The impact of agrochemical pollutant mixtures on the selection of insecticide resistance in the malaria vector Anopheles gambiae: insights from experimental evolution and transcriptomics.

BACKGROUND: There are several indications that pesticides used in agriculture contribute to the emergence and spread of resistance of mosquitoes to vector control insecticides. However, the impact of such an indirect selection pressure has rarely been quantified and the molecular mechanisms involved are still poorly characterized. In this context, experimental selection with different agrochemical mixtures was conducted in Anopheles gambiae. The multi-generational impact of agrochemicals on insecticide resistance was evaluated by phenotypic and molecular approaches. METHODS: Mosquito larvae were selected for 30 generations with three different agrochemical mixtures containing (i) insecticides, (ii) non-insecticides compounds, and (iii) both insecticide and non-insecticide compounds. Every five generations, the resistance of adults to deltamethrin and bendiocarb was monitored using bioassays. The frequencies of the kdr (L995F) and ace1 (G119S) target-site mutations were monitored every 10 generations. RNAseq was performed on all lines at generation 30 in order to identify gene transcription level variations and polymorphisms associated with each selection regime. RESULTS: Larval selection with agrochemical mixtures did not affect bendiocarb resistance and did not select for ace1 mutation. Contrastingly, an increased deltamethrin resistance was observed in the three selected lines. Such increased resistance was not majorly associated with the presence of kdr L995F mutation in selected lines. RNA-seq identified 63 candidate resistance genes over-transcribed in at least one selected line. These include genes coding for detoxification enzymes or cuticular proteins previously associated with insecticide resistance, and other genes potentially associated with chemical stress response. Combining an allele frequency filtering with a Bayesian FST-based genome scan allowed to identify genes under selection across multiple genomic loci, supporting a multigenic adaptive response to agrochemical mixtures. CONCLUSION: This study supports the role of agrochemical contaminants as a significant larval selection pressure favouring insecticide resistance in malaria vectors. Such selection pressures likely impact kdr mutations and detoxification enzymes, but also more generalist mechanisms such as cuticle resistance, which could potentially lead to cross-tolerance to unrelated insecticide compounds. Such indirect effect of global landscape pollution on mosquito resistance to public health insecticides deserves further attention since it can affect the nature and dynamics of resistance alleles circulating in malaria vectors and impact the efficacy of control vector strategies.

Deltamethrin and transfluthrin select for distinct transcriptomic responses in the malaria vector Anopheles gambiae.

BACKGROUND: The widespread use of pyrethroid insecticides in Africa has led to the development of strong resistance in Anopheles mosquitoes. Introducing new active ingredients can contribute to overcome this phenomenon and ensure the effectiveness of vector control strategies. Transfluthrin is a polyfluorinated pyrethroid whose structural conformation was thought to prevent its metabolism by cytochrome P450 monooxygenases in malaria vectors, thus representing a potential alternative for managing P450-mediated resistance occurring in the field. In this study, a controlled selection was used to compare the dynamics of resistance between transfluthrin and the widely used pyrethroid deltamethrin in the mosquito Anopheles gambiae. Then, the associated molecular mechanisms were investigated using target-site mutation genotyping and RNA-seq. METHODS: A field-derived line of An. gambiae carrying resistance alleles at low frequencies was used as starting material for a controlled selection experiment. Adult females were selected across 33 generations with deltamethrin or transfluthrin, resulting in three distinct lines: the Delta-R line (selected with deltamethrin), the Transflu-R line (selected with transfluthrin) and the Tiassale-S line (maintained without selection). Deltamethrin and transfluthrin resistance levels were monitored in each selected line throughout the selection process, as well as the frequency of the L1014F kdr mutation. At generation 17, cross-resistance to other public health insecticides was investigated and transcriptomes were sequenced to compare gene transcription variations and polymorphisms associated with adaptation to each insecticide. RESULTS: A rapid increase in resistance to deltamethrin and transfluthrin was observed throughout the selection process in each selected line in association with an increased frequency of the L1014F kdr mutation. Transcriptomic data support a broader response to transfluthrin selection as compared to deltamethrin selection. For instance, multiple detoxification enzymes and cuticle proteins were specifically over-transcribed in the Transflu-R line including the known pyrethroid metabolizers CYP6M2, CYP9K1 and CYP6AA1 together with other genes previously associated with resistance in An. gambiae. CONCLUSION: This study confirms that recurrent exposure of adult mosquitoes to pyrethroids in a public health context can rapidly select for various resistance mechanisms. In particular, it indicates that in addition to target site mutations, the polyfluorinated pyrethroid transfluthrin can select for a broad metabolic response, which includes some P450s previously associated to resistance to classical pyrethroids. This unexpected finding highlights the need for an in-depth study on the adaptive response of mosquitoes to newly introduced active ingredients in order to effectively guide and support decision-making programmes in malaria control.

Changes in amyloidosis phenotype over 11 years in a cardiac amyloidosis referral centre cohort in France.

BACKGROUND: Early cardiac amyloidosis (CA) diagnosis enables patients to access effective treatments for better long-term outcomes, yet it remains under-recognised, misdiagnosed and inadequately managed. AIM: To reduce diagnostic delays, we aimed to describe the epidemiological and clinical characteristics and changes over an 11-year period. METHODS: This was a retrospective, observational cohort study of all patients referred to the Henri-Mondor Hospital for suspected CA. RESULTS: Overall, 3194 patients were identified and 3022 were included and analysed. Our patients came from varied ethnic backgrounds, and more than half (55.2%) had confirmed CA. Over 11 years, referrals increased 4.4-fold, mostly from cardiologists. Notably, wild-type transthyretin amyloidosis (ATTRwt) became the predominant diagnosis, with referrals increasing 15-fold from 20 in 2010-2012 to 308 in 2019-2020. The number of amyloid light chain (AL) diagnoses increased, whilst variant transthyretin amyloidosis (ATTRv) numbers remained relatively stable. Concerning disease severity, AL patients presented more frequently with severe cardiac involvement whereas an increasing number of ATTRwt patients presented with National Amyloid Centre stage I (22.0% in 2013-2014 to 45.9% in 2019-2020). Lastly, among patients diagnosed with ATTRv in 2019-2020, 83.9% had ATTR Val122Ile cardiac phenotype. CONCLUSIONS: This study shows that increasing cardiologist awareness and referrals have increased CA diagnoses. With improved awareness and non-invasive diagnostic techniques, more patients with ATTRwt with milder disease and more ATTRv Val122Ile mutations are being referred and diagnosed. Although more AL cases are being recognised, patients are diagnosed with severe cardiac involvement.

A major 6 Mb superlocus is involved in pyrethroid resistance in the common bed bug Cimex lectularius.

In the last few years, the bed bug Cimex lectularius has been an increasing problem worldwide, mainly due to the development of insecticide resistance to pyrethroids. The characterization of resistance alleles is a prerequisite to improve surveillance and resistance management. To identify genomic variants associated with pyrethroid resistance in Cimex lectularius, we compared the genetic composition of two recent and resistant populations with that of two ancient-susceptible strains using a genome-wide pool-seq design. We identified a large 6 Mb "superlocus" showing particularly high genetic differentiation and association with the resistance phenotype. This superlocus contained several clustered resistance genes and was also characterized by a high density of structural variants (inversions, duplications). The possibility that this superlocus constitutes a resistance "supergene" that evolved after the clustering of alleles adapted to insecticide and after reduction in recombination is discussed.

Integrated Plan of Insecticide Resistance Surveillance in Mosquito Vectors in France.

Mosquito-borne diseases such as malaria, dengue, or chikungunya have been re-emerging all over the world, including in Europe. Managing resistance to public health pesticides in mosquitoes is essential and requires global, integrated, and coordinated actions and strong engagement of decision-makers, scientists, and public health operators. In this context, the present work aims at proposing an integrated plan of resistance surveillance in France and in the French Overseas territories in order to provide graduated and appropriate responses according to the situation. Briefly, the plan relies on periodic monitoring of insecticide resistance at the population level in predefined sites using adequate biological, molecular, and/or biochemical approaches and a stratification of the level of resistance risk at the scale of territory to adjust surveillance and vector control actions. The plan relies on the latest methods and indicators used for resistance monitoring as recommended by the World Health Organization in order to prevent or slow down its extension in space and time. The plan has been developed for France but can be easily adapted to other countries in order to provide a coordinated response to the growing problem of mosquito resistance in Europe.

Patients with cardiac amyloidosis are at a greater risk of mortality and hospital readmission after acute heart failure.

AIMS: Cardiac amyloidosis (CA) is an under-diagnosed cause of heart failure (HF) and has a worse prognosis than other forms of HF. The frequency of death or rehospitalization following discharge for acute heart failure (AHF) in CA (relative to other causes) has not been documented. The study aims to compare hospital readmission and death rates 90 days after discharge for AHF in patients with vs. without CA and to identify risk factors associated with these events in each group. METHODS AND RESULTS: Patients with HF and CA (HF + CA+) were recruited from the ICREX cohort, after screening of their medical records. The cases were matched 1:5 by sex and age with control HF patients without CA (HF + CA-). There were 27 HF + CA + and 135 HF + CA- patients from the ICREX cohort included in the study. Relative to the HF + CA- group, HF + CA+ patients had a higher heart rate (P = 0.002) and N-terminal prohormone of brain natriuretic peptide levels (P < 0.001) and lower blood pressure (P < 0.001), weight, and body mass index values (P < 0.001) on discharge. Ninety days after discharge, the HF + CA+ group displayed a higher death rate, a higher all-cause hospital readmission rate, and a higher hospital readmission rate for AHF. Death and hospital readmissions occurred sooner after discharge in the HF + CA+ group than in the HF + CA- group. CONCLUSIONS: The presence of CA in patients with HF was associated with a three-fold greater risk of death and a two-fold greater risk of all-cause hospital readmission 90 days after discharge. These findings emphasize the importance of close, active management of patients with CA and AHF.

More than a third of middle-aged adults (50-65) have understated executive dysfunction.

OBJECTIVES: Understated executive dysfunction (UED) is predictive of cognitive decline and death. We aimed to assess the prevalence of UED, assessed with the clock-drawing test (CDT) and the Frontal Assessment Battery (FAB) in middle-aged adults and to investigate associated characteristics. METHODS: Cross-sectional analysis of data on 516 community-dwellers aged 50-65, lacking cognitive complaints, who were included prospectively (2010-2017) after a multidimensional geriatric assessment at a "healthy ageing" outpatient clinic. Age- and educational-level-adjusted logistic models were used to assess factors associated with UED. RESULTS: The CDT and FAB were impaired in 27.7% and 14.7% of the participants (median age: 59.7 years). The prevalence [95% confidence interval (CI)] of UED was 36.2% [32.2-40.5%]. After adjustment for age and education, participants with UED were more likely to be obese (odds ratio [95%CI] = 1.89 [1.12-3.19], P = 0.02), and to have a metabolic syndrome (1.98 [1.06-3.72], P = 0.03). CONCLUSION: More than one third of middle-aged adults without cognitive complaints have UED, which was linked to obesity and metabolic syndrome. Cognitive screening tests targeting executive functions might be useful for early detection of UED and the initiation of multidomain interventions improving cognitive performance.

Practical management of frailty in older patients with heart failure: Statement from a panel of multidisciplinary experts on behalf the Heart Failure Working Group of the French Society of Cardiology and on behalf French Society of Geriatrics and Gerontology.

AIMS: The heart failure (HF) prognosis in older patients remains poor with a high 5-years mortality rate more frequently attributed to noncardiovascular causes. The complex interplay between frailty and heart failure contribute to poor health outcomes of older adults with HF independently of ejection fraction. The aim of this position paper is to propose a practical management of frailty in older patients with heart failure. METHODS: A panel of multidisciplinary experts on behalf the Heart Failure Working Group of the French Society of Cardiology and on behalf French Society of Geriatrics and Gerontology conducted a systematic literature search on the interlink between frailty and HF, met to propose an early frailty screening by non-geriatricians and to propose ways to implement management plan of frailty. Statements were agreed by expert consensus. RESULTS: Clinically relevant aspects of interlink between frailty and HF have been reported to identify the population eligible for screening and the most suitable screening test(s). The frailty screening program proposed focuses on frailty model defined by an accumulation of deficits including geriatric syndromes, comorbidities, for older patients with HF in different settings of care. The management plan of frailty includes optimization of HF pharmacological treatments and non-surgical device treatment as well as optimization of a global patient-centred biopsychosocial blended collaborative care pathway. CONCLUSION: The current manuscript provides practical recommendations on how to screen and optimize frailty management in older patients with heart failure.

Exposure of Anopheles gambiae larvae to a sub-lethal dose of an agrochemical mixture induces tolerance to adulticides used in vector control management.

The heavy use of pesticides in agricultural areas often leads to the contamination of nearby mosquito larvae breeding sites. Exposure to complex mixtures of agrochemicals can affect the insecticide sensitivity of mosquito larvae. Our study objective was to determine whether agrochemical residues in Anopheline larval breeding sites can affect the tolerance of adults to commonly used adulticides. We focussed on Fludora® Fusion, a vector control insecticide formulation combining two insecticides (deltamethrin and clothianidin) with different modes of action. An. gambiae larvae were exposed to a sub-lethal dose of a mixture of agrochemical pesticides used in a highly active agricultural area on the Ivory Coast. Comparative bioassays with Fludora Fusion mixture and its two insecticide components (deltamethrin and clothianidin) were carried out between adult mosquitoes exposed or not to the agrochemicals at the larval stage. A transcriptomic analysis using RNA sequencing was then performed on larvae and adults to study the molecular mechanisms underlying the phenotypic changes observed. Bioassays revealed a significantly increased tolerance of adult females to clothianidin (2.5-fold) and Fludora Fusion mixture (2.2-fold) following larval exposure to agrochemicals. Significantly increased tolerance to deltamethrin was not observed suggesting that insecticide exposure affects the adult efficacy of the Fludora Fusion mixture mainly through mechanisms acting on clothianidin. Transcriptomic analysis revealed the potential of agrochemicals to induce various resistance mechanisms including cuticle proteins, detoxification action and altered insecticide sequestration. These results suggest that although the Fludora Fusion mixture is effective for adult vector control, its efficacy may be locally affected by the ecological context. The present study also suggests that, although the complex interactions between the use of agrochemicals and vector control insecticides are difficult to decipher in the field, they still must be considered in the context of insecticide resistance management programmes.

Genomic Shifts, Phenotypic Clines, and Fitness Costs Associated With Cold Tolerance in the Asian Tiger Mosquito.

Climatic variation is a key driver of genetic differentiation and phenotypic traits evolution, and local adaptation to temperature is expected in widespread species. We investigated phenotypic and genomic changes in the native range of the Asian tiger mosquito, Aedes albopictus. We first refine the phylogeographic structure based on genome-wide regions (1,901 double-digest restriction-site associated DNA single nucleotide polymophisms [ddRAD SNPs]) from 41 populations. We then explore the patterns of cold adaptation using phenotypic traits measured in common garden (wing size and cold tolerance) and genotype-temperature associations at targeted candidate regions (51,706 exon-capture SNPs) from nine populations. We confirm the existence of three evolutionary lineages including clades A (Malaysia, Thailand, Cambodia, and Laos), B (China and Okinawa), and C (South Korea and Japan). We identified temperature-associated differentiation in 15 out of 221 candidate regions but none in ddRAD regions, supporting the role of directional selection in detected genes. These include genes involved in lipid metabolism and a circadian clock gene. Most outlier SNPs are differently fixed between clades A and C, whereas clade B has an intermediate pattern. Females are larger at higher latitude yet produce no more eggs, which might favor the storage of energetic reserves in colder climate. Nondiapausing eggs from temperate populations survive better to cold exposure than those from tropical populations, suggesting they are protected from freezing damages but this cold tolerance has a fitness cost in terms of egg viability. Altogether, our results provide strong evidence for the thermal adaptation of A. albopictus across its wide temperature range.

High DDT resistance without apparent association to kdr and Glutathione-S-transferase (GST) gene mutations in Aedes aegypti population at hotel compounds in Zanzibar.

Global efforts to control Aedes mosquito-transmitted pathogens still rely heavily on insecticides. However, available information on vector resistance is mainly restricted to mosquito populations located in residential and public areas, whereas commercial settings, such as hotels are overlooked. This may obscure the real magnitude of the insecticide resistance problem and lead to ineffective vector control and resistance management. We investigated the profile of insecticide susceptibility of Aedes aegypti mosquitoes occurring at selected hotel compounds on Zanzibar Island. At least 100 adults Ae. aegypti females from larvae collected at four hotel compounds were exposed to papers impregnated with discriminant concentrations of DDT (4%), permethrin (0.75%), 0.05 deltamethrin (0.05%), propoxur (0.1%) and bendiocarb (0.1%) to determine their susceptibility profile. Allele-specific qPCR and sequencing analysis were applied to determine the possible association between observed resistance and presence of single nucleotide polymorphisms (SNPs) in the voltage-gated sodium channel gene (VGSC) linked to DDT/pyrethroid cross-resistance. Additionally, we explored the possible involvement of Glutathione-S-Transferase gene (GSTe2) mutations for the observed resistance profile. In vivo resistance bioassay indicated that Ae. aegypti at studied sites were highly resistant to DDT, mortality rate ranged from 26.3% to 55.3% and, moderately resistant to deltamethrin with a mortality rate between 79% to and 100%. However, genotyping of kdr mutations affecting the voltage-gated sodium channel only showed a low frequency of the V1016G mutation (n = 5; 0.97%). Moreover, for GSTe2, seven non-synonymous SNPs were detected (L111S, C115F, P117S, E132A, I150V, E178A and A198E) across two distinct haplotypes, but none of these were significantly associated with the observed resistance to DDT. Our findings suggest that cross-resistance to DDT/deltamethrin at hotel compounds in Zanzibar is not primarily mediated by mutations in VGSC. Moreover, the role of identified GSTe2 mutations in the resistance against DDT remains inconclusive. We encourage further studies to investigate the role of other potential insecticide resistance markers.

Screening and management of peripheral arterial obstructive disease in the lower limb wounds amongst diabetic elderly patients / Dépistage et prise en charge de l'artériopathie oblitérante des membres inférieurs dans le cadre des plaies du membre inférieur chez le sujet âgé diabétique

Introduction: Diabetes, a high prevalence chronic disease, especially in the elderly, is a risk factor of chronic lower limb wounds, whose management involves screening and treatment of peripheral arterial obstructive disease (PAOD), which must be systematic. Aim : Evaluate the screening and the management of PAOD amongst those patients, hospitalized in a Geriatric Department. Methods: Observational, retrospective, monocentric study, including all the elderly above 75 years old, with diabetes, and a wound in the lower limb, hospitalized from 01/01/2018 to 29/02/2020 at Henri Mondor hospital in Créteil. Results: Over the study period, 2567 patients were hospitalized, including 501 diabetic patients (19,5 %). 38 patients were included. Amongst them, 66 % had a bedsore, 18 % a leg ulcer, and 24 % a diabetic foot ulcer. Concerning the screening of PAOD, 66 % was screened for peripheral pulses, 8 % had an ankle-brachial index, and 45 % at least an imaging including 39 % arterial doppler. Amongst the 21 patients with PAOD, only one had a complete medical treatment, 6 had a revascularization including 5 amputations. Conclusion: Management of PAOD in the wound of lower limb amongst diabetic elderly patients is insufficient. Although it can be difficult to revascularize them, the screening must be systematic. Educate geriatric doctors in the screening of PAOD and build an expert team amongst them would help to improve that problematic.

Objectifs: Évaluer le dépistage et la prise en charge de l'artériopathie oblitérante des membres inférieurs (AOMI) chez les patients âgés diabétiques, hospitalisés en court séjour gériatrique. Méthodes: Étude observationnelle, rétrospective et monocentrique sur le service de gériatrie de l'hôpital Henri-Mondor, du 1er janvier 2018 au 29 février 2020. Inclusion des patients de plus de 75 ans, diabétiques, avec une plaie du membre inférieur. Résultats: 2 567 patients ont été hospitalisés, dont 501 diabétiques (19,5 %). Trente-huit (38) patients ont été inclus. Parmi eux, 66 % présentaient une escarre, 18 % un ulcère et 24 % une plaie du pied diabétique. Dans le dépistage de l'AOMI, 66 % des patients avaient eu une recherche des pouls périphériques, 8 % un indice de pression systolique et 45 % au moins une imagerie dont 39 % un Doppler artériel. Parmi les 21 patients avec AOMI, un seul avait un traitement médicamenteux complet, un autre avait bénéficié d'un geste de revascularisation et cinq avaient subi une amputation. Conclusion: La prise en charge de l'AOMI dans la plaie du membre inférieur chez le sujet âgé diabétique est insuffisante. La réalisation d'un geste vasculaire peut être compliquée, mais le dépistage est simple et devrait être systématique.

Experimental evolution supports the potential of neonicotinoid-pyrethroid combination for managing insecticide resistance in malaria vectors.

The introduction of neonicotinoids for managing insecticide resistance in mosquitoes is of high interest as they interact with a biochemical target not previously used in public health. In this concern, Bayer developed a combination of the neonicotinoid clothianidin and the pyrethroid deltamethrin (brand name Fludora Fusion) as a new vector control tool. Although this combination proved to be efficient against pyrethroid-resistant mosquitoes, its ability to prevent the selection of pyrethroid and neonicotinoid resistance alleles was not investigated. In this context, the objective of this work was to study the dynamics and the molecular mechanisms of resistance of An. gambiae to the separated or combined components of this combination. A field-derived An. gambiae line carrying resistance alleles to multiple insecticides at low frequencies was used as a starting for 33 successive generations of controlled selection. Resistance levels to each insecticide and target site mutation frequencies were monitored throughout the selection process. Cross resistance to other public health insecticides were also investigated. RNA-seq was used to compare gene transcription variations and polymorphisms across all lines. This study confirmed the potential of this insecticide combination to impair the selection of resistance as compared to its two separated components. Deltamethrin selection led to the rapid enrichment of the kdr L1014F target-site mutation. Clothianidin selection led to the over-transcription of multiple cytochrome P450s including some showing high homology with those conferring neonicotinoid resistance in other insects. A strong selection signature associated with clothianidin selection was also observed on a P450 gene cluster previously associated with resistance. Within this cluster, the gene CYP6M1 showed the highest selection signature together with a transcription profile supporting a role in clothianidin resistance. Modelling the impact of point mutations selected by clothianidin on CYP6M1 protein structure showed that selection retained a protein variant with a modified active site potentially enhancing clothianidin metabolism. In the context of the recent deployment of neonicotinoids for mosquito control and their frequent usage in agriculture, the present study highlights the benefit of combining them with other insecticides for preventing the selection of resistance and sustaining vector control activities.

Frailty in Wild-Type Transthyretin Cardiac Amyloidosis: The Tip of the Iceberg.

ATTRwt-CA occurs in elderly patients and leads to severe heart failure. The disease mechanism involves cardiac and extracardiac infiltration by amyloid fibrils. The objectives of this study are to describe the frailty phenotype in patients with ATTRwt-CA and to assess the associations between frailty parameters, the severity of cardiac involvement, and the course of amyloid disease. We used multidimensional geriatric tools to prospectively assess frailty in patients with ATTRwt-CA consulting (in 2018-2019) in the French National Reference Center for Cardiac Amyloidosis. We included 36 patients (35 males; median age: 82 years (76-86). A third of the patients were categorized as NYHA class III or IV, and 39% had an LVEF below 45%. The median serum NTproBNP was 3188 (1341-8883) pg/mL. The median duration of amyloidosis was 146 months (73-216). The frequency of frailty was 50% and 33% according to the physical frailty phenotype and the Short Emergency Geriatric Assessment questionnaire, respectively. Frailty affected a large number of domains, namely autonomy (69%), balance (58%), muscle weakness (74%), malnutrition (39%), dysexecutive syndrome (72%), and depression (49%). The severity of CA was significantly associated with many frailty parameters independently of age. Balance disorders and poor mobility were also significantly associated with a longer course of amyloid disease. Frailty is frequent in patients with ATTRwt-CA. Some frailty parameters were significantly associated with a longer course of amyloid disease and CA severity. Taking into account frailty in the assessment and management of ATTRwt should improve patients' quality of life.

Impact of selection regime and introgression on deltamethrin resistance in the arbovirus vector Aedes aegypti - a comparative study between contrasted situations in New Caledonia and French Guiana.

BACKGROUND: Pyrethroid insecticides such as deltamethrin have been massively used against Aedes aegypti leading to the spread of resistance alleles worldwide. In an insecticide resistance management context, we evaluated the temporal dynamics of deltamethrin resistance using two distinct populations carrying resistant alleles at different frequencies. Three different scenarios were followed: a continuous selection, a full release of selection, or a repeated introgression with susceptible individuals. The responses of each population to these selection regimes were measured across five generations by bioassays and by monitoring the frequency of knockdown resistance (kdr) mutations and the transcription levels and copy number variations of key detoxification enzymes. RESULTS: Knockdown resistance mutations, overexpression and copy number variations of detoxification enzymes as a mechanism of metabolic resistance to deltamethrin was found and maintained under selection across generations. On comparison, the release of insecticide pressure for five generations did not affect resistance levels and resistance marker frequencies. However, introgressing susceptible alleles drastically reduced deltamethrin resistance in only three generations. CONCLUSION: The present study confirmed that strategies consisting to stop deltamethrin spraying are likely to fail when the frequencies of resistant alleles are too high and the fitness cost associated to resistance is low. In dead-end situations like in French Guiana where alternative insecticides are not available, alternative control strategies may provide a high benefit for vector control, particularly if they favor the introgression of susceptible alleles in natural populations. © 2021 Society of Chemical Industry.

Good performance in the management of acute heart failure in cardiogeriatric departments: the ICREX-94 experience.

CONTEXT: A growing number of elderly patients hospitalized for Acute Heart Failure (AHF) are being managed in cardiogeriatrics departments, but their characteristics and prognosis are poorly known. This study aimed to investigate the profile and outcome (rehospitalization at 90 days) of patients hospitalized for AHF in cardiogeriatrics departments in the Val-de-Marne area in the suburbs of Paris, and to compare them to AHF patients hospitalized in cardiology departments in the same area. METHODS: Observational study, ICREX-94, conducted in seven cardiology departments in France and three specific cardiogeriatrics departments in Val-de-Marne. RESULTS: A total of 308 patients were hospitalized for AHF between October 2017 and January 2019. During the 90 days following discharge, 29.6% patients were readmitted to the hospital. Compared with patients hospitalized in cardiology departments, patients in cardiogeriatrics departments were older (p < 0.001), less independent (living more often alone or in an institution) (p < 0.001), more often depressed (p < 0.001), had more often major neurocognitive disorder (p < 0.001), had a higher Human Development Index (HDI, p < 0.001), and were less often diagnosed with amyloidosis (p < 0.001). There was no difference in outcome whether patients were discharged from cardiology or cardiogeriatrics departments. The most frequent precipitating factors underlying AHF decompensation between the first and second hospitalization were arrhythmia and infection. CONCLUSION: AHF patients discharged from cardiogeriatrics departments, compared to cardiology departments, showed clinical differences but had the same prognosis regarding AHF rehospitalization at 90 days.

Molecular bases of P450-mediated resistance to the neonicotinoid insecticide imidacloprid in the mosquito Ae. aegypti.

Resistance to chemical insecticides including pyrethroids, the main insecticide class used against mosquitoes, has re-kindled interest in the use of neonicotinoids. In this context, the present study aimed to characterize the molecular basis of neonicotinoid resistance in the mosquito Aedes aegypti. Resistance mechanisms were studied by combining transcriptomic and genomic data obtained from a laboratory strain selected at the larval stage after 30 generations of exposure to imidacloprid (Imida-R line). After thirty generations of selection, larvae of the Imida-R line showed an 8-fold increased resistance to imidacloprid and a significant cross-tolerance to the pyrethroids permethrin and deltamethrin. Cross-resistance to pyrethroids was only observed in adults when larvae were previously exposed to imidacloprid suggesting a low but inducible expression of resistance alleles at the adult stage. Resistance of the Imida-R line was associated with a slower larval development time in females. Multiple detoxification enzymes were over-transcribed in larvae in association with resistance including the P450s CYP6BB2, CYP9M9 and CYP6M11 previously associated with pyrethroid resistance. Some of them together with their redox partner NADPH P450 reductase were also affected by non-synonymous mutations associated with resistance. Combining genomic and transcriptomic data allowed identifying promoter variations associated with the up-regulation of CYP6BB2 in the resistant line. Overall, these data confirm the key role of P450s in neonicotinoid resistance in Ae. aegypti and their potential to confer cross-resistance to pyrethroids, raising concerns about the use of neonicotinoids for resistance management in this mosquito species.

A genomic amplification affecting a carboxylesterase gene cluster confers organophosphate resistance in the mosquito Aedes aegypti: From genomic characterization to high-throughput field detection.

By altering gene expression and creating paralogs, genomic amplifications represent a key component of short-term adaptive processes. In insects, the use of insecticides can select gene amplifications causing an increased expression of detoxification enzymes, supporting the usefulness of these DNA markers for monitoring the dynamics of resistance alleles in the field. In this context, the present study aims to characterize a genomic amplification event associated with resistance to organophosphate insecticides in the mosquito Aedes aegypti and to develop a molecular assay to monitor the associated resistance alleles in the field. An experimental evolution experiment using a composite population from Laos supported the association between the over-transcription of multiple contiguous carboxylesterase genes on chromosome 2 and resistance to multiple organophosphate insecticides. Combining whole genome sequencing and qPCR on specific genes confirmed the presence of a ~100-Kb amplification spanning at least five carboxylesterase genes at this locus with the co-existence of multiple structural duplication haplotypes. Field data confirmed their circulation in South-East Asia and revealed high copy number polymorphism among and within populations suggesting a trade-off between this resistance mechanism and associated fitness costs. A dual-color multiplex TaqMan assay allowing the rapid detection and copy number quantification of this amplification event in Ae. aegypti was developed and validated on field populations. The routine use of this novel assay will improve the tracking of resistance alleles in this major arbovirus vector.