Investigating the prevalence of erectile dysfunction among men exposed to organophosphate insecticides.

INTRODUCTION: Erectile dysfunction (ED) poses a significant disease morbidity and contributor to male infertility, where an estimated 20-40% of men are affected annually. While several risk factors have been identified in the etiology of ED (e.g., aging, heart disease, diabetes, and obesity), the complete pathogenesis remains to be elucidated. Over the last few decades, the contribution of environmental exposures to the pathogenesis of ED has gained some attention, though population studies are limited and results are mixed. Among environmental contaminants, organophosphate (OP) insecticides represent one of the largest chemical classes, and chlorpyrifos is the most commonly used OP in the U.S. OP exposure has been implicated in driving biological processes, including inflammation, reactive oxygen species production, and endocrine and metabolism disruption, which have been demonstrated to adversely affect the hypothalamus and testes and may contribute to ED. Currently, studies evaluating the association between OPs and ED within the U.S. general population are sparse. METHODS: Data were leveraged from the National Health and Nutrition Examination Survey (NHANES), which is an annually conducted, population-based cross-sectional study. Urinary levels of 3,5,6-trichloro-2-pyridinol (TCPy), a specific metabolite of the most pervasive OP insecticide chlorpyrifos, were quantified as measures of OP exposure. ED was defined by responses to questionnaire data, where individuals who replied "sometimes able" or "never able" to achieve an erection were classified as ED. Chi-square, analysis of variance (ANOVA), and multivariable, weighted linear and logistic regression analyses were used to compare sociodemographic variables between quartiles of TCPy exposure, identify risk factors for TCPy exposure and ED, and to analyze the relationship between TCPy and ED. RESULTS: A total of 671 adult men were included in final analyses, representing 28,949,379 adults after survey weighting. Approximately 37% of our cohort had ED. Smoking, diabetes, aging, Mexican-American self-identification, and physical inactivity were associated with higher ED prevalence. Analysis of TCPy modeled as a continuous variable revealed nonsignificant associations with ED (OR = 1.02 95% CI [0.95, 1.09]). Stratification of total TCPy into quartiles revealed increased odds of ED among adults in the second and fourth quartiles, using the first quartile as the reference (OR = 2.04 95% CI [1.11, 3.72], OR = 1.51 95% CI [0.58, 3.93], OR = 2.62 95% CI [1.18, 5.79], for quartiles 2, 3, and 4, respectively). CONCLUSIONS: The results of our study suggest a potential role for chlorpyrifos and other OPs the pathogenesis of ED. Future studies are warranted to validate these findings, determine clinical significance, and to investigate potential mechanisms underlying these associations.

Sedentary Time and Prescription Medication Use Among US Adults: 2017-2018 National Health and Nutrition Examination Survey.

BACKGROUND: Prescription medication usage has been used as a predictor of disease prevalence and overall health status. Evidence suggests an inverse relationship exists between polypharmacy, which is the use of 5 or more medications, and physical activity participation. However, there is limited evidence examining the relationship between sedentary time and polypharmacy in adults. The aim of this study was to examine the associations between sedentary time and polypharmacy in a large nationally representative sample of US adults. METHODS: Study sample (N = 2879) included nonpregnant adult (≥20 y old) participants from the 2017-2018 National Health and Nutrition Examination Survey. Self-reported minutes per day of sedentary time were converted to hours per day. The dependent variable was polypharmacy (≥5 medications). RESULTS: Analysis revealed that for every hour of sedentary time, there was 4% greater odds of polypharmacy (odds ratio, 1.04; 95% confidence interval, 1.00-1.07, P = .04) after adjusting for age, race/ethnicity, education, waist circumference, and the interaction term between race/ethnicity and education. CONCLUSION: Our findings suggest increased sedentary time is associated with an increased risk of polypharmacy among a large nationally representative sample of US adults.

Do Parents Enhance Cognitive Behavior Therapy for Youth Anxiety? An Overview of Systematic Reviews Over Time.

The last 20 years has seen debate regarding the merits of involving parents in cognitive behavior therapy (CBT) for youth anxiety played out across systematic reviews which have high impact. These reviews examined varying treatment formats in relation to parent involvement, including youth only CBT (Y-CBT), parent only CBT (P-CBT) and family CBT (youth and parent; F-CBT). This is a novel overview of systematic reviews examining evidence for parental involvement in CBT for youth anxiety over the period this was studied. Two independent coders systematically searched for studies in medical and psychological databases using the categories "Review", "Youth", "Anxiety", "Cognitive Behavior Therapy" and "Parent/Family". Of the 2,189 unique articles identified, there were 25 systematic reviews since 2005 which compared the effects of CBT for youth anxiety with varying parent involvement. Despite systematically studying the same phenomenon, the reviews were heterogeneous in outcome, design, inclusion criteria and often had methodological limitations. Of the 25 reviews, 21 found no difference between formats and 22 reviews were considered inconclusive. Yet while there were typically no statistical differences, consistent patterns in the direction of effects were detected over time. P-CBT was less effective than other formats, suggesting the importance of directly treating anxious youths. Early reviews favored F-CBT over Y-CBT, however, later reviews did not show this trend. We consider the effects of moderators including exposure therapy, long-term outcomes and the child's age. We consider how to manage heterogeneity in primary studies and reviews to better detect treatment differences where they exist.Trial registration This protocol is registered with the Open Science Framework: osf.io/2u58t.

AmelHap: Leveraging drone whole-genome sequence data to create a honey bee HapMap.

Honey bee, Apis mellifera, drones are typically haploid, developing from an unfertilized egg, inheriting only their queen's alleles and none from the many drones she mated with. Thus the ordered combination or 'phase' of alleles is known, making drones a valuable haplotype resource. We collated whole-genome sequence data for 1,407 drones, including 45 newly sequenced Scottish drones, collectively representing 19 countries, 8 subspecies and various hybrids. Following alignment to Amel_HAv3.1, variant calling and quality filtering, we retained 17.4 M high quality variants across 1,328 samples with a genotyping rate of 98.7%. We demonstrate the utility of this haplotype resource, AmelHap, for genotype imputation, returning >95% concordance when up to 61% of data is missing in haploids and up to 12% of data is missing in diploids. AmelHap will serve as a useful resource for the community for imputation from low-depth sequencing or SNP chip data, accurate phasing of diploids for association studies, and as a comprehensive reference panel for population genetic and evolutionary analyses.

A retrospective study of helmet use and head injury in severe equestrian trauma.

Objectives: The aim of the study was to examine helmet use, incidence of injury, and patient outcomes in a rural cohort of equestrian accidents. Material and Methods: EHR records of patients admitted to a Level II ACS trauma center in the North-west United States were reviewed for helmet use. Injuries were categorized according to International Classification of Diseases-9/10 code. Results: Of 53 identified cases, helmets only reduced superficial injury (χ2 (1) = 4.837, P = 0.028). Intracranial injury rates were not different between those with and without helmets (P > 0.05). Conclusion: In equine related injury, helmets protect against superficial injury but not intracranial injury in Western riders. More investigation is needed to assess why this is the case and determine ways to decrease intracranial injury.

Impact of self-reported environmental mould exposure on COPD outcomes.

BACKGROUND: Indoor and outdoor mould exposure can affect respiratory symptoms, but its contribution to COPD outcomes such as exacerbation rates or antibiotics courses is not well defined. Some patients with COPD develop chronic pulmonary aspergillosis (CPA), but the contribution of environmental exposure is not known. METHODS: We correlated activities or exposures related to mould with COPD outcomes in patients with COPD with or without CPA using a questionnaire. RESULTS: One hundred and forty patients were included and 60 had CPA in addition to COPD. Seventy-six were male and mean age was 66.9 years (range 40-87). Thirty-nine (28%) were active cigarette smokers. On multivariate analysis, occupational contact with agricultural resources (p = 0.017), vacuuming once weekly or more often (p = 0.026) and not asking visitors to remove shoes on home entry (p = 0.035) were significantly more common in participants reporting ≥ 4 office visits for COPD symptoms in the last year. Living within one mile of industrial composting sites (p = 0.013), vacuuming once weekly or more often (p = 0.016) and not asking visitors to remove shoes on home entry (p = 0.028) were significantly more common in participants reporting ≥4 antibiotics courses in the last year. Patients with CPA showed a trend for residence within one mile of farms or agricultural areas (P = 0.088, OR 2, 95% CI 0.9-4.4). CONCLUSION: Activities potentially leading to mould exposure were common in a population with COPD with or without CPA and were associated with adverse COPD outcomes. Environmental mould exposure may play a role in the development of CPA in patients with COPD.

Depression, anxiety and PTSD symptoms before and during the COVID-19 pandemic in the UK.

BACKGROUND: The impact of the coronavirus disease 2019 (COVID-19) pandemic on mental health is still being unravelled. It is important to identify which individuals are at greatest risk of worsening symptoms. This study aimed to examine changes in depression, anxiety and post-traumatic stress disorder (PTSD) symptoms using prospective and retrospective symptom change assessments, and to find and examine the effect of key risk factors. METHOD: Online questionnaires were administered to 34 465 individuals (aged 16 years or above) in April/May 2020 in the UK, recruited from existing cohorts or via social media. Around one-third (n = 12 718) of included participants had prior diagnoses of depression or anxiety and had completed pre-pandemic mental health assessments (between September 2018 and February 2020), allowing prospective investigation of symptom change. RESULTS: Prospective symptom analyses showed small decreases in depression (PHQ-9: -0.43 points) and anxiety [generalised anxiety disorder scale - 7 items (GAD)-7: -0.33 points] and increases in PTSD (PCL-6: 0.22 points). Conversely, retrospective symptom analyses demonstrated significant large increases (PHQ-9: 2.40; GAD-7 = 1.97), with 55% reported worsening mental health since the beginning of the pandemic on a global change rating. Across both prospective and retrospective measures of symptom change, worsening depression, anxiety and PTSD symptoms were associated with prior mental health diagnoses, female gender, young age and unemployed/student status. CONCLUSIONS: We highlight the effect of prior mental health diagnoses on worsening mental health during the pandemic and confirm previously reported sociodemographic risk factors. Discrepancies between prospective and retrospective measures of changes in mental health may be related to recall bias-related underestimation of prior symptom severity.

A bacterial extracellular vesicle-based intranasal vaccine against SARS-CoV-2 protects against disease and elicits neutralizing antibodies to wild-type and Delta variants.

Several vaccines have been introduced to combat the coronavirus infectious disease-2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current SARS-CoV-2 vaccines include mRNA-containing lipid nanoparticles or adenoviral vectors that encode the SARS-CoV-2 Spike (S) protein of SARS-CoV-2, inactivated virus, or protein subunits. Despite growing success in worldwide vaccination efforts, additional capabilities may be needed in the future to address issues such as stability and storage requirements, need for vaccine boosters, desirability of different routes of administration, and emergence of SARS-CoV-2 variants such as the Delta variant. Here, we present a novel, well-characterized SARS-CoV-2 vaccine candidate based on extracellular vesicles (EVs) of Salmonella typhimurium that are decorated with the mammalian cell culture-derived Spike receptor-binding domain (RBD). RBD-conjugated outer membrane vesicles (RBD-OMVs) were used to immunize the golden Syrian hamster (Mesocricetus auratus) model of COVID-19. Intranasal immunization resulted in high titres of blood anti-RBD IgG as well as detectable mucosal responses. Neutralizing antibody activity against wild-type and Delta variants was evident in all vaccinated subjects. Upon challenge with live virus, hamsters immunized with RBD-OMV, but not animals immunized with unconjugated OMVs or a vehicle control, avoided body mass loss, had lower virus titres in bronchoalveolar lavage fluid, and experienced less severe lung pathology. Our results emphasize the value and versatility of OMV-based vaccine approaches.

Spontaneous and TMS-related EEG changes as new biomarkers to measure anti-epileptic drug effects.

Robust biomarkers for anti-epileptic drugs (AEDs) activity in the human brain are essential to increase the probability of successful drug development. The frequency analysis of electroencephalographic (EEG) activity, either spontaneous or evoked by transcranial magnetic stimulation (TMS-EEG) can provide cortical readouts for AEDs. However, a systematic evaluation of the effect of AEDs on spontaneous oscillations and TMS-related spectral perturbation (TRSP) has not yet been provided. We studied the effects of Lamotrigine, Levetiracetam, and of a novel potassium channel opener (XEN1101) in two groups of healthy volunteers. Levetiracetam suppressed TRSP theta, alpha and beta power, whereas Lamotrigine decreased delta and theta but increased the alpha power. Finally, XEN1101 decreased TRSP delta, theta, alpha and beta power. Resting-state EEG showed a decrease of theta band power after Lamotrigine intake. Levetiracetam increased theta, beta and gamma power, while XEN1101 produced an increase of delta, theta, beta and gamma power. Spontaneous and TMS-related cortical oscillations represent a powerful tool to characterize the effect of AEDs on in vivo brain activity. Spectral fingerprints of specific AEDs should be further investigated to provide robust and objective biomarkers of biological effect in human clinical trials.

A bacterial extracellular vesicle-based intranasal vaccine against SARS-CoV-2 protects against disease and elicits neutralizing antibodies to wild-type and Delta variants.

Several vaccines have been introduced to combat the coronavirus infectious disease-2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current SARS-CoV-2 vaccines include mRNA-containing lipid nanoparticles or adenoviral vectors that encode the SARS-CoV-2 Spike (S) protein of SARS-CoV-2, inactivated virus, or protein subunits. Despite growing success in worldwide vaccination efforts, additional capabilities may be needed in the future to address issues such as stability and storage requirements, need for vaccine boosters, desirability of different routes of administration, and emergence of SARS-CoV-2 variants such as the Delta variant. Here, we present a novel, well-characterized SARS-CoV-2 vaccine candidate based on extracellular vesicles (EVs) of Salmonella typhimurium that are decorated with the mammalian cell culture-derived Spike receptor-binding domain (RBD). RBD-conjugated outer membrane vesicles (RBD-OMVs) were used to immunize the golden Syrian hamster ( Mesocricetus auratus ) model of COVID-19. Intranasal immunization resulted in high titers of blood anti-RBD IgG as well as detectable mucosal responses. Neutralizing antibody activity against wild-type and Delta variants was evident in all vaccinated subjects. Upon challenge with live virus, hamsters immunized with RBD-OMV, but not animals immunized with unconjugated OMVs or a vehicle control, avoided body mass loss, had lower virus titers in bronchoalveolar lavage fluid, and experienced less severe lung pathology. Our results emphasize the value and versatility of OMV-based vaccine approaches.

The utility of a standardised breath sampler in school age children within a real-world prospective study.

Clinical assessment of children with asthma is problematic, and non-invasive biomarkers are needed urgently. Monitoring exhaled volatile organic compounds (VOCs) is an attractive alternative to invasive tests (blood and sputum) and may be used as frequently as required. Standardised reproducible breath-sampling is essential for exhaled-VOC analysis, and although the ReCIVA (Owlstone Medical Limited) breath-sampler was designed to satisfy this requirement, paediatric use was not in the original design brief. The efficacy of the ReCIVA at sampling breath from children has been studied, and 90 breath-samples from 64 children (5-15 years) with, and without asthma (controls), were collected with two different ReCIVA units. Seventy samples (77.8%) contained the specified 1 l of sampled-breath. Median sampling times were longer in children with acute asthma (770.2 s, range: 532.2-900.1 s) compared to stable asthma (690.6 s, range: 477.5-900.1 s;p= 0.01). The ReCIVA successfully detected operational faults, in 21 samples. A leak, caused by a poor fit of the face mask seal was the most common (15); the others were USB communication-faults (5); and, a single instance of a file-creation error. Paediatric breath-profiles were reliably monitored, however synchronisation of sampling to breathing-phases was sometimes lost, causing some breaths not to be sampled, and some to be sampled continuously. This occurred in 60 (66.7%) of the samples and was a source of variability. Importantly, multi-variate modelling of untargeted VOC analysis indicated the absence of significant batch effects for eight operational variables. The ReCIVA appears suitable for paediatric breath-sampling. Post-processing of breath-sample meta-data is recommended to assess the quality of sample-acquisition. Further, future studies should explore the effect of pump-synchronisation faults on recovered VOC profiles, and mask sizes to fit all ages will reduce the potential for leaks and importantly, provide higher levels of comfort to children with asthma.

Winds at the Mars 2020 Landing Site. 2. Wind Variability and Turbulence.

Wind speeds measured by the Mars 2020 Perseverance rover in Jezero crater were fitted as a Weibull distribution. InSight wind data acquired in Elysium Planitia were also used to contextualize observations. Jezero winds were found to be much calmer on average than in previous landing sites, despite the intense aeolian activity observed. However, a great influence of turbulence and wave activity was observed in the wind speed variations, thus driving the probability of reaching the highest wind speeds at Jezero, instead of sustained winds driven by local, regional, or large-scale circulation. The power spectral density of wind speed fluctuations follows a power-law, whose slope deviates depending on the time of day from that predicted considering homogeneous and isotropic turbulence. Daytime wave activity is related to convection cells and smaller eddies in the boundary layer, advected over the crater. The signature of convection cells was also found during dust storm conditions, when prevailing winds were consistent with a tidal drive. Nighttime fluctuations were also intense, suggesting strong mechanical turbulence. Convective vortices were usually involved in rapid wind fluctuations and extreme winds, with variations peaking at 9.2 times the background winds. Transient high wind events by vortex-passages, turbulence, and wave activity could be driving aeolian activity at Jezero. We report the detection of a strong dust cloud of 0.75-1.5 km in length passing over the rover. The observed aeolian activity had major implications for instrumentation, with the wind sensor suffering damage throughout the mission, probably due to flying debris advected by winds.

Total brachial artery reactivity and incident heart failure and heart failure subtypes: multi-ethnic study of atherosclerosis.

Endothelial dysfunction may be a phenotypic expression of heart failure (HF). Total brachial artery reactivity (TBAR) is a non-invasive measurement of endothelial function that has been associated with increased risk of cardiovascular outcomes. Limited information is currently available on the impact of TBAR on incident HF and its subtypes. The aim of this study was to investigate whether TBAR is associated with overall incident HF, and the two HF subtypes, HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) in a community-based study. The sample included 5499 participants (45-84 years of age) from the Multi-Ethnic Study of Atherosclerosis who were free of cardiovascular disease at baseline. Brachial artery was imaged via ultrasound after five minutes of cuff occlusion at the right forearm. TBAR was calculated as the difference between maximum and minimum brachial artery diameters following cuff release, divided by the minimum diameter multiplied by 100%. A dichotomous TBAR variable was created based on the median value (below or above 7.9%). Participants with EF ≤ 40% were considered HFrEF and those with EF ≥ 50% were considered HFpEF. Cox proportional hazards regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). Over a mean follow-up period of 12.5 years, incident HF was diagnosed in 250 participants: 98 classified as HFrEF, 106 as HFpEF, and 46 with unknown or borderline EF (41-49%). Crude analysis revealed that those with TBAR below the median had a significantly greater risk of HF (HR 1.46; 95% CI 1.13-1.88, p < 0.01) and HFrEF (HR 1.61; 95% CI 1.07-2.43, p < 0.05). Following adjustment for known HF risk factors (e.g., age, sex, race, blood pressure), the strength of these relationships was attenuated. Borderline significant results were revealed in those with HFpEF (HR 1.43; 95% CI 0.97-2.12, p = 0.06). Kaplan-Meier curves suggest significantly lower risks of developing HF and HFrEF in those with TBAR above the median (log-rank p ≤ 0.05 for both). When examined as a continuous variable, with a cut point of 50% for EF, every 1-standard deviation (9.7%) increase in TBAR resulted in a 19 and 29% decrease in risk of HF (p < 0.05) and HFrEF (p = 0.05), respectively. Lower TBAR values were associated with higher rates of incident HF and HFrEF, suggesting a possible role of endothelial dysfunction in HF pathogenesis. The impact of other known HF risk factors may mediate this relationship, thus further research is warranted.

Defining the decision problem: a scoping review of economic evaluations for Clostridioides difficile interventions.

BACKGROUND: Clostridioides difficile infection is the leading cause of healthcare-associated infectious diarrhoea. Several preventative and treatment interventions exist; however, decisions for their use are typically made independent of other interventions along the care pathway. AIM: To assess how the scope of the decision problem is defined in economic evaluations of C. difficile interventions. METHODS: A scoping review was conducted following the Joanna Briggs Institute framework using a comprehensive literature search with C. difficile and economic evaluation as key search concepts. Study selection and extraction were performed independently by two reviewers. An in-depth analysis of all cost-utility and cost-effectiveness analyses was conducted. Care pathway domains (i.e. infection prevention and control, antimicrobial stewardship programmes, prevention, diagnostics, treatment) were defined iteratively, and each study was classified according to the scope of the decision problem: (i) one intervention, one domain; (ii) one intervention, multiple domains; (iii) multiple interventions, one domain; and (iv) multiple interventions, multiple domains. RESULTS: In total, 3886 studies were identified. Of these, 116 studies were included in the descriptive overview, and 46 were included in the in-depth analysis. Most studies limited the scope of the decision problem to one intervention (43/46; 93%). Only three studies (3/46; 7%) assessed multiple interventions - either as bundled vs standalone interventions for prevention (i.e. a single domain), or as sequences of treatments for initial and recurrent infection (i.e. multiple domains). No study assessed multiple interventions across prevention and treatment domains. CONCLUSIONS: Economic evaluations for C. difficile infection assess narrowly defined decision problems which may have implications for optimal healthcare resource allocation.

Evaluation of Pirfenidone and Nintedanib in a Human Lung Model of Fibrogenesis.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with a poor prognosis and increasing incidence. Pirfenidone and nintedanib are the only approved treatments for IPF but have limited efficacy and their mechanisms of action are poorly understood. Here we have examined the effects of pirfenidone and nintedanib in a human model of lung fibrogenesis, and compared these with the putative anti-fibrotic compounds Lipoxin A4 (LXA4), and senicapoc, a KCa3.1 ion channel blocker. Methods: Early fibrosis was induced in cultured human lung parenchyma using TGFß1 for 7 days, ± pirfenidone, nintedanib, or LXA4. Pro-fibrotic responses were examined by RT-PCR, immunohistochemistry and soluble collagen secretion. Results: Thirty six out of eighty four IPF and fibrosis-associated genes tested were significantly upregulated by TGFß1 in human lung parenchyma with a ≥0.5 log2FC (n = 32). Nintedanib (n = 13) reduced the mRNA expression of 14 fibrosis-associated genes including MMPs (MMP1,-4,-13,-14), integrin α2, CXCR4 and PDGFB, but upregulated α-smooth muscle actin (αSMA). Pirfenidone only reduced mRNA expression for MMP3 and -13. Senicapoc (n = 11) previously attenuated the expression of 28 fibrosis-associated genes, including αSMA, several growth factors, collagen type III, and αV/ß6 integrins. Pirfenidone and nintedanib significantly inhibited TGFß1-induced fibroblast proliferation within the tissue, but unlike senicapoc, neither pirfenidone nor nintedanib prevented increases in tissue αSMA expression. LXA4 was ineffective. Conclusions: Pirfenidone and nintedanib demonstrate modest anti-fibrotic effects and provide a benchmark for anti-fibrotic activity of new drugs in human lung tissue. Based on these data, we predict that the KCa3.1 blocker senicapoc will show greater benefit than either of these licensed drugs in IPF.

CYP51 Paralogue Structure Is Associated with Intrinsic Azole Resistance in Fungi.

Azoles are the most commonly used clinical antifungal therapy and also play an important role in control of plant pathogens. Intrinsic resistance to the azole class of fungicides, which target lanosterol demethylase (CYP51), is observed in many fungal species; however, the mechanisms underpinning this phenomenon are unknown. In this study, 5 azole-resistant Penicillium isolates from patients attending the UK National Aspergillosis Centre that could not be morphologically identified to species level were analyzed by genome sequencing. The genomes and CYP51 paralogue structure from these isolates were compared with those of 46 representative fungal isolates to identify to species level and examine possible mechanisms of drug resistance. Analysis of CYP51 paralogues showed that azole-resistant isolates from this study (n = 2) and from public databases (n = 6) contained a new CYP51 paralogue, CYP51D, which was associated with azole resistance in 6/8 cases and never occurred in azole-sensitive species (46/46 tested). Furthermore, one isolate from this study and an azole-resistant Aspergillus fumigatiaffinis isolate were shown to encode a CYP51A paralogue, CYP51A2. Introduction of CYP51A2 to the closely related but azole-sensitive Aspergillus fumigatus resulted in azole resistance. The identification of novel CYP51A and CYP51D paralogues in resistant fungi and the observation that resistance to azoles can be conferred by introducing a CYP51A paralogue from a resistant species into an azole-sensitive species are a potentially important new azole resistance mechanism. IMPORTANCE Azole antifungals are the main treatment for fungal disease in humans. Many species are intrinsically resistant to azoles-in other words all members of the species are resistant without prior exposure-and we do not understand why. In this study, we serendipitously discovered that many intrinsically resistant species have alternative or extra copies of the azole target gene, CYP51. Transfer of one of these genes from a resistant species to a sensitive one resulted in drug resistance, showing that the extra copies of CYP51 can confer drug resistance. Understanding how clinically important species are resistant to therapy allows us to predict whether a species could be resistant from genome sequence.

[Pheochromocytomas and paragangliomas in pregnancy: About four cases and key messages on management]. / Phéochromocytomes et paragangliomes pendant la grossesse : à propos de quatre cas et messages clés sur la prise en charge.

OBJECTIFS: The diagnosis of a pheochromocytoma or paraganglioma secreting during pregnancy is a rare and serious situation, involving maternal-fetal prognosis. The purpose of this case series is to discuss the management of these patients. METHODS: This is a retrospective study of cases of pheochromocytoma (n=2) or paraganglioma (n=2) managed during pregnancy between 2013 and 2020 in one center (Lille, France). RESULTS: We report four cases of patients with a diagnosis of pheochromocytoma or paraganglioma during pregnancy, at respectively 4, 28, 31 and 34 weeks of amenorrhea (AS). Their pregnancies were affected by a sudden onset of hypertension sometimes associated with headaches, sweating, and palpitations. All patients delivered by Caesarean section after calcium channel blocker impregnation, with a good outcome. Tumor removal took place at a distance from delivery for each patient. CONCLUSIONS: The therapeutic strategy includes antihypertensive treatment with calcium channel blockers or alphablockers and surgical curative treatment linked to gestational age. Multidisciplinary management as well as early diagnosis can improve the maternal-fetal prognosis. The preferred way of delivery is Caesarean section, but vaginal delivery can also be considered. Removal should ideally take place at a distance from the birth. The analysis of these cases has led to the development of a protocol for monitoring and management of parturients with diagnosis of pheochromocytoma or paraganglioma during pregnancy.

Multi-model Meteorological and Aeolian Predictions for Mars 2020 and the Jezero Crater Region.

Nine simulations are used to predict the meteorology and aeolian activity of the Mars 2020 landing site region. Predicted seasonal variations of pressure and surface and atmospheric temperature generally agree. Minimum and maximum pressure is predicted at Ls ∼ 145 ∘ and 250 ∘ , respectively. Maximum and minimum surface and atmospheric temperature are predicted at Ls ∼ 180 ∘ and 270 ∘ , respectively; i.e., are warmest at northern fall equinox not summer solstice. Daily pressure cycles vary more between simulations, possibly due to differences in atmospheric dust distributions. Jezero crater sits inside and close to the NW rim of the huge Isidis basin, whose daytime upslope (∼east-southeasterly) and nighttime downslope (∼northwesterly) winds are predicted to dominate except around summer solstice, when the global circulation produces more southerly wind directions. Wind predictions vary hugely, with annual maximum speeds varying from 11 to 19 ms - 1 and daily mean wind speeds peaking in the first half of summer for most simulations but in the second half of the year for two. Most simulations predict net annual sand transport toward the WNW, which is generally consistent with aeolian observations, and peak sand fluxes in the first half of summer, with the weakest fluxes around winter solstice due to opposition between the global circulation and daytime upslope winds. However, one simulation predicts transport toward the NW, while another predicts fluxes peaking later and transport toward the WSW. Vortex activity is predicted to peak in summer and dip around winter solstice, and to be greater than at InSight and much greater than in Gale crater. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11214-020-00788-2.

Convergent evolution of pain-inducing defensive venom components in spitting cobras.

Convergent evolution provides insights into the selective drivers underlying evolutionary change. Snake venoms, with a direct genetic basis and clearly defined functional phenotype, provide a model system for exploring the repeated evolution of adaptations. While snakes use venom primarily for predation, and venom composition often reflects diet specificity, three lineages of cobras have independently evolved the ability to spit venom at adversaries. Using gene, protein, and functional analyses, we show that the three spitting lineages possess venoms characterized by an up-regulation of phospholipase A2 (PLA2) toxins, which potentiate the action of preexisting venom cytotoxins to activate mammalian sensory neurons and cause enhanced pain. These repeated independent changes provide a fascinating example of convergent evolution across multiple phenotypic levels driven by selection for defense.