CD4
+ T cells differentiate into multiple effector types, but it is unclear how they form memory T cells during infection in vivo. Profiling virus-specific CD4
+ T cells revealed that effector cells ...with T helper 1 (Th1) or T follicular helper (Tfh) cell characteristics differentiated into memory cells, although expression of Tfh cell markers declined over time. In contrast to virus-specific effector CD8
+ T cells, increased IL-7R expression was not a reliable marker of CD4
+ memory precursor cells. However, decreased Ly6C and T-bet (
Tbx21) expression distinguished a subset of Th1 cells that displayed greater longevity and proliferative responses to secondary infection. Moreover, the gene expression profile of Ly6C
loT-bet
int Th1 effector cells was virtually identical to mature memory CD4
+ T cells, indicating early maturation of memory CD4
+ T cell features in this subset during acute viral infection. This study provides a framework for memory CD4
+ T cell development after acute viral infection.
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► Increased IL-7R expression does not mark CD4
+ memory precursor cells ► T-bet acts in a graded manner to regulate formation of Th1 and Tfh cell subsets ► Ly6C
loT-bet
int Th1 effector CD4
+ cells have enhanced longevity and recall responses ► Ly6C
loT-bet
int Th1 effector and memory CD4
+ cells share similar gene expression
The efficacy of β-lactam antibiotics is threatened by the emergence and global spread of metallo-β-lactamase (MBL) mediated resistance, specifically New Delhi metallo-β-lactamase-1 (NDM-1). By ...utilization of fragment-based drug discovery (FBDD), a new class of inhibitors for NDM-1 and two related β-lactamases, IMP-1 and VIM-2, was identified. On the basis of 2,6-dipicolinic acid (DPA), several libraries were synthesized for structure–activity relationship (SAR) analysis. Inhibitor 36 (IC50 = 80 nM) was identified to be highly selective for MBLs when compared to other Zn(II) metalloenzymes. While DPA displayed a propensity to chelate metal ions from NDM-1, 36 formed a stable NDM-1:Zn(II):inhibitor ternary complex, as demonstrated by 1H NMR, electron paramagnetic resonance (EPR) spectroscopy, equilibrium dialysis, intrinsic tryptophan fluorescence emission, and UV–vis spectroscopy. When coadministered with 36 (at concentrations nontoxic to mammalian cells), the minimum inhibitory concentrations (MICs) of imipenem against clinical isolates of Eschericia coli and Klebsiella pneumoniae harboring NDM-1 were reduced to susceptible levels.
•The CHIME framework is useful for understanding personal recovery in bipolar disorder.•POETIC: Purpose, Optimism and hope, Empowerment, Tensions, Identity, Connectedness.•POETIC extends the ...transdiagnostic CHIME recovery framework with a Tensions domain.•All POETIC personal recovery processes capture negative and positive experiences.•Ambivalence about mania, self-management and work are important in bipolar disorder.
Personal recovery, living a satisfying, hopeful life alongside symptoms, has become an increasingly valued aim across mental health care agendas internationally. However, there is little understanding of how people experience personal recovery alongside the mood challenges characteristic of a bipolar disorder diagnosis. Personal recovery frameworks have been developed for populations with mixed psychiatric diagnoses, predominantly psychotic disorders.
This systematic review of qualitative data used the widely adopted personal recovery processes Connectedness, Hope and optimism, Identity, Meaning and purpose, Empowerment (CHIME) in a “best fit” framework synthesis to understand personal recovery experiences in bipolar disorder. Included studies were coded with deductive framework analysis based on the CHIME processes and inductive thematic analysis for aspects beyond the a priori framework.
A comprehensive search of six literature databases led to inclusion of twelve articles published 2010-2020. Deductive coding supported the fit with the CHIME framework but revealed difficulties, losses, and tensions within and across recovery processes. The proposed framework for personal recovery in bipolar disorder, Purpose and meaning, Optimism and hope, Empowerment, Tensions, Identity, Connectedness (POETIC), organises all CHIME processes around these tensions.
Diversity among study participants was limited with majority middle-aged, female, Western participants.
The compact POETIC personal recovery framework tailored for bipolar disorder is directly applicable to clinical practice with personal recovery objectives. It highlights the need for professionals to introduce personal recovery in a realistic and balanced way to address recent criticism by service user organisations of personal recovery as overly optimistic.
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The transcription factor T-bet is critical for cytotoxic T lymphocyte (CTL) differentiation, but it is unclear how it operates in a graded manner in the formation of both terminal effector and memory ...precursor cells during viral infection. We find that, at high concentrations, T-bet induced expression of Zeb2 mRNA, which then triggered CTLs to adopt terminally differentiated states. ZEB2 and T-bet cooperate to switch on a terminal CTL differentiation program, while simultaneously repressing genes necessary for central memory CTL development. Chromatin immunoprecipitation sequencing showed that a large proportion of these genes were bound by T-bet, and this binding was altered by ZEB2 deficiency. Furthermore, T-bet overexpression could not fully bypass ZEB2 function. Thus, the coordinated actions of T-bet and ZEB2 outline a novel genetic pathway that forces commitment of CTLs to terminal differentiation, thereby restricting their memory cell potential.
Among Gram-negative bacteria, carbapenem-resistant infections pose a serious and life-threatening challenge. Here, the CRACKLE network reports a sentinel detection and characterization of a ...carbapenem-resistant
ST147 isolate harboring
and
from a young man who underwent abdominal surgery in India.
was located on an IncFII plasmid of ≈90 kb, whereas
was chromosomally encoded. Resistome and genome analysis demonstrated multiple copies of the transposable element IS
and a "hot-spot region" in the IncFII plasmid.
Abstract
In an infection with an Enterobacter sp. isolate producing Klebsiella pneumoniae Carbapenemase–4 and New Delhi Metallo-β-Lactamase–1 in the United States, recognition of the molecular basis ...of carbapenem resistance allowed for successful treatment by combining ceftazidime-avibactam and aztreonam. Antimicrobial synergy testing and therapeutic drug monitoring assessed treatment adequacy.
The emergence of multidrug-resistant (MDR) Klebsiella pneumoniae has resulted in a more frequent reliance on treatment using colistin. However, resistance to colistin (Col(r)) is increasingly ...reported from clinical settings. The genetic mechanisms that lead to Col(r) in K. pneumoniae are not fully characterized. Using a combination of genome sequencing and transcriptional profiling by RNA sequencing (RNA-Seq) analysis, distinct genetic mechanisms were found among nine Col(r) clinical isolates. Col(r) was related to mutations in three different genes in K. pneumoniae strains, with distinct impacts on gene expression. Upregulation of the pmrH operon encoding 4-amino-4-deoxy-L-arabinose (Ara4N) modification of lipid A was found in all Col(r) strains. Alteration of the mgrB gene was observed in six strains. One strain had a mutation in phoQ. Common among these seven strains was elevated expression of phoPQ and unaltered expression of pmrCAB, which is involved in phosphoethanolamine addition to lipopolysaccharide (LPS). In two strains, separate mutations were found in a previously uncharacterized histidine kinase gene that is part of a two-component regulatory system (TCRS) now designated crrAB. In these strains, expression of pmrCAB, crrAB, and an adjacent glycosyltransferase gene, but not that of phoPQ, was elevated. Complementation with the wild-type allele restored colistin susceptibility in both strains. The crrAB genes are present in most K. pneumoniae genomes, but not in Escherichia coli. Additional upregulated genes in all strains include those involved in cation transport and maintenance of membrane integrity. Because the crrAB genes are present in only some strains, Col(r) mechanisms may be dependent on the genetic background.
The Military Training Task Force of the Defense Safety Oversight Council chartered a Joint Services Physical Training Injury Prevention Working Group to: (1) establish the evidence base for making ...recommendations to prevent injuries; (2) prioritize the recommendations for prevention programs and policies; and (3) substantiate the need for further research and evaluation on interventions and programs likely to reduce physical training-related injuries.
A work group was formed to identify, evaluate, and assess the level of scientific evidence for various physical training-related injury prevention strategies through an expedited systematic review process. Of 40 physical training-related injury prevention strategies identified, education, leader support, and surveillance were determined to be essential elements of a successful injury prevention program and not independent interventions. As a result of the expedited systematic reviews, one more essential element (research) was added for a total of four. Six strategies were not reviewed. The remaining 31 interventions were categorized into three levels representing the strength of recommendation: (1) recommended; (2) not recommended; and (3) insufficient evidence to recommend or not recommend.
Education, leadership support, injury surveillance, and research were determined to be critical components of any successful injury prevention program. Six interventions (i.e., prevent overtraining, agility-like training, mouthguards, semirigid ankle braces, nutrient replacement, and synthetic socks) had strong enough evidence to become working group recommendations for implementation in the military services. Two interventions (i.e., back braces and pre-exercise administration of anti-inflammatory medication) were not recommended due to evidence of ineffectiveness or harm, 23 lacked sufficient scientific evidence to support recommendations for all military services at this time, and six were not evaluated.
Six interventions should be implemented in all four military services immediately to reduce physical training-related injuries. Two strategies should be discouraged by all leaders at all levels. Of particular note, 23 popular physical training-related injury prevention strategies need further scientific investigation, review, and group consensus before they can be recommended to the military services or similar civilian populations. The expedited systematic process of evaluating interventions enabled the working group to build consensus around those injury prevention strategies that had enough scientific evidence to support a recommendation.
Objectives
To investigate the β-lactamase background of ertapenem non-susceptible isolates for the presence of the most commonly detected carbapenemase genes, bla
KPC, bla
OXA-48 and bla
VIM, and the ...newly described bla
NDM-1.
Methods
Two hundred and thirty-five ertapenem-non-susceptible (MIC ≥0.5 mg/L) isolates of Enterobacteriaceae from the worldwide Study for Monitoring Antimicrobial Resistance Trends (SMART) 2009 programme were screened using a multiplex PCR for the presence of bla
KPC, bla
OXA-48, bla
VIM and bla
NDM-1 genes. Extended-spectrum β-lactamase (ESBL) and AmpC genes (bla
ESBL and bla
AmpC) were identified using the Check-MDR CT101 microarray. DNA sequencing was performed to identify the bla
ESBL, bla
KPC and bla
NDM-1 genes. Molecular typing was also performed to genetically characterize these isolates.
Results
Sixty-six isolates (28%) had a carbapenemase gene, with bla
NDM-1 identified in 33 isolates including 2 isolates carrying both bla
NDM-1 and bla
OXA-48; other carbapenemase genes found included bla
KPC (n = 23), bla
VIM (n = 7) and bla
OXA-48 (n = 3). All bla
NDM-1-carrying isolates were from patients in India and comprised five different species. With the exception of one isolate carrying only bla
NDM-1, all bla
NDM-1 carbapenemase-possessing isolates carried additional β-lactamases in various combinations: bla
ESBL and bla
AmpC (n = 18); bla
ESBL (n = 10); bla
ESBL, bla
AmpC and bla
OXA-48 (n = 2); and bla
AmpC (n = 2). Except for bla
OXA-48-carrying isolates, novel multilocus sequence types or enterobacterial repetitive intergenic consensus PCR patterns were observed along with clonal dissemination within and among sites.
Conclusions
A range of carbapenemase genes, associated with diverse ESBLs and/or AmpC backgrounds, were found among Enterobacteriaceae isolated during the study. Many of these ertapenem non-susceptible strains were clonally related and carried various combinations of β-lactamases.
Several large-scale Alzheimer disease (AD) secondary prevention trials have begun to target individuals at the preclinical stage. The success of these trials depends on validated outcome measures ...that are sensitive to early clinical progression in individuals who are initially asymptomatic.
To investigate the utility of the Cognitive Function Instrument (CFI) to track early changes in cognitive function in older individuals without clinical impairment at baseline.
Longitudinal study from February 2002 through February 2007 at participating Alzheimer's Disease Cooperative Study sites. Individuals were followed up annually for 48 months after the baseline visit. The study included 468 healthy older individuals (Clinical Dementia Rating scale CDR global scores of 0, above cutoff on the modified Mini-Mental State Examination and Free and Cued Selective Reminding Test) (mean SD age, 79.4 3.6 years; age range, 75.0-93.8 years). All study participants and their study partners completed the self and partner CFIs annually. Individuals also underwent concurrent annual neuropsychological assessment and APOE genotyping.
The CFI scores between clinical progressors (CDR score, ≥0.5) and nonprogressors (CDR score, 0) and between APOE ε4 carriers and noncarriers were compared. Correlations of change between the CFI scores and neuropsychological performance were assessed longitudinally.
At 48 months, group differences between clinical progressors and non-progressors were significant for self (2.13, SE=0.45, P<.001), partner (5.08, SE=0.59, P<.001), and self plus partner (7.04, SE=0.83, P<.001) CFI total scores. At month 48, APOE ε4 carriers had greater progression than noncarriers on the partner (1.10, SE=0.44, P<.012) and self plus partner (1.56, SE=0.63, P<.014) CFI scores. Both self and partner CFI change were associated with longitudinal cognitive decline (self, ρ=0.32, 95% CI, 0.13 to 0.46; partner, ρ=0.56, 95% CI, 0.42 to 0.68), although findings suggest self-report may be more accurate early in the process, whereas accuracy of partner report improves when there is progression to cognitive impairment.
Demonstrating long-term clinical benefit will be critical for the success of recently launched secondary prevention trials. The CFI appears to be a brief, but informative potential outcome measure that provides insight into functional abilities at the earliest stages of disease.
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