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Nature Communications Jun 2024HIV-1 Vpr promotes efficient spread of HIV-1 from macrophages to T cells by transcriptionally downmodulating restriction factors that target HIV-1 Envelope protein...
HIV-1 Vpr promotes efficient spread of HIV-1 from macrophages to T cells by transcriptionally downmodulating restriction factors that target HIV-1 Envelope protein (Env). Here we find that Vpr induces broad transcriptomic changes by targeting PU.1, a transcription factor necessary for expression of host innate immune response genes, including those that target Env. Consistent with this, we find silencing PU.1 in infected macrophages lacking Vpr rescues Env. Vpr downmodulates PU.1 through a proteasomal degradation pathway that depends on physical interactions with PU.1 and DCAF1, a component of the Cul4A E3 ubiquitin ligase. The capacity for Vpr to target PU.1 is highly conserved across primate lentiviruses. In addition to impacting infected cells, we find that Vpr suppresses expression of innate immune response genes in uninfected bystander cells, and that virion-associated Vpr can degrade PU.1. Together, we demonstrate Vpr counteracts PU.1 in macrophages to blunt antiviral immune responses and promote viral spread.
Topics: Humans; Macrophages; vpr Gene Products, Human Immunodeficiency Virus; HIV-1; Trans-Activators; Proto-Oncogene Proteins; Immunity, Innate; Ubiquitin-Protein Ligases; HIV Infections; HEK293 Cells; Virion; Protein Serine-Threonine Kinases
PubMed: 38951492
DOI: 10.1038/s41467-024-49635-w -
Influenza and Other Respiratory Viruses Jul 2024The cost of medically attended RSV LRI (lower respiratory infection) is critical in determining the economic value of new RSV immunoprophylaxes. However, most studies...
BACKGROUND
The cost of medically attended RSV LRI (lower respiratory infection) is critical in determining the economic value of new RSV immunoprophylaxes. However, most studies have focused on intermittent RSV encounters, not the episode of care that captures the entirety of RSV illness.
METHODS
We created age- and condition-specific cohorts of children under 5 years of age using MarketScan® data (2015-2019). We contrasted aggregating healthcare costs over RSV-LRTI episodes to ascertaining costs based on RSV-specific encounters only. Economic burden was estimated by multiplying costs per encounter or per episode by their respective incidence rates.
RESULTS
Average cost was higher per episode than per encounter regardless of settings (inpatient: $28,586 vs. $18,056 and outpatient/ED: $2099 vs. $407 for infants). Across ages, the economic burden was highest for infants and RSV-LRTI requiring inpatient care, but the burden in outpatient/ED settings was disproportionately higher than costs due to higher incidence rates (for inpatient vs. outpatient episodes: $226,403 vs. $101,269; for inpatient vs. outpatient encounters: $151,878 vs. $38,819 per 1000 infant-years). For high-risk children, cost and burden were up to 3-10 times higher, respectively.
CONCLUSIONS
With a comprehensive stratification by settings and risk condition, the encounter- versus episode-based estimates provide a robust range for policymakers' economic appraisal of new RSV immunoprophylaxes.
Topics: Humans; Respiratory Syncytial Virus Infections; Infant; Child, Preschool; United States; Cost of Illness; Female; Male; Health Care Costs; Insurance, Health; Hospitalization; Infant, Newborn; Respiratory Tract Infections; Incidence; Respiratory Syncytial Virus, Human
PubMed: 38951044
DOI: 10.1111/irv.13347 -
BMJ Open Jul 2024To determine acceptability and feasibility of a theatre-based wellness programme to support the health and well-being of people with long COVID.
OBJECTIVES
To determine acceptability and feasibility of a theatre-based wellness programme to support the health and well-being of people with long COVID.
DESIGN
Single-group, repeated-measures feasibility study.
SETTING
Community centre and online.
PARTICIPANTS
Adults with diagnosed long COVID experiencing breathlessness, pain and/or loneliness.
INTERVENTION
Six-week participatory creative programme delivered to one online and one in-person group facilitated by movement, voice and drama consultants using breathing, visualisation, singing, poetry, storytelling and movement exercises.
PRIMARY OUTCOME MEASURES
Programme acceptability and feasibility measured via uptake, reasons for non-attendance and barriers to engagement.
SECONDARY OUTCOME MEASURES
Feasibility of recruitment and data collection procedures measured through proportion of missing data and follow-up rates, mechanisms of action of the programme identified through qualitative interviews, changes in mental health, well-being, quality of life, loneliness, social support, fatigue, breathlessness and post-COVID-19 functional status at 8-week follow-up.
RESULTS
21 people expressed interest in participating, 20 people took part in the programme, 19 completed baseline and 16 completed follow-up assessments. Participants attended an average of 4.8 of 6 sessions (SD=1.5, range 2-6). Exploratory analyses demonstrated significant improvements in self-rated health (t-test mean difference=0.12, 95% CI=0.00, 0.23, p=0.04) and chronic fatigue symptoms (mean difference=-3.50, 95% CI=-6.97, -0.03, p=0.05) at 8 weeks. Key mechanisms of action that supported health and well-being included: increased sense of community, illness acceptance, experiencing joy, increased confidence in managing everyday life, increased ability to relax and reconnection with previous identity. Barriers to engagement included: activities being outside of the participant's comfort zone, ongoing long COVID symptoms, emotional consequences of sharing experiences and connectivity and connecting online.
CONCLUSIONS
A 6-week theatre-based programme was perceived as acceptable to most participants and resulted in some positive psychosocial impacts. The findings provide a rationale for supporting the ongoing development and scale-up of this and related arts programmes to support people living with long COVID.
Topics: Humans; COVID-19; Feasibility Studies; Male; Female; Middle Aged; Aged; Quality of Life; Health Promotion; SARS-CoV-2; Drama; Loneliness; Patient Acceptance of Health Care; Adult; Social Support
PubMed: 38951002
DOI: 10.1136/bmjopen-2023-083224 -
BMJ Global Health Jun 2024
Topics: Humans; COVID-19; Pandemics; SARS-CoV-2; Global Health; International Cooperation
PubMed: 38950914
DOI: 10.1136/bmjgh-2024-015458 -
BMJ Global Health Jun 2024The COVID-19 pandemic resulted in extreme strain on health systems including the health workforce, essential health services and vaccination coverage. We examined...
Service disruptions, trauma and burnout during the COVID-19 pandemic among healthcare providers delivering immunisation and maternal and child health services in Indonesia.
BACKGROUND
The COVID-19 pandemic resulted in extreme strain on health systems including the health workforce, essential health services and vaccination coverage. We examined disruptions to immunisation and maternal and child health (MCH) services, concerns of personal well-being and delivery of healthcare during the pandemic as well as factors associated with self-reported trauma or burnout among healthcare providers (HCPs).
METHODS
In March-April 2022, we conducted a cross-sectional survey among HCPs in two provinces of Indonesia. HCPs involved in COVID-19 or routine immunisation and MCH services were randomly selected from district/city health office registration lists. We descriptively analysed service disruptions experienced by HCPs as well as trauma, burnout and concerns of personal well-being and delivery of healthcare during the pandemic. Multivariate logistic regression analyses were undertaken to identify factors associated with trauma or burnout.
RESULTS
We recruited 604 HCPs. Mobilisation of staff from routine health services to COVID-19 response duties was a key reason for service disruptions (87.9%). Strategies such as community outreach and task shifting were implemented to overcome disruptions. Trauma or burnout during the pandemic was reported by 64.1% HCPs, with 23.5% reporting worse mental or emotional health.Factors associated with trauma or burnout included delivery of COVID-19 immunisation (adjusted OR (aOR) 2.54, 95% CI 1.08 to 5.94); and delivery of both COVID-19 immunisation and routine immunisation compared with no involvement in vaccination programmes (aOR 2.42, 95% CI 1.06 to 5.52); poor treatment in the workplace (aOR 2.26, 95% CI 1.51 to 3.38) and lower confidence to respond to patient queries on COVID-19 immunisation (aOR 1.51, 95% CI 1.03 to 2.22).
CONCLUSION
HCPs experienced service disruptions, trauma and burnout and implemented strategies to minimise disruptions to service delivery and improve patient experiences. Our study highlights the need to ensure that workforce resilience and strategies to protect and support HCPs are considered for pandemic planning, preparedness and management.
Topics: Humans; COVID-19; Indonesia; Female; Burnout, Professional; Health Personnel; Adult; Male; Cross-Sectional Studies; Maternal-Child Health Services; Middle Aged; SARS-CoV-2; Immunization; Pandemics
PubMed: 38950913
DOI: 10.1136/bmjgh-2023-014318 -
Molecular Metabolism Jun 2024Aberrant glucolipid metabolism in the heart is a characteristic factor in diabetic cardiomyopathy (DbCM). Super-enhancers-driven noncoding RNAs (seRNAs) are emerging as...
OBJECTIVE
Aberrant glucolipid metabolism in the heart is a characteristic factor in diabetic cardiomyopathy (DbCM). Super-enhancers-driven noncoding RNAs (seRNAs) are emerging as powerful regulators in the progression of cardiac diseases. However, the functions of seRNAs in DbCM have not been fully elucidated.
METHODS
Super enhancers and their associated seRNAs were screened and identified by H3K27ac ChIP-seq data in the Encyclopedia of DNA Elements (ENCODE) dataset. A dual-luciferase reporter assay was performed to analyze the function of super-enhancers on the transcription of peroxisome proliferator-activated receptor α-related seRNA (PPARα-seRNA). A DbCM mouse model was established using db/db leptin receptor-deficient mice. Adeno-associated virus serotype 9-seRNA (AAV9-seRNA) was injected via the tail vein to evaluate the role of seRNA in DbCM. The underlying mechanism was explored through RNA pull-down, RNA and chromatin immunoprecipitation, and chromatin isolation by RNA purification.
RESULTS
PPARα-seRNA was regulated by super-enhancers and its levels were increased in response to high glucose and palmitic acid stimulation in cardiomyocytes. Functionally, PPARα-seRNA overexpression aggravated lipid deposition, reduced glucose uptake, and repressed energy production. In contrast, PPARα-seRNA knockdown ameliorated metabolic disorder in vitro. In vivo, overexpression of PPARα-seRNA exacerbated cardiac metabolic disorder and deteriorated cardiac dysfunction, myocardial fibrosis, and hypertrophy in DbCM. Mechanistically, PPARα-seRNA bound to the histone demethylase KDM4B (Lysine-specific demethylase 4B) and decreased H3K9me3 levels in the promoter region of PPARα, ultimately enhancing its transcription.
CONCLUSIONS
Our study revealed the pivotal function of a super-enhancer-driven long noncoding RNA (lncRNA), PPARα-seRNA, in the deterioration of cardiac function and the exacerbation of metabolic abnormalities in diabetic cardiomyopathy, which recruited KDM4B to the promoter region of PPARα and repression of its transcription. This suggests a promising therapeutic strategy for the treatment of DbCM.
PubMed: 38950776
DOI: 10.1016/j.molmet.2024.101978 -
PLoS Pathogens Jul 2024The regulation of inflammatory responses and pulmonary disease during SARS-CoV-2 infection is incompletely understood. Here we examine the roles of the prototypic pro-...
The regulation of inflammatory responses and pulmonary disease during SARS-CoV-2 infection is incompletely understood. Here we examine the roles of the prototypic pro- and anti-inflammatory cytokines IFNγ and IL-10 using the rhesus macaque model of mild COVID-19. We find that IFNγ drives the development of 18fluorodeoxyglucose (FDG)-avid lesions in the lungs as measured by PET/CT imaging but is not required for suppression of viral replication. In contrast, IL-10 limits the duration of acute pulmonary lesions, serum markers of inflammation and the magnitude of virus-specific T cell expansion but does not impair viral clearance. We also show that IL-10 induces the subsequent differentiation of virus-specific effector T cells into CD69+CD103+ tissue resident memory cells (Trm) in the airways and maintains Trm cells in nasal mucosal surfaces, highlighting an unexpected role for IL-10 in promoting airway memory T cells during SARS-CoV-2 infection of macaques.
PubMed: 38950078
DOI: 10.1371/journal.ppat.1012339 -
PloS One 2024This study aimed to measure student satisfaction with a revised ophthalmology delivery format, which due to the pandemic had previously relied on a remote online flipped...
PURPOSE
This study aimed to measure student satisfaction with a revised ophthalmology delivery format, which due to the pandemic had previously relied on a remote online flipped classroom (OFC) format compared to a blended learning format. This educational strategy combined online learning with in-person seminars and practical patient centred sessions. Our previous investigations demonstrated a significant lack of student satisfaction with a curriculum solely reliant on a remote OFC, as such we hypothesised that a blended learning approach would result in improved levels of student satisfaction and knowledge gain.
METHODS
Non-randomised intervention study of two groups; group 1 = OFC group and group 2 = BL group, compared perspectives of 4th year ophthalmology students using a validated course evaluation questionnaire (CEQ).
RESULTS
A total of 59 students from the BL group (n = 257; response rate = 23.0%) and 28 from the OFC group agreed to participate in the study (n = 114; response rate = 24.6%). Participants in the BL group felt it was easier to determine the standard of work that was expected (77.42% v 60.71%) and demonstrated significantly increased satisfaction with staff motivation of students (95.16% v 64.29%, p <0.001) and provision of feedback (74.19% v 46.43%, p = 0.004), compared to the OFC group. Furthermore, students in the BL group also felt the course significantly improved their analytical skills (64.52% v 42.85%, p = 0.023) and ability to work as part of team (69.36% v 25%, p <0.001) as well as reporting reduced dissatisfaction with the level of choice afforded in terms of how they would learn (33.88% v 60.71%, p = 0.31) and the how they were assessed (59.68% v 89.28%, p = 0.004). No evidence of a statistical difference in exam score was observed.
CONCLUSIONS
The COVID-19 pandemic necessitated an unavoidable pivot to online and distance learning, to meet the challenges presented by government mandates and social distancing requirements. Since many of these directives have been reversed, it is important to evaluate the effectiveness and learner perceptions' of the online and distance learning interventions. In this study we demonstrated a significant student preference for BL compared to the OFC approach, with comparable student performances determined by MCQ examinations. Our findings suggest a preference for reintroducing in-person and patient engagement activities in post-pandemic health professions education.
Topics: Humans; Ophthalmology; Students, Medical; Education, Distance; Male; Female; Personal Satisfaction; Surveys and Questionnaires; Curriculum; COVID-19; Learning; Adult; Education, Medical, Undergraduate; Young Adult; SARS-CoV-2; Educational Measurement
PubMed: 38950050
DOI: 10.1371/journal.pone.0305755 -
PloS One 2024Compelling evidence shows that the COVID-19 pandemic has detrimental effects on the mental health of university students. However, little is known about the...
INTRODUCTION
Compelling evidence shows that the COVID-19 pandemic has detrimental effects on the mental health of university students. However, little is known about the psychological distress experienced by students from high schools during the pandemic. This study, therefore, sought to examine the prevalence of depression, anxiety and stress and their associated factors among students from high schools in Rwanda.
METHODS AND MATERIALS
A retrospective, cross-sectional study was conducted on 384 students randomly selected from high schools. Data were collected using standardized measures of mental disorders and their associated factors. Bivariate and multivariate analyses based on the odds ratio were used to indicate the associated factors of anxiety, depression, and stress.
RESULTS
The results indicated that slightly above half of the participants (51%, n = 195) had clinically significant symptoms of depression, 30.3% (n = 116) had stress and 67.3% (n = 259) had anxiety. Our analyses identified several key risk factors associated with increased odds of these mental disorders. These include exposure to domestic violence, COVID-19 symptoms like cough and myalgia, eating twice per day, having one of the three mental disorders, gender, with females showing higher susceptibility, and direct contact with the people who positively tested covid-19. Conversely, protective factors such as heightened awareness about Covid-19, positive mental health, social support, eating three times, belonging to the third Ubudehe category, and a high resilience emerged as significant elements mitigating the risks of these mental health challenges within our sample. Intriguingly, religious affiliation emerged as a notable factor, with students affiliated with the Witness of Jehovah and Adventist denominations exhibited lower risks for depression and anxiety.
CONCLUSION
Our findings highlighted a high prevalence of depression, anxiety, and stress among students from secondary schools. Interestingly, this study also revealed the associated risk and protective factors of depression, anxiety, and stress in Rwandan students in high schools. Therefore, mental health interventions targeting the impact of COVID-19 on students, as young people are needed.
Topics: Humans; COVID-19; Rwanda; Female; Male; Students; Anxiety; Adolescent; Depression; Stress, Psychological; Prevalence; Cross-Sectional Studies; Retrospective Studies; Risk Factors; Protective Factors; Pandemics; SARS-CoV-2; Young Adult
PubMed: 38950039
DOI: 10.1371/journal.pone.0306389 -
PloS One 2024In the Republic of Ireland, the COVID-19 crisis led to sexual health service closures while clinical staff were redeployed to the pandemic response. Gay, bisexual and...
BACKGROUND
In the Republic of Ireland, the COVID-19 crisis led to sexual health service closures while clinical staff were redeployed to the pandemic response. Gay, bisexual and other men who have sex with men (gbMSM) face pre-existing sexual health inequalities which may have been exacerbated. The aim of this study is to understand sexual health service accessibility for gbMSM in Ireland during the COVID-19 crisis.
METHODS
EMERGE recruited 980 gbMSM in Ireland (June-July 2021) to an anonymous online survey investigating well-being and service access through geo-location sexual networking apps (Grindr/Growlr), social media (Facebook/Instagram/Twitter) and collaborators. We fit multiple regression models reporting odds ratios (ORs) to understand how demographic and behavioural characteristics (age, sexual orientation, HIV testing history/status, region of residence, region of birth and education) were associated with ability to access services.
RESULTS
Of the respondents, 410 gbMSM accessed sexual health services with some or no difficulty and 176 attempted but were unable to access services during the COVID-19 crisis. A further 382 gbMSM did not attempt to access services and were excluded from this sample and analysis. Baseline: mean age 35.4 years, 88% gay, 83% previously tested for HIV, 69% Dublin-based, 71% born in Ireland and 74% with high level of education. In multiple regression, gbMSM aged 56+ years (aOR = 0.38, 95%CI:0.16, 0.88), not previously tested for HIV (aOR = 0.46, 95%CI:0.23, 0.93) and with medium and low education (aOR = 0.55 95%CI:0.35, 0.85) had lowest odds of successfully accessing services. GbMSM with HIV were most likely to be able to access services successfully (aOR = 2.68 95%CI:1.83, 6.08). Most disrupted services were: STI testing, HIV testing and PrEP.
CONCLUSIONS
Service access difficulties were found to largely map onto pre-existing sexual health inequalities for gbMSM. Future service development efforts should prioritise (re)engaging older gbMSM, those who have not previously tested for HIV and those without high levels of education.
Topics: Humans; Male; COVID-19; Ireland; Adult; Middle Aged; Health Services Accessibility; Homosexuality, Male; Sexual Health; Surveys and Questionnaires; Young Adult; Sexual and Gender Minorities; Adolescent; SARS-CoV-2; Pandemics; HIV Infections; Aged; Bisexuality
PubMed: 38950031
DOI: 10.1371/journal.pone.0306280