COVID-19 olfactory dysfunction: associations between coping, quality of life, and mental health.

BACKGROUND: Persistent olfactory dysfunction (OD) is a common symptom following SARS-CoV-2 infection that can greatly impact quality of life (QoL). Because coping strategies have been shown to moderate the effect of disease symptoms on functional and affective outcomes, this study aims to determine whether specific coping strategies are associated with and moderate QoL outcomes. METHODOLOGY: Participants with prior SARS-CoV-2 infection underwent psychophysical olfactory testing with Sniffin' Sticks and completed questionnaires to elicit subjective olfactory function, coping strategies, olfactory-specific QoL, general QoL, and mental health. RESULTS: There were 93 participants included in the study. Olfactory specific QoL scores were significantly worse among individuals with subjective and psychophysically measured OD compared to those with subjective and psychophysically confirmed normosmia. Olfactory-specific QoL, general QoL, and anxiety symptom scores were positively correlated with avoidant and disengagement coping among individuals with subjective and psychophysically measured OD. Depression symptom scores were positively correlated with avoidant and disengagement coping and negatively correlated with approach and engagement coping. There were no significant moderating effects on the association between olfactory performance and QoL or mental health screening assessment. CONCLUSIONS: Approach and engagement coping mechanisms are associated with improved depression, whereas avoidant and disengagement coping tracks with worse QoL and mental health screening assessment, offering an opportunity to counsel patients accordingly.

Genome-scale analysis of essential gene knockout mutants to identify an antibiotic target process.

We describe a genome-scale approach to identify the essential biological process targeted by a new antibiotic. The procedure is based on the identification of essential genes whose inactivation sensitizes a Gram-negative bacterium (Acinetobacter baylyi) to a drug and employs recently developed transposon mutant screening and single-mutant validation procedures. The approach, based on measuring the rates of loss of newly generated knockout mutants in the presence of antibiotic, provides an alternative to traditional procedures for studying essential functions using conditional expression or activity alleles. As a proof of principle study, we evaluated whether mutations enhancing sensitivity to the ß-lactam antibiotic meropenem corresponded to the known essential target process of the antibiotic (septal peptidoglycan synthesis). We found that indeed mutations inactivating most genes needed for peptidoglycan synthesis and cell division strongly sensitized cells to meropenem. Additional classes of sensitizing mutations in essential genes were also identified, including those that inactivated capsule synthesis, DNA replication, or envelope stress response regulation. The essential capsule synthesis mutants appeared to enhance meropenem sensitivity by depleting a precursor needed for both capsule and peptidoglycan synthesis. The replication mutants may sensitize cells by impairing division. Nonessential gene mutations sensitizing cells to meropenem were also identified in the screen and largely corresponded to functions subordinately associated with the essential target process, such as in peptidoglycan recycling. Overall, these results help validate a new approach to identify the essential process targeted by an antibiotic and define the larger functional network determining sensitivity to it.

Ethical issues in genomics research on neurodevelopmental disorders: a critical interpretive review.

BACKGROUND: Genomic research on neurodevelopmental disorders (NDDs), particularly involving minors, combines and amplifies existing research ethics issues for biomedical research. We performed a review of the literature on the ethical issues associated with genomic research involving children affected by NDDs as an aid to researchers to better anticipate and address ethical concerns. RESULTS: Qualitative thematic analysis of the included articles revealed themes in three main areas: research design and ethics review, inclusion of research participants, and communication of research results. Ethical issues known to be associated with genomic research in general, such as privacy risks and informed consent/assent, seem especially pressing for NDD participants because of their potentially decreased cognitive abilities, increased vulnerability, and stigma associated with mental health problems. Additionally, there are informational risks: learning genetic information about NDD may have psychological and social impact, not only for the research participant but also for family members. However, there are potential benefits associated with research participation, too: by enrolling in research, the participants may access genetic testing and thus increase their chances of receiving a (genetic) diagnosis for their neurodevelopmental symptoms, prognostic or predictive information about disease progression or the risk of concurrent future disorders. Based on the results of our review, we developed an ethics checklist for genomic research involving children affected by NDDs. CONCLUSIONS: In setting up and designing genomic research efforts in NDD, researchers should partner with communities of persons with NDDs. Particular attention should be paid to preventing disproportional burdens of research participation of children with NDDs and their siblings, parents and other family members. Researchers should carefully tailor the information and informed consent procedures to avoid therapeutic and diagnostic misconception in NDD research. To better anticipate and address ethical issues in specific NDD studies, we suggest researchers to use the ethics checklist for genomic research involving children affected by NDDs presented in this paper.

A profile of mental health and behaviour in Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a neurogenetic syndrome with an associated behavioural phenotype and a high incidence of behaviours of concern and psychiatric co-morbidity. These associated behaviours and co-morbidities are not well addressed by existing interventions, and they impact significantly on affected individuals and their caregivers. METHODS: We undertook a national survey of the needs of individuals with PWS and their families in Ireland. In this paper, we report on the parent/caregiver-reported mental health, behavioural and access to services. RESULTS: Over 50% of individuals with PWS in this survey had at least one reported psychiatric diagnosis, the most common diagnosis was anxiety. The most commonly reported behaviours in children were skin picking, repetitive questioning, difficulty transitioning and non-compliance. The same four behaviours were reported by caregivers as being the most commonly occurring in adolescents and adults in addition to food-seeking behaviours. Increased needs for mental health services were also reported by caregivers. Individuals with PWS had an average wait of 22 months for an appointment with a psychologist and 4 months for an appointment with a psychiatrist. CONCLUSION: This study highlighted high levels of psychiatric co-morbidities and behavioural concerns in individuals with PWS in Ireland. The findings of this study suggest that there is an urgent need to provide specialist psychiatric and behavioural interventions to manage complex mental health and behavioural needs to better support individuals with PWS and reduce caregiver burden.

Wrestling with the complexity of evaluation for organizations at the boundary of science, policy, and practice.

Boundary organizations are situated between science, policy, and practice and have a goal of supporting communication and collaboration among these sectors. They have been promoted as a way to improve the effectiveness of conservation efforts by building stronger relationships between scientists, policy makers, industry, and practitioners (Cook et al. 2013). Although their promise has been discussed in theory, the work of and expectations for boundary organizations are less defined in practice. Biodiversity conservation is characterized by complexity, uncertainty, dissent, and tight budgets, so boundary organizations face the challenging task of demonstrating their value to diverse stakeholders. We examined the challenges boundary organizations face when seeking to evaluate their work and thus aimed to encourage more productive conversations about evaluation of boundary organizations and their projects. Although no off-the-shelf solution is available for a given boundary organization, we identified 4 principles that will support effective evaluation for boundary organizations: engage diverse stakeholders, support learning and reflection, assess contribution to change, and align evaluation with assumption and values.

Power supplies and equipment for military field research: lessons from the British Service Dhaulagiri Research Expedition 2016.

INTRODUCTION: The British Service Dhaulagiri Research Expedition (BSDMRE) took place from 27 March to 31 May 2016. The expedition involved 129 personnel, with voluntary participation in nine different study protocols. Studies were conducted in three research camps established at 3600, 4600 and 5140 m and involved taking and storing blood samples, cardiac echocardiography and investigations involving a balance plate. Research in this remote environment requires careful planning in order to provide a robust and resilient power plan. In this paper we aim to report the rationale for the choices we made in terms of power supply, the equipment used and potential military applicability. METHODS: This is a descriptive account from the expedition members involved in planning and conducting the medical research. RESULTS: Power calculations were used to determine estimates of requirement prior to the expedition. The primary sources used to generate power were internal combustion engine (via petrol fuelled electric generators) and solar panels. Having been generated, power was stored using lithium-ion batteries. Special consideration was given to the storage of samples taken in the field, for which electric freezers and dry shippers were used. All equipment used functioned well during the expedition, with the challenges of altitude, temperature and transport all overcome due to extensive prior planning. CONCLUSIONS: Power was successfully generated, stored and delivered during the BSDMRE, allowing extensive medical research to be undertaken. The challenges faced and overcome are directly applicable to delivering military medical care in austere environments, and lessons learnt can help with the planning and delivery of future operations, training exercises or expeditions.

Dysregulated bioenergetics: a key regulator of joint inflammation.

OBJECTIVES: This study examines the relationship between synovial hypoxia and cellular bioenergetics with synovial inflammation. METHODS: Primary rheumatoid arthritis synovial fibroblasts (RASF) were cultured with hypoxia, dimethyloxalylglycine (DMOG) or metabolic intermediates. Mitochondrial respiration, mitochondrial DNA mutations, cell invasion, cytokines, glucose and lactate were quantified using specific functional assays. RASF metabolism was assessed by the XF24-Flux Analyzer. Mitochondrial structural morphology was assessed by transmission electron microscopy (TEM). In vivo synovial tissue oxygen (tpO2 mmHg) was measured in patients with inflammatory arthritis (n=42) at arthroscopy, and markers of glycolysis/oxidative phosphorylation (glyceraldehyde 3-phosphate dehydrogenase (GAPDH), PKM2, GLUT1, ATP) were quantified by immunohistology. A subgroup of patients underwent contiguous MRI and positron emission tomography (PET)/CT imaging. RASF and human dermal microvascular endothelial cells (HMVEC) migration/angiogenesis, transcriptional activation (HIF1α, pSTAT3, Notch1-IC) and cytokines were examined in the presence of glycolytic inhibitor 3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO). RESULTS: DMOG significantly increased mtDNA mutations, mitochondrial membrane potential, mitochondrial mass, reactive oxygen species and glycolytic RASF activity with concomitant attenuation of mitochondrial respiration and ATP activity (all p<0.01). This was coupled with altered mitochondrial morphology. Hypoxia-induced lactate levels (p<0.01), which in turn induced basic fibroblast growth factor (bFGF) secretion and RASF invasiveness (all p<0.05). In vivo glycolytic markers were inversely associated with synovial tpO2 levels <20 mm Hg, in contrast ATP was significantly reduced (all p<0.05). Decrease in GAPDH and GLUT1 was paralleled by an increase in in vivo tpO2 in tumour necrosis factor alpha inhibitor (TNFi) responders. Novel PET/MRI hybrid imaging demonstrated close association between metabolic activity and inflammation. 3PO significantly inhibited RASF invasion/migration, angiogenic tube formation, secretion of proinflammatory mediators (all p<0.05), and activation of HIF1α, pSTAT3 and Notch-1IC under normoxic and hypoxic conditions. CONCLUSIONS: Hypoxia alters cellular bioenergetics by inducing mitochondrial dysfunction and promoting a switch to glycolysis, supporting abnormal angiogenesis, cellular invasion and pannus formation.

The phenotypic manifestations of rare genic CNVs in autism spectrum disorder.

Significant evidence exists for the association between copy number variants (CNVs) and Autism Spectrum Disorder (ASD); however, most of this work has focused solely on the diagnosis of ASD. There is limited understanding of the impact of CNVs on the 'sub-phenotypes' of ASD. The objective of this paper is to evaluate associations between CNVs in differentially brain expressed (DBE) genes or genes previously implicated in ASD/intellectual disability (ASD/ID) and specific sub-phenotypes of ASD. The sample consisted of 1590 cases of European ancestry from the Autism Genome Project (AGP) with a diagnosis of an ASD and at least one rare CNV impacting any gene and a core set of phenotypic measures, including symptom severity, language impairments, seizures, gait disturbances, intelligence quotient (IQ) and adaptive function, as well as paternal and maternal age. Classification analyses using a non-parametric recursive partitioning method (random forests) were employed to define sets of phenotypic characteristics that best classify the CNV-defined groups. There was substantial variation in the classification accuracy of the two sets of genes. The best variables for classification were verbal IQ for the ASD/ID genes, paternal age at birth for the DBE genes and adaptive function for de novo CNVs. CNVs in the ASD/ID list were primarily associated with communication and language domains, whereas CNVs in DBE genes were related to broader manifestations of adaptive function. To our knowledge, this is the first study to examine the associations between sub-phenotypes and CNVs genome-wide in ASD. This work highlights the importance of examining the diverse sub-phenotypic manifestations of CNVs in ASD, including the specific features, comorbid conditions and clinical correlates of ASD that comprise underlying characteristics of the disorder.

Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders.

Schizophrenia (SZ) and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders that may share an underlying pathology suggested by shared genetic risk variants. We sequenced the exonic regions of 215 genes in 147 ASD cases, 273 SZ cases and 287 controls, to identify rare risk mutations. Genes were primarily selected for their function in the synapse and were categorized as: (1) Neurexin and Neuroligin Interacting Proteins, (2) Post-synaptic Glutamate Receptor Complexes, (3) Neural Cell Adhesion Molecules, (4) DISC1 and Interactors and (5) Functional and Positional Candidates. Thirty-one novel loss-of-function (LoF) variants that are predicted to severely disrupt protein-coding sequence were detected among 2 861 rare variants. We found an excess of LoF variants in the combined cases compared with controls (P=0.02). This effect was stronger when analysis was limited to singleton LoF variants (P=0.0007) and the excess was present in both SZ (P=0.002) and ASD (P=0.001). As an individual gene category, Neurexin and Neuroligin Interacting Proteins carried an excess of LoF variants in cases compared with controls (P=0.05). A de novo nonsense variant in GRIN2B was identified in an ASD case adding to the growing evidence that this is an important risk gene for the disorder. These data support synapse formation and maintenance as key molecular mechanisms for SZ and ASD.

The autism brain imaging data exchange: towards a large-scale evaluation of the intrinsic brain architecture in autism.

Autism spectrum disorders (ASDs) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, lifelong nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. Although the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE)-a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) data sets with corresponding structural MRI and phenotypic information from 539 individuals with ASDs and 573 age-matched typical controls (TCs; 7-64 years) (http://fcon_1000.projects.nitrc.org/indi/abide/). Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 male subjects with ASDs and 403 male age-matched TCs. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo- and hyperconnectivity in the ASD literature; both were detected, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASDs (mid- and posterior insula and posterior cingulate cortex), and highlighted less commonly explored regions such as the thalamus. The survey of the ABIDE R-fMRI data sets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international data sets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.

In situ production of human ß defensin-3 in lager yeasts provides bactericidal activity against beer-spoiling bacteria under fermentation conditions.

AIMS: To examine the use of a natural antimicrobial peptide, human ß-defensin-3 (HBD3), as a means of preventing spoilage from bacterial contamination in brewery fermentations and in bottled beer. METHODS AND RESULTS: A chemically synthesised HBD3 peptide was tested for bactericidal activity against common Gram-positive and Gram-negative beer-spoiling bacteria, including species of Lactobacillus, Pediococcus and Pectinatus. The peptide was effective at the µmol l(-1) range in vitro, reducing bacterial counts by 95%. A gene construct encoding a secretable form of HBD3 was integrated into the genome of the lager yeast Saccharomyces pastorianus strain CMBS-33. The integrated gene was expressed under fermentation conditions and was secreted from the cell into the medium, but a significant amount remains associated with yeast cell surface. We demonstrate that under pilot-scale fermentation conditions, secreted HBD3 possesses bactericidal activity against beer-spoiling bacteria. Furthermore, when added to bottled beer, a synthetic form of HBD3 reduces the growth of beer-spoiling bacteria. CONCLUSIONS: Defensins provide prophylactic protection against beer-spoiling bacteria under brewing conditions and also in bottled beer. SIGNIFICANCE AND IMPACT OF THE STUDY: The results have direct application to the brewing industry where beer spoilage due to bacterial contamination continues to be a major problem in breweries around the world.

Antipsychotic prescribing in GMS paediatric and young adult population in Ireland 2005-2015: repeated cross-sectional study.

OBJECTIVES: To examine the rates of antipsychotic prescribing in the Irish paediatric and young adult population enrolled in the Irish General Medical Services Scheme pharmacy claims database from the Health Service Executive Primary Care Reimbursement Services database, with a focus on age and sex differences. To examine concomitant prescribing of certain other related medicines in this population. METHODS: Data were obtained from the Irish General Medical Services (GMS) scheme pharmacy claims database from the Health Service Executive (HSE) - Primary Care Reimbursement Services (PCRS). Participants included children aged <16 years and youth aged 16-24 years availing of medicines under the HSE-PCRS GMS scheme between January 2005 and December 2015. Outcome measures included prescribing rates of antipsychotics from 2005 to 2015, differences in prescribing rates between different ages and sexes, and percentage of concomitant prescriptions for antidepressants, psychostimulants, anxiolytics and hypnosedatives. RESULTS: Overall the trend in prescribing rates of antipsychotic medications was stable at 3.94/1000 in 2005 compared with 3.97/1000 in 2015 for children <16 years, and 48.37/1000 eligible population in 2005 compared to 39.64/1000 in 2015 for those aged 16-24. There was a significant decrease in prescribing rates for males in the 16-24 age group. CONCLUSIONS: While rates of antipsychotic prescribing have decreased or remained stable over the timeframe of the study, we did find a significant proportion of this population were prescribed antipsychotics. This study also shows that co-prescribing of antidepressants increased and highlights the need for guidelines for antipsychotic prescribing in children and youth in terms of clinical indication, monitoring, co-prescribing and treatment duration.

Mental health aspects of autistic spectrum disorders in children.

BACKGROUND: Previous studies have reported variable and at times opposite findings on comorbid psychiatric problems in children with autistic spectrum disorders (ASD). AIMS: This study aimed to examine patterns of comorbid psychiatric problems in children with ASD and their parents compared with IQ matched controls and their parents. METHODS: Behavioural/emotional problems were evaluated in a sample of children with ASD [a diagnosis of ASD was given if they met criteria for ASD on both of the ADI-R (Autism Diagnostic Interview-Revised) and ADOS (Autism Diagnostic Observational Schedule)] and an age and IQ matched control group using the Child Behavior Checklist (CBCL/6-18). Parental psychological distress for both groups was evaluated with the Brief Symptom Inventory (BSI). RESULTS: There were 59 (88%) boys and 8 (12%) girls in the ASD group. Similarly, 57 (85%) of the control group were male and 10 (15%) were female. The groups did not differ significantly on mean age, mean IQ scores, gender and parents mean age. Results of the CBCL/6-18 revealed that the majority of parents reported their child with ASD as having either internalising (clinical range: 47.8%; borderline range: 16.4%) or externalising problems (clinical range: 10.4%; borderline range: 20.9%). In the control group more parents reported their children having externalising (clinical range: 46.3%; borderline range: 16.4%) than internalising problems (clinical range: 35.8%; borderline range: 11.9%). Almost a half of the ASD group met CBCL DSM criteria for clinically significant attention deficit hyperactivity disorder (44.78%) and anxiety (46.2%) problems. Based on the Brief Symptom Inventory Global Severity Index 22.4% of fathers and 23.8% of mothers of ASD children produced scores that were indicative of possible psychopathology. CONCLUSIONS: High rates of clinically significant psychiatric problems were detected in ASD children, with anxiety and attention deficit hyperactivity disorder being the most frequently detected syndromes.

Autism spectrum disorders: current issues and future directions.

This edition of Irish Journal of Psychological Medicine is a Special Themed Issue on Autism Spectrum Disorders (ASD). Mental health services are not currently meeting the needs of autistic people across the lifespan. We have limited evidence based treatments for core symptoms and comorbidities and there is lack of awareness and under-recognition of ASD, particularly in adults and certain groups of individuals. The key themes in this edition focus on challenges with recognition and diagnosis and address these from both clinical and research perspectives. Co-occurring conditions also feature, which are also under-recognised and can contribute to less optimal outcomes. New and existing research developments in stratification for clinical trials and neuroimaging are also discussed. We hope this Issue highlights relevant current issues in ASD, and provides insights which can help address the challenges in providing evidence based pathways to better meet the needs of autistic people into the future.

Can stratification biomarkers address the heterogeneity of autism spectrum disorder?

The search for biomarkers for autism spectrum disorder (henceforth autism) has received a lot of attention due to their potential clinical relevance. The clinical and aetiological heterogeneity of autism suggests the presence of subgroups. The lack of identification of a valid diagnostic biomarker for autism, and the inconsistencies seen in studies assessing differences between autism and typically developing control groups, may be partially explained by the vast heterogeneity observed in autism. The focus now is to better understand the clinical and biological heterogeneity and identify stratification biomarkers, which are measures that describe subgroups of individuals with shared biology. Using stratification approaches to assess treatment within pre-defined subgroups could clarify who may benefit from different treatments and therapies, and ultimately lead to more effective individualised treatment plans.

Evaluating potential of multi-parametric MRI using co-registered histology: Application to a mouse model of glioblastoma.

BACKGROUND: Conventional MRI fails to detect regions of glioblastoma cell infiltration beyond the contrast-enhanced T1 solid tumor region, with infiltrating tumor cells often migrating along host blood vessels. PURPOSE: MRI is capable of generating a range of image contrasts which are commonly assessed individually by qualitative visual inspection. It has long been hypothesized that better diagnoses could be achieved by combining these multiple images, so called multi-parametric or multi-spectral MRI. However, the lack of clinical histology and the difficulties of co-registration, has meant this hypothesis has never been rigorously tested. Here we test this hypothesis, using a previously published multi-dimensional dataset consisting of registered MR images and histology. STUDY TYPE: Animal Model. SUBJECTS: Mice bearing orthotopic glioblastoma xenografts generated from a patient-derived glioblastoma cell line. FIELD STRENGTH/SEQUENCES: 7 Tesla, T1/T2 weighted, T2 mapping, contrast enhance T1, diffusion-weighted, diffusion tensor imaging. ASSESSMENT: Immunohistochemistry sections were stained for Human Leukocyte Antigen (probing human-derived tumor cells). To achieve quantitative MRI-tissue comparison, multiple histological slices cut in the MRI plane were stacked to produce tumor cell density maps acting as 'ground truth'. STATISTICAL TESTS: Sensitivity, specificity, accuracy and Dice similarity indices were calculated. ANOVA, t-test, Bonferroni correction and Pearson coefficients were used for statistical analysis. RESULTS: Correlation coefficient analysis with co-registered 'ground truth' histology showed interactive regression maps had higher correlation coefficients and sensitivity values than T2W, ADC, FA, and T2map. Further, the interaction regression maps showed statistical improved detection of tumor volume. DATA CONCLUSION: Voxel-by-voxel analysis provided quantitative evidence confirming the hypothesis that mpMRI can, potentially, better distinguish between the tumor region and normal tissue.

Genetic Dissection of Antibiotic Adjuvant Activity.

Small molecule adjuvants that enhance the activity of established antibiotics represent promising agents in the battle against antibiotic resistance. Adjuvants generally act by inhibiting antibiotic resistance processes, and specifying the process acted on is a critical step in defining an adjuvant's mechanism of action. This step is typically carried out biochemically by identifying molecules that bind adjuvants and then inferring their roles in resistance. Here, we present a complementary genetic strategy based on identifying mutations that both sensitize cells to antibiotic and make them "adjuvant blind." We tested the approach in Acinetobacter baumannii AB5075 using two adjuvants: a well-characterized ß-lactamase inhibitor (avibactam) and a compound enhancing outer membrane permeability (aryl 2-aminoimidazole AI-1). The avibactam studies showed that the adjuvant potentiated one ß-lactam (ceftazidime) through action on a single ß-lactamase (GES-14) and a second (meropenem) by targeting two different enzymes (GES-14 and OXA-23). Mutations impairing disulfide bond formation (DsbAB) also reduced potentiation, possibly by impairing ß-lactamase folding. Mutations reducing AI-1 potentiation of canonical Gram-positive antibiotics (vancomycin and clarithromycin) blocked lipooligosaccharide (LOS/LPS) synthesis or its acyl modification. The results indicate that LOS-mediated outer membrane impermeability is targeted by the adjuvant and show the importance of acylation in the resistance. As part of the study, we employed Acinetobacter baylyi as a model to verify the generality of the A. baumannii results and identified the principal resistance genes for ceftazidime, meropenem, vancomycin, and clarithromycin in A. baumannii AB5075. Overall, the work provides a foundation for analyzing adjuvant action using a comprehensive genetic approach. IMPORTANCE One strategy to confront the antibiotic resistance crisis is through the development of adjuvant compounds that increase the efficacy of established drugs. A key step in the development of a natural product adjuvant as a drug is identifying the resistance process it undermines to enhance antibiotic activity. Previous procedures designed to accomplish this have relied on biochemical identification of cell components that bind adjuvant. Here, we present a complementary strategy based on identifying mutations that eliminate adjuvant activity.

Influenza-like illness in a community surrounding a school-based outbreak of 2009 pandemic influenza A (H1N1) virus-Chicago, Illinois, 2009.

In April 2009, following the first school closure due to 2009 pandemic influenza A (H1N1) (pH1N1) in Chicago, Illinois, area hospitals were inundated with patients presenting with influenza-like illness (ILI). The extent of disease spread into the surrounding community was unclear. We performed a household survey to estimate the ILI attack rate among community residents and compared reported ILI with confirmed pH1N1 cases and ILI surveillance data (ie, hospital ILI visits, influenza testing, and school absenteeism). The estimated ILI attack rate was 4.6% (95% confidence interval, 2.8%-7.4%), with cases distributed throughout the 5-week study period. In contrast, 36 (84%) of 43 confirmed pH1N1 cases were identified the week of the school closure. Trends in surveillance data peaked during the same week and rapidly decreased to near baseline. Public awareness and health care practices impact standard ILI surveillance data. Community-based surveys are a valuable tool to help assess the burden of ILI in a community.

Stacked in-plane histology for quantitative validation of non-invasive imaging biomarkers: Application to an infiltrative brain tumour model.

BACKGROUND: While it is generally agreed that histopathology is the gold standard for assessing non-invasive imaging biomarkers, most validation has been by qualitative visual comparison. To date, the difficulties involved in accurately co-registering histology sections with imaging slices have prevented a voxel-by-voxel assessment of imaging modalities. By contrast with previous studies, which focus on improving the registration algorithms, we have taken the approach of improving the quality of the histological processing and analysis. NEW METHOD: To account for imaging slice orientation and thickness, multiple histology sections were cut in the MR imaging plane and averaged to produce stacked in-plane histology (SIH) maps. When combined with intensity sensitive staining this approach gives histopathology maps, which can be used as the gold standard to validate imaging biomarkers. RESULTS: We applied this pipeline to a patient-derived mouse model of glioblastoma multiforme (GBM). Increasing the number of stacked histology sections significantly increased SIH measured tumour volume. The SIH technique proposed here resulted in reduced variability of volume measurements and this allowed significant improvements in the quantitative volumetric assessment of multiple MRI modalities. Further, high quality registration enabled a voxel-wise comparison between MRI and histopathology maps. Previous approaches to the validation of imaging biomarkers with histology, have been either qualitative or of limited accuracy. Here we propose a pipeline that allows for a more accurate validation via co-registration with SIH maps, potentially allowing validation in a voxel-wise mode. CONCLUSION: This work demonstrates that methodically produced SIH maps facilitate the quantitative histopathologic assessment of imaging biomarkers.