Background. During the 2012-2013 influenza season, there was cocirculation of influenza A(H3N2) and 2 influenza lineage viruses in the United States. Methods. Patients with acute cough illness for ≤7 ...days were prospectively enrolled and had swab samples obtained at outpatient clinics in 5 states. Influenza vaccination dates were confirmed by medical records. The vaccine effectiveness (VE) was estimated as 100% × (1 - adjusted odds ratio) for vaccination in cases versus test-negative controls. Results. Influenza was detected in 2307 of 6452 patients (36%); 1292 (56%) had influenza A(H3N2), 582 (25%) had influenza B/Yamagata, and 303 (13%) had influenza B/Victoria. VE was 49% (95% confidence interval CI, 43%-55%) overall, 39% (95% CI, 29%-47%) against influenza A(H3N2), 66% (95% CI, 58%-73%) against influenza B/Yamagata (vaccine lineage), and 51% (95% CI, 36%-63%) against influenza B/Victoria. VE against influenza A(H3N2) was highest among persons aged 50-64 years (52%; 95% CI, 33%-65%) and persons aged 6 months-8 years (51%; 95% CI, 32%-64%) and lowest among persons aged ≥65 years (11%; 95% CI, -41% to 43%). In younger age groups, there was evidence of residual protection from receipt of the 2011-2012 vaccine 1 year earlier. Conclusions. The 2012-2013 vaccines were moderately effective in most age groups. Cross-lineage protection and residual effects from prior vaccination were observed and warrant further investigation.
•We reviewed relations between endogenous/exogenous cortisol and human brain function.•Studies reported inconsistent findings, due to heterogeneity in methods and analyses.•Associations between ...cortisol and amygdala activity were most consistently found.
To arrive at a coherent understanding of the relation between glucocorticoids and the human brain, we systematically reviewed the literature for studies examining the associations between endogenous or exogenous cortisol and human brain function. Higher levels of endogenous cortisol during psychological stress were related to increased activity in the middle temporal gyrus and perigenual anterior cingulate cortex (ACC), decreased activity in the ventromedial prefrontal cortex, and altered function (i.e., mixed findings, increased or decreased) in the amygdala, hippocampus and inferior frontal gyrus. Moreover, endogenous cortisol response to psychological stress was related to increased activity in the inferior temporal gyrus and altered function in the amygdala during emotional tasks that followed psychological stress. Exogenous cortisol administration was related to increased activity in the postcentral gyrus, superior frontal gyrus and ACC, and altered function in the amygdala and hippocampus during conditioning, emotional and reward-processing tasks after cortisol administration. These findings were in line with those from animal studies on amygdala activity during and after stress.
Genetic conflict between viruses and their hosts drives evolution and genetic innovation. Prokaryotes evolved CRISPR-mediated adaptive immune systems for protection from viral infection, and viruses ...have evolved diverse anti-CRISPR (Acr) proteins that subvert these immune systems. The adaptive immune system in Pseudomonas aeruginosa (type I-F) relies on a 350 kDa CRISPR RNA (crRNA)-guided surveillance complex (Csy complex) to bind foreign DNA and recruit a trans-acting nuclease for target degradation. Here, we report the cryo-electron microscopy (cryo-EM) structure of the Csy complex bound to two different Acr proteins, AcrF1 and AcrF2, at an average resolution of 3.4 Å. The structure explains the molecular mechanism for immune system suppression, and structure-guided mutations show that the Acr proteins bind to residues essential for crRNA-mediated detection of DNA. Collectively, these data provide a snapshot of an ongoing molecular arms race between viral suppressors and the immune system they target.
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•Cryo-EM structure of crRNA-guided surveillance complex bound to two anti-CRISPRs•Anti-CRISPRs bind to residues that are essential for crRNA-guided DNA binding•Cas7f backbone subunits have unique fold, suggesting a unique evolutionary trajectory•AcrF2 is a molecular mimic of double-stranded DNA
The high-resolution structures of a CRISPR surveillance complex with two viral anti-CRISPR proteins reveal different strategies for silencing CRISPR immune function.
Technology is being increasingly investigated as an option to allow stroke survivors to exploit their full potential for recovery by facilitating home-based upper limb practice. This review seeks to ...explore the factors that influence perseverance with technology-facilitated home-based upper limb practice after stroke.
A systematic mixed studies review with sequential exploratory synthesis was undertaken. Studies investigating adult stroke survivors with upper limb disability undertaking technology-facilitated home-based upper limb practice administered ≥ 3 times/week over a period of ≥ 4 weeks were included. Qualitative outcomes were stroke survivors' and family members' perceptions of their experience utilising technology to facilitate home-based upper limb practice. Quantitative outcomes were adherence and dropouts, as surrogate measures of perseverance. The Mixed Methods Appraisal Tool was used to assess quality of included studies.
Forty-two studies were included. Six studies were qualitative and of high quality; 28 studies were quantitative and eight were mixed methods studies, all moderate to low quality. A conceptual framework of perseverance with three stages was formed: (1) getting in the game; (2) sticking with it, and; (3) continuing or moving on. Conditions perceived to influence perseverance, and factors mediating these conditions were identified at each stage. Adherence with prescribed dose ranged from 13 to 140%. Participants were found to be less likely to adhere when prescribed sessions were more frequent (6-7 days/week) or of longer duration (≥ 12 weeks).
From the mixed methods findings, we propose a framework for perseverance with technology-facilitated home-based upper limb practice. The framework offers opportunities for clinicians and researchers to design strategies targeting factors that influence perseverance with practice, in both the clinical prescription of practice and technology design. To confirm the clinical utility of this framework, further research is required to explore perseverance and the factors influencing perseverance. Registration: PROSPERO CRD42017072799- https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=72799.
The Wistar-Kyoto (WKY) rat is an established depression model characterized by elevated anxiety- and depression-like behavior across a variety of tests. Here we further characterized specific ...behavioral and functional domains relevant to depression that are altered in WKY rats. Moreover, since early-life experience potently shapes emotional behavior, we also determined whether aspects of WKYs' phenotype were modifiable by early-life factors using neonatal handling or maternal separation. We first compared WKYs' behavior to that of Sprague-Dawley (SD), Wistar, and Spontaneously Hypertensive (SHR) rats in: the open field test, elevated plus maze, novelty-suppressed feeding test, a social interaction test, and the forced swim test (FST). WKYs exhibited high baseline immobility in the FST and were the only strain to show increased immobility on FST Day 2 vs. Day 1 (an indicator of learned helplessness). WKYs also showed greater social avoidance, along with enlarged adrenal glands and hearts relative to other strains. We next tested whether neonatal handling or early-life maternal separation stress influenced WKYs' behavior. Neither manipulation affected their anxiety- and depressive-like behaviors, likely due to a strong genetic underpinning of their phenotype. Our findings indicate that WKY rats are a useful model that captures specific functional domains relevant to clinical depression including: psychomotor retardation, behavioral inhibition, learned helplessness, social withdrawal, and physiological dysfunction. WKY rats appear to be resistant to early-life manipulations (i.e., neonatal handling) that are therapeutic in other strains, and may be a useful model for the development of personalized anti-depressant therapies for treatment resistant depression.
Underrepresented groups may be dissuaded from clinical trial participation without perceived value. We therefore comprehensively assessed gynecologic cancer clinical trial protocols for the inclusion ...of items of value most important to Black individuals.
ClinicalTrials.gov was queried for NCI-sponsored gynecologic cancer clinical trials in the US between Jan.1994 and Nov.2021. Pre-specified return of value (ROV) items were abstracted from each protocol. Inclusion proportions were calculated for each ROV item and temporal changes assessed with chi-square tests. Temporality of proportional trends was further assessed by slope and departure from linearity calculations.
279 gynecologic cancer clinical trials were included. Most commonly trials had first accrual in 2001–2007 (37%) and involved ovarian cancer (48%), phase II studies (53%), and chemotherapy (60%) or targeted therapy (34%). Trials often included ROV items in basic information (99%), medical record information (99%), and imaging (82%). 41% of trials included ROV items in biomarker testing, 20% genetic testing, and 20% in patient-reported outcome questionnaires. Over time, there were significant increases in the proportion of trials that included genetic (3% to 51%; p < 0.001) and biomarker testing (14 to 78%, p < 0.001). Information on lifestyle risk factors was rare (1%). No trials included ROV items in ancestry, how to connect with other participants, or remuneration.
Gynecologic cancer clinical trials include few design elements that provide high value to Black individuals like lifestyle risk factors, ancestry, and remuneration. In any multi-pronged effort to improve diversity in clinical trial enrollment, inclusion of items valued by Black individuals should be considered.
•Black women are underrepresented in gynecologic cancer clinical trials despite disproportionately worse cancer outcomes•Survey-based ‘return of value’ items show trial design factors that increase desire to participate among Black individuals•Gynecologic cancer clinical trials lack facilitators, information, and results Black individuals perceive as most valuable•Lack of valuable facilitators, information, and results may contribute to low accrual of Black women in cancer research•The results can be used to create person-centered, community-informed clinical trial design for gynecologic cancer research
Background. Each year, the US Influenza Vaccine Effectiveness Network examines the effectiveness of influenza vaccines in preventing medically attended acute respiratory illnesses caused by ...influenza. Methods. Patients with acute respiratory illnesses of ≤7 days' duration were enrolled at ambulatory care facilities in 5 communities. Specimens were collected and tested for influenza by real-time reverse-transcriptase polymerase chain reaction. Receipt of influenza vaccine was defined based on documented evidence of vaccination in medical records or immunization registries. Vaccine effectiveness was estimated in adjusted logistic regression models by comparing the vaccination coverage in those who tested positive for influenza with those who tested negative. Results. The 2011–2012 season was mild and peaked late, with circulation of both type A viruses and both lineages of type B. Overall adjusted vaccine effectiveness was 47% (95% confidence interval CI, 36–56) in preventing medically attended influenza; vaccine effectiveness was 65% (95% CI, 44–79) against type A (H1N1) pdm09 but only 39% (95% CI, 23–52) against type A (H3N2). Estimates of vaccine effectiveness against both type B lineages were similar (overall, 58%; 95% CI, 35–73). An apparent negative effect of prior year vaccination on current year effectiveness estimates was noted, particularly for A (H3N2) outcomes. Conclusions. Vaccine effectiveness in the 2011–2012 season was modest overall, with lower effectiveness against the predominant A (H3N2) virus. This may be related to antigenic drift, but past history of vaccination might also play a role.
Both human and animal studies support the relationship between depression and reward processing abnormalities, giving rise to the expectation that neural signals of these processes may serve as ...biomarkers or mechanistic treatment targets. Given the great promise of this research line, we scrutinized those findings and the theoretical claims that underlie them. To achieve this, we applied the framework provided by classical work on causality as well as contemporary approaches to prediction. We identified a number of conceptual, practical, and analytical challenges to this line of research and used a preregistered meta-analysis to quantify the longitudinal associations between reward processing abnormalities and depression. We also investigated the impact of measurement error on reported data. We found that reward processing abnormalities do not reach levels that would be useful for clinical prediction, yet the available evidence does not preclude a possible causal role in depression.
New chemotherapeutics active against multidrug-resistant Mycobacterium tuberculosis are urgently needed. We report on the identification of an adamantyl urea compound that shows potent bactericidal ...activity against M. tuberculosis and a unique mode of action, namely the abolition of the translocation of mycolic acids from the cytoplasm, where they are synthesized to the periplasmic side of the plasma membrane and are in turn transferred onto cell wall arabinogalactan or used in the formation of virulence-associated, outer membrane, trehalose-containing glycolipids. Whole-genome sequencing of spontaneous-resistant mutants of M. tuberculosis selected in vitro followed by genetic validation experiments revealed that our prototype inhibitor targets the inner membrane transporter MmpL3. Conditional gene expression of mmpL3 in mycobacteria and analysis of inhibitor-treated cells validate MmpL3 as essential for mycobacterial growth and support the involvement of this transporter in the translocation of trehalose monomycolate across the plasma membrane.
•Low (vs. high) novelty-reactive rats exhibit distinct amygdalar transcriptomes.•DNA methylation patterns differed across the genome of low (vs. high) reactive rats.•Low novelty-reactive rats ...displayed many hypomethylated genomic sites.•Increased dietary methyl donors improved helpless behavior in low reactive rats.
Understanding biological mechanisms that shape vulnerability to emotional dysfunction is critical for elucidating the neurobiology of psychiatric illnesses like anxiety and depression. To elucidate molecular and epigenetic alterations in the brain that contribute to individual differences in emotionality, our laboratory utilized a rodent model of temperamental differences. Rats bred for low response to novelty (Low Responders, LRs) are inhibited in novel situations and display high anxiety, helplessness, and diminished sociability compared to High Novelty Responder (HR) rats. Our current transcriptome profiling experiment identified widespread gene expression differences in the amygdala of adult HR/LR rats; we hypothesize that HR/LR gene expression and downstream behavioral differences stem from distinct epigenetic (specifically DNA methylation) patterning in the HR/LR brain. Although we found similar levels of DNA methyltransferase proteins in the adult HR/LR amygdala, next-generation sequencing analysis of the methylome revealed 793 differentially methylated genomic sites between the groups. Most of the differentially methylated sites were hypermethylated in HR versus LR, so we next tested the hypothesis that enhancing DNA methylation in LRs would improve their anxiety/depression-like phenotype. We found that increasing DNA methylation in LRs (via increased dietary methyl donor content) improved their anxiety-like behavior and decreased their typically high levels of Forced Swim Test (FST) immobility; however, dietary methyl donor depletion exacerbated LRs’ high FST immobility. These data are generally consistent with findings in depressed patients showing that treatment with DNA methylation-promoting agents improves depressive symptoms, and highlight epigenetic mechanisms that may contribute to individual differences in risk for emotional dysfunction.
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