Impact of extended lung protection during mechanical ventilation on lung recovery in patients with COVID-19 ARDS: a phase II randomized controlled trial.

BACKGROUND: Protective ventilation seems crucial during early Acute Respiratory Distress Syndrome (ARDS), but the optimal duration of lung protection remains undefined. High driving pressures (ΔP) and excessive patient ventilatory drive may hinder lung recovery, resulting in self-inflicted lung injury. The hidden nature of the ΔP generated by patient effort complicates the situation further. Our study aimed to assess the feasibility of an extended lung protection strategy that includes a stepwise protocol to control the patient ventilatory drive, assessing its impact on lung recovery. METHODS: We conducted a single-center randomized study on patients with moderate/severe COVID-19-ARDS with low respiratory system compliance (CRS < 0.6 (mL/Kg)/cmH2O). The intervention group received a ventilation strategy guided by Electrical Impedance Tomography aimed at minimizing ΔP and patient ventilatory drive. The control group received the ARDSNet low-PEEP strategy. The primary outcome was the modified lung injury score (mLIS), a composite measure that integrated daily measurements of CRS, along with oxygen requirements, oxygenation, and X-rays up to day 28. The mLIS score was also hierarchically adjusted for survival and extubation rates. RESULTS: The study ended prematurely after three consecutive months without patient enrollment, attributed to the pandemic subsiding. The intention-to-treat analysis included 76 patients, with 37 randomized to the intervention group. The average mLIS score up to 28 days was not different between groups (P = 0.95, primary outcome). However, the intervention group showed a faster improvement in the mLIS (1.4 vs. 7.2 days to reach 63% of maximum improvement; P < 0.001), driven by oxygenation and sustained improvement of X-ray (P = 0.001). The intervention group demonstrated a sustained increase in CRS up to day 28 (P = 0.009) and also experienced a shorter time from randomization to room-air breathing (P = 0.02). Survival at 28 days and time until liberation from the ventilator were not different between groups. CONCLUSIONS: The implementation of an individualized PEEP strategy alongside extended lung protection appears viable. Promising secondary outcomes suggested a faster lung recovery, endorsing further examination of this strategy in a larger trial. Clinical trial registration This trial was registered with ClinicalTrials.gov (number NCT04497454) on August 04, 2020.

Investigating relationships between the host genome, rumen microbiome, and dairy cow feed efficiency using mediation analysis with structural equation modeling.

The rumen microbiome is crucial for converting feed into absorbable nutrients used for milk synthesis, and the efficiency of this process directly impacts the profitability and sustainability of the dairy industry. Recent studies have found that the rumen microbial composition explains part of the variation in feed efficiency traits, including dry matter intake, milk energy, and residual feed intake. The main goal of this study was to reveal relationships between the host genome, rumen microbiome, and dairy cow feed efficiency using structural equation models. Our specific objectives were to (i) infer the mediation effects of the rumen microbiome on feed efficiency traits, (ii) estimate the direct and total heritability of feed efficiency traits, and (iii) calculate the direct and total breeding values of feed efficiency traits. Data consisted of dry matter intake, milk energy, and residual feed intake records, SNP genotype data, and 16S rRNA rumen microbial abundances from 448 mid-lactation Holstein cows from 2 research farms. We implemented structural equation models such that the host genome directly affects the phenotype (GP → P) and the rumen microbiome (GM → P), while the microbiome affects the phenotype (M → P), partially mediating the effect of the host genome on the phenotype (G → M → P). We found that 7 to 30% of microbes within the rumen microbial community had structural coefficients different from zero. We classified these microbes into 3 groups that could have different uses in dairy farming. Microbes with heritability <0.10 but significant causal effects on feed efficiency are attractive for external interventions. On the other hand, 2 groups of microbes with heritability ≥0.10, significant causal effects, and genetic covariances and causal effects with the same or opposite sign to feed efficiency are attractive for selective breeding, improving or decreasing the trait heritability and response to selection, respectively. In general, the inclusion of the different microbes in genomic models tends to decrease the trait heritability rather than increase it, ranging from -15% to +5%, depending on the microbial group and phenotypic trait. Our findings provide more understanding to target rumen microbes that can be manipulated, either through selection or management interventions, to improve feed efficiency traits.

Shifts in uterine microbiome associated with pregnancy outcomes at first insemination and clinical cure in dairy cows with metritis.

Objectives were to assess differences in uterine microbiome associated with clinical cure and pregnancy outcomes in dairy cows treated for metritis. Cows with metritis (reddish-brownish, watery, and fetid vaginal discharge) were paired with cows without metritis based on parity and days postpartum. Uterine contents were collected through transcervical lavage at diagnosis, five days later following antimicrobial therapy (day 5), and at 40 days postpartum. Uterine microbiome was assessed by sequencing the V4 hypervariable region of the 16S rRNA gene. Although alpha-diversity based on Chao1, Shannon, and inverse Simpson indexes at diagnosis did not differ between cows with and without metritis, disease was associated with differences in beta-diversity. Prevalence of Porphyromonas, Bacteroides, and Veillonella was greater in cows with metritis. Streptococcus, Sphingomonas, and Ureaplasma were more prevalent in cows without metritis. Differences in beta-diversity between cows with and without metritis persisted on day 5. Uterine microbiome was not associated with clinical cure. Richness and alpha-diversity, but not beta-diversity, of uterine microbiome 40 days postpartum were associated with metritis and pregnancy. No relationship between uterine microbiome and pregnancy outcomes was observed. Results indicate that factors other than changes in intrauterine bacterial community underlie fertility loss and clinical cure in cows with metritis.

Macrophage-derived human resistin promotes perivascular adipose tissue dysfunction in experimental inflammatory arthritis.

Cardiovascular disease (CVD) is the leading cause of death in rheumatoid arthritis (RA). Resistin is an adipokine that induces adipose tissue inflammation and activation of monocytes/macrophages via adenylate cyclase-associated protein-1 (CAP1). Resistin levels are increased in RA and might cause perivascular adipose tissue (PVAT) dysfunction, leading to vascular damage and CVD. This study aimed to investigate the role of resistin in promoting PVAT dysfunction by increasing local macrophage and inflammatory cytokines content in antigen-induced arthritis (AIA). Resistin pharmacological effects were assessed by using C57Bl/6J wild-type (WT) mice, humanized resistin mice expressing human resistin in monocytes-macrophages (hRTN+/-/-), and resistin knockout mice (RTN-/-) with AIA and respective controls. We investigated AIA disease activity and functional, cellular, and molecular parameters of the PVAT. Resistin did not contribute to AIA disease activity and its concentrations were augmented in the PVAT and plasma of WT AIA and hRTN+/-/- AIA animals. In vitro exposure of murine arteries to resistin impaired vascular function by decreasing the anti-contractile effect of PVAT. WT AIA mice and hRTN+/-/- AIA mice exhibited PVAT dysfunction and knockdown of resistin prevented it. Macrophage-derived cytokines, markers of types 1 and 2 macrophages, and CAP1 expression were increased in the PVAT of resistin humanized mice with AIA, but not in knockout mice for resistin. This study reveals that macrophage-derived resistin promotes PVAT inflammation and dysfunction regardless of AIA disease activity. Resistin might represent a translational target to reduce RA-driven vascular dysfunction and CVD.

Biofragmentation of Polystyrene Microplastics: A Silent Process Performed by Chironomus sancticaroli Larvae.

Polystyrene (PS) is one of the main synthetic polymers produced around the world, and it is present in the composition of a wide variety of single-use objects. When released into the environment, these materials are degraded by environmental factors, resulting in microplastics. We investigated the ability of Chironomus sancticaroli (Diptera, Chironomidae) to promote the fragmentation of PS microspheres (24.5 ± 2.9 µm) and the toxic effects associated with exposure to this polymer. C. sancticaroli larvae were exposed to 3 different concentrations of PS (67.5, 135, and 270 particles g-1 of dry sediment) for 144 h. Significant lethality was observed only at the highest concentration. A significant reduction in PS particle size as well as evidence of deterioration on the surface of the spheres, such as grooves and cracks, was observed. In addition, changes in oxidative stress biomarkers (SOD, CAT, MDA, and GST) were also observed. This is the first study to report the ability of Chironomus sp. to promote the biofragmentation of microplastics. The information obtained demonstrates that the macroinvertebrate community can play a key role in the degradation of plastic particles present in the sediment of freshwater environments and can also be threatened by such particle pollution.

New species of the wasp-mimic Parahephaestion Melzer, 1930 (Coleoptera: Cerambycidae), from Minas Gerais, Brazil, with new records.

A new species, Parahephaestion mimicus sp. nov., is described. Two species are newly recorded for the Brazilian state of Minas Gerais: Sphalloeme costipennis Melzer, 1928 (Cerambycinae, Oemini) and Oreodera omissa Melzer, 1932 (Lamiinae, Acrocinini). Six species are new records for the RPPN Sanctuary of Caraa, (Brazil, Minas Gerais): Thalusia atrata (Melzer, 1918) (Cerambycinae, Rhopalophorini), Trachelissa pustulata (Audinet-Serville, 1834) (Cerambycinae, Trachyderini), Ateralphus dejeani (Lane, 1973) (Lamiinae, Acanthoderini), Phacellocera plumicornis (Klug, 1825) (Lamiinae, Anisocerini), Oncideres impluviata (Germar, 1823), and Psyllotoxus griseocinctus Thomson, 1868 (Lamiinae, Onciderini).

An artificial intelligence approach of feature engineering and ensemble methods depicts the rumen microbiome contribution to feed efficiency in dairy cows.

Genetic selection has remarkably helped U.S. dairy farms to decrease their carbon footprint by more than doubling milk production per cow over time. Despite the environmental and economic benefits of improved feed and milk production efficiency, there is a critical need to explore phenotypical variance for feed utilization to advance the long-term sustainability of dairy farms. Feed is a major expense in dairy operations, and their enteric fermentation is a major source of greenhouse gases in agriculture. The challenges to expanding the phenotypic database, especially for feed efficiency predictions, and the lack of understanding of its drivers limit its utilization. Herein, we leveraged an artificial intelligence approach with feature engineering and ensemble methods to explore the predictive power of the rumen microbiome for feed and milk production efficiency traits, as rumen microbes play a central role in physiological responses in dairy cows. The novel ensemble method allowed to further identify key microbes linked to the efficiency measures. We used a population of 454 genotyped Holstein cows in the U.S. and Canada with individually measured feed and milk production efficiency phenotypes. The study underscored that the rumen microbiome is a major driver of residual feed intake (RFI), the most robust feed efficiency measure evaluated in the study, accounting for 36% of its variation. Further analyses showed that several alpha-diversity metrics were lower in more feed-efficient cows. For RFI, [Ruminococcus] gauvreauii group was the only genus positively associated with an improved feed efficiency status while seven other taxa were associated with inefficiency. The study also highlights that the rumen microbiome is pivotal for the unexplained variance in milk fat and protein production efficiency. Estimation of the carbon footprint of these cows shows that selection for better RFI could reduce up to 5 kg of diet consumed per cow daily, potentially reducing up to 37.5% of CH4. These findings shed light that the integration of artificial intelligence approaches, microbiology, and ruminant nutrition can be a path to further advance our understanding of the rumen microbiome on nutrient requirements and lactation performance of dairy cows to support the long-term sustainability of the dairy community.

Deucravacitinib for Moderate-to-Severe Psoriasis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

There is contrasting evidence regarding the efficacy and safety of JAK (Janus kinase) inhibitors in the treatment of psoriasis. This systematic review and meta-analysis assessed deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, as the therapy of choice for moderate-to-severe psoriasis. PubMed, Embase, and Cochrane databases were searched for randomized controlled trials, including patients with moderate-to-severe psoriasis. Outcomes of interest were serious adverse events (SAEs), the severity of illness, as measured by the validated questionnaires: Psoriasis Area and Severity Index (PASI) and scalp-specific Physician's Global Assessment (ss-PGA); and quality of life, measured by the Dermatology Life Quality Index (DLQI). Four studies with 1663 patients were included in the meta-analysis, of whom 1123 (67.5%) were treated with deucravacitinib during a 12-to-16-week follow-up. The mean age was 45.4 ± 13.3 years, and 70.2% were male. Two-thirds had a history of scalp psoriasis. Achievement of PASI 75 was significantly higher in the deucravacitinib group, as compared with placebo (RR 5.7; 95% CI 4.32-7.53; P<0.001). Similarly, ss-PGA 0/1 (RR 3.86; 95%CI 3.02-4.94; P<0.001) and DLQI 0/1 (RR 3.89; 2.89-5.22; P<0.001) were also significantly more frequent in the deucravacitinib group. The incidence of SAEs was similar between groups. These findings suggest that patients with moderate-to-severe psoriasis treated with deucravacitinib for 12 to 16 weeks had significantly decreased severity of illness and improved quality of life, without a concerning increase in the incidence of SAEs. J Drugs Dermatol. 2024;23(2):67-73.  doi:10.36849/JDD.7539.

A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution.

Frozen shoulder is a spontaneously self-resolving chronic inflammatory fibrotic human disease, which distinguishes the condition from most fibrotic diseases that are progressive and irreversible. Using single-cell analysis, we identify pro-inflammatory MERTKlowCD48+ macrophages and MERTK + LYVE1 + MRC1+ macrophages enriched for negative regulators of inflammation which co-exist in frozen shoulder capsule tissues. Micro-cultures of patient-derived cells identify integrin-mediated cell-matrix interactions between MERTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in frozen shoulder resolution. Cross-tissue analysis reveals a shared gene expression cassette between shoulder capsule MERTK+ macrophages and a respective population enriched in synovial tissues of rheumatoid arthritis patients in disease remission, supporting the concept that MERTK+ macrophages mediate resolution of inflammation and fibrosis. Single-cell transcriptomic profiling and spatial analysis of human foetal shoulder tissues identify MERTK + LYVE1 + MRC1+ macrophages and DKK3+ and POSTN+ fibroblast populations analogous to those in frozen shoulder, suggesting that the template to resolve fibrosis is established during shoulder development. Crosstalk between MerTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts could facilitate resolution of frozen shoulder, providing a basis for potential therapeutic resolution of persistent fibrotic diseases.

Influence of Fractional Inspired Oxygen Tension on Lung Perfusion Distribution, Regional Ventilation, and Lung Volume during Mechanical Ventilation of Supine Healthy Swine.

BACKGROUND: Lower fractional inspired oxygen tension (Fio2) during general anesthesia can reduce lung atelectasis. The objectives are to evaluate the effect of two Fio2 (0.4 and 1) during low positive end-expiratory pressure (PEEP) ventilation over lung perfusion distribution, volume, and regional ventilation. These variables were evaluated at two PEEP levels and unilateral lung atelectasis. METHODS: In this exploratory study, 10 healthy female piglets (32.3 ± 3.4 kg) underwent mechanical ventilation in two atelectasis models: (1) bilateral gravitational atelectasis (n = 6), induced by changes in PEEP and Fio2 in three combinations: high PEEP with low Fio2 (Fio2 = 0.4), zero PEEP (PEEP0) with low Fio2 (Fio2 = 0.4), and PEEP0 with high Fio2 (Fio2 = 1); and (2) unilateral atelectasis (n = 6), induced by left bronchial occlusion, with the left lung aerated (Fio2 = 0.21) and low aerated (Fio2 = 1; n = 5 for this step). Measurements were conducted after 10 min in each step, encompassing assessment of respiratory mechanics, oxygenation, and hemodynamics; lung ventilation and perfusion by electrical impedance tomography; and lung aeration and perfusion by computed tomography. RESULTS: During bilateral gravitational atelectasis, PEEP reduction increased atelectasis in dorsal regions, decreased respiratory compliance, and distributed lung ventilation to ventral regions with a parallel shift of perfusion to the same areas. With PEEP0, there were no differences between low and high Fio2 in respiratory compliance (23.9 ± 6.5 ml/cm H2O vs. 21.9 ± 5.0; P = 0.441), regional ventilation, and regional perfusion, despite higher lung collapse (18.6 ± 7.6% vs. 32.7 ± 14.5%; P = 0.045) with high Fio2. During unilateral lung atelectasis, the deaerated lung had a lower shunt (19.3 ± 3.6% vs. 25.3 ± 5.5%; P = 0.045) and lower computed tomography perfusion to the left lung (8.8 ± 1.8% vs. 23.8 ± 7.1%; P = 0.007). CONCLUSIONS: PEEP0 with low Fio2, compared with high Fio2, did not produce significant changes in respiratory system compliance, regional lung ventilation, and perfusion despite significantly lower lung collapse. After left bronchial occlusion, the shrinkage of the parenchyma with Fio2 = 1 enhanced hypoxic pulmonary vasoconstriction, reducing intrapulmonary shunt and perfusion of the nonventilated areas.

The rhythms of histones in regeneration: The epigenetic modifications determined by clock genes.

The evolutionary establishment of an internal biological clock is a primordial event tightly associated with a 24-h period. Changes in the circadian rhythm can affect cellular functions, including proliferation, DNA repair and redox state. Even isolated organs, tissues and cells can maintain an autonomous circadian rhythm. These cell-autonomous molecular mechanisms are driven by intracellular clock genes, such as BMAL1. Little is known about the role of core clock genes and epigenetic modifications in the skin. Our focus was to identify BMAL1-driven epigenetic modifications associated with gene transcription by mapping the acetylation landscape of histones in epithelial cells responding to injury. We explored the role of BMAL1 in epidermal wound and tissue regeneration using a loss-of-function approach in vivo. We worked with BMAL1 knockout mice and a contraction-resistance wound healing protocol, determining the histone modifications using specific antibodies to detect the acetylation levels of histones H3 and H4. We found significant differences in the acetylation levels of histones in both homeostatic and injured skin with deregulated BMAL1. The intact skin displayed varied acetylation levels of histones H3 and H4, including hyperacetylation of H3 Lys 9 (H3K9). The most pronounced changes were observed at the repair site, with notable alterations in the acetylation pattern of histone H4. These findings reveal the importance of histone modifications in response to injury and indicate that modulation of BMAL1 and its associated epigenetic events could be therapeutically harnessed to improve skin regeneration.

Has the Rio Doce "time bomb" been defused? Using a weight-of-evidence approach to determine sediment quality.

The Fundão mine tailings dam rupture of 2015, in the Rio Doce basin, Brazil, resulted in the deposition of tailings downstream of the dam. It has yet to be determined if metals associated with the tailings have contributed toxicity to organisms, burying a time bomb that could be ticking. Currently the data on toxicity to benthic and aquatic organisms have not been assessed sufficiently to allow an informed assessment using an approach based on weight-of-evidence. This study was conducted to ascertain if sediments at "hot spots" that received Fundão tailings reflected elevated concentrations of metals and if these concentrations were sufficient to result in toxicity to freshwater organisms. The lines-of-evidence considered included assessing metals concentrations in relation to sediment quality criteria, establishing biogeochemical characterizations, completing an evaluation of potential metal release upon resuspension to provide information on bioavailability, and identifying acute and chronic toxicity effects using sensitive native species for waters (water flea, Daphnia similis) and sediments (burrowing midge larvae, Chironomus sancticaroli). Only porewater concentrations of iron and manganese exceeded Brazilian surface water criteria, whereas most trace elements exhibited no enrichment or elevated environmental indexes. The concentrations of bioavailable metals were assessed to be low, and metal concentrations did not increase in the overlying water upon resuspension; rather, they decreased through time. Toxicity testing in resuspended waters and bulk sediments resulted in no acute or chronic toxicity to either benthic or aquatic species. The low metal bioavailability and absence of toxicity of the tailings-enriched sediments was attributed to the strong binding and rapid removal of potentially toxic metal ions caused by oxyhydroxides and particles in the presence of iron-rich particulates. The findings of these sediment hot-spot studies indicate the Fundão dam release of tailings more than six years ago is not causing the current release of toxic concentrations of metals into the freshwaters of the Rio Doce. Integr Environ Assess Manag 2024;20:148-158. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Acyltransferase families that act on thioesters: Sequences, structures, and mechanisms.

Acyltransferases (AT) are enzymes that catalyze the transfer of acyl group to a receptor molecule. This review focuses on ATs that act on thioester-containing substrates. Although many ATs can recognize a wide variety of substrates, sequence similarity analysis allowed us to classify the ATs into fifteen distinct families. Each AT family is originated from enzymes experimentally characterized to have AT activity, classified according to sequence similarity, and confirmed with tertiary structure similarity for families that have crystallized structures available. All the sequences and structures of the AT families described here are present in the thioester-active enzyme (ThYme) database. The AT sequences and structures classified into families and available in the ThYme database could contribute to enlightening the understanding acyl transfer to thioester-containing substrates, most commonly coenzyme A, which occur in multiple metabolic pathways, mostly with fatty acids.

Host and rumen microbiome contributions to feed efficiency traits in Holstein cows.

It is now widely accepted that dairy cow performance is influenced by both the host genome and rumen microbiome composition. The contributions of the genome and the microbiome to the phenotypes of interest are quantified by heritability (h2) and microbiability (m2), respectively. However, if the genome and microbiome are included in the model, then the h2 reflects only the contribution of the direct genetic effects quantified as direct heritability (hd2), and the holobiont effect reflects the joint action of the genome and the microbiome, quantified as the holobiability (ho2). The objectives of this study were to estimate h2, hd2,m2, and ho2 for dry matter intake, milk energy, and residual feed intake; and to evaluate the predictive ability of different models, including genome, microbiome, and their interaction. Data consisted of feed efficiency records, SNP genotype data, and 16S rRNA rumen microbial abundances from 448 mid-lactation Holstein cows from 2 research farms. Three kernel models were fit to each trait: one with only the genomic effect (model G), one with the genomic and microbiome effects (model GM), and one with the genomic, microbiome, and interaction effects (model GMO). The model GMO, or holobiont model, showed the best goodness-of-fit. The hd2 estimates were always 10% to 15% lower than h2 estimates for all traits, suggesting a mediated genetic effect through the rumen microbiome, and m2 estimates were moderate for all traits, and up to 26% for milk energy. The ho2 was greater than the sum of hd2 and m2, suggesting that the genome-by-microbiome interaction had a sizable effect on feed efficiency. Kernel models fitting the rumen microbiome (i.e., models GM and GMO) showed larger predictive correlations and smaller prediction bias than the model G. These findings reveal a moderate contribution of the rumen microbiome to feed efficiency traits in lactating Holstein cows and strongly suggest that the rumen microbiome mediates part of the host genetic effect.

Pendelluft in hypoxemic patients resuming spontaneous breathing: proportional modes versus pressure support ventilation.

BACKGROUND: Internal redistribution of gas, referred to as pendelluft, is a new potential mechanism of effort-dependent lung injury. Neurally-adjusted ventilatory assist (NAVA) and proportional assist ventilation (PAV +) follow the patient's respiratory effort and improve synchrony compared with pressure support ventilation (PSV). Whether these modes could prevent the development of pendelluft compared with PSV is unknown. We aimed to compare pendelluft magnitude during PAV + and NAVA versus PSV in patients with resolving acute respiratory distress syndrome (ARDS). METHODS: Patients received either NAVA, PAV + , or PSV in a crossover trial for 20-min using comparable assistance levels after controlled ventilation (> 72 h). We assessed pendelluft (the percentage of lost volume from the non-dependent lung region displaced to the dependent region during inspiration), drive (as the delta esophageal swing of the first 100 ms [ΔPes 100 ms]) and inspiratory effort (as the esophageal pressure-time product per minute [PTPmin]). We performed repeated measures analysis with post-hoc tests and mixed-effects models. RESULTS: Twenty patients mechanically ventilated for 9 [5-14] days were monitored. Despite matching for a similar tidal volume, respiratory drive and inspiratory effort were slightly higher with NAVA and PAV + compared with PSV (ΔPes 100 ms of -2.8 [-3.8--1.9] cm H2O, -3.6 [-3.9--2.4] cm H2O and -2.1 [-2.5--1.1] cm H2O, respectively, p < 0.001 for both comparisons; PTPmin of 155 [118-209] cm H2O s/min, 197 [145-269] cm H2O s/min, and 134 [93-169] cm H2O s/min, respectively, p < 0.001 for both comparisons). Pendelluft magnitude was higher in NAVA (12 ± 7%) and PAV + (13 ± 7%) compared with PSV (8 ± 6%), p < 0.001. Pendelluft magnitude was strongly associated with respiratory drive (ß = -2.771, p-value < 0.001) and inspiratory effort (ß = 0.026, p < 0.001), independent of the ventilatory mode. A higher magnitude of pendelluft in proportional modes compared with PSV existed after adjusting for PTPmin (ß = 2.606, p = 0.010 for NAVA, and ß = 3.360, p = 0.004 for PAV +), and only for PAV + when adjusted for respiratory drive (ß = 2.643, p = 0.009 for PAV +). CONCLUSIONS: Pendelluft magnitude is associated with respiratory drive and inspiratory effort. Proportional modes do not prevent its occurrence in resolving ARDS compared with PSV.

Dynamic relative regional lung strain estimated by computed tomography and electrical impedance tomography in ARDS patients.

BACKGROUND: In the acute distress respiratory syndrome (ARDS), specific lung regions can be exposed to excessive strain due to heterogeneous disease, gravity-dependent lung collapse and injurious mechanical ventilation. Computed tomography (CT) is the gold standard for regional strain assessment. An alternative tool could be the electrical impedance tomography (EIT). We aimed to determine whether EIT-based methods can predict the dynamic relative regional strain (DRRS) between two levels of end-expiratory pressure (PEEP) in gravity-non-dependent and dependent lung regions. METHODS: Fourteen ARDS patients underwent CT and EIT acquisitions (at end-inspiratory and end-expiratory) at two levels of PEEP: a low-PEEP based on ARDS-net strategy and a high-PEEP titrated according to EIT. Three EIT-based methods for DRRS were compared to relative CT-based strain: (1) the change of the ratio between EIT ventilation and end-expiratory lung impedance in arbitrary units ([ΔZAU low-PEEP/EELIAU low-PEEP]/[ΔZAU high-PEEP/EELIAU high-PEEP]), (2) the change of ΔZ/EELI ratio calibrated to mL ([ΔZml low-PEEP/EELIml low-PEEP]/[ΔZml high-PEEP/EELIml high-PEEP]) using CT data, and (3) the relative change of ∆ZAU (∆ZAU low-PEEP/∆ZAU high-PEEP). We performed linear regressions analysis and calculated bias and limits of agreement to assess the performance of DRRS by EIT in comparison with CT. RESULTS: The DRRS assessed by (ΔZml low-PEEP/EELIml low-PEEP)/(ΔZml high-PEEP/EELIml high-PEEP) and ∆ZAU low-PEEP/∆ZAU high-PEEP showed good relationship and agreement with the CT method (R2 of 0.9050 and 0.8679, respectively, in non-dependent region; R2 of 0.8373 and 0.6588, respectively, in dependent region; biases ranging from - 0.11 to 0.51 and limits of agreement ranging from - 0.73 to 1.16 for both methods and lung regions). Conversely, DRRS based on EELIAU ([ΔZAU low-PEEP/EELIAU low-PEEP]/[ΔZAU high-PEEP/EELIAU high-PEEP]) exhibited a weak negative relationship and poor agreement with the CT method for both non-dependent and dependent regions (R2 ~ 0.3; bias of 3.11 and 2.08, and limits of agreement of - 2.13 to 8.34 and from - 1.49 to 5.64, respectively). CONCLUSION: Changes in DRRS during a PEEP trial in ARDS patients could be monitored using EIT, based on changes in ΔZmL/EELIml and ∆ZAU. The relative change ∆ZAU offers the advantage of not requiring CT data for calibration.

Penicillin-binding protein (PBP) inhibitor development: A 10-year chemical perspective.

Bacterial cell wall formation is essential for cellular survival and morphogenesis. The peptidoglycan (PG), a heteropolymer that surrounds the bacterial membrane, is a key component of the cell wall, and its multistep biosynthetic process is an attractive antibacterial development target. Penicillin-binding proteins (PBPs) are responsible for cross-linking PG stem peptides, and their central role in bacterial cell wall synthesis has made them the target of successful antibiotics, including ß-lactams, that have been used worldwide for decades. Following the discovery of penicillin, several other compounds with antibiotic activity have been discovered and, since then, have saved millions of lives. However, since pathogens inevitably become resistant to antibiotics, the search for new active compounds is continuous. The present review highlights the ongoing development of inhibitors acting mainly in the transpeptidase domain of PBPs with potential therapeutic applications for the development of new antibiotic agents. Both the critical aspects of the strategy, design, and structure-activity relationships (SAR) are discussed, covering the main published articles over the last 10 years. Some of the molecules described display activities against main bacterial pathogens and could open avenues toward the development of new, efficient antibacterial drugs.

Neanderthal introgression in SCN9A impacts mechanical pain sensitivity.

The Nav1.7 voltage-gated sodium channel plays a key role in nociception. Three functional variants in the SCN9A gene (encoding M932L, V991L, and D1908G in Nav1.7), have recently been identified as stemming from Neanderthal introgression and to associate with pain symptomatology in UK BioBank data. In 1000 genomes data, these variants are absent in Europeans but common in Latin Americans. Analysing high-density genotype data from 7594 Latin Americans, we characterized Neanderthal introgression in SCN9A. We find that tracts of introgression occur on a Native American genomic background, have an average length of ~123 kb and overlap the M932L, V991L, and D1908G coding positions. Furthermore, we measured experimentally six pain thresholds in 1623 healthy Colombians. We found that Neanderthal ancestry in SCN9A is significantly associated with a lower mechanical pain threshold after sensitization with mustard oil and evidence of additivity of effects across Nav1.7 variants. Our findings support the reported association of Neanderthal Nav1.7 variants with clinical pain, define a specific sensory modality affected by archaic introgression in SCN9A and are consistent with independent effects of the Neanderthal variants on Nav1.7 function.