Response activation and inhibition are functions fundamental to executive control that are disrupted in Parkinson disease (PD). We used magnetoencephalography to examine event related changes in ...oscillatory power amplitude, peak latency and frequency in cortical networks subserving these functions and identified abnormalities associated with PD. Participants (N = 18 PD, 18 control) performed a cue/target task that required initiation of an un-cued movement (activation) or inhibition of a cued movement. Reaction times were variable but similar across groups. Task related responses in gamma, alpha, and beta power were found across cortical networks including motor cortex, supplementary and pre- supplementary motor cortex, posterior parietal cortex, prefrontal cortex and anterior cingulate. PD-related changes in power and latency were noted most frequently in the beta band, however, abnormal power and delayed peak latency in the alpha band in the pre-supplementary motor area was suggestive of a compensatory mechanism. PD peak power was delayed in pre-supplementary motor area, motor cortex, and medial frontal gyrus only for activation, which is consistent with deficits in un-cued (as opposed to cued) movement initiation characteristic of PD.
Prostate cancer screening remains controversial because potential mortality or quality-of-life benefits may be outweighed by harms from overdetection and overtreatment.
To evaluate the effect of a ...single prostate-specific antigen (PSA) screening intervention and standardized diagnostic pathway on prostate cancer-specific mortality.
The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) included 419 582 men aged 50 to 69 years and was conducted at 573 primary care practices across the United Kingdom. Randomization and recruitment of the practices occurred between 2001 and 2009; patient follow-up ended on March 31, 2016.
An invitation to attend a PSA testing clinic and receive a single PSA test vs standard (unscreened) practice.
Primary outcome: prostate cancer-specific mortality at a median follow-up of 10 years. Prespecified secondary outcomes: diagnostic cancer stage and Gleason grade (range, 2-10; higher scores indicate a poorer prognosis) of prostate cancers identified, all-cause mortality, and an instrumental variable analysis estimating the causal effect of attending the PSA screening clinic.
Among 415 357 randomized men (mean SD age, 59.0 5.6 years), 189 386 in the intervention group and 219 439 in the control group were included in the analysis (n = 408 825; 98%). In the intervention group, 75 707 (40%) attended the PSA testing clinic and 67 313 (36%) underwent PSA testing. Of 64 436 with a valid PSA test result, 6857 (11%) had a PSA level between 3 ng/mL and 19.9 ng/mL, of whom 5850 (85%) had a prostate biopsy. After a median follow-up of 10 years, 549 (0.30 per 1000 person-years) died of prostate cancer in the intervention group vs 647 (0.31 per 1000 person-years) in the control group (rate difference, -0.013 per 1000 person-years 95% CI, -0.047 to 0.022; rate ratio RR, 0.96 95% CI, 0.85 to 1.08; P = .50). The number diagnosed with prostate cancer was higher in the intervention group (n = 8054; 4.3%) than in the control group (n = 7853; 3.6%) (RR, 1.19 95% CI, 1.14 to 1.25; P < .001). More prostate cancer tumors with a Gleason grade of 6 or lower were identified in the intervention group (n = 3263/189 386 1.7%) than in the control group (n = 2440/219 439 1.1%) (difference per 1000 men, 6.11 95% CI, 5.38 to 6.84; P < .001). In the analysis of all-cause mortality, there were 25 459 deaths in the intervention group vs 28 306 deaths in the control group (RR, 0.99 95% CI, 0.94 to 1.03; P = .49). In the instrumental variable analysis for prostate cancer mortality, the adherence-adjusted causal RR was 0.93 (95% CI, 0.67 to 1.29; P = .66).
Among practices randomized to a single PSA screening intervention vs standard practice without screening, there was no significant difference in prostate cancer mortality after a median follow-up of 10 years but the detection of low-risk prostate cancer cases increased. Although longer-term follow-up is under way, the findings do not support single PSA testing for population-based screening.
ISRCTN Identifier: ISRCTN92187251.
The human genome folds to create thousands of intervals, called “contact domains,” that exhibit enhanced contact frequency within themselves. “Loop domains” form because of tethering between two ...loci—almost always bound by CTCF and cohesin—lying on the same chromosome. “Compartment domains” form when genomic intervals with similar histone marks co-segregate. Here, we explore the effects of degrading cohesin. All loop domains are eliminated, but neither compartment domains nor histone marks are affected. Loss of loop domains does not lead to widespread ectopic gene activation but does affect a significant minority of active genes. In particular, cohesin loss causes superenhancers to co-localize, forming hundreds of links within and across chromosomes and affecting the regulation of nearby genes. We then restore cohesin and monitor the re-formation of each loop. Although re-formation rates vary greatly, many megabase-sized loops recovered in under an hour, consistent with a model where loop extrusion is rapid.
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•We track the 4D Nucleome during cohesin loss and recovery, with 10 kb/20 min resolution•After cohesin loss, loop domains disappear; effects on transcription are modest•During cohesin recovery, loop domains form in minutes, consistent with fast extrusion•Superenhancers form loops, interchromosomal links, and higher-order hubs
Mapping the nucleome in 4D during cohesin loss and recovery reveals that cohesin degradation eliminates loop domains but has only modest transcriptional consequences.
Several next-generation (universal) influenza vaccines and broadly neutralizing antibodies (bNAbs) are in clinical development. Some of these mediate inhibitions of virus replication at the postentry ...stage or use Fc-dependent mechanisms. Nonneutralizing antibodies have the potential to mediate enhancement of viral infection or disease. In the current study, two monoclonal antibodies (MAbs) 72/8 and 69/1, enhanced respiratory disease (ERD) in mice following H3N2 virus challenge by demonstrating increased lung pathology and changes in lung cytokine/chemokine levels. MAb 78/2 caused changes in the lung viral loads in a dose-dependent manner. Both MAbs increased HA sensitivity to trypsin cleavage at a higher pH range, suggesting MAb-induced conformational changes. pHrodo-labeled virus particles’ entry and residence time in the endocytic compartment were tracked during infection of Madin-Darby canine kidney (MDCK) cells. Both MAbs reduced H3N2 virus residence time in the endocytic pathway, suggesting faster virus fusion kinetics. Structurally, 78/2 and 69/1 Fabs bound the globular head or base of the head domain of influenza hemagglutinin (HA), respectively, and induced destabilization of the HA stem domain. Together, this study describes Mab-induced destabilization of the influenza HA stem domain, faster kinetics of influenza virus fusion, and ERD in vivo. The in vivo animal model and in vitro assays described could augment preclinical safety evaluation of antibodies and next-generation influenza vaccines that generate antibodies which do not block influenza virus–receptor interaction.
Escherichia colisequence type 131 (ST131) has emerged globally as the most predominant extraintestinal pathogenic lineage within this clinically important species, and its association with ...fluoroquinolone and extended-spectrum cephalosporin resistance impacts significantly on treatment. The evolutionary histories of this lineage, and of important antimicrobial resistance elements within it, remain unclearly defined. This study of the largest worldwide collection (n= 215) of sequenced ST131E. coliisolates to date demonstrates that the clonal expansion of two previously recognized antimicrobial-resistant clades, C1/H30R and C2/H30Rx, started around 25 years ago, consistent with the widespread introduction of fluoroquinolones and extended-spectrum cephalosporins in clinical medicine. These two clades appear to have emerged in the United States, with the expansion of the C2/H30Rx clade driven by the acquisition of ablaCTX-M-15-containing IncFII-like plasmid that has subsequently undergone extensive rearrangement. Several other evolutionary processes influencing the trajectory of this drug-resistant lineage are described, including sporadic acquisitions of CTX-M resistance plasmids and chromosomal integration ofblaCTX-Mwithin subclusters followed by vertical evolution. These processes are also occurring for another family of CTX-M gene variants more recently observed among ST131, theblaCTX-M-14/14-likegroup. The complexity of the evolutionary history of ST131 has important implications for antimicrobial resistance surveillance, epidemiological analysis, and control of emerging clinical lineages ofE. coli These data also highlight the global imperative to reduce specific antibiotic selection pressures and demonstrate the important and varied roles played by plasmids and other mobile genetic elements in the perpetuation of antimicrobial resistance within lineages.
Escherichia coli, perennially a major bacterial pathogen, is becoming increasingly difficult to manage due to emerging resistance to all preferred antimicrobials. Resistance is concentrated within specificE. colilineages, such as sequence type 131 (ST131). Clarification of the genetic basis for clonally associated resistance is key to devising intervention strategies. We used high-resolution genomic analysis of a large global collection of ST131 isolates to define the evolutionary history of extended-spectrum beta-lactamase production in ST131. We documented diverse contributory genetic processes, including stable chromosomal integrations of resistance genes, persistence and evolution of mobile resistance elements within sublineages, and sporadic acquisition of different resistance elements. Both global distribution and regional segregation were evident. The diversity of resistance element acquisition and propagation within ST131 indicates a need for control and surveillance strategies that target both bacterial strains and mobile genetic elements.
Schinzel-Giedion syndrome is characterized by severe mental retardation, distinctive facial features and multiple congenital malformations; most affected individuals die before the age of ten. We ...sequenced the exomes of four affected individuals (cases) and found heterozygous de novo variants in SETBP1 in all four. We also identified SETBP1 mutations in eight additional cases using Sanger sequencing. All mutations clustered to a highly conserved 11-bp exonic region, suggesting a dominant-negative or gain-of-function effect.
The International Agency for Research on Cancer (IARC) Monographs program assembles expert working groups who publish a critical review and evaluation of data on agents of interest. These ...comprehensive reviews provide a unique opportunity to identify research needs to address classification uncertainties. A multidisciplinary expert review and workshop held in 2009 identified research gaps and needs for 20 priority occupational chemicals, metals, dusts, and physical agents, with the goal of stimulating advances in epidemiological studies of cancer and carcinogen mechanisms. Overarching issues were also described.
In this commentary we review the current status of the evidence for the 20 priority agents identified in 2009. We examine whether identified Research Recommendations for each agent were addressed and their potential impact on resolving classification uncertainties.
We reviewed the IARC classifications of each of the 20 priority agents and identified major new epidemiological and human mechanistic studies published since the last evaluation. Information sources were either the published Monograph for agents that have been reevaluated or, for agents not yet reevaluated, Advisory Group reports and literature searches. Findings are described in view of recent methodological developments in Monographs evidence evaluation processes.
The majority of the 20 priority agents were reevaluated by IARC since 2009. The overall carcinogen classifications of 9 agents advanced, and new cancer sites with either "sufficient" or "limited" evidence of carcinogenicity were also identified for 9 agents. Examination of published findings revealed whether evidence gaps and Research Recommendations have been addressed and highlighted remaining uncertainties. During the past decade, new research addressed a range of the 2009 recommendations and supported updated classifications for priority agents. This supports future efforts to systematically apply findings of Monograph reviews to identify research gaps and priorities relevant to evaluation criteria established in the updated IARC Monograph Preamble. https://doi.org/10.1289/EHP12547.
Tropical epibenthic dinoflagellate communities produce a plethora of bioactive secondary metabolites, including the toxins ciguatoxins (CTXs) and potentially gambierones, that can contaminate fishes, ...leading to ciguatera poisoning (CP) when consumed by humans. Many studies have assessed the cellular toxicity of causative dinoflagellate species to better understand the dynamics of CP outbreaks. However, few studies have explored extracellular toxin pools which may also enter the food web, including through alternative and unanticipated routes of exposure. Additionally, the extracellular exhibition of toxins would suggest an ecological function and may prove important to the ecology of the CP-associated dinoflagellate species. In this study, semi-purified extracts obtained from the media of a
strain (DISL57) isolated from the U.S. Virgin Islands were assessed for bioactivity via a sodium channel specific mouse neuroblastoma cell viability assay and associated metabolites evaluated by targeted and non-targeted liquid chromatography tandem and high-resolution mass spectrometry. We found that extracts of
media exhibit both veratrine enhancing bioactivity and non-specific bioactivity. LC-HR-MS analysis of the same extract fractions identified gambierone and multiple undescribed peaks with mass spectral characteristics suggestive of structural similarities to polyether compounds. These findings implicate
as a potential contributor to CP and highlight extracellular toxin pools as a potentially significant source of toxins that may enter the food web through multiple exposure pathways.
Infection with Extended-spectrum beta-lactamase -producing
(ESBL-E) is common in infants and leads to increased intensive care unit admission and mortality, but the role of maternal transmission in ...colonization of infants is unclear. Using paired isolates from 50 pairs of mothers and neonates admitted to a Cambodian hospital, we investigated antimicrobial resistance in
and
using whole genome sequencing. We detected a wide variety of ESBL-E genes present in this population along with high levels of multidrug resistance. From 21 pairs where the same organism was present in both mother and neonate, we identified eight pairs with identical or near-identical isolates from both individuals suggestive of transmission at or around birth, including a pair with transmission of multiple strains. We found no evidence for transmission of plasmids only from mother to infant. This suggests vertical transmission outside hospitals as a common cause of ESBL-E colonization in neonates.
The association between increasing water intensive land‐cover, such as the use of turf grass and trees, and increasing water use is a growing concern for water‐stressed arid cities. Appropriate ...regulatory measures addressing residential landscaping, such as those applied by Homeowner Associations (HOAs), may serve to reduce municipal water use, joining other water‐use reducing measures under consideration by arid cities. This research assesses quantitatively the role that Covenants, Conditions, and Restrictions (CCRs) applied to landscaping by HOAs play on water consumption. Statistical comparisons and models of n=1973 parcels in Goodyear, Arizona, USA, reveal that: HOA yards have less vegetation cover and those households use less peak‐season water (July) than those households in non‐HOA neighborhoods. This hold true even though the HOA CCRs regulate only the minimum required front‐yard vegetation and most residents maintain more than the minimum vegetation level. Furthermore, front‐yard landscaping tends to be mimicked in the backyard such that total yard landscaping tracks best with total household water use. Results of the study suggest that HOA landscaping regulations have the potential to reduce peak‐season water use by up to 24% if CCRs were to set maximum vegetation regulations rather than minimum and if compliance were enforced. Lowering residential water consumption in this way potentially involves tradeoffs with the cooling effects of vegetation and its consequences on the urban heat island effect, on energy use, and on home values.
Key Points:
HOAs should emphasize maximum vegetation amounts
HOAs should prescribe vegetation amounts for the total yard not just the front yard
HOAs should limit the surface area of open water features particularly swimming pools
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