% CI 88.2–100.0%], which was significantly better than beginners, intermediate and advanced users (p

Abstract Purpose A hallmark of acute respiratory distress syndrome (ARDS) is hypoxaemic respiratory failure due to pulmonary vascular hyperpermeability. The tyrosine kinase inhibitor imatinib reversed pulmonary capillary leak in preclinical studies and improved clinical outcomes in hospitalized COVID-19 patients. We investigated the effect of intravenous (IV) imatinib on pulmonary edema in COVID-19 ARDS. Methods This was a multicenter, randomized, double-blind, placebo-controlled trial. Invasively ventilated patients with moderate-to-severe COVID-19 ARDS were randomized to 200 mg IV imatinib or placebo twice daily for a maximum of seven days. The primary outcome was the change in extravascular lung water index (∆EVLWi) between days 1 and 4. Secondary outcomes included safety, duration of invasive ventilation, ventilator-free days (VFD) and 28-day mortality. Posthoc analyses were performed in previously identified biological subphenotypes. Results 66 patients were randomized to imatinib (n = 33) or placebo (n = 33). There was no difference in ∆EVLWi between the groups (0.19 ml/kg, 95% CI − 3.16 to 2.77, p = 0.89). Imatinib treatment did not affect duration of invasive ventilation (p = 0.29), VFD (p = 0.29) or 28-day mortality (p = 0.79). IV imatinib was well-tolerated and appeared safe. In a subgroup of patients characterized by high IL-6, TNFR1 and SP-D levels (n = 20), imatinib significantly decreased EVLWi per treatment day (− 1.17 ml/kg, 95% CI − 1.87 to − 0.44). Conclusions IV imatinib did not reduce pulmonary edema or improve clinical outcomes in invasively ventilated COVID-19 patients. While this trial does not support the use of imatinib in the general COVID-19 ARDS population, imatinib reduced pulmonary edema in a subgroup of patients, underscoring the potential value of predictive enrichment in ARDS trials. Trial registration NCT04794088 , registered 11 March 2021. European Clinical Trials Database (EudraCT number: 2020-005447-23).

Abstract Background Caesarean section (CS) rates are rising. Shared decision making (SDM) is a component of patient-centered communication which requires adequate information and awareness. Women in Ghana have varying perceptions about the procedure. We sought to explore mothers’ knowledge. perceptions and SDM-influencing factors about CSs. Methods A transdisciplinary mixed-methods study was conducted at the maternity unit of Korle-Bu Teaching Hospital in Accra, Ghana from March to May, 2019. Data collection was done in four phases: in-depth interviews (n = 38), pretesting questionnaires (n = 15), three focus group discussions (n = 18) and 180 interviewer administered questionnaires about SDM preferences. Factors associated with SDM were analyzed using Pearson’s Chi-square test and multiple logistic regression. Results Mothers depicted a high level of knowledge regarding medical indications for their CS but had low level of awareness of SDM. The perception of a CS varied from dangerous, unnatural and taking away their strength to a life-saving procedure. The mothers had poor knowledge about pain relief in labour and at Caesarean section. Health care professionals attributed the willingness of mothers to be involved in SDM to their level of education. Husbands and religious leaders are key stakeholders in SDM. Insufficient consultation time was a challenge to SDM according to health care professionals and post-partum mothers. Women with parity ≥ 5 have a reduced desire to be more involved in shared decision making for Caesarean section. AOR = 0.09, CI (0.02–0.46). Conclusion There is a high knowledge about the indications for CS but low level of awareness of and barriers to SDM. The fewer antenatal care visits mothers had, the more likely they were to desire more involvement in decision making. Aligned to respectful maternity care principles, greater involvement of pregnant women and their partners in decision making process could contribute to a positive pregnancy experience. Education, including religious leaders and decision- making tools could contribute to the process of SDM.

True aneurysms of the dorsalis pedis artery (DPA) are very rare phenomena with no obvious pathophysiology. Prompt diagnosis and treatment are important due to the high risk of thrombosis, distal embolization, hemorrhage, and rupture. We present a case of a true DPA saccular aneurysm in a 58-year-old man and highlight the feasibility of using a reversed great saphenous vein bypass graft in specifically treating true DPA aneurysms. Our treatment resulted in near-immediate resolution of the patient’s foot pain and mass without complications and maintaining arterial patency.

[This corrects the article DOI: 10.1371/journal.pone.0273966.].

IntroductionMechanical power of ventilation, a summary parameter reflecting the energy transferred from the ventilator to the respiratory system, has associations with outcomes. INTELLiVENT-Adaptive Support Ventilation is an automated ventilation mode that changes ventilator settings according to algorithms that target a low work-and force of breathing. The study aims to compare mechanical power between automated ventilation by means of INTELLiVENT-Adaptive Support Ventilation and conventional ventilation in critically ill patients.Materials and methodsInternational, multicenter, randomized crossover clinical trial in patients that were expected to need invasive ventilation > 24 hours. Patients were randomly assigned to start with a 3-hour period of automated ventilation or conventional ventilation after which the alternate ventilation mode was selected. The primary outcome was mechanical power in passive and active patients; secondary outcomes included key ventilator settings and ventilatory parameters that affect mechanical power.ResultsA total of 96 patients were randomized. Median mechanical power was not different between automated and conventional ventilation (15.8 [11.5-21.0] versus 16.1 [10.9-22.6] J/min; mean difference -0.44 (95%-CI -1.17 to 0.29) J/min; P = 0.24). Subgroup analyses showed that mechanical power was lower with automated ventilation in passive patients, 16.9 [12.5-22.1] versus 19.0 [14.1-25.0] J/min; mean difference -1.76 (95%-CI -2.47 to -10.34J/min; P < 0.01), and not in active patients (14.6 [11.0-20.3] vs 14.1 [10.1-21.3] J/min; mean difference 0.81 (95%-CI -2.13 to 0.49) J/min; P = 0.23).ConclusionsIn this cohort of unselected critically ill invasively ventilated patients, automated ventilation by means of INTELLiVENT-Adaptive Support Ventilation did not reduce mechanical power. A reduction in mechanical power was only seen in passive patients.Study registrationClinicaltrials.gov (study identifier NCT04827927), April 1, 2021.Url of trial registry recordhttps://clinicaltrials.gov/study/NCT04827927?term=intellipower&rank=1.

BackgroundMost of the current bacteriophages (phages) are mostly isolated from environments. However, phages isolated from feces might be more specific to the bacteria that are harmful to the host. Meanwhile, some phages from the environment might affect non-pathogenic bacteria for the host.MethodsHere, bacteriophages isolated from mouse feces were intratracheally (IT) or intravenously (IV) administered in pneumonia mice caused by Pseudomonas aeruginosa at 2 hours post-intratracheal bacterial administration. As such, the mice with phage treatment, using either IT or IV administration, demonstrated less severe pneumonia as indicated by mortality, serum cytokines, bacteremia, bacterial abundance in bronchoalveolar lavage fluid (BALF), and neutrophil extracellular traps (NETs) in lung tissue (immunofluorescence of neutrophil elastase and myeloperoxidase).ResultsInterestingly, the abundance of phages in BALF from the IT and IV injections was similar, supporting a flexible route of phage administration. With the incubation of bacteria with neutrophils, the presence of bacteriophages significantly improved bactericidal activity, but not NETs formation, with the elevated supernatant IL-6 and TNF-α, but not IL-1β. In conclusion, our findings suggest that bacteriophages against Pseudomonas aeruginosa can be discovered from feces of the host.ConclusionsThe phages attenuate pneumonia partly through an enhanced neutrophil bactericidal activity, but not via inducing NETs formation. The isolation of phages from the infected hosts themselves might be practically useful for future treatment. More studies are warranted.

BackgroundIn low- and middle-income countries twin births have a high risk of complications partly due to barriers to accessing hospital care. This study compares pregnancy outcomes, maternal and neonatal morbidity and mortality of twin to singleton pregnancy in refugee and migrant clinics on the Thai Myanmar border.MethodsA retrospective review of medical records of all singleton and twin pregnancies delivered or followed at antenatal clinics of the Shoklo Malaria Research Unit from 1986 to 2020, with a known outcome and estimated gestational age. Logistic regression was done to compare the odds of maternal and neonatal outcomes between twin and singleton pregnancies.ResultsBetween 1986 and 2020 this unstable and migratory population had a recorded outcome of pregnancy of 28 weeks or more for 597 twin births and 59,005 singleton births. Twinning rate was low and stable (ConclusionIn this fragile setting where access to hospital care is difficult, three in four twins birthed vaginally. Twin pregnancies have a higher maternal morbidity and perinatal mortality, especially the second twin, compared to singleton pregnancies.

Objectives To estimate the cost-effectiveness of a primary care intervention for male lower urinary tract symptoms (LUTS) compared with usual care.Design Economic evaluation alongside a cluster randomised controlled trial from a UK National Health Service (NHS) perspective with a 12-month time horizon.Setting Thirty NHS general practice sites in England.Participants 1077 men aged 18 or older identified in primary care with bothersome LUTS.Interventions A standardised and manualised intervention for the treatment of bothersome LUTS was compared with usual care. The intervention group (n=524) received a standardised information booklet with guidance on conservative treatment for LUTS, urinary symptom assessment and follow-up contacts for 12 weeks. The usual care group (n=553) followed local guidelines between general practice sites.Measures Resource use was obtained from electronic health records, trial staff and participants, and valued using UK reference costs. Quality-adjusted life-years (QALYs) were calculated from the EQ-5D-5L questionnaire. Adjusted mean differences in costs and QALYs and incremental net monetary benefit were estimated.Results 866 of 1077 (80.4%) participants had complete data and were included in the base-case analysis. Over the 12-month follow-up period, intervention and usual care arms had similar mean adjusted costs and QALYs. Mean differences were lower in the intervention arm for adjusted costs −£29.99 (95% CI −£109.84 to £22.63) while higher in the intervention arm for adjusted QALYs 0.001 (95% CI −0.011 to 0.014). The incremental net monetary benefit statistic was £48.01 (95% CI −£225.83 to £321.85) at the National Institute for Health and Care Excellence UK threshold of £20 000 per QALY. The cost-effectiveness acceptability curve showed a 63% probability of the intervention arm being cost-effective at this threshold.Conclusions Costs and QALYs were similar between the two arms at 12 months follow-up. This indicates that the intervention can be implemented in general practice at neutral cost.Trial registration number ISRCTN11669964.

Purpose:: Evaluation of a catheter design which protects its tip with the retaining balloon when inflated, and has eyeholes at the base of the balloon to improve drainage. Materials and methods:: Preclinical tests included assessment of retaining balloon performance, and microbiological blockage. Clinical testing evaluated short-term use and safety in hospital (stage 1) or the patient’s usual residence (stage 2). Results:: The retaining balloon supported static loads of 0.7kg, with reduced trauma when modelling forced evulsion. In vitro time to blockage with P. Mirabilis was significantly slower for FLUME compared with latex Foley catheters, but not the silicone Foley. Stage 1 testing (10 patients) confirmed balloon inflation, drainage, retention and removal, with no serious adverse events caused by catheterisation; one balloon failed to inflate, one patient could not be catheterised. Of five patients at stage 2, one had the catheter for 28 days without complication, one experienced spontaneous balloon deflation (14th day) and three needed early removal (blood clot, bypassing, difficulty connecting the drainage bag). Bacterial profiles of two FLUME catheters retained at least 2 weeks matched the Foley catheters. Acquired catheter colouration (two FLUME, one Foley) was not associated with biochemical change in the material. Conclusion:: FLUME catheter performed well in preclinical blockage and balloon tests. Tests in 15 patients confirmed basic function and additional training was not needed for staff familiar with Foley catheterisation. Clinical issues commonly seen with catheters included failed catheterisation, clot blockage and bypassing. In addition, an unintended balloon deflation and a failure of bag connection occurred. Plain language summary:: This article describes a new catheter design which aims to improve patient comfort and safety, and maximise bladder drainage, by protecting the bladder from the exposed catheter tip and by locating the drainage holes better. Various tests were done to check the catheter retaining balloon was safe and how well the catheter did when exposed to bacteria that could block it. The catheter was also used in people for the first time, to check it could be put in safely and functioned as intended. The results showed the FLUME catheter did well in the balloon and blockage tests. Tests in 15 patients confirmed basic function and showed placement was easy for staff familiar with conventional catheters. There were some clinical issues typical of urinary catheters and some possible improvements were identified.

Mainstreaming nature-based solutions in cities has grown in scale and magnitude in recent times but is still considered to be the main challenge for transitioning our cities and their communities to be more climate resilient and liveable: environmentally, economically, and socially. Furthermore, taking nature-based solutions to the next level, and scaling them out to all urban contexts to achieve a greater impact, is proving to be slow and often conflicts with other transitioning initiatives such as energy generation, mobility and transport initiatives, and infilling to combat sprawl. So, the task is neither easy nor straightforward; there are many barriers to this novel transition, especially when it comes to collaborative approaches to implementing nature-based solutions with diverse urban communities and within city authorities themselves. This paper reports on a new process that is systematically co-produced and captured as a framework for planning nature-based solutions that emerged during the Connecting Nature project. The Connecting Nature Framework is a three-stage, iterative process that involves seven key activity areas for mainstreaming nature-based solutions: technical solutions, governance, financing and business models, nature-based enterprises, co-production, reflexive monitoring, and impact assessment. The tested and applied framework is designed to address and overcome barriers to the implementation of nature-based solutions in cities via a co-created, iterative, and reflective approach. The planning process guided by the proposed framework has already yielded promising results with some of the cities of the project, though further usage and its adoption by other cities is needed to explore its potential in different contexts especially in the Global South. The paper concludes with suggestions on how this may be realised.

Abstract Background Cluster-C personality disorders (PDs), characterized by a high level of fear and anxiety, are related to high levels of distress, societal dysfunctioning and chronicity of various mental health disorders. Evidence for the optimal treatment is extremely scarce. Nevertheless, the need to treat these patients is eminent. In clinical practice, group therapy is one of the frequently offered approaches, with two important frameworks: schema therapy and psychodynamic therapy. These two frameworks suggest different mechanisms of change, but until now, this has not yet been explored. The purpose of the present G-FORCE trial is to find evidence on the differential (cost)effectiveness of two forms of schema group therapy and psychodynamic group therapy in the routine clinical setting of an outpatient clinic and to investigate the underlying working mechanisms and predictors of outcome of these therapies. Methods In this mono-centre pragmatic randomized clinical trial, 290 patients with Cluster-C PDs or other specified PD with predominantly Cluster-C traits, will be randomized to one of three treatment conditions: group schema therapy for Cluster-C (GST-C, 1 year), schema-focused group therapy (SFGT, 1.5 year) or psychodynamic group therapy (PG, 2 years). Randomization will be pre-stratified on the type of PD. Change in severity of PD (APD-IV) over 24 months will be the primary outcome measure. Secondary outcome measures are personality functioning, psychiatric symptoms and quality of life. Potential predictors and mediators are selected and measured repeatedly. Also, a cost-effectiveness study will be performed, primarily based on a societal perspective, using both clinical effects and quality-adjusted life years. The time-points of assessment are at baseline, start of treatment and after 1, 3, 6, 9, 12, 18, 24 and 36 months. Discussion This study is designed to evaluate the effectiveness and cost-effectiveness of three formats of group psychotherapy for Cluster-C PDs. Additionally, predictors, procedure and process variables are analysed to investigate the working mechanisms of the therapies. This is the first large RCT on group therapy for Cluster-C PDs and will contribute improving the care of this neglected patient group. The absence of a control group can be considered as a limitation. Trial registration CCMO, NL72826.029.20 . Registered on 31 August 2020, first participant included on 18 October 2020.

Abstract Studies of primary visual cortex have furthered our understanding of amblyopia, long-lasting visual impairment caused by imbalanced input from the two eyes during childhood, which is commonly treated by patching the dominant eye. However, the relative impacts of monocular vs. binocular visual experiences on recovery from amblyopia are unclear. Moreover, while sleep promotes visual cortex plasticity following loss of input from one eye, its role in recovering binocular visual function is unknown. Using monocular deprivation in juvenile male mice to model amblyopia, we compared recovery of cortical neurons’ visual responses after identical-duration, identical-quality binocular or monocular visual experiences. We demonstrate that binocular experience is quantitatively superior in restoring binocular responses in visual cortex neurons. However, this recovery was seen only in freely-sleeping mice; post-experience sleep deprivation prevented functional recovery. Thus, both binocular visual experience and subsequent sleep help to optimally renormalize bV1 responses in a mouse model of amblyopia.

Abstract Background Cluster-C personality disorders (PDs) are highly prevalent in clinical practice and are associated with unfavourable outcome and chronicity of all common mental health disorders (e.g. depression and anxiety disorders). Although several forms of individual psychotherapy are commonly offered in clinical practice for this population, evidence for differential effectiveness of different forms of psychotherapy is lacking. Also, very little is known about the underlying working mechanisms of these psychotherapies. Finding evidence on the differential (cost)-effectiveness for this group of patients and the working mechanisms of change is important to improve the quality of care for this vulnerable group of patients. Objective In this study, we will compare the differential (cost)-effectiveness of three individual psychotherapies: short-term psychodynamic supportive psychotherapy (SPSP), affect phobia therapy (APT) and schema therapy (ST). Although these psychotherapies are commonly used in clinical practice, evidence for the Cluster-C PDs is limited. Additionally, we will investigate predictive factors, non-specific and therapy-specific mediators. Methods This is a mono-centre randomized clinical trial with three parallel groups: (1) SPSP, (2) APT, (3) ST. Randomization on patient level will be pre-stratified according to type of PD. The total study population to be included consists of 264 patients with Cluster-C PDs or other specified PD with mainly Cluster-C traits, aged 18–65 years, seeking treatment at NPI, a Dutch mental health care institute specialized in PDs. SPSP, APT and ST (50 sessions per treatment) are offered twice a week in sessions of 50 min for the first 4 to 5 months. After that, session frequency decreases to once a week. All treatments have a maximum duration of 1 year. Change in the severity of the PD (ADP-IV) will be the primary outcome measure. Secondary outcome measures are personality functioning, psychiatric symptoms and quality of life. Several potential mediators, predictors and moderators of outcome are also assessed. The effectiveness study is complemented with a cost-effectiveness/utility study, using both clinical effects and quality-adjusted life-years, and primarily based on a societal approach. Assessments will take place at baseline, start of treatment and at 1, 3, 6, 9, 12, 18, 24 and 36 months. Discussion This is the first study comparing psychodynamic treatment to schema therapy for Cluster-C PDs. The naturalistic design enhances the clinical validity of the outcome. A limitation is the lack of a control group for ethical reasons. Trial registration NL72823.029.20 [Registry ID: CCMO]. Registered on 31 August 2020. First participant included on 23 October 2020.

Inhalation injury is a major contributor to mortality following burn injury. Despite recognised clinical criteria to guide the intubation of burn patients, concerns remain regarding overutilisation of intubation. Complications can arise as a result of intubation, including ventilator-associated pneumonia (VAP). This study reviews the indications for intubation against the internationally accepted criteria (American Burns Association (ABA) and Denver criteria) for burn patients treated at the Royal Adelaide Hospital (RAH) burns unit between 2017 and 2020. Burn patients who were intubated on arrival to the RAH or in a pre-hospital setting were identified using the BRANZ database. Indications for intubation were compared to the ABA and Denver criteria. A total of 61 patients were identified with a mean total body surface area of 17.8%. A total of 95% of patients met one of the ABA and Denver criteria. The most common ABA and Denver criteria for intubation was deep facial burns or singed facial hair, respectively. Most adult patients with burns admitted to the RAH are intubated per published criteria. Early nasoendoscopy/bronchoscopy may be useful in determining patients who can be safely extubated within 48 h.

Abstract Background Fluid therapy is a common intervention in critically ill patients. It is increasingly recognised that deresuscitation is an essential part of fluid therapy and delayed deresuscitation is associated with longer invasive ventilation and length of intensive care unit (ICU) stay. However, optimal timing and rate of deresuscitation remain unclear. Lung ultrasound (LUS) may be used to identify fluid overload. We hypothesise that daily LUS-guided deresuscitation is superior to deresuscitation without LUS in critically ill patients expected to undergo invasive ventilation for more than 24 h in terms of ventilator free-days and being alive at day 28. Methods The “effect of lung ultrasound-guided fluid deresuscitation on duration of ventilation in intensive care unit patients” (CONFIDENCE) is a national, multicentre, open-label, randomised controlled trial (RCT) in adult critically ill patients that are expected to be invasively ventilated for at least 24 h. Patients with conditions that preclude a negative fluid balance or LUS examination are excluded. CONFIDENCE will operate in 10 ICUs in the Netherlands and enrol 1000 patients. After hemodynamic stabilisation, patients assigned to the intervention will receive daily LUS with fluid balance recommendations. Subjects in the control arm are deresuscitated at the physician’s discretion without the use of LUS. The primary endpoint is the number of ventilator-free days and being alive at day 28. Secondary endpoints include the duration of invasive ventilation; 28-day mortality; 90-day mortality; ICU, in hospital and total length of stay; cumulative fluid balance on days 1–7 after randomisation and on days 1–7 after start of LUS examination; mean serum lactate on days 1–7; the incidence of reintubations, chest drain placement, atrial fibrillation, kidney injury (KDIGO stadium ≥ 2) and hypernatremia; the use of invasive hemodynamic monitoring, and chest-X-ray; and quality of life at day 28. Discussion The CONFIDENCE trial is the first RCT comparing the effect of LUS-guided deresuscitation to routine care in invasively ventilated ICU patients. If proven effective, LUS-guided deresuscitation could improve outcomes in some of the most vulnerable and resource-intensive patients in a manner that is non-invasive, easy to perform, and well-implementable. Trial registration ClinicalTrials.gov NCT05188092. Registered since January 12, 2022

Monitoring for thrombosis and hemolysis is crucial for patients under extracorporeal or mechanical circulatory support, but it can be costly. We investigated correlations between hemolysis index (HI) and plasma-free hemoglobin (PFH) levels on one hand, and between the HI and plasma lactate dehydrogenase (LDH) levels on the other, in critically ill patients with and without extracorporeal or mechanical circulatory support. Additionally, we calculated the cost reductions if monitoring through HI were to replace monitoring through PFH or plasma LDH. In a single-center study, HI was compared with PFH and plasma LDH levels in blood samples taken for routine purposes in critically ill patients with and without extracorporeal or mechanical circulatory support. A cost analysis, restricted to direct costs associated with each measurement, was made for an average 10-bed ICU. This study included 147 patients: 56 patients with extracorporeal or mechanical circulatory support (450 measurements) and 91 patients without extracorporeal or mechanical circulatory support (562 measurements). The HI correlated well with PFH levels (r = 0.96; p < 0.01) and poorly with plasma LDH levels (r = 0.07; p < 0.01) in patients with extracorporeal or mechanical circulatory support. Similarly, HI correlated well with PFH levels (r = 0.97; p < 0.01) and poorly with plasma LDH levels (r = −0.04; p = 0.39) in patients without extracorporeal or mechanical circulatory support. ROC analyses demonstrated a strong performance of HI, with the curve indicating excellent discrimination in the whole cohort (area under the ROC of 0.969) as well as in patients under ECMO or mechanical circulatory support (area under the ROC of 0.988). Although the negative predictive value of HI for predicting PFH levels > 10 mg/dL was high, its positive predictive value was found to be poor at various cutoffs. A simple cost analysis showed substantial cost reduction if HI were to replace PFH or plasma LDH for hemolysis monitoring. In conclusion, in this cohort of critically ill patients with and without extracorporeal or mechanical circulatory support, HI correlated well with PFH levels, but poorly with plasma LDH levels. Given the high correlation and substantial cost reductions, a strategy utilizing HI may be preferable for monitoring for hemolysis compared to monitoring strategies based on PFH or plasma LDH. The PPV of HI, however, is unacceptably low to be used as a diagnostic test.

Eddavidite is a new mineral species (IMA2018-010) with ideal formula, Cu12Pb2O15Br2, and cubic Fm3¯m symmetry: a = 9.2407(9) Å; V = 789.1(2) Å3; Z = 2. Eddavidite is the bromine analog of murdochite, Cu12Pb2O15Cl2, with which it forms a solid solution series. The type locality is the Southwest mine, Bisbee, Cochise County, Arizona, U.S.A. Eddavidite also occurs in the Ojuela mine, Mapimí, Durango, Mexico. Eddavidite occurs as domains within mixed murdochite–eddavidite crystals. The empirical formula, normalized to 12 Cu apfu, is Cu12(Pb1.92Fe0.06Si0.06)(O15.08F0.02)-(Br0.99Cl0.89☐0.12). Type locality samples contain up to 67% eddavidite component, while Ojuela mine samples contain up to 62%. Mixed eddavidite–murdochite crystals show forms {100} and {111}; the habit grades from cubic through cuboctahedral to octahedral. Mixed eddavidite–-murdochite crystals exhibit good cleavage on {111}. Eddavidite is black, opaque with submetallic luster, and visually indistinguishable from intergrown murdochite. Its Mohs hardness is 4; dmeas. = 6.33 g/cm3, dcalc. = 6.45 g/cm3. The crystal structure, refined to R = 0.0112, consists of corner-sharing square planar CuO4 units, arranged in Cu12O24 metal oxide clusters, which encapsulate Br atoms. PbO8 cubes share edges with Cu12O24 clusters in a continuous framework. Eddavidite incorporates bromine remaining after desiccation of paleo-seawater at its two known localities, which were both once situated along the Western Interior Seaway.