Genetic manipulation of gut microbes enables single-gene interrogation in a complex microbiome.

Hundreds of microbiota genes are associated with host biology/disease. Unraveling the causal contribution of a microbiota gene to host biology remains difficult because many are encoded by nonmodel gut commensals and not genetically targetable. A general approach to identify their gene transfer methodology and build their gene manipulation tools would enable mechanistic dissections of their impact on host physiology. We developed a pipeline that identifies the gene transfer methods for multiple nonmodel microbes spanning five phyla, and we demonstrated the utility of their genetic tools by modulating microbiome-derived short-chain fatty acids and bile acids in vitro and in the host. In a proof-of-principle study, by deleting a commensal gene for bile acid synthesis in a complex microbiome, we discovered an intriguing role of this gene in regulating colon inflammation. This technology will enable genetically engineering the nonmodel gut microbiome and facilitate mechanistic dissection of microbiota-host interactions.

Effector Protein Serine Carboxypeptidase FgSCP Is Essential for Full Virulence in F. graminearum and Is Involved in Modulating Plant Immune Responses.

Fusarium head blight (FHB) caused by Fusarium graminearum is a significant pathogen affecting wheat crops. During the infection process, effector proteins are secreted to modulate plant immunity and promote infection. The toxin deoxynivalenol (DON) is produced in infected wheat grains, posing a threat to human and animal health. Serine carboxypeptidases (SCPs) belong to the α/ß hydrolase family of proteases and are widely distributed in plant and fungal vacuoles as well as animal lysosomes. Research on SCPs mainly focuses on the isolation, purification of a small number of fungi as well as their study in plants.However, their functions in F. graminearum, a fungal pathogen, remain relatively unknown. In this study, the biological functions of the FgSCP gene in F. graminearum were investigated. The study revealed that mutations in FgSCP affected nutritional growth, sexual reproduction, and stress tolerance of F. graminearum. Furthermore, the deletion of FgSCP resulted in reduced pathogenicity and hindered the biosynthesis of DON. The upregulation of FgSCP expression three days after infection indicated its involvement in host invasion, possibly acting as a "smokescreen" to deceive the host and suppress the expression of host defensive genes. Subsequently, we confirmed the secretion ability of FgSCP and its ability to inhibit the cell death induced by INF1 in Nicotiana. benthamiana cells, indicating its potential role as an effector protein in suppressing plant immune responses and promoting infection. In summary, we have identified FgSCP as an essential effector protein in F. graminearum, playing critical roles in growth, virulence, secondary metabolism, and host invasion.

Advancing Red-Emitting Fluoride Phosphors for Highly Stable White Light-Emitting Diodes: Crystal Reconstruction and Covalence Enhancement Strategy.

Mn4+-activated fluoride red phosphors exhibit excellent luminescence properties. However, a persistent technical challenge lies in their poor moisture resistance. Current strategies primarily focus on surface modifications to effectively shield the [MnF6]2- species from water molecules while neglecting the underlying structure of the fluoride matrix. In this study, we introduce Si4+ and Ge4+ ions into the K2TiF6:Mn4+ crystal to create covalent fluoride solid solutions, namely, K2Ti1-xSixF6:Mn4+ and K2Ti1-yGeyF6:Mn4+, through crystal reconstruction. The findings reveal that the incorporation of Si4+ leads to increased particle size, enhanced luminescence intensity (by 40%), and improved moisture resistance. Furthermore, after undergoing 1000 h of aging at high temperature and high humidity conditions, the white LED featuring the K2Ti0.97Si0.03F6:Mn4+ phosphor demonstrates remarkable durability by retaining 90% of its initial luminous efficacy. This performance surpasses that of the device utilizing the K2TiF6:Mn4+ phosphor, which only retains 74% of its original efficacy. The crystal reconstruction method and covalent enhancement strategy proposed in this work contribute to enhancing the luminescence efficiency and moisture resistance of fluoride phosphors, thereby offering new insights for advancing the development of high-efficiency and highly stable white light LED devices.

Long-Distance Transport of Puccinia striiformis f. sp. tritici by Upper Airflow on the Yunnan-Guizhou Plateau Disrupts the Balance of Agricultural Ecology in Central China.

Long-distance dispersal of plant pathogens in the air can establish diseases in other areas and lead to an increased risk of large-scale epidemics. Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is one of the most destructive diseases of wheat in China. Hubei is an important overwintering region for Pst in China, and this overwintering region is a determinant of stripe rust severity in eastern China. In 2017, stripe rust disease caused a pandemic in the Hubei region and resulted in great yield losses of wheat. To explain the disease pandemic, a total of 595 single-lesion samples of stripe rust were collected in spring, including 204 in five provinces in 2017 and 391 in four provinces in 2018, and genotyped with 13 simple sequence repeat makers. The samples were classified into 12 subpopulations based on the locations and year of collection. Genetic diversity was determined for the collection and each subpopulation. Differentiation and gene flow were determined between subpopulations. STRUCTURE analyses and discriminant analysis of principal components were conducted, and the results were used to infer the relationships between subpopulations. Our study revealed a new route of Pst transmission from the Yunnan-Guizhou Plateau to the Hubei region. The Pst inoculum of northwestern Hubei came from Gansu in the northwest, whereas the inoculum in southern Hubei came from the Yunnan-Guizhou Plateau via upper airflow. After the initial inocula infected wheat plants and multiplied in northern and southern Hubei, urediniospores produced in these regions further spread together along the middle reach of Hanshui Valley and made exchanges there. The finding of the new transmission route of Pst is important for improving integrated stripe rust disease management, which should have a profound impact on the balance of agricultural ecology in China.

A Comprehensive Non-targeted Analysis Study of the Prenatal Exposome.

Recent technological advances in mass spectrometry have enabled us to screen biological samples for a very broad spectrum of chemical compounds allowing us to more comprehensively characterize the human exposome in critical periods of development. The goal of this study was three-fold: (1) to analyze 590 matched maternal and cord blood samples (total 295 pairs) using non-targeted analysis (NTA); (2) to examine the differences in chemical abundance between maternal and cord blood samples; and (3) to examine the associations between exogenous chemicals and endogenous metabolites. We analyzed all samples with high-resolution mass spectrometry using liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF/MS) in both positive and negative electrospray ionization modes (ESI+ and ESI-) and in soft ionization (MS) and fragmentation (MS/MS) modes for prioritized features. We confirmed 19 unique compounds with analytical standards, we tentatively identified 73 compounds with MS/MS spectra matching, and we annotated 98 compounds using an annotation algorithm. We observed 103 significant associations in maternal and 128 in cord samples between compounds annotated as endogenous and compounds annotated as exogenous. An example of these relationships was an association between three poly and perfluoroalkyl substances (PFASs) and endogenous fatty acids in both the maternal and cord samples indicating potential interactions between PFASs and fatty acid regulating proteins.

Suspect Screening, Prioritization, and Confirmation of Environmental Chemicals in Maternal-Newborn Pairs from San Francisco.

Our proof-of-concept study develops a suspect screening workflow to identify and prioritize potentially ubiquitous chemical exposures in matched maternal/cord blood samples, a critical period of development for future health risks. We applied liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (LC-QTOF/MS) to perform suspect screening for ∼3500 industrial chemicals on pilot data from 30 paired maternal and cord serum samples (n = 60). We matched 662 suspect features in positive ionization mode and 788 in negative ionization mode (557 unique formulas overall) to compounds in our database, and selected 208 of these for fragmentation analysis based on detection frequency, correlation in feature intensity between maternal and cord samples, and peak area differences by demographic characteristics. We tentatively identified 73 suspects through fragmentation spectra matching and confirmed 17 chemical features (15 unique compounds) using analytical standards. We tentatively identified 55 compounds not previously reported in the literature, the majority which have limited to no information about their sources or uses. Examples include (i) 1-(1-acetyl-2,2,6,6-tetramethylpiperidin-4-yl)-3-dodecylpyrrolidine-2,5-dione (known high production volume chemical) (ii) methyl perfluoroundecanoate and 2-perfluorooctyl ethanoic acid (two PFAS compounds); and (iii) Sumilizer GA 80 (plasticizer). Thus, our workflow demonstrates an approach to evaluating the chemical exposome to identify and prioritize chemical exposures during a critical period of development.

Modified cobalt-manganese oxide-coated carbon felt anodes: an available method to improve the performance of microbial fuel cells.

The novel MnCo2O4 (MCO/CF), CNTs-MnCo2O4 (CNTs-MCO/CF) and MnFe2O4-MnCo2O4 (MFO-MCO/CF) electrodes were prepared on carbon felt (CF) by simple hydrothermal and coating method as anodes for MFC. The modified anodes combine the electrocatalytic properties of transition metal oxides (TMOs), the high electrical conductivity of CNTs and the good biocompatibility of CF. These anodes play a synergistically role in the synthesis of structural, to realize high-efficiency electron transfer, low resistance and sufficient space for microbial colonization, while also ensuring high power density. The maximum power density of the composite electrodes CNTs-MCO/CF and MFO-MCO/CF were 4268 mW/m3 and 3660 mW/m3, respectively. The synergistic effect of multi-component effectively improves the performance of MFC. This work not only offers a good design and preparation concept for functional TMOs composite electrodes, but also provides an important guide for the fabrication of CNTs-doped MFC anodes.

Integrating Exposure Knowledge and Serum Suspect Screening as a New Approach to Biomonitoring: An Application in Firefighters and Office Workers.

Firefighters (FF) are exposed to recognized and probable carcinogens, yet there are few studies of chemical exposures and associated health concerns in women FFs, such as breast cancer. Biomonitoring often requires a priori selection of compounds to be measured, and so, it may not detect relevant, lesser known, exposures. The Women FFs Biomonitoring Collaborative (WFBC) created a biological sample archive and conducted a general suspect screen (GSS) to address this data gap. Using liquid chromatography-quadrupole time-of-flight tandem mass spectrometry, we sought to identify candidate chemicals of interest in serum samples from 83 women FFs and 79 women office workers (OW) in San Francisco. We identified chemical peaks by matching accurate mass from serum samples against a custom chemical database of 722 slightly polar phenolic and acidic compounds, including many of relevance to firefighting or breast cancer etiology. We then selected tentatively identified chemicals for confirmation based on the following criteria: (1) detection frequency or peak area differences between OW and FF; (2) evidence of mammary carcinogenicity, estrogenicity, or genotoxicity; and (3) not currently measured in large biomonitoring studies. We detected 620 chemicals that matched 300 molecular formulas in the WFBC database, including phthalate metabolites, phosphate flame-retardant metabolites, phenols, pesticides, nitro and nitroso compounds, and per- and polyfluoroalkyl substances. Of the 20 suspect chemicals selected for validation, 8 were confirmed-including two alkylphenols, ethyl paraben, BPF, PFOSAA, benzophenone-3, benzyl p-hydroxybenzoate, and triphenyl phosphate-by running a matrix spike of the reference standards and using m/z, retention time, and the confirmation of at least two fragment ions as criteria for matching. GSS provides a powerful high-throughput approach to identify and prioritize novel chemicals for biomonitoring and health studies.

Mediating roles of preterm birth and restricted fetal growth in the relationship between maternal education and infant mortality: A Danish population-based cohort study.

BACKGROUND: Socioeconomic disparities in infant mortality have persisted for decades in high-income countries and may have become stronger in some populations. Therefore, new understandings of the mechanisms that underlie socioeconomic differences in infant deaths are essential for creating and implementing health initiatives to reduce these deaths. We aimed to explore whether and the extent to which preterm birth (PTB) and small for gestational age (SGA) at birth mediate the association between maternal education and infant mortality. METHODS AND FINDINGS: We developed a population-based cohort study to include all 1,994,618 live singletons born in Denmark in 1981-2015. Infants were followed from birth until death, emigration, or the day before the first birthday, whichever came first. Maternal education at childbirth was categorized as low, medium, or high. An inverse probability weighting of marginal structural models was used to estimate the controlled direct effect (CDE) of maternal education on offspring infant mortality, further split into neonatal (0-27 days) and postneonatal (28-364 days) deaths, and portion eliminated (PE) by eliminating mediation by PTB and SGA. The proportion eliminated by eliminating mediation by PTB and SGA was reported if the mortality rate ratios (MRRs) of CDE and PE were in the same direction. The MRRs between maternal education and infant mortality were 1.63 (95% CI 1.48-1.80, P < 0.001) and 1.19 (95% CI 1.08-1.31, P < 0.001) for low and medium versus high education, respectively. The estimated proportions of these total associations eliminated by reducing PTB and SGA together were 55% (MRRPE = 1.27, 95% CI 1.15-1.40, P < 0.001) for low and 60% (MRRPE = 1.11, 95% CI 1.01-1.22, P = 0.037) for medium versus high education. The proportions eliminated by eliminating PTB and SGA separately were, respectively, 46% and 11% for low education (versus high education) and 48% and 13% for medium education (versus high education). PTB and SGA together contributed more to the association of maternal educational disparities with neonatal mortality (proportion eliminated: 75%-81%) than with postneonatal mortality (proportion eliminated: 21%-23%). Limitations of the study include the untestable assumption of no unmeasured confounders for the causal mediation analysis, and the limited generalizability of the findings to other countries with varying disparities in access and quality of perinatal healthcare. CONCLUSIONS: PTB and SGA may play substantial roles in the relationship between low maternal education and infant mortality, especially for neonatal mortality. The mediating role of PTB appeared to be much stronger than that of SGA. Public health strategies aimed at reducing neonatal mortality in high-income countries may need to address socially related prenatal risk factors of PTB and impaired fetal growth. The substantial association of maternal education with postneonatal mortality not accounted for by PTB or SGA could reflect unaddressed educational disparities in infant care or other factors.

G-computation of average treatment effects on the treated and the untreated.

BACKGROUND: Average treatment effects on the treated (ATT) and the untreated (ATU) are useful when there is interest in: the evaluation of the effects of treatments or interventions on those who received them, the presence of treatment heterogeneity, or the projection of potential outcomes in a target (sub-) population. In this paper we illustrate the steps for estimating ATT and ATU using g-computation implemented via Monte Carlo simulation. METHODS: To obtain marginal effect estimates for ATT and ATU we used a three-step approach: fitting a model for the outcome, generating potential outcome variables for ATT and ATU separately, and regressing each potential outcome variable on treatment intervention. RESULTS: The estimates for ATT, ATU and average treatment effect (ATE) were of similar magnitude, with ATE being in between ATT and ATU as expected. In our illustrative example, the effect (risk difference [RD]) of a higher education on angina among the participants who indeed have at least a high school education (ATT) was -0.019 (95% CI: -0.040, -0.007) and that among those who have less than a high school education in India (ATU) was -0.012 (95% CI: -0.036, 0.010). CONCLUSIONS: The g-computation algorithm is a powerful way of estimating standardized estimates like the ATT and ATU. Its use should be encouraged in modern epidemiologic teaching and practice.

Shift work and 20-year incidence of acute myocardial infarction: results from the Kuopio Ischemic Heart Disease Risk Factor Study.

OBJECTIVES: It remains unclear whether different types of shift work impose similar risks for cardiovascular events in middle-aged workers, especially those with pre-existing ischaemic heart disease (IHD). This study investigated the relations between different shift types and incident acute myocardial infarction (AMI) among men with and without pre-existing IHD, respectively. METHODS: We analysed data on 1891 men, aged 42-60 years at baseline, in the prospective Kuopio Ischemic Heart Disease Risk Factor Study cohort, using Cox proportional hazard models with adjustment for demographic, biological, behavioural and psychosocial job factors. We evaluated the associations of baseline shift work with 20-year incidence of AMI, and their modification by pre-existing IHD, using both stratified analysis and models with product terms between shift work and IHD. RESULTS: Travelling work (at least 3 nights per week away from home) was strongly positively associated with AMI among men with IHD (HR=2.45, 95% CI 1. 08 to 5.59) but not among men without (HR=0.93, 95% CI 0.43 to 2.00). No clear associations were found between other types of shift work and AMI for both men with and without IHD. On both additive and multiplicative scales, baseline IHD status positively modified the association of travelling work with AMI (relative excess risk for interaction=3.23, 95% CI -0.50 to 6.97, p for multiplicative interaction=0.044). CONCLUSIONS: We found mixed results for the associations between different types of shift work and AMI among those with and without pre-existing IHD. Future research should investigate these associations and effect modification for a broad spectrum of work schedules.

G-computation demonstration in causal mediation analysis.

Recent work has considerably advanced the definition, identification and estimation of controlled direct, and natural direct and indirect effects in causal mediation analysis. Despite the various estimation methods and statistical routines being developed, a unified approach for effect estimation under different effect decomposition scenarios is still needed for epidemiologic research. G-computation offers such unification and has been used for total effect and joint controlled direct effect estimation settings, involving different types of exposure and outcome variables. In this study, we demonstrate the utility of parametric g-computation in estimating various components of the total effect, including (1) natural direct and indirect effects, (2) standard and stochastic controlled direct effects, and (3) reference and mediated interaction effects, using Monte Carlo simulations in standard statistical software. For each study subject, we estimated their nested potential outcomes corresponding to the (mediated) effects of an intervention on the exposure wherein the mediator was allowed to attain the value it would have under a possible counterfactual exposure intervention, under a pre-specified distribution of the mediator independent of any causes, or under a fixed controlled value. A final regression of the potential outcome on the exposure intervention variable was used to compute point estimates and bootstrap was used to obtain confidence intervals. Through contrasting different potential outcomes, this analytical framework provides an intuitive way of estimating effects under the recently introduced 3- and 4-way effect decomposition. This framework can be extended to complex multivariable and longitudinal mediation settings.

Work schedules and 11-year progression of carotid atherosclerosis in middle-aged Finnish men.

OBJECTIVES: This study investigated the relationship between different work schedules and progression of carotid atherosclerosis, an early indicator of cardiovascular disease (CVD). METHODS: We studied 621 men, aged 42-60 years, in the prospective Kuopio Ischemic Heart Disease Risk Factor Study cohort. Using multivariable regressions adjusting for 22 covariates including total time worked during follow-up, we evaluated the associations of baseline work schedules with 11-year progression of ultrasonographically assessed carotid intima-media thickness (IMT), and their variation by preexisting CVD. RESULTS: Standard daytime work, weekend shifts, and evening/night/rotating shifts were associated with 31%, 37%, and 33% increases in IMT, respectively. Compared to daytime workers, weekend workers experienced a faster progression of carotid atherosclerosis [relative change ratio (RCR) = 1.05, 95% CI: 1.00-1.09)]. This ratio was higher among men who had preexisting CVD. CONCLUSIONS: Weekend shifts, more than standard daytime work, appear to accelerate carotid atherosclerosis progression among middle-aged Finnish men, especially those with pre-existing CVD.

Body Mass Index and Poor Self-Rated Health in 49 Low-Income and Middle-Income Countries, By Sex, 2002-2004.

This study investigated whether the relationship between body mass index (BMI) and poor self-rated health differed by sex in low-income countries and middle-income countries. We analyzed data from the World Health Survey (2002-2004) on 160,099 participants from 49 low-income and middle-income countries by using random-intercept multilevel logistic regressions. We found a U-shaped relationship between BMI and poor self-rated health among both sexes in both low-income and middle-income countries, but the relationship differed by sex in strength and direction between low-income countries and middle-income countries. Differential perception of body weight and general health might explain some of the observed sex differences.

Involvement of patients or their representatives in quality management functions in EU hospitals: implementation and impact on patient-centred care strategies.

OBJECTIVE: The objective of this study was to describe the involvement of patients or their representatives in quality management (QM) functions and to assess associations between levels of involvement and the implementation of patient-centred care strategies. DESIGN: A cross-sectional, multilevel STUDY DESIGN: that surveyed quality managers and department heads and data from an organizational audit. SETTING: Randomly selected hospitals (n = 74) from seven European countries (The Czech Republic, France, Germany, Poland, Portugal, Spain and Turkey). PARTICIPANTS: Hospital quality managers (n = 74) and heads of clinical departments (n = 262) in charge of four patient pathways (acute myocardial infarction, stroke, hip fracture and deliveries) participated in the data collection between May 2011 and February 2012. MAIN OUTCOME MEASURES: Four items reflecting essential patient-centred care strategies based on an on-site hospital visit: (1) formal survey seeking views of patients and carers, (2) written policies on patients' rights, (3) patient information literature including guidelines and (4) fact sheets for post-discharge care. The main predictors were patient involvement in QM at the (i) hospital level and (ii) pathway level. RESULTS: Current levels of involving patients and their representatives in QM functions in European hospitals are low at hospital level (mean score 1.6 on a scale of 0 to 5, SD 0.7), but even lower at departmental level (mean 0.6, SD 0.7). We did not detect associations between levels of involving patients and their representatives in QM functions and the implementation of patient-centred care strategies; however, the smallest hospitals were more likely to have implemented patient-centred care strategies. CONCLUSIONS: There is insufficient evidence that involving patients and their representatives in QM leads to establishing or implementing strategies and procedures that facilitate patient-centred care; however, lack of evidence should not be interpreted as evidence of no effect.

The effect of certification and accreditation on quality management in 4 clinical services in 73 European hospitals.

OBJECTIVE: To investigate the relationship between ISO 9001 certification, healthcare accreditation and quality management in European hospitals. DESIGN: A mixed method multi-level cross-sectional design in seven countries. External teams assessed clinical services on the use of quality management systems, illustrated by four clinical pathways. SETTING AND PARTICIPANTS: Seventy-three acute care hospitals with a total of 291 services managing acute myocardial infarction (AMI), hip fracture, stroke and obstetric deliveries, in Czech Republic, France, Germany, Poland, Portugal, Spain and Turkey. MAIN OUTCOME MEASURE: Four composite measures of quality and safety [specialized expertise and responsibility (SER), evidence-based organization of pathways (EBOP), patient safety strategies (PSS) and clinical review (CR)] applied to four pathways. RESULTS: Accreditation in isolation showed benefits in AMI and stroke more than in deliveries and hip fracture; the greatest significant association was with CR in stroke. Certification in isolation showed little benefit in AMI but had more positive association with the other conditions; greatest significant association was in PSS with stroke. The combination of accreditation and certification showed least benefit in EBOP, but significant benefits in SER (AMI), in PSS (AMI, hip fracture and stroke) and in CR (AMI and stroke). CONCLUSIONS: Accreditation and certification are positively associated with clinical leadership, systems for patient safety and clinical review, but not with clinical practice. Both systems promote structures and processes, which support patient safety and clinical organization but have limited effect on the delivery of evidence-based patient care. Further analysis of DUQuE data will explore the association of certification and accreditation with clinical outcomes.

Elimination of surface defects in luminescent crystals through solid-liquid interface friction.

In this work, we report a simple yet robust strategy for eliminating surface defects in red-emitting fluorides through solid-liquid interface friction under elevated temperature and high pressure. This method is minimally dependent on the solvent type and especially excels at stripping away the abundant surface defects caused by mechanical crushing.

Delayed treatment initiation of oral anticoagulants among Medicare patients with atrial fibrillation.

Study objective: This study aimed to identify factors associated with delayed oral anticoagulant (OAC) treatment initiation among atrial fibrillation (AF) patients in United States (US) clinical practice. Participants: Medicare beneficiaries newly diagnosed with AF without moderate-to-severe mitral stenosis or a mechanical heart valve, were aged ≥65 years and prescribed OAC on or after 10/1/2015 through 2019 were included. Delayed and early OAC initiation were defined as >3 months and 0-3 months initiation from first AF diagnosis, respectively. Main outcome measures: Association between delayed OAC initiation and patient demographics, clinical and index OAC coverage and formulary characteristics was examined using multivariable logistic regression. Results: A total of 446,441 patients met the inclusion criteria; 30.0 % (N = 131,969) were identified as delayed and 70.0 % (N = 314,472) as early OAC initiation. Median age for both cohorts was 78 years. In the early and delayed OAC cohorts, 47.1 % and 47.6 % were male and 88.8 % and 86.6 %, were White, respectively. Factors associated with delayed OAC initiation (odds ratio; 95 % confidence interval) included Black race (1.29; 1.25 to 1.33), west region (1.29; 1.26 to 1.32), comorbidities such as dementia (1.27; 1.23 to 1.30), recent bleeding hospitalization (1.22; 1.18 to 1.27), prior authorization (1.69; 1.66 to 1.71), tier 4 formulary for index OAC at AF diagnosis (1.26; 1.22 to 1.30). Conclusion: Our study revealed that nearly one-third of Medicare patients with AF experienced delayed OAC initiation. Key patient characteristics found to be associated with delayed OAC initiation included race and ethnicity, comorbidities, and formulary restrictions.

Safety and efficacy of restarting immune checkpoint inhibitors in non-small cell lung cancer patients following immune-related adverse events: a systematic review and meta-analysis.

OBJECTIVE: This meta-analysis aims to evaluate the safety and efficacy of restarting immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC) after experiencing immune-related adverse events (irAEs). METHODS: A comprehensive search of PubMed, Web of Science, Embase, and the Cochrane Library was conducted to identify studies investigating the safety and efficacy of restarting ICIs in NSCLC patients after irAEs. Outcome measures, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) after ICI restarting, were extracted. Meta-analysis was performed using the R meta-package. RESULTS: Four studies involving a total of 326 subjects were included, comprising 137 patients who restarted ICI treatment after irAEs and 189 patients who did not restart ICI treatment. The results revealed that ICI restarting was associated with an increased ORR (OR = 2.36, 95% CI 1.49-3.84), prolonged PFS (HR = 0.60, 95% CI 0.42-0.86), and prolonged OS (HR = 0.65, 95% CI 0.43-0.99) compared to non-restarting. The incidence of irAEs after ICI restarting was 45% (95% CI 0.27-0.63). CONCLUSION: Restarting ICI treatment after discontinuation due to previous irAEs appears to be a reasonable option for NSCLC patients. However, a comprehensive assessment of the potential benefits and risks to individual patients is crucial, and close monitoring of irAEs is warranted.

Fusarium pseudograminearum biomass and toxin accumulation in wheat tissues with and without Fusarium crown rot symptoms.

Fusarium crown rot (FCR) is an important and devastating disease of wheat (Triticum aestivum) caused by the fungus Fusarium pseudograminearum and related pathogens. Using two distinct susceptible cultivars, we investigated the isolation frequencies of F. pseudograminearum and quantified its biomass accumulation and the levels of the associated toxins deoxynivalenol (DON) and DON-3-glucoside (D3G) in inoculated field-grown wheat plants. We detected F. pseudograminearum in stem, peduncle, rachis, and husk tissues, but not in grains, whereas DON and D3G accumulated in stem, rachis, husk, and grain tissues. Disease severity was positively correlated with the frequency of pathogen isolation, F. pseudograminearum biomass, and mycotoxin levels. The amount of F. pseudograminearum biomass and mycotoxin contents in asymptomatic tissue of diseased plants were associated with the distance of the tissue from the diseased internode and the disease severity of the plant. Thus, apparently healthy tissue may harbor F. pseudograminearum and contain associated mycotoxins. This research helps clarify the relationship between F. pseudograminearum occurrence, F. pseudograminearum biomass, and mycotoxin accumulation in tissues of susceptible wheat cultivars with or without disease symptoms, providing information that can lead to more effective control measures.