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In this study, investigators compared genome sequencing with cytogenetic analysis in 263 patients with acute myeloid leukemia or myelodysplastic syndromes. Prospective sequencing detected new genetic information that was not revealed by cytogenetic analysis in nearly 25% of the patients, which altered the risk category for most of these patients.

Bacterial meningitis remains a major cause of morbidity and mortality in young infants. Understanding the epidemiology and burden of disease is important. Prospective, enhanced, national population-based active surveillance was undertaken to determine the incidence, etiology, and outcome of bacterial meningitis in infants aged <90 days in the United Kingdom and Ireland. During July 2010-July 2011, 364 cases were identified (annual incidence, 0.38/1000 live births; 95% confidence interval [CI], .35-.42). In England and Wales, the incidence of confirmed neonatal bacterial meningitis was 0.21 (n = 167; 95% CI, .18-.25). A total of 302 bacteria were isolated in 298 (82%) of the cases. The pathogens responsible varied by route of admission, gestation at birth, and age at infection. Group B Streptococcus (GBS) (150/302 [50%]; incidence, 0.16/1000 live births; 95% CI, .13-.18) and Escherichia coli (41/302 [14%]; incidence, 0.04/1000; 95% CI, .03-.06) were responsible for approximately two-thirds of identified bacteria. Pneumococcal (28/302 [9%]) and meningococcal (23/302 [8%]) meningitis were rare in the first month, whereas Listeria meningitis was seen only in the first month of life (11/302 [4%]). In hospitalized preterm infants, the etiology of both early- and late-onset meningitis was more varied. Overall case fatality was 8% (25/329) and was higher for pneumococcal meningitis (5/26 [19%]) than GBS meningitis (7/135 [5%]; P = .04) and for preterm (15/90 [17%]) compared with term (10/235 [4%]; P = .0002) infants. The incidence of bacterial meningitis in young infants remains unchanged since the 1980s and is associated with significant case fatality. Prevention strategies and guidelines to improve the early management of cases should be prioritized.

Cryptococcosis is a major worldwide disseminated invasive fungal infection. Cryptococcosis, particularly in its most lethal manifestation of cryptococcal meningitis, accounts for substantial mortality and morbidity. The breadth of the clinical cryptococcosis syndromes, the different patient types at-risk and affected, and the vastly disparate resource settings where clinicians practice pose a complex array of challenges. Expert contributors from diverse regions of the world have collated data, reviewed the evidence, and provided insightful guideline recommendations for health practitioners across the globe. This guideline offers updated practical guidance and implementable recommendations on the clinical approaches, screening, diagnosis, management, and follow-up care of a patient with cryptococcosis and serves as a comprehensive synthesis of current evidence on cryptococcosis. This Review seeks to facilitate optimal clinical decision making on cryptococcosis and addresses the myriad of clinical complications by incorporating data from historical and contemporary clinical trials. This guideline is grounded on a set of core management principles, while acknowledging the practical challenges of antifungal access and resource limitations faced by many clinicians and patients. More than 70 societies internationally have endorsed the content, structure, evidence, recommendation, and pragmatic wisdom of this global cryptococcosis guideline to inform clinicians about the past, present, and future of care for a patient with cryptococcosis.

Meningitis remains one of the most feared infectious diseases worldwide, yet there are few population-based studies on the epidemiology, causes, or trends over time in meningitis, especially in industrialised countries. Our aim was to do such a study using routinely reported data available in England and Wales. In England and Wales, UK National Health Service hospitals routinely report laboratory-confirmed pathogens electronically to Public Health England. Records of all positive bacterial, mycobacterial, and fungal results from cerebrospinal fluid or from blood cultures in patients with clinical meningitis were extracted for analysis. The percentage change in annual incidence was estimated using linear regression analysis of the log of the annual incidence. During 2004–11, 7061 cases of meningitis were reported (mean annual incidence 1·62 per 100 000 people, 95% CI 1·58–1·66), including 2594 cases in children (37%). The incidence of bacterial (1·44 per 100 000 people, 1·41–1·48), fungal (0·09, 0·08–0·10), and mycobacterial (0·09, 0·08–0·09) meningitis remained stable overall and across the age groups, apart from significant year-on-year increases in children younger than 3 months (978 cases; incidence 72·2 per 100 000 people; annual increase 7·4%, 5·1–9·8; p<0·0001) driven mainly by group B streptococci (GBS), and in adults aged 65 years or older (752 cases; incidence 1·2 per 100 000 people; annual increase 3·0%, 1·4–4·8; p<0·0001) primarily because of Escherichia coli. By contrast, meningococcal meningitis rates declined steadily, but remained the most common cause of meningitis in children. Overall, five groups of bacteria accounted for 60% (3790/6286) of bacterial meningitis cases: Neisseria meningitidis (1350 cases, 22%), Streptococcus pneumoniae (1143, 18%), Staphylococcus aureus (652, 10%), GBS (326, 5%), and E coli (319, 5%). In England and Wales, laboratory-based surveillance shows a remarkably stable incidence of bacterial, fungal, and mycobacterial meningitis in recent years, although there were differences in individual trends among the main pathogens causing meningitis in different age groups. None.

Promotion of physical activity is a priority for health agencies. We searched for reviews of physical activity interventions, published between 2000 and 2011, and identified effective, promising, or emerging interventions from around the world. The informational approaches of community-wide and mass media campaigns, and short physical activity messages targeting key community sites are recommended. Behavioural and social approaches are effective, introducing social support for physical activity within communities and worksites, and school-based strategies that encompass physical education, classroom activities, after-school sports, and active transport. Recommended environmental and policy approaches include creation and improvement of access to places for physical activity with informational outreach activities, community-scale and street-scale urban design and land use, active transport policy and practices, and community-wide policies and planning. Thus, many approaches lead to acceptable increases in physical activity among people of various ages, and from different social groups, countries, and communities.

Targeted gene delivery to the brain is a critical tool for neuroscience research and has significant potential to treat human disease. However, the site-specific delivery of common gene vectors such as adeno-associated viruses (AAVs) is typically performed via invasive injections, which limit its applicable scope of research and clinical applications. Alternatively, focused ultrasound blood-brain-barrier opening (FUS-BBBO), performed noninvasively, enables the site-specific entry of AAVs into the brain from systemic circulation. However, when used in conjunction with natural AAV serotypes, this approach has limited transduction efficiency and results in substantial undesirable transduction of peripheral organs. Here, we use high throughput in vivo selection to engineer new AAV vectors specifically designed for local neuronal transduction at the site of FUS-BBBO. The resulting vectors substantially enhance ultrasound-targeted gene delivery and neuronal tropism while reducing peripheral transduction, providing a more than ten-fold improvement in targeting specificity in two tested mouse strains. In addition to enhancing the only known approach to noninvasively target gene delivery to specific brain regions, these results establish the ability of AAV vectors to be evolved for specific physical delivery mechanisms. Targeted gene delivery to the brain is a critical tool for neuroscience research and has significant potential to treat human disease. Here the authors engineer the protein shell of a common gene therapy vector for enhanced efficiency and specificity of brain delivery in ultrasound-targeted brain regions.

An increasingly popular method of assessing cognitive functions in rodents is the automated touchscreen platform, on which a number of different cognitive tests can be run in a manner very similar to touchscreen methods currently used to test human subjects. This methodology is low stress (using appetitive rather than aversive reinforcement), has high translational potential and lends itself to a high degree of standardization and throughput. Applications include the study of cognition in rodent models of psychiatric and neurodegenerative diseases (e.g., Alzheimer's disease, schizophrenia, Huntington's disease, frontotemporal dementia), as well as the characterization of the role of select brain regions, neurotransmitter systems and genes in rodents. This protocol describes how to perform four touchscreen assays of learning and memory: visual discrimination, object-location paired-associates learning, visuomotor conditional learning and autoshaping. It is accompanied by two further protocols (also published in this issue) that use the touchscreen platform to assess executive function, working memory and pattern separation.

The Community Multiscale Air Quality (CMAQ) model is a comprehensive multipollutant air quality modeling system developed and maintained by the US Environmental Protection Agency's (EPA) Office of Research and Development (ORD). Recently, version 5.1 of the CMAQ model (v5.1) was released to the public, incorporating a large number of science updates and extended capabilities over the previous release version of the model (v5.0.2). These updates include the following: improvements in the meteorological calculations in both CMAQ and the Weather Research and Forecast (WRF) model used to provide meteorological fields to CMAQ, updates to the gas and aerosol chemistry, revisions to the calculations of clouds and photolysis, and improvements to the dry and wet deposition in the model. Sensitivity simulations isolating several of the major updates to the modeling system show that changes to the meteorological calculations result in enhanced afternoon and early evening mixing in the model, periods when the model historically underestimates mixing. This enhanced mixing results in higher ozone (O3) mixing ratios on average due to reduced NO titration, and lower fine particulate matter (PM2. 5) concentrations due to greater dilution of primary pollutants (e.g., elemental and organic carbon). Updates to the clouds and photolysis calculations greatly improve consistency between the WRF and CMAQ models and result in generally higher O3 mixing ratios, primarily due to reduced cloudiness and attenuation of photolysis in the model. Updates to the aerosol chemistry result in higher secondary organic aerosol (SOA) concentrations in the summer, thereby reducing summertime PM2. 5 bias (PM2. 5 is typically underestimated by CMAQ in the summer), while updates to the gas chemistry result in slightly higher O3 and PM2. 5 on average in January and July. Overall, the seasonal variation in simulated PM2. 5 generally improves in CMAQv5.1 (when considering all model updates), as simulated PM2. 5 concentrations decrease in the winter (when PM2. 5 is generally overestimated by CMAQ) and increase in the summer (when PM2. 5 is generally underestimated by CMAQ). Ozone mixing ratios are higher on average with v5.1 vs. v5.0.2, resulting in higher O3 mean bias, as O3 tends to be overestimated by CMAQ throughout most of the year (especially at locations where the observed O3 is low); however, O3 correlation is largely improved with v5.1. Sensitivity simulations for several hypothetical emission reduction scenarios show that v5.1 tends to be slightly more responsive to reductions in NOx (NO + NO2), VOC and SOx (SO2 + SO4) emissions than v5.0.2, representing an improvement as previous studies have shown CMAQ to underestimate the observed reduction in O3 due to large, widespread reductions in observed emissions.

The Adolescent Brain Cognitive Development (ABCD) Study ® is a 10-year longitudinal study of children recruited at ages 9 and 10. A battery of neuroimaging tasks are administered biennially to track neurodevelopment and identify individual differences in brain function. This study reports activation patterns from functional MRI (fMRI) tasks completed at baseline, which were designed to measure cognitive impulse control with a stop signal task (SST; N  = 5,547), reward anticipation and receipt with a monetary incentive delay (MID) task ( N  = 6,657) and working memory and emotion reactivity with an emotional N-back (EN-back) task ( N  = 6,009). Further, we report the spatial reproducibility of activation patterns by assessing between-group vertex/voxelwise correlations of blood oxygen level-dependent (BOLD) activation. Analyses reveal robust brain activations that are consistent with the published literature, vary across fMRI tasks/contrasts and slightly correlate with individual behavioral performance on the tasks. These results establish the preadolescent brain function baseline, guide interpretation of cross-sectional analyses and will enable the investigation of longitudinal changes during adolescent development. This paper reports activation patterns for fMRI tasks assessing response inhibition, working memory and reward processing obtained at baseline in the longitudinal ABCD Study, providing a reference for research into adolescent brain development.

Although tissue-resident memory T cells (T RM cells) are critical in fighting infection, their fate after local pathogen re-encounter is unknown. Here we found that skin T RM cells engaged virus-infected cells, proliferated in situ in response to local antigen encounter and did not migrate out of the epidermis, where they exclusively reside. As a consequence, secondary T RM cells formed from pre-existing T RM cells, as well as from precursors recruited from the circulation. Newly recruited antigen-specific or bystander T RM cells were generated in the skin without displacement of the pre-existing T RM cell pool. Thus, pre-existing skin T RM cell populations are not displaced after subsequent infections, which enables multiple T RM cell specificities to be stably maintained within the tissue. Mackay, Mueller and colleagues show that tissue-resident memory T cells proliferate in situ in response to local antigen and persist during subsequent antigen encounters.