A multinational Delphi consensus to end the COVID-19 public health threat.

Despite notable scientific and medical advances, broader political, socioeconomic and behavioural factors continue to undercut the response to the COVID-19 pandemic1,2. Here we convened, as part of this Delphi study, a diverse, multidisciplinary panel of 386 academic, health, non-governmental organization, government and other experts in COVID-19 response from 112 countries and territories to recommend specific actions to end this persistent global threat to public health. The panel developed a set of 41 consensus statements and 57 recommendations to governments, health systems, industry and other key stakeholders across six domains: communication; health systems; vaccination; prevention; treatment and care; and inequities. In the wake of nearly three years of fragmented global and national responses, it is instructive to note that three of the highest-ranked recommendations call for the adoption of whole-of-society and whole-of-government approaches1, while maintaining proven prevention measures using a vaccines-plus approach2 that employs a range of public health and financial support measures to complement vaccination. Other recommendations with at least 99% combined agreement advise governments and other stakeholders to improve communication, rebuild public trust and engage communities3 in the management of pandemic responses. The findings of the study, which have been further endorsed by 184 organizations globally, include points of unanimous agreement, as well as six recommendations with >5% disagreement, that provide health and social policy actions to address inadequacies in the pandemic response and help to bring this public health threat to an end.

A large source of cloud condensation nuclei from new particle formation in the tropics.

Cloud condensation nuclei (CCN) can affect cloud properties and therefore Earth's radiative balance1-3. New particle formation (NPF) from condensable vapours in the free troposphere has been suggested to contribute to CCN, especially in remote, pristine atmospheric regions4, but direct evidence is sparse, and the magnitude of this contribution is uncertain5-7. Here we use in situ aircraft measurements of vertical profiles of aerosol size distributions to present a global-scale survey of NPF occurrence. We observe intense NPF at high altitudes in tropical convective regions over both Pacific and Atlantic oceans. Together with the results of chemical-transport models, our findings indicate that NPF persists at all longitudes as a global-scale band in the tropical upper troposphere, covering about 40 per cent of Earth's surface. Furthermore, we find that this NPF in the tropical upper troposphere is a globally important source of CCN in the lower troposphere, where CCN can affect cloud properties. Our findings suggest that the production of CCN as new particles descend towards the surface is not adequately captured in global models, which tend to underestimate both the magnitude of tropical upper tropospheric NPF and the subsequent growth of new particles to CCN sizes.

Shift-Level Team Familiarity Is Associated with Improved Outcomes in Mechanically Ventilated Adults.

RATIONALE: Organizing intensive care unit (ICU) interprofessional teams is a high priority due to workforce needs, but the role of interprofessional familiarity remains unexplored. OBJECTIVE: Determine if mechanically ventilated patients cared for by teams with greater familiarity have improved outcomes, such as lower mortality, shorter duration of mechanical ventilation (MV), and greater spontaneous breathing trial (SBT) implementation. METHODS: We used electronic health records data of 5 ICUs in an academic medical center to map interprofessional teams and their ICU networks, measuring team familiarity as network coreness and mean team value. We used patient-level regression models to link team familiarity with patient outcomes, accounting for patient/unit factors. We also performed a split-sample analysis by using 2018 team familiarity data to predict 2019 outcomes. MEASUREMENTS: Team familiarity was measured as the average number of patients shared by each clinician with all other clinicians in the ICU (i.e., coreness) and the average number of patients shared by any two members of the team (i.e., mean team value). MAIN RESULTS: Among 4,485 encounters, unadjusted mortality was 12.9%, average duration of MV was 2.32 days and SBT implementation was 89%; average team coreness was 467.2 (SD = 96.15) and average mean team value was 87.02 (SD=42.42). A standard-deviation increase in team coreness was significantly associated with a 4.5% greater probability of SBT implementation, 23% shorter MV duration, and 3.8% lower probability of dying; mean team value was significantly associated with lower mortality. Split-sample results were attenuated but congruent in direction and interpretation. CONCLUSIONS: Interprofessional familiarity was associated with improved outcomes; assignment models that prioritize familiarity might be a novel solution.

Pathological Character of Modifications to Coincident General Relativity: Cosmological Strong Coupling and Ghosts in f(Q) Theories.

The intrinsic presence of ghosts in the symmetric teleparallel framework is elucidated. We illustrate our general arguments in f(Q) theories by studying perturbations in the three inequivalent spatially flat cosmologies. Two of these branches exhibit reduced linear spectra, signalling they are infinitely strongly coupled. For the remaining branch we unveil the presence of seven gravitational degrees of freedom and show that at least one of them is a ghost. Our results rule out f(Q) cosmologies and clarify the number of propagating degrees of freedom in these theories.

Volatile biomarkers of Gram-positive bacteria of clinical relevance as a tool for infection diagnosis.

AIM: Volatile organic compounds (VOCs) are being studied as potential biomarkers in many infections. Therefore, this study aimed to analyze the volatile profile of three Gram-positive bacteria of clinical relevance to identify potential volatile biomarkers that allow their differentiation. METHODS AND RESULTS: L. monocytogenes, S. aureus, and E. faecalis clinical isolates were inoculated in a thioglycollate medium until grown. Then, VOCs were extracted by solid-phase microextraction, and the data obtained were subjected to multivariate analysis. According to our results, there was a high production of aldehydes in E. faecalis. In the case of alcohols, they only increased in L. monocytogenes, while ketones were produced significantly in all three bacteria, mainly due to acetoin. Acids were produced significantly in E. faecalis and L. monocytogenes. CONCLUSIONS: Potential biomarkers of L. monocytogenes could be 1-butanol and 2-methylbutanoic acid. In the case of E. faecalis, the VOC most related to its presence was nonanal. Lastly, potential biomarkers of S. aureus could be isoamyl butanoate and methionol, although some pyrazines have also been associated with this bacterium. SIGNIFICANCE AND IMPACT OF THE STUDY: The identification of potential biomarkers of these clinically relevant bacteria could open the way for the diagnosis of these infections through the analysis of volatile compounds.

Defining the first bona fide cell model for SMARCA4-deficient, undifferentiated tumor.

The World Health Organization's tumor classification guidelines are frequently updated and renewed as knowledge of cancer biology advances. For instance, in 2021, a novel lung tumor subtype named SMARCA4-deficient, undifferentiated tumor (SMARCA4-dUT, code 8044/3) was included. To date, there is no defined cell model for SMARCA4-dUT that could be used to help thoracic clinicians and researchers in the study of this newly defined tumor type. As this tumor type was recently described, it is feasible that some cell models formerly classified as lung adenocarcinoma (LUAD) could now be better classified as SMARCA4-dUT. Thus, in this work, we aimed to identify a bona fide cell model for the experimental study of SMARCA4-dUT. We compared the differential expression profiles of 36 LUAD-annotated cell lines and 38 cell lines defined as rhabdoid in repositories. These comparative results were integrated with the mutation and expression profiles of the SWI/SNF complex members, and they were surveyed for the presence of the SMARCA4-dUT markers SOX2, SALL4, and CD34, measured by RT-qPCR and western blotting. Finally, the cell line with the paradigmatic SMARCA4-dUT markers was engrafted into immunocompromised mice to assess the histological morphology of the formed tumors and compare them with those formed by a bona fide LUAD cancer cell line. NCI-H522, formerly classified as LUAD, displayed expression profiles nearer to rhabdoid tumors than LUAD tumors. Furthermore, NCI-H522 has most of the paradigmatic features of SMARCA4-dUT: hemizygous inactivating mutation of SMARCA4, severe SMARCA2 downregulation, and high-level expression of stem cell markers SOX2 and SALL4. In addition, the engrafted tumors of NCI-H522 did not display a typical differentiated glandular structure as other bona fide LUAD cell lines (A549) do but had rather a largely undifferentiated morphology, characteristic of SMARCA4-dUT. Thus, we propose the NCI-H522 as the first bona fide cell line model of SMARCA4-dUT. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Analysis of a second-tier test panel in dried blood spot samples using liquid chromatography-tandem mass spectrometry in Catalonia's newborn screening programme.

OBJECTIVES: Acylcarnitine and amino acid analyses of dried blood spot (DBS) samples using tandem mass spectrometry in newborn screening (NBS) programmes can generate false positive (FP) results. Therefore, implementation of second-tier tests (2TTs) using DBS samples has become increasingly important to avoid FPs. The most widely used 2TT metabolites include methylmalonic acid, 3-hydroxypropionic acid, methylcitric acid, and homocysteine. METHODS: We simultaneously measured 46 underivatised metabolites, including organic acids, acylglycine and acylcarnitine isomers, homocysteine, and orotic acid, in DBS samples using tandem mass spectrometry. To validate this method, we analysed samples from 147 healthy newborns, 160 patients with genetic disorders diagnosed via NBS, 20 patients with acquired vitamin B12 deficiency, 10 newborns receiving antibiotic treatment, and nine external quality control samples. RESULTS: The validation study revealed that 31 metabolites showed good analytical performance. Furthermore, this method detected key metabolites for all diseases associated with increased levels of the following acylcarnitines: C3, C4, C5, C4DC/C5OH, and C5DC. The sensitivity of this method to detect all diseases was 100 %, and the specificity was 74-99 %, except for glutaric aciduria type 1. This method can also be used to diagnose mitochondrial fatty acid ß-oxidation disorders (FAODs) and urea cycle defects (UCDs). CONCLUSIONS: We have described a 2TT panel of 31 metabolites in DBS samples based on an easy and rapid method without derivatisation. Its implementation allowed us to distinguish between different organic acidurias, some FAODs, and UCDs. This new strategy has increased the efficiency of our NBS programme by reducing FP and false negative results, second sample requests, and the time required for diagnosis.

Tracheostomy in Patients with Acute Myocardial Infarction and Respiratory Failure.

OBJECTIVE: Patients with acute myocardial infarction (AMI) complicated by respiratory failure require antiplatelet regimens which often cannot be stopped and may increase bleeding from tracheostomy. However, there is limited available data on both the proportion of patients undergoing tracheostomy and the impact on antiplatelet regimens on outcomes. METHODS: Utilizing the Vizient® Clinical Data Base, we identified patients ≥18 years admitted from 2015 to 2019 with a primary diagnosis of AMI and requiring invasive mechanical ventilation (IMV). We assessed for the incidence of patients undergoing tracheostomy, outcomes stratified by the timing of tracheostomy (≤10 vs >10 days), and the association between dual antiplatelet therapy (DAPT) use and in-hospital mortality. RESULTS: We identified 26 435 patients presenting with AMI requiring IMV. The mean (SD) age was 66.8 (12.3) years and 33.4% were women. The incidence of tracheostomy was 6.0% (n = 1573), and the median IMV time to tracheostomy was 12 days, 55.6% of which underwent percutaneous and 44.4% underwent open tracheostomy. Over 90% (n = 1424) underwent tracheostomy (>10 days) and had a similar mortality when compared to early (≤10 days) tracheostomy (22.5% vs 22.8%, P = 0.94). On the day of tracheostomy, only 24.7% were given DAPT, which was associated with a lower mortality than those not on DAPT (17.4% vs 23.7%, P = 0.01). After multivariable adjustment, DAPT use on the day of tracheostomy remained associated with lower in-hospital mortality (odds ratio 0.68; 95% confidence interval: 0.49-0.94, P = 0.02). Tracheostomy complications were not different between groups (P > 0.05), but more patients in the DAPT group required post-tracheostomy blood transfusions (5.6% vs 2.7%, P = 0.01). CONCLUSION: Approximately 1 in 20 intubated AMI patients requires tracheostomy. The lack of DAPT interruption on the day of tracheostomy but not the timing of tracheostomy was associated with a lower in-hospital mortality. Our results suggest that DAPT should not be a barrier to tracheostomy for patients with AMI.

Corrigendum: mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer.

This corrects the article DOI: 10.1038/nature22964.

Exploring Rhodospirillum rubrum response to high doses of carbon monoxide under light and dark conditions.

Environmental concerns about residues and the traditional disposal methods are driving the search for more environmentally conscious processes, such as pyrolysis and gasification. Their main final product is synthesis gas (syngas) composed of CO, CO2, H2, and methane. Syngas can be converted into various products using CO-tolerant microorganisms. Among them, Rhodospirillum rubrum is highlighted for its biotechnological potential. However, the extent to which high doses of CO affect its physiology is still opaque. For this reason, we have studied R. rubrum behavior under high levels of this gas (up to 2.5 bar), revealing a profound dependence on the presence or absence of light. In darkness, the key variable affected was the lag phase, where the highest levels of CO retarded growth to more than 20 days. Under light, R. rubrum ability to convert CO into CO2 and H2 depended on the presence of an additional carbon source, such as acetate. In those conditions where CO was completely exhausted, CO2 fixation was unblocked, leading to a diauxic growth. To enhance R. rubrum tolerance to CO in darkness, a UV-accelerated adaptive laboratory evolution (UVa-ALE) trial was conducted to isolate clones with shorter lag phases, resulting in the isolation of clones 1.4-2B and 1.7-2A. The adaptation of 1.4-2B was mainly based on mutated enzymes with a metabolic function, while 1.7-3A was mostly affected at regulatory genes, including the anti-repressor PpaA/AerR. Despite these mutations having slight effects on biomass and pigment levels, they successfully provoked a significant reduction in the lag phase (-50%). KEYPOINTS: • CO affects principally R. rubrum lag phase (darkness) and growth rate (light) • CO is converted to CO2/H2 during acetate uptake and inhibits CO2 fixation (light) • UVa-ALE clones showed a 50% reduction in the lag phase (darkness).

The Effect of a Compression Bandage on Dual Energy X-ray Absorptiometry Body Composition Scores.

BACKGROUND: Dual-energy X-ray absorptiometry (DXA) measures are affected by the noise produced by external factors such as textile compression found in loose clothing. The study aimed to determine the effect of a compression bandage (CB) on body composition (BC) assessed by DXA. METHODS: Sixty volunteers (age=21.4±4.7yr.) underwent full-body DXA scans on a control (CTRL) condition and after wearing a 30-mmHg CB on the trunk, legs, and arms. ANOVA (2 genders by 2 experimental conditions) determined mean interactions in BC variables tissue body fat% (BF%), region body fat% (RBF%), body tissue (BT), fat mass (FM), lean mass (LM), bone mineral content (BMC), and total mass (TM). Absolute reliability in BC scores was studied by the typical error of the measurement (TEM), the coefficient of variability (CV), and Bland-Altman plots. RESULTS: ANOVA interactions were found on tissue total BF% (p=0.049), RBF% (p=0.048), android lean mass (p=0.004), and android total mass (p=0.019). The CV was small for tissue BF% (2.61±0.93%, CI95%=0.79, 4.43%), RBF% (2.66±1.78%, CI95%=-0.83, 6.15%), BT (4.82±2.19%, CI95%=0.54, 9.10kg), FM (4.17±2.25%, CI95%=-0.24, 8.58kg), LM (3.25±2.44%, CI95%=-1.53, 8.04kg), BMC (4.81±2.96%, CI95%=-0.99, 10.62kg), and TM (2.84±2.80%, CI95%=-2.65, 8.33kg). Bland-Altman plots showed random error for BF%, LM, and BMC. A bias of 0.5% was observed on BF% in males. CONCLUSION: A CB worn during a full-body DXA scan elicited similar BC scores than not wearing it. The variation in scores was <10% for most BC variables, and a trivial bias of 0.5% in BF% was detected in male scores.

Large contribution of biomass burning emissions to ozone throughout the global remote troposphere.

Ozone is the third most important anthropogenic greenhouse gas after carbon dioxide and methane but has a larger uncertainty in its radiative forcing, in part because of uncertainty in the source characteristics of ozone precursors, nitrogen oxides, and volatile organic carbon that directly affect ozone formation chemistry. Tropospheric ozone also negatively affects human and ecosystem health. Biomass burning (BB) and urban emissions are significant but uncertain sources of ozone precursors. Here, we report global-scale, in situ airborne measurements of ozone and precursor source tracers from the NASA Atmospheric Tomography mission. Measurements from the remote troposphere showed that tropospheric ozone is regularly enhanced above background in polluted air masses in all regions of the globe. Ozone enhancements in air with high BB and urban emission tracers (2.1 to 23.8 ppbv [parts per billion by volume]) were generally similar to those in BB-influenced air (2.2 to 21.0 ppbv) but larger than those in urban-influenced air (-7.7 to 6.9 ppbv). Ozone attributed to BB was 2 to 10 times higher than that from urban sources in the Southern Hemisphere and the tropical Atlantic and roughly equal to that from urban sources in the Northern Hemisphere and the tropical Pacific. Three independent global chemical transport models systematically underpredict the observed influence of BB on tropospheric ozone. Potential reasons include uncertainties in modeled BB injection heights and emission inventories, export efficiency of BB emissions to the free troposphere, and chemical mechanisms of ozone production in smoke. Accurately accounting for intermittent but large and widespread BB emissions is required to understand the global tropospheric ozone burden.

Effect of exercise-induced body fluid redistribution on body composition in males using dual energy X-ray absorptiometry.

We studied the effect of exercise-induced body fluid redistribution on dual-energy x-ray absorptiometry (DXA) body composition scores. Thirty males completed 30-min of upper-body exercise (UBE), lower-body exercise, and seated non-exercise control (NEC). ANOVA determined interactions between experimental conditions and measurements on body composition variables. For UBE, mean pre to post differences were found on tissue fat (M = 0.35 ± 0.12%; CI95%diff = 0.10 to 0.59%; p = 0.007), region fat (M = 0.32 ± 0.11%; CI95%diff = 0.09 to 0.55%; p = 0.008), lean mass (M = 0.27 ± 0.01 kg; CI95%diff = 0.18 to 0.37 kg; p ≤ 0.0001), and total mass (M = 0.27 ± 0.05 kg; CI95%diff = 0.17 to 0.36 kg; p ≤ 0.0001). Mean tissue pre to post differences were found for the total body in the NEC (M = 0.10 ± 0.04 kg; CI95%diff = 0.03 to 0.18 kg; p = 0.008), UBE (M = 0.19 ± 0.03 kg; CI95%diff = 0.14 to 0.24 kg; p ≤ 0.0001), and LBE (M = 0.31 ± 0.04 kg; CI95%diff = 0.24 to 0.39 kg; p ≤ 0.0001) conditions. High absolute reliability was found within experimental conditions. These findings have practical implications for technicians, since acute exercise elicited small changes in body composition scores using DXA.

Visualizing hypothesis tests in survival analysis under anticipated delayed effects.

What can be considered an appropriate statistical method for the primary analysis of a randomized clinical trial (RCT) with a time-to-event endpoint when we anticipate non-proportional hazards owing to a delayed effect? This question has been the subject of much recent debate. The standard approach is a log-rank test and/or a Cox proportional hazards model. Alternative methods have been explored in the statistical literature, such as weighted log-rank tests and tests based on the Restricted Mean Survival Time (RMST). While weighted log-rank tests can achieve high power compared to the standard log-rank test, some choices of weights may lead to type-I error inflation under particular conditions. In addition, they are not linked to a mathematically unambiguous summary measure. Test statistics based on the RMST, on the other hand, allow one to investigate the average difference between two survival curves up to a pre-specified time point τ $$ \tau $$ -a mathematically unambiguous summary measure. However, by emphasizing differences prior to τ $$ \tau $$ , such test statistics may not fully capture the benefit of a new treatment in terms of long-term survival. In this article, we introduce a graphical approach for direct comparison of weighted log-rank tests and tests based on the RMST. This new perspective allows a more informed choice of the analysis method, going beyond power and type I error comparison.

Progressive Pattern Interleaver with Multi-Carrier Modulation Schemes and Iterative Multi-User Detection in IoT 6G Environments with Multipath Channels.

Sixth-generation (6G) wireless networks demand a more efficient implementation of non-orthogonal multiple access (NOMA) schemes for severe multipath fading environments to serve multiple users. Using non-orthogonal multiple access (NOMA) schemes in IoT 6G networks is a promising solution to allow multiple users to share the same spectral and temporal resource, increasing spectral efficiency and improving the network's capacity. In this work, we have evaluated the performance of a novel progressive pattern interleaver (PPI) employed to distinguish the users in interleaved division multiple access (IDMA) schemes, suggested by 3GPP guidelines as a NOMA scheme, with two multi-carrier modulation schemes known as single-carrier frequency-division multiple access (SC-FDMA) and orthogonal frequency-division multiplexing (OFDM), resulting in SC-FDMA-IDMA and OFDM-IDMA schemes. Both schemes are multi-carrier schemes with orthogonal sub-carriers to deal against inter-symbol interference (ISI) and orthogonal interleavers for the simultaneous access of multiple users. It has been suggested through simulation outcomes that PPI performance is adequate with SC-FDMA-IDMA and OFDM-IDMA schemes in terms of bit error rate (BER) under multipath channel conditions. Moreover, regarding bandwidth requirement and the implementation complexity of the transmitted interleaver structure, PPI is superior to the conventional random interleaver (RI).

Genome-Wide Association Study Reveals Quantitative Trait Loci and Candidate Genes Associated with High Interferon-gamma Production in Holstein Cattle Naturally Infected with Mycobacterium Bovis.

Mycobacterium bovis (Mb) is the causative agent of bovine tuberculosis (bTb). Genetic selection aiming to identify less susceptible animals has been proposed as a complementary measure in ongoing programs toward controlling Mb infection. However, individual animal phenotypes for bTb based on interferon-gamma (IFNÉ£) and its use in bovine selective breeding programs have not been explored. In the current study, IFNÉ£ production was measured using a specific IFNÉ£ ELISA kit in bovine purified protein derivative (bPPD)-stimulated blood samples collected from Holstein cattle. DNA isolated from the peripheral blood samples collected from the animals included in the study was genotyped with the EuroG Medium Density bead Chip, and the genotypes were imputed to whole-genome sequences. A genome-wide association analysis (GWAS) revealed that the IFNÉ£ in response to bPPD was associated with a specific genetic profile (heritability = 0.23) and allowed the identification of 163 SNPs, 72 quantitative trait loci (QTLs), 197 candidate genes, and 8 microRNAs (miRNAs) associated with this phenotype. No negative correlations between this phenotype and other phenotypes and traits included in the Spanish breeding program were observed. Taken together, our results define a heritable and distinct immunogenetic profile associated with strong production of IFNÉ£ in response to Mb.

Ecospirituality and Health: A Systematic Review.

Environmental changes are affecting human health. A renewal of the way we understand and relate to the planet is needed. Ecospirituality brings together the terms spirituality and environment and is born as a means of solution to this dilemma. This systematic review aimed to find out the influence of ecospirituality on global health. A search of scientific literature was carried out in the main health science databases. A review was conducted to critically evaluate the studies that identified relevant ecospiritual aspects regarding health care for communities. After a systematic search and screening, and following specified methodological criteria, a total of 14 articles were selected in the review. The findings of the review suggest that a new perspective in our worldview such as ecospirituality will provide us with the necessary keys to improve health. To understand ecospirituality, we must keep in mind the indigenous way of life, which is the clear example to follow to achieve environmental health and global health. Ecospirituality leads to a healthier environment, and as this is directly related to health, there is also an improvement in global health.

Coronavirus Disease 2019 and Airborne Transmission: Science Rejected, Lives Lost. Can Society Do Better?

This is an account that should be heard of an important struggle: the struggle of a large group of experts who came together at the beginning of the COVID-19 pandemic to warn the world about the risk of airborne transmission and the consequences of ignoring it. We alerted the World Health Organization about the potential significance of the airborne transmission of SARS-CoV-2 and the urgent need to control it, but our concerns were dismissed. Here we describe how this happened and the consequences. We hope that by reporting this story we can raise awareness of the importance of interdisciplinary collaboration and the need to be open to new evidence, and to prevent it from happening again. Acknowledgement of an issue, and the emergence of new evidence related to it, is the first necessary step towards finding effective mitigation solutions.

Clinical and Ecological Impact of an Educational Program to Optimize Antibiotic Treatments in Nursing Homes (PROA-SENIOR): A Cluster, Randomized, Controlled Trial and Interrupted Time-Series Analysis.

BACKGROUND: Antimicrobial stewardship programs (ASPs) are recommended in nursing homes (NHs), although data are limited. We aimed to determine the clinical and ecological impact of an ASP for NHs. METHODS: We performed a cluster, randomized, controlled trial and a before-after study with interrupted time-series analyses in 14 NHs for 30 consecutive months from July 2018 to December 2020 in Andalusia, Spain. Seven facilities implemented an ASP with a bundle of 5 educational measures (general ASP) and 7 added 1-to-1 educational interviews (experimental ASP). The primary outcome was the overall use of antimicrobials, calculated monthly as defined daily doses (DDD) per 1000 resident days (DRD). RESULTS: The total mean antimicrobial consumption decreased by 31.2% (-16.72 DRD; P = .045) with respect to the preintervention period; the overall use of quinolones and amoxicillin-clavulanic acid dropped by 52.2% (P = .001) and 42.5% (P = .006), respectively; and the overall prevalence of multidrug-resistant organisms (MDROs) decreased from 24.7% to 17.4% (P = .012). During the intervention period, 12.5 educational interviews per doctor were performed in the experimental ASP group; no differences were found in the total mean antimicrobial use between groups (-14.62 DRD; P = .25). Two unexpected coronavirus disease 2019 waves affected the centers increasing the overall mean use of antimicrobials by 40% (51.56 DRD; P < .0001). CONCLUSIONS: This study suggests that an ASP for NHs appears to be associated with a decrease in total consumption of antimicrobials and prevalence of MDROs. This trial did not find benefits associated with educational interviews, probably due to the coronavirus disease 2019 pandemic. Clinical Trials Registration. NCT03543605.

Water potential governs the effector specificity of the transcriptional regulator XylR of Pseudomonas putida.

The biodegradative capacity of bacteria in their natural habitats is affected by water availability. In this work, we have examined the activity and effector specificity of the transcriptional regulator XylR of the TOL plasmid pWW0 of Pseudomonas putida mt-2 for biodegradation of m-xylene when external water potential was manipulated with polyethylene glycol PEG8000. By using non-disruptive luxCDEAB reporter technology, we noticed that the promoter activated by XylR (Pu) restricted its activity and the regulator became more effector-specific towards head TOL substrates when cells were grown under water subsaturation. Such a tight specificity brought about by water limitation was relaxed when intracellular osmotic stress was counteracted by the external addition of the compatible solute glycine betaine. With these facts in hand, XylR variants isolated earlier as effector-specificity responders to the non-substrate 1,2,4-trichlorobenzene under high matric stress were re-examined and found to be unaffected by water potential in vivo. All these phenomena could be ultimately explained as the result of water potential-dependent conformational changes in the A domain of XylR and its effector-binding pocket, as suggested by AlphaFold prediction of protein structures. The consequences of this scenario for the evolution of specificities in regulators and the emergence of catabolic pathways are discussed.