Long Intervals between Intravitreal Injections Using a Treat-and-Extend Protocol in a Real-Life Context in AMD: The LIRE Study.

INTRODUCTION: The aim of the study was to assess the outcome of long treat-and-extend (TE) anti-VEGF intravitreal injection (IVI) intervals (≥every 12 weeks [Q12W]) in neovascular age-related macular degeneration (nAMD). The aims of this retrospective study were to determine the proportion of nAMD eyes treated ≥ Q12W, to analyze their longitudinal, functional, and anatomical outcomes, and to compare functional and anatomical outcomes between eyes that rapidly versus slowly reached a Q12W regimen and between eyes directly treated with versus initiating lately the TE regimen. METHODS: All patients receiving IVIs for nAMD were screened. The longitudinal, functional, and anatomical characteristics of Q12W-treated eyes were reported at different timepoints. RESULTS: Ninety-one eyes were included (38% of our total nAMD cohort). The mean TE regimen time to reach a Q12W interval was 20.1 ± 16.2 months. During this time, a mean number of 12.1 ± 9.3 IVIs were needed. The mean best-corrected visual acuity was 68 letters at the time of diagnosis and was maintained (p > 0.05). Eyes that rapidly reached a Q12W interval had a shorter follow-up before TE regimen initiation (p = 0.04) and received fewer IVIs (p = 0.02) than eyes that slowly reached a Q12W interval. Eyes directly treated with the TE regimen reached a Q12W interval more rapidly than eyes with late TE initiation. The neovascularization subtype was not a predictor of outcome in TE-treated eyes. CONCLUSION: ≥Q12W eyes represent an important part of the nAMD population in our real-life study. No baseline anatomical characteristics were associated with the outcome under a TE regimen, although early TE regimen initiation allowed extending more rapidly the IVI interval.

Prevalence of mental disorders in closed educational centers in France.

INTRODUCTION: Closed educational centres (CEC) receive young offenders who most often have a conduct disorder (CD). Mental disorders other than conduct disorder are a negative factor in the effect of educational actions. Moreover, adverse life experiences are frequent vulnerability factors in this population. This article aims to document the prevalence and links between psychiatric disorders, exposure to trauma, and the psycho-behavioural characteristics of adolescents placed in CEC. METHOD: We conducted a multicentre epidemiological study on a sample of 101 adolescents placed in nine closed educational centres in France. Psychiatric disorders were measured by the MINI-KID 2 and Conners Rating Scale questionnaires. Several questionnaires were used to collect sociodemographic data and the psychological profile of each adolescent. RESULTS: Among the adolescents, 90.2% had at least one mental disorder with a predominance of conduct disorder (80%). Comorbidity was also frequently found: among the subjects with conduct disorder, 37% had at least one other psychiatric disorder. Interestingly, the intensity of conduct disorder and the Adverse Childhood Experiences (ACE) score were significantly correlated. Furthermore, two subgroups were identified: adolescents with isolated conduct disorder (44.6%) and adolescents with other psychiatric disorders (45.7%) with or without conduct disorder. The latter subgroup showed higher vulnerability and poorer outcomes in terms of attachment patterns, feelings of abandonment, hostility and impulsivity. CONCLUSION: This study is the first French epidemiological study of mental disorders in juvenile offenders. It suggests that the detection of psychiatric disorders in young people in CEC is an important prerequisite for the implementation of targeted interventions according to different profiles. Furthermore, collaboration between the medical-psychological and judicial fields, in the form of an operational partnership, is necessary to guarantee better support for these young people.

Large-scale study validates that regional fungicide applications are major determinants of resistance evolution in the wheat pathogen Zymoseptoria tritici in France.

In modern cropping systems, the near-universal use of plant protection products selects for resistance in pest populations. The emergence and evolution of this adaptive trait threaten treatment efficacy. We identified determinants of fungicide resistance evolution and quantified their effects at a large spatiotemporal scale. We focused on Zymoseptoria tritici, which causes leaf blotch in wheat. Phenotypes of qualitative or quantitative resistance to various fungicides were monitored annually, from 2004 to 2017, at about 70 sites throughout 22 regions of France (territorial units of 25 000 km2 on average). We modelled changes in resistance frequency with regional anti-Septoria fungicide use, yield losses due to the disease and the regional area under organic wheat. The major driver of resistance dynamics was fungicide use at the regional scale. We estimated its effect on the increase in resistance and relative apparent fitness of each resistance phenotype. The predictions of the model replicated the spatiotemporal patterns of resistance observed in field populations (R2 from 0.56 to 0.82). The evolution of fungicide resistance is mainly determined at the regional scale. This study therefore showed that collective management at the regional scale could effectively complete local actions.

Lack of admission biomarkers' clinical utility in outcomes prediction in patients suspected with infection in the emergency department.

INTRODUCTION: Initial procalcitonin (PCT) levels may fail in mortality and septic shock prediction and raise cost-effectiveness issues. Since measurement of lactate, C-reactive protein (CRP), white blood cells and neutrophils is common in the emergency department (ED), we compared prediction abilities of these biomarkers to PCT. METHODS: From January 1st to December 31st, 2018, an observational, single center, retrospective study was conducted in the adult ED of the Reims University Hospital (France). Endpoints were bacteremia, septic shock, and in-hospital mortality, related to the same ED visit. RESULTS: Over one year, 459 patients suspected with infection were included, of mean age 60.4 years (SD: 22.0), with 50.8% male, and 364 (79.3%) were hospitalized following ED visit. Overall, 45 (9.8%) patients had a bacteremia, 39 (8.5%) a septic shock and 54 (11.8%) died during their hospitalization. PCT and CRP showed the best discrimination for bacteremia, with an area under curve (AUC) of 0.68 for PCT and 0.65 for CRP. PCT and lactate showed similar good discriminative power for septic shock, with an AUC of 0.78 for both, and poor discrimination for in-hospital mortality, with an AUC of 0.62 for PCT and 0.69 for lactate. Systolic blood pressure and pulse oximetry showed similar discrimination for septic shock as PCT or lactate, while they showed higher discrimination for in-hospital mortality than PCT. CONCLUSION: Usual admission biomarkers lack clinical utility in predicting septic shock or in-hospital mortality. CRP and PCT are poorly efficient in predicting bacteremia.

EMERGEncy versus delayed coronary angiogram in survivors of out-of-hospital cardiac arrest with no obvious non-cardiac cause of arrest: Design of the EMERGE trial.

BACKGROUND: In adults, the most common cause of out-of-hospital cardiac arrests (OHCA) is acute coronary artery occlusion. If an immediate coronary angiogram (CAG) is recommended for survivors presenting a ST segment elevation on the electrocardiogram (ECG) performed after resuscitation, there is still a debate regarding the best strategy in patients without ST segment elevation. HYPOTHESIS: Performing an immediate CAG after an OHCA without ST segment elevation on the post-resuscitation ECG and no obvious non-cardiac cause of arrest could lead to a better 180-day survival rate with no or minimal neurological sequel as compared with a delayed CAG performed 48 to 96 hours after the arrest. DESIGN: The EMERGE trial is a prospective national, randomized, open and parallel group trial, in which 970 survivors of OHCA will be randomized (1:1) to either immediate (as soon as possible after return of spontaneous circulation) or delayed (48 to 96 h) CAG. Participants will be OHCA patients with no ST segment elevation on the post resuscitation ECG and no obvious non-cardiac cause of arrest. The primary endpoint of the study is the 180-day survival rate with no or minimal neurological sequel corresponding to Cerebral Performance Category (CPC) 1 or 2. The secondary endpoints are: occurrence of shock during the first 48 hours, ventricular tachycardia and/or fibrillation during the first 48 hours, change in left ventricular ejection fraction between baseline and 180 days assessed by echocardiogram, neurological status evaluated by the CPC score at intensive care unit (ICU) discharge and day 90 neurological status assessed by the Glasgow Outcome Scale Extended score (GOSE) at 90 and 180 days, overall survival rate, and hospital length of stay. SUMMARY: The EMERGE trial is a prospective, multicenter, randomized, controlled trial that will assess the 180-day survival rate with no or minimal neurologic sequel in patients resuscitated from an OHCA without ST segment elevation and who will be managed with either immediate or delayed CAG.

Transcutaneous tibial nerve stimulation: 2 years follow-up outcomes in the management of anticholinergic refractory overactive bladder.

PURPOSE: To evaluate long-term use, efficacy and tolerability of transcutaneous tibial nerve stimulation (TTNS) in the treatment of refractory overactive bladder (OAB). METHODS: We performed a prospective observational study and included all patients treated in a single center for OAB persisting after first-line anticholinergic treatment, with ≥ 24 months follow-up. The protocol consisted of daily stimulation at home. The primary outcome was treatment persistence. Amelioration was defined as an improvement in urinary symptom profile (USP) score. RESULTS: We assessed 84 consecutive patients. After a mean follow-up of 39.3 months and a mean treatment use of 8.3 months, almost two-thirds of patients (71.8%) had discontinued TTNS. Treatment continuation was > 12 months for 28 patients (33.3%) and > 18 months for 16 patients (19%). TTNS was successful following 3 months of treatment in 60 (71%) patients. Mean USP score stayed significantly lower than baseline until 12 months of treatment, but was not significant anymore after 18 months. Discontinuation therapy reasons were a lack of sufficient symptom relief for 59 (70%) patients, compliance difficulty for 5 (6%) patients and becoming asymptomatic for 6 (8%) patients. No serious adverse events occurred. CONCLUSIONS: The present study confirms the utility of TTNS as a treatment option for patients with resistant OAB. In the long-term use, few patients continued with therapy, mostly because of a decreased effectiveness with time.

Vascular Targeted Photodynamic Therapy with Padeliporfin for Low Risk Prostate Cancer Treatment: Midterm Oncologic Outcomes.

PURPOSE: We assessed the midterm oncologic outcomes of vascular targeted photodynamic therapy with padeliporfin for low risk prostate cancer treatment. MATERIALS AND METHODS: We prospectively assessed all patients treated with vascular targeted photodynamic therapy for low risk prostate cancer at our center. Patients were followed every 6 months. All patients underwent prostate biopsies 6 months after treatment or when there was biological or clinical progression. The primary end point was progression-free survival. Secondary end points were absent clinically significant cancer in the treated lobes, radical therapy and the prostate specific antigen rate. Variables were compared with the chi-square, Mann-Whitney or Wilcoxon test. Progression-free survival is reported with Kaplan-Meier curves. RESULTS: A total of 82 men were treated with vascular targeted photodynamic therapy. Median followup was 68 months (range 6 to 89). Median progression-free survival was 86 months (95% CI 82-90). Median prostate specific antigen decreased significantly by 41% 6 months after treatment and it remained stable during followup (p <0.001). A total of 115 lobes were treated and absent clinically significant cancer was achieved in 94 (82%). Of the 82 patients 20 (24%) underwent radical therapy, including radical prostatectomy in 18 and brachytherapy in 2, at a median of 22 months (range 6 to 86). Study limitations include a single arm design, small population size and midterm followup. CONCLUSIONS: Padeliporfin vascular targeted photodynamic therapy for low risk prostate cancer achieved an 82% rate of absent clinically significant cancer in treated lobes and 76% of patients avoided radical therapy at a median followup of 68 months. However, longer followup is required to determine long-term outcomes.

Factors associated with tracheal intubation-related complications in the prehospital setting: a prospective multicentric cohort study.

Background Emergency tracheal intubation is routinely performed in the prehospital setting. Airway management in the prehospital setting has substantial challenges. Objective The aim of the present study was to determine risk factors predicting tracheal intubation-related complications on the prehospital field. Setting A prospective, multicentric, cohort study which was conducted in three mobile ICUs (MICUs; service mobile d'urgence et de réanimation).Outcome measures and analysis Tracheal intubation-related complications were defined as the occurrence of at least one of the following events: oxygen desaturation (SpO2 < 90%) during tracheal intubation, aspiration (regurgitation visualized during laryngoscopy), and vomiting. Difficult intubation was defined as more than two failed direct laryngoscopic attempts, or the need for any alternative tracheal intubation method. Multivariate logistic regressions were used. Results During the 5-year study period, 1915 consecutive patients were intubated in the MICUs participating in the study. Overall, 1287 (70%) patients were successfully intubated after the first laryngoscopic attempt, with rates of 90, 74, 42, and 30% for Cormack-Lehane grade 1, 2, 3, and 4, respectively. Tracheal intubation was difficult in 663 cases (36%). Tracheal intubation-related complications occurred in 267 (14%) patients. In the multivariate analysis, we found that the leading risk factors for tracheal intubation-related complications were Cormack and Lehane grade 3 and 4 [odds ratio (OR) = 1.65; 95% confidence interval (CI), 1.05-2.61; and OR = 2.79; 95% CI, 1.56-4.98, respectively], a BMI of more than 30 (OR = 1.61; 95% CI, 1.13-2.28), when intubation was difficult (OR = 1.72; 95% CI, 1.15-2.57), and when tracheal intubation required more than one operator (OR = 2.30; 95% CI, 1.50-3.49).Conclusions In this prospective study, we found that Cormack and Lehane more than grade 2, BMI >30, difficult intubation, and tracheal intubation requiring more than one operator were all independent predictors of tracheal intubation-related complications in the prehospital setting. When these risk factors are identified on scene, adapted algorithms that anticipate the use of a bougie should be generalized to reduce morbidity on the prehospital field.

Association between Hpa Axis Functioning and Mental Health in Maltreated Children and Adolescents: A Systematic Literature Review.

BACKGROUND: Previous studies have demonstrated that children who experience maltreatment show a more elevated risk of psychopathological disorders than children from the general population. The HPA (hypothalamic-pituitary-adrenal) axis is not mature at birth and undergoes strong social regulation during the first years of life. Consequently, early exposure to stress could modify the usual adaptative response to stress. In stressful situations, perturbations in both cortisol response and cortisol circadian rhythm have been observed. Nevertheless, studies that have evaluated the links between child abuse, dysregulation of the HPA axis, and mental disorders have shown diverse results. Because of the variety of methods employed in the different studies, no formal comparisons have been made. In this systematic review, we have brought together these results. METHODS: We conducted a systematic review of studies analyzing the correlation between child abuse, mental disorders, and HPA axis activity in patients aged between 6 and 16 years. PubMed, Scopus, Cochrane, and Google Scholar were searched using relevant keywords and inclusion/exclusion criteria (from 2000 to 2020). RESULTS: Fifteen studies from the 351 identified were included. Most patients were children in the child welfare system. Children who had experienced child abuse presented with more severe mental disorders (particularly in the dimensional measure) than children who had not been abused. HPA axis activity was assessed by measuring basal cortisol for some studies and cortisol reactivity for other studies. For children experiencing child abuse, there was a possible association between abuse and a decrease in the reactivity of the HPA axis. In addition, early life stress could be associated with lower matinal cortisol. However, the association between mental disorders and cortisol secretion in maltreated children did not seem obvious. CONCLUSIONS: This systematic review demonstrates that mental disorders are more frequent and severe in cases where child abuse has occurred. Moreover, children who experienced child abuse seem to present changes in the reactivity of the HPA axis. Nevertheless, the potential correlation between these changes in the reactivity of the HPA axis and mental disorders in this population needs to be evaluated in further studies.

Association between admission biomarkers and clinical outcome in older adults diagnosed with an infection in the emergency department.

INTRODUCTION: In older adults, prognostic performances of admission biomarkers have been poorly investigated. This study aims to compare the prognostic abilities of usual admission biomarkers, especially PCT and CRP, for major clinical outcomes, comparing older to younger adults diagnosed with an infection in the ED, and to investigate the prognostic abilities of PCT and CRP depending on the glomerular filtration rate (GFR). METHODS: It was an observational, single-center, retrospective study, conducted in the Reims University Hospital, France. Endpoints were bacteremia, septic shock, and in-hospital mortality, related to the same ED visit. RESULTS: Over 1 year, 852 patients were included with 291 (34.2%) ≥75 years, and 127 (15.3%) patients had a GFR <30 mL.min-1.1.73 m2. Overall, 74 bacteremia, 56 septic shock and 82 in-hospital deaths have been observed. Prognostic abilities of admission biomarkers tended to be systematically lower in older compared to younger adults (PCT and CRP AUROC for bacteremia were, respectively, 0.71 and 0.62 in older adults vs 0.75 and 0.70 in younger adults; PCT and CRP AUROC for septic shock were, respectively, 0.71 and 0.66 in older adults vs 0.82 and 0.68 in younger adults). PCT showed a significant discriminating power for septic shock and in-hospital mortality only for GFR ≥ 30, and CRP showed a significant discriminating power for bacteremia and septic shock only for GFR ≥60. CONCLUSION: Caution must be taken when interpreting admission biomarkers, as their prognostic abilities are lower in older adults or in patients with renal insufficiency diagnosed with an infection.

Delayed hospitalisation for heart failure after transcatheter repair or medical treatment for secondary mitral regurgitation: a landmark analysis of the MITRA-FR trial.

BACKGROUND: In the MITRA-FR trial, transcatheter mitral valve repair (TMVR) was not associated with a 2-year clinical benefit in patients with secondary mitral regurgitation (SMR). AIMS: This landmark analysis aimed at investigating a potential reduction of the hospitalisation rate for heart failure (HF) between 12 and 24 months after inclusion in the MITRA-FR trial in patients randomised to the intervention group (TMVR with the MitraClip device), as compared with patients randomised to the control group (guideline-directed medical therapy [GDMT]). METHODS: The MITRA-FR trial randomised 307 patients with SMR for TMVR on top of GDMT (TMVR group; n=152) or for GDMT alone (control group; n=155). We conducted a 12-month landmark analysis in surviving patients who were not hospitalised for HF within the first 12 months of follow-up. The primary endpoint was the 1-year cumulative number of HF hospitalisations. RESULTS: A total of 140 patients (TMVR group: 67; GDMT group: 73) were selected for this landmark analysis with similar characteristics at inclusion in the trial. The primary endpoint was 28 events per 100 patient-years in the TMVR group, as compared with 60 events per 100 patient-years in the GDMT group (hazard ratio [HR] 0.46, 95% confidence interval [CI]: 0.20-1.02; p=0.057). CONCLUSIONS: In this landmark analysis of the MITRA-FR trial, the cumulative rate of HF hospitalisation between 12 and 24 months among patients treated with TMVR on top of GDMT was approximately half as many as those of patients treated with GDMT alone, a difference which did not reach statistical significance in the setting of a low number of events.

Emergency vs Delayed Coronary Angiogram in Survivors of Out-of-Hospital Cardiac Arrest: Results of the Randomized, Multicentric EMERGE Trial.

Importance: Although an emergency coronary angiogram (CAG) is recommended for patients who experience an out-of-hospital cardiac arrest (OHCA) with ST-segment elevation on the postresuscitation electrocardiogram (ECG), this strategy is still debated in patients without ST-segment elevation. Objective: To assess the 180-day survival rate with Cerebral Performance Category (CPC) 1 or 2 of patients who experience an OHCA without ST-segment elevation on ECG and undergo emergency CAG vs delayed CAG. Design, Setting, and Participants: The Emergency vs Delayed Coronary Angiogram in Survivors of Out-of-Hospital Cardiac Arrest (EMERGE) trial randomly assigned survivors of an OHCA without ST-segment elevation on ECG to either emergency or delayed (48 to 96 hours) CAG in 22 French centers. The trial took place from January 19, 2017, to November 23, 2020. Data were analyzed from November 24, 2020, to July 30, 2021. Main Outcomes and Measures: The primary outcome was the 180-day survival rate with CPC of 2 or less. The secondary end points were occurrence of shock, ventricular tachycardia, and/or fibrillation within 48 hours, change in left ventricular ejection fraction between baseline and 180 days, CPC scale at intensive care unit discharge and day 90, survival rate, and hospital length of stay. Results: A total of 279 patients (mean [SD] age, 64.7 [14.6] years; 195 men [69.9%]) were enrolled, with 141 (50.5%) in the emergency CAG group and 138 (49.5%) in the delayed CAG group. The study was underpowered. The mean (SD) time delay between randomization and CAG was 0.6 (3.7) hours in the emergency CAG group and 55.1 (37.2) hours in the delayed CAG group. The 180-day survival rates among patients with a CPC of 2 or less were 34.1% (47 of 141) in the emergency CAG group and 30.7% (42 of 138) in the delayed CAG group (hazard ratio [HR], 0.87; 95% CI, 0.65-1.15; P = .32). There was no difference in the overall survival rate at 180 days (emergency CAG, 36.2% [51 of 141] vs delayed CAG, 33.3% [46 of 138]; HR, 0.86; 95% CI, 0.64-1.15; P = .31) and in secondary outcomes between the 2 groups. Conclusions and Relevance: In this randomized clinical trial, for patients who experience an OHCA without ST-segment elevation on ECG, a strategy of emergency CAG was not better than a strategy of delayed CAG with respect to 180-day survival rate and minimal neurologic sequelae. Trial Registration: ClinicalTrials.gov Identifier: NCT02876458.

Fungicide-driven evolution and molecular basis of multidrug resistance in field populations of the grey mould fungus Botrytis cinerea.

The grey mould fungus Botrytis cinerea causes losses of commercially important fruits, vegetables and ornamentals worldwide. Fungicide treatments are effective for disease control, but bear the risk of resistance development. The major resistance mechanism in fungi is target protein modification resulting in reduced drug binding. Multiple drug resistance (MDR) caused by increased efflux activity is common in human pathogenic microbes, but rarely described for plant pathogens. Annual monitoring for fungicide resistance in field isolates from fungicide-treated vineyards in France and Germany revealed a rapidly increasing appearance of B. cinerea field populations with three distinct MDR phenotypes. All MDR strains showed increased fungicide efflux activity and overexpression of efflux transporter genes. Similar to clinical MDR isolates of Candida yeasts that are due to transcription factor mutations, all MDR1 strains were shown to harbor activating mutations in a transcription factor (Mrr1) that controls the gene encoding ABC transporter AtrB. MDR2 strains had undergone a unique rearrangement in the promoter region of the major facilitator superfamily transporter gene mfsM2, induced by insertion of a retrotransposon-derived sequence. MDR2 strains carrying the same rearranged mfsM2 allele have probably migrated from French to German wine-growing regions. The roles of atrB, mrr1 and mfsM2 were proven by the phenotypes of knock-out and overexpression mutants. As confirmed by sexual crosses, combinations of mrr1 and mfsM2 mutations lead to MDR3 strains with higher broad-spectrum resistance. An MDR3 strain was shown in field experiments to be selected against sensitive strains by fungicide treatments. Our data document for the first time the rising prevalence, spread and molecular basis of MDR populations in a major plant pathogen in agricultural environments. These populations will increase the risk of grey mould rot and hamper the effectiveness of current strategies for fungicide resistance management.

Clinical Outcome Predictive Value of Procalcitonin in Patients Suspected with Infection in the Emergency Department.

Procalcitonin (PCT) may be useful for early risk stratification in the emergency department (ED), but the transposition of published data to routine emergency practice is sometimes limited. An observational retrospective study was conducted in the adult ED of the Reims University Hospital (France). Over one year, 852 patients suspected of infection were included, of mean age 61.7 years (SD: 22.6), and 624 (73.2%) were hospitalized following ED visit. Overall, 82 (9.6%) patients died during their hospitalization with an odds ratio (OR) of 5.10 (95% CI: 2.19-11.87) for PCT ≥ 0.5, in multivariate logistic regression analyses. Moreover, 78 (9.2%) patients were admitted to an ICU, 74 (8.7%) had attributable bacteremia, and 56 (6.6%) evolved toward septic shock with an OR of 4.37 (2.08-9.16), 6.38 (2.67-15.24), and 6.38 (2.41-16.86), respectively, for PCT ≥ 0.5. The highest discriminatory values were found for patients with age <65 years, but PCT lost its discrimination power for in-hospital mortality in patients with a bronchopulmonary infection site or a temperature ≥37.8°C and for ICU admission in patients with severe clinical presentations. PCT could be helpful in risk stratification, but several limitations must be considered, including being sometimes outperformed by a simple clinical examination.

Goal-directed ultrasound protocol in patients with nontraumatic undifferentiated shock in the emergency department: prospective dual centre study.

BACKGROUND AND IMPORTANCE: Early identification of the cause of shock is associated with better prognosis. OBJECTIVE: The aim of this study was to explore the performances of an ultrasound protocol (echoSHOCK) to diagnose the cause of shock in the emergency department (ED). DESIGN, SETTINGS AND PARTICIPANTS: This was a prospective study performed in two EDs. Included patients were older than 18 years admitted with shock. After routine workup strategy, the suspected cause of shock and the planned treatment were reported. The echoSHOCK protocol, using only B mode, was then performed. After performing echoSHOCK, the investigator reported the same two items. INTERVENTION: echoSHOCK protocol that assessed: compressive pericardial effusion (tamponade), right ventricle dilatation and flattening of the septum, left ventricle dimension and systolic function, indices of hypovolemia. OUTCOMES MEASURE AND ANALYSIS: We defined four different causes for shock (tamponade, acute cor pulmonale, cardiogenic and hypovolemia). The primary endpoint was the degree of agreement of the routine workup and echoSHOCK with an expert panel. MAIN RESULTS: 85 patients [mean age of 73 (14) years] were included. Kappa coefficients between routine strategy and echoSHOCK for the cause of shock, with the expert panel were 0.33 (95% CI, 0.26-0.4) and 0.88 (95% CI, 0.83-0.93), respectively. Likewise, for the planned treatment, kappa were 0.21 (95% CI, 0.14-0.28) and 0.9 (95% CI, 0.85-0.94), respectively. The physician's confidence increased from 3.9 (2.1) before echoSHOCK to 9.3 (1.1) after, (P < 0.001). CONCLUSION: This study suggested that echoSHOCK significantly increased the ability to determine the cause of undifferentiated shock in the ED.

Exploring mechanisms of resistance to respiratory inhibitors in field strains of Botrytis cinerea, the causal agent of gray mold.

Respiratory inhibitors are among the fungicides most widely used for disease control on crops. Most are strobilurins and carboxamides, inhibiting the cytochrome b of mitochondrial complex III and the succinate dehydrogenase of mitochondrial complex II, respectively. A few years after the approval of these inhibitors for use on grapevines, field isolates of Botrytis cinerea, the causal agent of gray mold, resistant to one or both of these classes of fungicide were recovered in France and Germany. However, little was known about the mechanisms underlying this resistance in field populations of this fungus. Such knowledge could facilitate resistance risk assessment. The aim of this study was to investigate the mechanisms of resistance occurring in B. cinerea populations. Highly specific resistance to strobilurins was correlated with a single mutation of the cytb target gene. Changes in its intronic structure may also have occurred due to an evolutionary process controlling selection for resistance. Specific resistance to carboxamides was identified for six phenotypes, with various patterns of resistance levels and cross-resistance. Several mutations specific to B. cinerea were identified within the sdhB and sdhD genes encoding the iron-sulfur protein and an anchor protein of the succinate dehydrogenase complex. Another as-yet-uncharacterized mechanism of resistance was also recorded. In addition to target site resistance mechanisms, multidrug resistance, linked to the overexpression of membrane transporters, was identified in strains with low to moderate resistance to several respiratory inhibitors. This diversity of resistance mechanisms makes resistance management difficult and must be taken into account when developing strategies for Botrytis control.

Metabolism of fungicidal cyanooximes, cymoxanil and analogues in various strains of Botrytis cinerea.

BACKGROUND: The metabolism of cymoxanil [1-(2-cyano-2-methoxyiminoacetyl)-3-ethylurea] and fungicidal cyanooxime analogues was monitored on three phenotypes of Botrytis cinerea Pers. ex Fr. differing in their sensitivity towards cymoxanil. For this purpose, labelled [2-(14)C]cymoxanil was added either to the culture medium of these strains or to its cell-free extract. RESULTS: In the culture medium of the most sensitive strain, four main metabolites were detected. Three were isolated and identified. Cymoxanil was quickly metabolised by at least three concurrent enzymatic pathways: (i) cyclisation leading, after hydrolysis, to ethylparabanic acid, (ii) reduction giving demethoxylated cymoxanil, (iii) hydrolysis followed by reduction and then acetylation leading to N-acetylcyanoglycine. In the cell-free extract of the same strain, only the first and the second of these enzymatic reactions occurred. By comparing the metabolic profile of the most sensitive strain with that of the less sensitive ones, it was shown that the decrease in sensitivity to cymoxanil correlates with a reduced acetylcyanoglycine formation. Among all metabolites, only N-acetylcyanoglycine is active against the most sensitive strain. Moreover, in a culture of this strain, two other fungicidal cyanooximes were also metabolised into this metabolite. CONCLUSION: The formation of N-acetylcyanoglycine may play an important role in the fungitoxicity of cymoxanil and cyanooxime derivatives.

Spatiotemporal dynamics of fungicide resistance in the wheat pathogen Zymoseptoria tritici in France.

BACKGROUND: Management of pesticide resistance is a major issue in modern agricultural systems, particularly in the context of the broader challenge of reducing pesticide use. However, such management must be adapted to resistance dynamics, which remains challenging to predict due to its dependence on many biological traits of pests, interactions with the environment and pesticide use. We retrospectively studied the evolution of reported resistances to four modes of action (benzimidazoles, quinone outside inhibitors, sterol demethylation inhibitors and succinate dehydrogenase inhibitors), in French populations of the wheat pathogen Zymoseptoria tritici. RESULTS: We used statistical models to analyse the Performance trial network data set (2004-2017; ∼ 70 locations in France yearly). They highlighted contrasting behaviours between phenotypes, for example: (i) stable spatial distributions and colonization front structures over time, and (ii) different frequency growth rates at the national scale and between regions. CONCLUSION: We provide a quantitative description of the spatiotemporal patterns of resistance evolution for fungicides with several modes of action. Moreover, we highlight some unexpected resistance dynamics in France, with major differences between the north and south. This complex pattern of resistance evolution in French populations is consistent with previous descriptions of dynamics at the European scale. These results should make it easier to anticipate evolution locally and to improve the management of resistance. © 2019 Society of Chemical Industry.

Genetic analysis of fenhexamid-resistant field isolates of the phytopathogenic fungus Botrytis cinerea.

The hydroxyanilide fenhexamid, one of the latest antibotrytis fungicides, active especially against leotiomycete plant-pathogenic fungi, inhibits 3-ketoreductase of the C-4-demethylation enzyme complex during ergosterol biosynthesis. We isolated Botrytis cinerea strains resistant to various levels of fenhexamid from French and German vineyards. The sequence of the gene encoding 3-ketoreductase, erg27, varied according to levels of resistance. Highly resistant isolates, termed HydR3(+), all presented a modification of the phenylalanine at the C terminus of the putative transmembrane domain at position 412, either to serine (85% of the isolates), to isoleucine (11.5% of the isolates), or to valine (3.5% of the isolates). The introduction of the erg27(HydR3(+)) allele into a fenhexamid-sensitive strain by means of a replicative plasmid conferred fenhexamid resistance on the resulting transformants, showing that the mutations at position 412 are responsible for fenhexamid resistance. Weakly to moderately resistant isolates, termed HydR3(-), showed different point mutations between the strains in the sequenced regions of the erg27 gene, corresponding to amino acid changes between positions 195 and 400 of the protein. The erg27(HydR3(-)) alleles on the replicative vector introduced into a sensitive strain did not confer resistance to fenhexamid. Genetic crosses between HydR3(-) and sensitive strains showed strict correlation between the sequenced mutation in the erg27 gene and the resistance phenotypes, suggesting that these mutations are linked to fenhexamid resistance. The HydR3 mutations possibly modify the affinity of the 3-ketoreductase enzyme for its specific inhibitor, fenhexamid.