From ICU Syndromes to ICU Subphenotypes: Consensus Report and Recommendations For Developing Precision Medicine in ICU.

Critical care uses syndromic definitions to describe patient groups for clinical practice and research. There is growing recognition that a "precision medicine" approach is required and that integrated biologic and physiologic data identify reproducible subpopulations that may respond differently to treatment. This article reviews the current state of the field and considers how to successfully transition to a precision medicine approach. In order to impact clinical care, identified subpopulations must do more than differentiate prognosis. They must differentiate response to treatment, ideally by defining subgroups with distinct functional or pathobiological mechanisms (endotypes). There are now multiple examples of reproducible subpopulations of sepsis, acute respiratory distress syndrome, and acute kidney or brain injury described using clinical, physiological, and/or biological data. Many of these subpopulations have demonstrated the potential to define differential treatment response, largely in retrospective studies, and that the same treatment-responsive subpopulations may cross multiple clinical syndromes (treatable traits). To bring about a change in clinical practice, a precision medicine approach must be evaluated in prospective clinical studies requiring novel adaptive trial designs. Several such studies are underway but there are multiple challenges to be tackled. Such subpopulations must be readily identifiable and be applicable to all critically ill populations around the world. Subdividing clinical syndromes into subpopulations will require large patient numbers. Global collaboration of investigators, clinicians, industry and patients over many years will therefore be required to transition to a precision medicine approach and ultimately realize treatment advances seen in other medical fields. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

The optimal glycemic target in critically ill patients: an updated network meta-analysis.

Acute glycemic control significantly affects the clinical outcomes of critically ill patients. This updated network meta-analysis examines the benefits and harms of four target blood glucose levels (< 110, 110-144, 144-180, and > 180 mg/dL). Analyzing data of 27,541 patients from 37 trials, the surface under the cumulative ranking curve for mortality and hypoglycemia was highest at a target blood glucose level of 144-180 mg/dL, while for infection and acute kidney injury at 110-144 mg/dL. Further evidence is needed to determine whether 110-144 or 144-180 mg/dL is superior as an optimal glucose target, considering prioritized outcomes.

Botrytis cinerea detoxifies the sesquiterpenoid phytoalexin rishitin through multiple metabolizing pathways.

Botrytis cinerea is a necrotrophic pathogen that infects across a broad range of plant hosts, including high-impact crop species. Its generalist necrotrophic behavior stems from its ability to detoxify structurally diverse phytoalexins. The current study aims to provide evidence of the ability of B. cinerea to tolerate the sesquiterpenoid phytoalexin rishitin, which is produced by potato and tomato. While the growth of potato pathogens Phytophthora infestans (late blight) and Alternaria solani (early blight) was severely inhibited by rishitin, B. cinerea was tolerant to rishitin. After incubation of rishitin with the mycelia of B. cinerea, it was metabolized to at least six oxidized forms. Structural analysis of these purified rishitin metabolites revealed a variety of oxidative metabolism including hydroxylation at C7 or C12, ketone formation at C5, and dihydroxylation at the 10,11-olefin. Six rishitin metabolites showed reduced toxicity to P. infestans and A. solani, indicating that B. cinerea has at least 5 distinct enzymatic reactions to detoxify rishitin. Four host-specialized phytopathogenic Botrytis species, namely B. elliptica, B. allii, B. squamosa, and B. tulipae also had at least a partial ability to metabolize rishitin as B. cinerea, but their metabolic capacity was significantly weaker than that of B. cinerea. These results suggest that the ability of B. cinerea to rapidly metabolize rishitin through multiple detoxification mechanisms could be critical for its pathogenicity in potato and tomato.

Bone density estimation using tissue heat capacity.

Osteoporosis onset is relatively asymptomatic, the condition often being identified only once a significant fracture occurs, leading to a potentially serious prognosis. Currently, early identification of osteoporosis is complicated by the difficulty in measuring bone density without using x-ray absorptiometry or quantitative ultrasound, so a simpler method for estimating bone density is needed. Given that bone is reported to have a lower specific heat than other tissues, we investigated the possibility of estimating bone density using this difference in tissue thermal properties. The tibia medial surface (shin) and medial malleolus (ankle) of 68 healthy volunteers were cooled using an ice bag, and skin surface temperatures and heat flow were recorded. These measurements were then used to calculate the heat energy transferred per unit temperature. Bone density was estimated by quantitative ultrasound using the T score OSISD, which is the participant's osteo sono-assessment index (OSI) compared to the average OSI of young adults. The heat energy transfer per unit temperature at the shin, but not the ankle, showed a significant negative correlation with T score OSISD (r = -0.413, p = 0.001). Multiple regression analysis showed that heat energy transfer per unit temperature at the shin was a significant predictor of T score OSISD, along with age and height. These results show that tissue thermal property measurements are useful for estimating bone density.

Haplotype-based phylogenetic analysis and population genomics uncover the origin and domestication of sweetpotato.

The hexaploid sweetpotato (Ipomoea batatas) is one of the most important root crops worldwide. However, its genetic origin remains controversial, and its domestication history remains unknown. In this study, we used a range of genetic evidence and a newly developed haplotype-based phylogenetic analysis to identify two probable progenitors of sweetpotato. The diploid progenitor was likely closely related to Ipomoea aequatoriensis and contributed the B1 subgenome, IbT-DNA2, and the lineage 1 type of chloroplast genome to sweetpotato. The tetraploid progenitor of sweetpotato was most likely I. batatas 4x, which donated the B2 subgenome, IbT-DNA1, and the lineage 2 type of chloroplast genome. Sweetpotato most likely originated from reciprocal crosses between the diploid and tetraploid progenitors, followed by a subsequent whole-genome duplication. In addition, we detected biased gene exchanges between the subgenomes; the rate of B1 to B2 subgenome conversions was nearly three times higher than that of B2 to B1 subgenome conversions. Our analyses revealed that genes involved in storage root formation, maintenance of genome stability, biotic resistance, sugar transport, and potassium uptake were selected during the speciation and domestication of sweetpotato. This study sheds light on the evolution of sweetpotato and paves the way for improvement of this crop.

Induction of plant disease resistance by mixed oligosaccharide elicitors prepared from plant cell wall and crustacean shells.

Basal plant immune responses are activated by the recognition of conserved microbe-associated molecular patterns (MAMPs), or breakdown molecules released from the plants after damage by pathogen penetration, so-called damage-associated molecular patterns (DAMPs). While chitin-oligosaccharide (CHOS), a primary component of fungal cell walls, is most known as MAMP, plant cell wall-derived oligosaccharides, cello-oligosaccharides (COS) from cellulose, and xylo-oligosaccharide (XOS) from hemicellulose are representative DAMPs. In this study, elicitor activities of COS prepared from cotton linters, XOS prepared from corn cobs, and chitin-oligosaccharide (CHOS) from crustacean shells were comparatively investigated. In Arabidopsis, COS, XOS, or CHOS treatment triggered typical defense responses such as reactive oxygen species (ROS) production, phosphorylation of MAP kinases, callose deposition, and activation of the defense-related transcription factor WRKY33 promoter. When COS, XOS, and CHOS were used at concentrations with similar activity in inducing ROS production and callose depositions, CHOS was particularly potent in activating the MAPK kinases and WRKY33 promoters. Among the COS and XOS with different degrees of polymerization, cellotriose and xylotetraose showed the highest activity for the activation of WRKY33 promoter. Gene ontology enrichment analysis of RNAseq data revealed that simultaneous treatment of COS, XOS, and CHOS (oligo-mix) effectively activates plant disease resistance. In practice, treatment with the oligo-mix enhanced the resistance of tomato to powdery mildew, but plant growth was not inhibited but rather tended to be promoted, providing evidence that treatment with the oligo-mix has beneficial effects on improving disease resistance in plants, making them a promising class of compounds for practical application.

Sink-source imbalance triggers delayed photosynthetic induction: Transcriptomic and physiological evidence.

Sink-source imbalance causes accumulation of nonstructural carbohydrates (NSCs) and photosynthetic downregulation. However, despite numerous studies, it remains unclear whether NSC accumulation or N deficiency more directly decreases steady-state maximum photosynthesis and photosynthetic induction, as well as underlying gene expression profiles. We evaluated the relationship between photosynthetic capacity and NSC accumulation induced by cold girdling, sucrose feeding, and low nitrogen treatment in Glycine max and Phaseolus vulgaris. In G. max, changes in transcriptome profiles were further investigated, focusing on the physiological processes of photosynthesis and NSC accumulation. NSC accumulation decreased the maximum photosynthetic capacity and delayed photosynthetic induction in both species. In G. max, such photosynthetic downregulation was explained by coordinated downregulation of photosynthetic genes involved in the Calvin cycle, Rubisco activase, photochemical reactions, and stomatal opening. Furthermore, sink-source imbalance may have triggered a change in the balance of sugar-phosphate translocators in chloroplast membranes, which may have promoted starch accumulation in chloroplasts. Our findings provide an overall picture of photosynthetic downregulation and NSC accumulation in G. max, demonstrating that photosynthetic downregulation is triggered by NSC accumulation and cannot be explained solely by N deficiency.

Time definition of reintubation most relevant to patient outcomes in critically ill patients: a multicenter cohort study.

BACKGROUND: Reintubation is a common complication in critically ill patients requiring mechanical ventilation. Although reintubation has been demonstrated to be associated with patient outcomes, its time definition varies widely among guidelines and in the literature. This study aimed to determine the association between reintubation and patient outcomes as well as the consequences of the time elapsed between extubation and reintubation on patient outcomes. METHODS: This was a multicenter retrospective cohort study of critically ill patients conducted between April 2015 and March 2021. Adult patients who underwent mechanical ventilation and extubation in intensive care units (ICUs) were investigated utilizing the Japanese Intensive Care PAtient Database. The primary and secondary outcomes were in-hospital and ICU mortality. The association between reintubation and clinical outcomes was studied using Cox proportional hazards analysis. Among the patients who underwent reintubation, a Cox proportional hazard analysis was conducted to evaluate patient outcomes according to the number of days from extubation to reintubation. RESULTS: Overall, 184,705 patients in 75 ICUs were screened, and 1849 patients underwent reintubation among 48,082 extubated patients. After adjustment for potential confounders, multivariable analysis revealed a significant association between reintubation and increased in-hospital and ICU mortality (adjusted hazard ratio [HR] 1.520, 95% confidence interval [CI] 1.359-1.700, and adjusted HR 1.325, 95% CI 1.076-1.633, respectively). Among the reintubated patients, 1037 (56.1%) were reintubated within 24 h after extubation, 418 (22.6%) at 24-48 h, 198 (10.7%) at 48-72 h, 111 (6.0%) at 72-96 h, and 85 (4.6%) at 96-120 h. Multivariable Cox proportional hazard analysis showed that in-hospital and ICU mortality was highest in patients reintubated at 72-96 h (adjusted HR 1.528, 95% CI 1.062-2.197, and adjusted HR 1.334, 95% CI 0.756-2.352, respectively; referenced to reintubation within 24 h). CONCLUSIONS: Reintubation was associated with a significant increase in in-hospital and ICU mortality. The highest mortality rates were observed in patients who were reintubated between 72 and 96 h after extubation. Further studies are warranted for the optimal observation of extubated patients in clinical practice and to strengthen the evidence for mechanical ventilation.

Both incompatible and compatible rhizobia inhabit the intercellular spaces of leguminous root nodules.

In addition to rhizobia, many types of co-existent bacteria are found in leguminous root nodules, but their habitats are unclear. To investigate this phenomenon, we labeled Bradyrhizobium diazoefficiens USDA122 and Bradyrhizobium sp. SSBR45 with Discosoma sp. red fluorescent protein (DsRed) or enhanced green fluorescent protein (eGFP). USDA122 enhances soybean growth by forming effective root nodules, but SSBR45 does not form any nodules. Using low-magnification laser scanning confocal microscopy, we found that infected cells in the central zone of soybean nodules appeared to be occupied by USDA122. Notably, high-magnification microscopy after co-inoculation of non-fluorescent USDA122 and fluorescence-labeled SSBR45 also revealed that SSBR45 inhabits the intercellular spaces of healthy nodules. More unexpectedly, co-inoculation of eGFP-labeled USDA122 and DsRed-labeled SSBR45 (and vice versa) revealed the presence of USDA122 bacteria in both the symbiosomes of infected cells and in the apoplasts of healthy nodules. We then next inspected nodules formed after a mixed inoculation of differently-labeled USDA122, without SSBR45, and confirmed the inhabitation of the both populations of USDA122 in the intercellular spaces. In contrast, infected cells were occupied by single-labeled USDA122. We also observed Mesorhizobium loti in the intercellular spaces of active wild-type nodules of Lotus japonicus using transmission electron microscopy. Compatible intercellular rhizobia have been described during nodule formation of several legume species and in some mutants, but our evidence suggests that this type of colonization may occur much more commonly in leguminous root nodules.

Botrytis cinerea tolerates phytoalexins produced by Solanaceae and Fabaceae plants through an efflux transporter BcatrB and metabolizing enzymes.

Botrytis cinerea, a plant pathogenic fungus with a wide host range, has reduced sensitivity to fungicides as well as phytoalexins, threatening cultivation of economically important fruits and vegetable crops worldwide. B. cinerea tolerates a wide array of phytoalexins, through efflux and/or enzymatic detoxification. Previously, we provided evidence that a distinctive set of genes were induced in B. cinerea when treated with different phytoalexins such as rishitin (produced by tomato and potato), capsidiol (tobacco and bell pepper) and resveratrol (grape and blueberry). In this study, we focused on the functional analyses of B. cinerea genes implicated in rishitin tolerance. LC/MS profiling revealed that B. cinerea can metabolize/detoxify rishitin into at least 4 oxidized forms. Heterologous expression of Bcin08g04910 and Bcin16g01490, two B. cinerea oxidoreductases upregulated by rishitin, in a plant symbiotic fungus Epichloë festucae revealed that these rishitin-induced enzymes are involved in the oxidation of rishitin. Expression of BcatrB, encoding an exporter of structurally unrelated phytoalexins and fungicides, was significantly upregulated by rishitin but not by capsidiol and was thus expected to be involved in the rishitin tolerance. Conidia of BcatrB KO (ΔbcatrB) showed enhanced sensitivity to rishitin, but not to capsidiol, despite their structural similarity. ΔbcatrB showed reduced virulence on tomato, but maintained full virulence on bell pepper, indicating that B. cinerea activates BcatrB by recognizing appropriate phytoalexins to utilize it in tolerance. Surveying 26 plant species across 13 families revealed that the BcatrB promoter is mainly activated during the infection of B. cinerea in plants belonging to the Solanaceae, Fabaceae and Brassicaceae. The BcatrB promoter was also activated by in vitro treatments of phytoalexins produced by members of these plant families, namely rishitin (Solanaceae), medicarpin and glyceollin (Fabaceae), as well as camalexin and brassinin (Brassicaceae). Consistently, ΔbcatrB showed reduced virulence on red clover, which produces medicarpin. These results suggest that B. cinerea distinguishes phytoalexins and induces differential expression of appropriate genes during the infection. Likewise, BcatrB plays a critical role in the strategy employed by B. cinerea to bypass the plant innate immune responses in a wide variety of important crops belonging to the Solanaceae, Brassicaceae and Fabaceae.

Draft Genome Sequences of Neofusicoccum parvum Strains Isolated from Mango and Rice-Paper Plant (Tetrapanax papyrifer).

Neofusicoccum parvum is a polyxenous phytopathogenic fungus that infects important fruits, such as grapes and mangoes. Here, we report the genome sequences of N. parvum strains that were isolated from mango in Okinawa, Japan (strain PPO83), and an invasive weed (rice-paper plant [Tetrapanax papyrifer]) in Nagoya, Japan (strain NSSI1).

Characterization of photosynthetic Bradyrhizobium sp. strain SSBR45 isolated from the root nodules of Aeschynomene indica.

We isolated a novel strain of Bradyrhizobium sp., SSBR45, from the nodulated roots of Aeschynomene indica and labeled it with Discosoma sp. red fluorescent protein (dsRED) or enhanced green fluorescent protein (eGFP) and determined its draft genomic sequence. The labeled SSBR45 stimulated the growth of A. indica markedly on a nitrogen-free medium, as observed by visualizing the fluorescent root nodules. The nodulated roots also exhibited high acetylene reduction activities. The SSBR45 genome included genes involved in nitrogen fixation, photosynthesis, and type IV secretion system; however, it did not consist of canonical nodABC genes and type III secretion system genes. SSBR45, a novel species of the genus Bradyrhizobium, consisted of an average nucleotide identity and average amino acid identity of 87% and 90%, respectively, with the closest strain B. oligotrophicum S58.

Synthesis of aglycones, structure-activity relationships, and mode of action of lycosides as inhibitors of the asexual reproduction of Phytophthora.

Phytophthora are plant pathogens that damage agricultural products. Lycosides (1a-d), found in vegetable juice, have the potential to curb the rapid outbreak and crop damage caused by the asexual reproduction of Phytophthora. Here, aglycones 2a, b with slightly higher activity than lycosides were synthesized as a diastereomeric mixture (mix-2) possessing activity (IC50 = 4.1 µm) comparable with that of lycosides. The importance of the cyclohexanone structure and side-chain length was demonstrated via structure-activity relationship analysis using synthetic intermediates. In addition, the action mechanism of lycosides was investigated using transcriptome analysis, which revealed a contribution to proline biosynthesis inhibition, a process crucial for the asexual reproduction of Phytophthora. These findings indicate that lycosides (and aglycone) are environmentally benign agents that can be used for protecting agricultural products from Phytophthora pathogens.

Nurse intervention process for the thoughts and concerns of people with cancer at the end of their life: A structural equation modeling approach.

Over the last decade, the importance of Advanced Care Planning has been recognized in Japan. However, it is still difficult for healthcare providers and patients to verbalize how they want to spend the last days of their lives and what unfinished business they have left to accomplish. This study aimed to clarify how nurses intervened to assist patients with cancer at the end of life to express their thoughts and concerns. Twenty-four nurses were interviewed regarding how they intervened for patients' thoughts and concerns, and data were analyzed qualitatively using a modified grounded theory approach. A 25-item scale was selected, and the questionnaires, which included the scale, were distributed to nurses in general wards, palliative care units, and home visiting nurse services. A total of 1864 responses were analyzed. Factor analysis and structural equation model analysis were used, and three factors were identified: "assessment and intervention," "basic care," and "knowledge and communication," which led to the formulation of an intervention structure model for uncovering thoughts and concerns. These results indicate the importance of basic care and communication during interventions for patients.

Association between tracheostomy and survival in patients with coronavirus disease 2019 who require prolonged mechanical ventilation for more than 14 days: A multicenter cohort study.

OBJECTIVE: Tracheostomy is a common procedure with potential prognostic advantages for patients who require prolonged mechanical ventilation (PMV). Early recommendations for patients with coronavirus disease 2019 (COVID-19) suggested delayed or limited tracheostomy considering the risk for viral transmission to clinicians. However, updated guidelines for tracheostomy with appropriate personal protective equipment have revised its indications. This study aimed to evaluate the association between tracheostomy and prognosis in patients with COVID-19 requiring PMV. METHODS: This was a multicenter, retrospective cohort study using data from the nationwide Japanese Intensive Care PAtient Database. We included adult patients aged ≥16 years who were admitted to the intensive care unit (ICU) due to COVID-19 and who required PMV (for >14 days or until performance of tracheostomy). The primary outcome was hospital mortality, and the association between implementation of tracheostomy and patient prognosis was assessed using weighted Cox proportional hazards regression analysis with inverse probability of treatment weighting (IPTW) using the propensity score to address confounders. RESULTS: Between January 2020 and February 2021, 453 patients with COVID-19 were observed. Data from 109 patients who required PMV were analyzed: 66 (60.6%) underwent tracheostomy and 38 (34.9%) died. After adjusting for potential confounders using IPTW, tracheostomy implementation was found to significantly reduce hospital mortality (hazard ratio [HR]: 0.316, 95% confidence interval [CI]: 0.163-0.612). Patients who underwent tracheostomy had a similarly decreased ICU and 28-day mortality (HR: 0.269, 95% CI: 0.124-0.581; HR 0.281, 95% CI: 0.094-0.839, respectively). A sensitivity analysis using different definitions of PMV duration consistently showed reduced mortality in patients who underwent tracheostomy. CONCLUSION: The implementation of tracheostomy was associated with favorable patient prognosis among patients with COVID-19 requiring PMV. Our findings support proactive tracheostomy in critically ill patients with COVID-19 requiring mechanical ventilation for >14 days.

Noninvasive blood pressure measurement in patients with continuous-flow left ventricular assist devices.

Oscillatory blood pressure (OBP) with a slow cuff-deflation system has been proposed as noninvasive measurement of mean arterial pressure (MAP) in patients with continuous-flow left ventricular assist devices (LVADs). However, the challenge is that the measurement is not obtainable in certain patients. We hypothesized that the combined use of color Doppler imaging during OBP measurement (CDBP) could derive MAP accurately. We conducted a prospective observational study in critically ill patients (30 patients with continuous-flow LVADs and 30 control patients without LVADs). Triplicate OBP and CDBP measurements were performed and invasive blood pressure (IBP) was recorded. The overall success rate of OBP was 63.3% in the LVAD group and 98.9% in the control group. The CDBP was successfully obtained in 100% of all study patients. The CDBP in the LVAD group was closest to the MAP of measured IBP, while that in the control group was closest to the systolic IBP. The mean absolute differences in OBP and CDBP from the closest IBP were similar in both the control and LVAD groups. In nonpulsatile LVAD patients with a pulse pressure IBP < 10 mmHg, the success rate of OBP measurement was only 10.0%, and CDBP showed significantly reduced error in MAP measurement (mean absolute difference: OBP 23.2 ± 8.7 vs CDBP 5.2 ± 3.6 mmHg, p < 0.001). The validity of OBP measurement with a slow cuff-deflation system limited particularly in nonpulsatile LVAD patients. The concurrent use of color Doppler imaging is encouraged for more accurate measurement of MAP in patients with continuous-flow LVADs.

Timing of tracheostomy and patient outcomes in critically ill patients requiring extracorporeal membrane oxygenation: a single-center retrospective observational study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is an integral method of life support in critically ill patients with severe cardiopulmonary failure; however, such patients generally require prolonged mechanical ventilation and exhibit high mortality rates. Tracheostomy is commonly performed in patients on mechanical ventilation, and its early implementation has potential advantages for favorable patient outcomes. This study aimed to investigate the association between tracheostomy timing and patient outcomes, including mortality, in patients requiring ECMO. METHODS: We conducted a single-center retrospective observational study of consecutively admitted patients who were supported by ECMO and underwent tracheostomy during intensive care unit (ICU) admission at a tertiary care center from April 2014 until December 2021. The primary outcome was hospital mortality. Using the quartiles of tracheostomy timing, the patients were classified into four groups for comparison. The association between the quartiles of tracheostomy timing and mortality was explored using multivariable logistic regression models. RESULTS: Of the 293 patients treated with ECMO, 98 eligible patients were divided into quartiles 1 (≤ 15 days), quartile 2:16-19 days, quartile 3:20-26 days, and 4 (> 26 days). All patients underwent surgical tracheostomy and 35 patients underwent tracheostomy during ECMO. The complications of tracheostomy were comparable between the groups, whereas the duration of ECMO and ICU length of stay increased significantly as the quartiles of tracheostomy timing increased. Patients in quartile 1 had the lowest hospital mortality rate (19.2%), whereas those in quartile 4 had the highest mortality rate (50.0%). Multivariate logistic regression analysis showed a significant association between the increment of the quartiles of tracheostomy timing and hospital mortality (adjusted odds ratio for quartile increment:1.55, 95% confidence interval 1.03-2.35, p for trend = 0.037). CONCLUSIONS: The timing of tracheostomy in patients requiring ECMO was significantly associated with patient outcomes in a time-dependent manner. Further investigation is warranted to determine the optimal timing of tracheostomy in terms of mortality.

Prevalence and Risk Factor Analysis of Post-Intensive Care Syndrome in Patients with COVID-19 Requiring Mechanical Ventilation: A Multicenter Prospective Observational Study.

INTRODUCTION: Post-intensive care syndrome (PICS) is an emerging problem in critically ill patients and the prevalence and risk factors are unclear in patients with severe coronavirus disease 2019 (COVID-19). This multicenter prospective observational study aimed to investigate the prevalence and risk factors of PICS in ventilated patients with COVID-19 after ICU discharge. METHODS: Questionnaires were administered twice in surviving patients with COVID-19 who had required mechanical ventilation, concerning Barthel Index, Short-Memory Questionnaire, and Hospital Anxiety and Depression Scale scores. The risk factors for PICS were examined using a multivariate logistic regression analysis. RESULTS: The first and second PICS surveys were obtained at 5.5 and 13.5 months (mean) after ICU discharge, with 251 and 209 patients completing the questionnaires and with a prevalence of PICS of 58.6% and 60.8%, respectively, along with the highest percentages of cognitive impairment. Delirium (with an odds ratio of (OR) 2.34, 95% CI 1.1-4.9, and p = 0.03) and the duration of mechanical ventilation (with an OR of 1.29, 95% CI 1.05-1.58, and p = 0.02) were independently identified as the risk factors for PICS in the first PICS survey. CONCLUSION: Approximately 60% of the ventilated patients with COVID-19 experienced persistent PICS, especially delirium, and required longer mechanical ventilation.

Inhibitors of Asexual Reproduction of the Plant Pathogen Phytophthora from Tomato Juice: Structure-Activity Relationships and Transcriptome Analysis.

Phytophthora is a genus of fungus-like microorganisms that damages important crops, such as potatoes and tomatoes. Its asexual reproduction, which results in the production of numerous motile zoospores, is the cause of quick and severe outbreaks and crop damage. The search for substances that selectively inhibit the asexual reproduction of Phytophthora led to the isolation of the known natural products naringenin and flazin from tomato juice. They inhibit the sporangia formation of Phytophthora capsici at IC50 values of 8.8 and 7.2 µM. The study of the structure-activity relationship of 11 flavonoids, including naringenin, demonstrated that genistein was the most active (IC50 = 4.6 µM) and flavonols/flavanonols possessing the 3-hydroxy function showed little activity (IC50 = from 100 to >1000 µM). To demonstrate the mechanism of asexual reproduction inhibition by genistein, transcriptome analysis was carried out, which revealed the downregulation of some genes related to cell differentiation. The results suggest that certain flavonoids are environmentally benign agents that could be used to protect agricultural products from Phytophthora pathogens.