Evidence suggests the bactericidal activity of mitochondria-derived reactive oxygen species (mROS) directly contributes to killing phagocytozed bacteria. Infection-responsive components that regulate ...this process remain incompletely understood. We describe a role for the mitochondria-localizing enzyme encoded by Immunoresponsive gene 1 (IRG1) during the utilization of fatty acids as a fuel for oxidative phosphorylation (OXPHOS) and associated mROS production. In a zebrafish infection model, infection-responsive expression of zebrafish irg1 is specific to macrophage-lineage cells and is regulated cooperatively by glucocorticoid and JAK/STAT signaling pathways. Irg1-depleted macrophage-lineage cells are impaired in their ability to utilize fatty acids as an energy substrate for OXPHOS-derived mROS production resulting in defective bactericidal activity. Additionally, the requirement for fatty acid β-oxidation during infection-responsive mROS production and bactericidal activity toward intracellular bacteria is conserved in murine macrophages. These results reveal IRG1 as a key component of the immunometabolism axis, connecting infection, cellular metabolism, and macrophage effector function.
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•GC-driven C/EBPβ and JAK/STAT pathways regulate macrophage irg1 expression•Irg1-depleted macrophages have reduced mROS-dependent bactericidal activity•Macrophages utilize fatty acid β-oxidation to “fuel” Irg1-dependent mROS production•Murine macrophages require β-oxidation for elevated mROS and bactericidal activity
Nanoscale coordination polymers (NCPs) have been demonstrated as an interesting platform for drug delivery, as they possess many advantages over small-molecule chemotherapeutics, such as high ...payloads, lower systemic toxicity, tunability, and enhanced tumor uptake. Existing formulations for the delivery of methotrexate (MTX), an antifolate cancer drug, have very low drug loadings. Herein, we report the incorporation of MTX as a building block in an NCP formulation with exceptionally high drug loadings (up to 79.1 wt%) and the selective delivery of the NCP to cancer cells. Encapsulation of the NCP in a functionalized lipid bilayer allows for targeted delivery and controlled release to cancer cells. A phosphor can be doped into the NCPs for monitoring particle uptake by optical imaging. The lipid-coated and anisamide-targeted NCPs have superior
efficacy against acute lymphoblastic leukemia cells when compared to free drug.
The goals of the study were to examine test-retest reliability, informant agreement and convergent and discriminant validity of nine DSM-IV-TR psychiatric disorders classified by parent and youth ...versions of the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID). Using samples drawn from the general population and child mental health outpatient clinics, 283 youth aged 9 to 18 years and their parents separately completed the MINI-KID with trained lay interviewers on two occasions 7 to 14 days apart. Test-retest reliability estimates based on kappa (κ) went from 0.33 to 0.79 across disorders, samples and informants. Parent-youth agreement on disorders was low (average κ = 0.20). Confirmatory factor analysis provided evidence supporting convergent and discriminant validity. The MINI-KID disorder classifications yielded estimates of test-retest reliability and validity comparable to other standardized diagnostic interviews in both general population and clinic samples. These findings, in addition to the brevity and low administration cost, make the MINI-KID a good candidate for use in epidemiological research and clinical practice.
Public Significance Statement
This study found that the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID), a standardized diagnostic interview used to assess childhood mental disorder, is valid and reliable in both general population and clinic samples. This, in addition to its brevity and low cost, makes the use of the MINI-KID in research and clinical practice appealing.
•Increased disclosure of stuttering was related to elevated quality of life.•Individuals with support group experience disclosed their stuttering more.•Concealment of stuttering from others is not ...uncommon.
This study investigated the disclosure practices of people who stutter, and the relationship between disclosure of stuttering and quality of life.
Participants were 322 adults who stutter recruited from speech-language pathologists and support group leaders. Participants completed a survey that contained items measuring level of disclosure of stuttering, as well as a global measure of self-rated quality of life. Participants were grouped into low, average, and high quality of life subgroups. Analysis of variance tests compared disclosure levels among these subgroups.
The low quality of life subgroup reported significantly lower levels of disclosure compared to both the average and high quality of life subgroups. Participants with self-help/support group experience for stuttering demonstrated significantly higher levels of disclosure of stuttering compared to individuals without such experience. In addition, a substantial number of participants in the overall sample reported that they more than rarely feel the need to conceal stuttering from others (40%), and that no one knows that they stutter in many areas of life (37%).
Attempts to conceal stuttering in at least some life situations are not uncommon among adults who stutter. However, being involved in self-help support groups may be a helpful way of increasing disclosure of stuttering. Speech-language pathologists should become aware of the positive relationship between disclosure of stuttering and quality of life and its relevance in assessment and treatment when working with people who stutter.
Several important pathogens cause disease by surviving and replicating within host cells. Bacterial proliferation is the product of both replication and killing undergone by the population. However, ...these processes are difficult to distinguish, and are usually assessed together by determination of net bacterial load. In addition, measurement of net load does not reveal heterogeneity within pathogen populations. This is particularly important in persistent infections in which slow or nongrowing bacteria are thought to have a major impact. Here we report the development of a reporter system based on fluorescence dilution that enables direct quantification of the replication dynamics of Salmonella enterica serovar Typhimurium (S. Typhimurium) in murine macrophages at both the population and single-cell level. We used this technique to demonstrate that a major S. Typhimurium virulence determinant, the Salmonella pathogenicity island 2 type III secretion system, is required for bacterial replication but does not have a major influence on resistance to killing. Furthermore, we found that, upon entry into macrophages, many bacteria do not replicate, but appear to enter a dormant-like state. These could represent an important reservoir of persistent bacteria. The approach could be extended to other pathogens to study the contribution of virulence and host resistance factors to replication and killing, and to identify and characterize nonreplicating bacteria associated with chronic or latent infections.
Robust tick surveillance enhances diagnosis and prevention of tick-borne pathogens, yet surveillance efforts in the United States are highly uneven, resulting in large surveillance vacuums, one of ...which spans the state of New Mexico. As part of a larger effort to fill this vacuum, we conducted both active and passive tick sampling in New Mexico, focusing on the southern portion of the state. We conducted active tick sampling using dragging and CO₂ trapping at 45 sites across Hidalgo, Doña Ana, Otero, and Eddy counties between June 2021 to May 2022. Sampling occurred intermittently, with at least one sampling event each month from June to October 2021, pausing in winter and resuming in March through May 2022. We also conducted opportunistic, passive tick sampling in 2021 and 2022 from animals harvested by hunters or captured or collected by researchers and animals housed in animal hospitals, shelters, and farms. All pools of ticks were screened for Rickettsia rickettsii, Rickettsia parkeri, Rickettsia amblyommatis, Ehrlichia ewingii, and Ehrlichia chaffeensis. Active sampling yielded no ticks. Passive sampling yielded 497 ticks comprising Carios kelleyi from pallid bats, Rhipicephalus sanguineus from dogs, mule deer, and Rocky Mountain elk, Otobius megnini from dogs, cats, horses, and Coues deer, Dermacentor parumapertus from dogs and black-tailed jackrabbits, Dermacentor albipictus from domesticated cats, mule deer and Rocky Mountain elk, and Dermacentor spp. from American black bear, Rocky Mountain elk, and mule deer. One pool of D. parumapterus from a black-tailed jackrabbit in Luna County tested positive for R. parkeri, an agent of spotted fever rickettsiosis. Additionally, a spotted fever group Rickettsia was detected in 6 of 7 C. kelleyi pools. Two ticks showed morphological abnormalities; however, these samples did not test positive for any of the target pathogens, and the cause of the abnormalities is unknown. Passive surveillance yielded five identified species of ticks from three domestic and six wild mammal species. Our findings update tick distributions and inform the public, medical, and veterinary communities of the potential tick-borne pathogens present in southern New Mexico.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Bathing babies less frequently and intensively in the first six months of life may prevent eczema, but this has not yet been definitively tested in a randomised controlled trial. Such a trial would ...require evidence-based support to help parents engage with a minimal bathing routine. The present study reports the development of this support.
We adopted a four-stage design process: (i) Pregnant women and their families (n = 31) were interviewed to ascertain key barriers and facilitators towards following the minimal bathing intervention. (ii) These barriers and facilitators were mapped to behaviour change techniques, focussing on the intervention types of education, persuasion and environmental restructuring, alongside appropriate modes of delivery, and prototype intervention materials were developed. (iii) We iteratively refined these materials in a workshop with multidisciplinary experts and Patient and Public Involvement and Engagement (PPIE) representatives (n = 13) and an (iv) intervention walkthrough with families (n = 5). The design process was informed by the Behaviour Change Wheel, Theoretical framework of acceptability and the Template for intervention description and replication.
Social influences and motivational factors are likely to influence both uptake and adherence to the intervention. Anticipated emotional reward from participating in research for the benefit of others was indicated to be a strong facilitator for intervention uptake. Alternatives to bathing, having fun with the baby and the night-time routine, alongside family support, were notable facilitators suggested to aid adherence to the intervention. Barriers included hygiene concerns and anticipated negative social appraisal. Barriers and facilitators were mapped to thirty-six behaviour change techniques, focussing on the intervention types of education, persuasion and environmental restructuring, all of which were embedded into the package of support. The prototype intervention materials received positive feedback from the expert workshop and study walkthrough with families. The final package of support comprises printed and digital prompts and cues, a study booklet, video, and digital tool for self-monitoring.
The intervention design process incorporated the 'real world' views and experiences of families, experts and PPIE representatives, alongside criteria for designing behavioural interventions. The effectiveness of the package of support will be tested in a feasibility trial and embedded process evaluation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aim
Evaluation of comfort and pain in neonates is important for management. Specific signs of persistent pain in neonates remain undefined; few validated clinical tools assess persistent pain. We ...sought to determine (i) difficulty perceived by staff and parents in assessing comfort/persistent pain in babies, (ii) strategies employed when no clinical tool is used and (iii) variation between clinicians’ assessments.
Methods
Parent and staff questionnaires addressed difficulty in assessing pain/comfort in neonates and strategies used in making assessments.
Results
A total of 47 of 50 (94%) parents and 83 of 91 (91%) staff participated; 50% of staff reported it was moderately/very difficult to assess persistent pain, and 13% very easy; 75% of parents found it moderately/very easy and 23% difficult to assess their baby's comfort; 15% of parents thought staff found pain assessment difficult. Staff described 94 different factors indicative of comfort and 139 factors of persistent pain. Terminology differed widely and was often nonspecific; 67% of staff described forming a ‘general impression’.
Conclusion
Pain assessment is challenging for staff. Most parents feel confident in assessing their babies’ comfort, but may overestimate the ease with which staff can do so. Indicators of persistent pain/comfort are poorly defined; staff use differing, subjective assessments, which may complicate communication between carers.
Studies measuring psychological distress in individuals with cystic fibrosis (CF) have found high rates of both depression and anxiety. Psychological symptoms in both individuals with CF and parent ...caregivers have been associated with decreased lung function, lower body mass index, worse adherence, worse health-related quality of life, more frequent hospitalisations and increased healthcare costs. To identify and treat depression and anxiety in CF, the CF Foundation and the European CF Society invited a panel of experts, including physicians, psychologists, psychiatrists, nurses, social workers, a pharmacist, parents and an individual with CF, to develop consensus recommendations for clinical care. Over 18 months, this 22-member committee was divided into four workgroups: Screening; Psychological Interventions; Pharmacological Treatments and Implementation and Future Research, and used the Population, Intervention, Comparison, Outcome methodology to develop questions for literature search and review. Searches were conducted in PubMed, PsychINFO, ScienceDirect, Google Scholar, Psychiatry online and ABDATA by a methodologist at Dartmouth. The committee reviewed 344 articles, drafted statements and set an 80% acceptance for each recommendation statement as a consensus threshold prior to an anonymous voting process. Fifteen guideline recommendation statements for screening and treatment of depression and anxiety in individuals with CF and parent caregivers were finalised by vote. As these recommendations are implemented in CF centres internationally, the process of dissemination, implementation and resource provision should be closely monitored to assess barriers and concerns, validity and use.
•Higher epileptiform abnormality burden is associated with worse outcomes in subarachnoid hemorrhage.•Epileptiform abnormalities are frequently treated with anti-epileptic drugs.•Prospective studies ...are needed to delineate the clinical risks and benefits of treatment.
To quantify the burden of epileptiform abnormalities (EAs) including seizures, periodic and rhythmic activity, and sporadic discharges in patients with aneurysmal subarachnoid hemorrhage (aSAH), and assess the effect of EA burden and treatment on outcomes.
Retrospective analysis of 136 high-grade aSAH patients. EAs were defined using the American Clinical Neurophysiology Society nomenclature. Burden was defined as prevalence of <1%, 1–9%, 10–49%, 50–89%, and >90% for each 18–24 hour epoch. Our outcome measure was 3-month Glasgow Outcome Score.
47.8% patients had EAs. After adjusting for clinical covariates EA burden on first day of recording and maximum daily burden were associated with worse outcomes. Patients with higher EA burden were more likely to be treated with anti-epileptic drugs (AEDs) beyond the standard prophylactic protocol. There was no difference in outcomes between patients continued on AEDs beyond standard prophylaxis compared to those who were not.
Higher burden of EAs in aSAH independently predicts worse outcome. Although nearly half of these patients received treatment, our data suggest current AED management practices may not influence outcome.
EA burden predicts worse outcomes and may serve as a target for prospective interventional controlled studies to directly assess the impact of AEDs, and create evidence-based treatment protocols.
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