bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quercetin targets SarA of methicillin-resistant
Staphylococcus aureus
to mitigate biofilm formation
Authors: Liu Panpan , Kang Xinyun , Chen Xiaohui , Luo Xiaofeng , Li Caixia , Wang Guiqin 
Published: November 2023

ABSTRACT

The emergence of methicillin-resistant
Staphylococcus aureus
(MRSA) led to the failure of conventional antibiotic treatment, resulting in serious morbidity and mortality. The biofilm formation of
S. aureus
is a potential mechanism for drug resistance. SarA is an important regulatory protein for the formation of
S. aureus
biofilm. In this study, the global regulator SarA was used as a target to virtually screen natural active monomers. SarA inhibitor quercetin (QEN) was assessed. Molecular docking and kinetic simulation showed that QEN was stably bound to the formation site of SarA dimer. Spectral analysis verified that QEN was bound to SarA and changed its conformation.
In vitro
biofilm, the culture showed that 4 µg/mL QEN significantly inhibited biofilm formation, and the production of extracellular polymers and eDNA concentration significantly reduced. Scanning electron microscopy and laser confocal microscopy further confirmed the inhibitory effect of QEN on biofilm formation. At the same time, a decrease in the transcription level of
sarA
and its downstream genes related to biofilm regulation and a decrease in the expression level of SarA were also observed, confirming the QEN-induced inhibition of
sarA
. In conclusion, the results of this study revealed SarA-mediated anti-biofilm effect of QEN on MRSA.

IMPORTANCE

Anti-biofilm is an important strategy against
Staphylococcus aureus
chronic infection. SarA is a positive regulator of biofilm formation in
S. aureus
. In this study, we identified the SarA inhibitor quercetin using computer simulation screening. Previous studies have shown that quercetin inhibits biofilm; however, the underlying mechanism remains unknown. This study revealed the inhibitory effect of quercetin on the SarA protein. We also isolated the SarA protein and confirmed its interaction with quercetin
in vitro
. Besides, the inhibitory effect of quercetin on the transcription and translation levels of the SarA protein was also determined. The effects of quercetin on
S. aureus
biofilm inhibition and biofilm components were consistent with the changes in the transcription level of biofilm-related genes regulated by SarA. In summary, our study revealed the mechanism by which quercetin affects biofilm formation by inhibiting the transcriptional regulator SarA of
S. aureus
.
Zika virus infection triggers caspase cleavage of STAT1
Authors: Shu Jun , Ma Xiao , Zou Jingyi , Yuan Zhenghong , Yi Zhigang 
Published: November 2023

ABSTRACT
Zika virus (ZIKV) is an important pathogen that causes Guillain-Barre syndrome in adults and congenital Zika syndrome in newborns. Interferon (IFN) triggers intracellular antiviral signaling through two essential mediators STAT1 and STAT2, which are critical for host innate antiviral immunity. ZIKV has been reported to antagonize host IFN signaling by diverse mechanisms, including NS5-dependent and -independent ablation of STAT2. Whether flaviviruses target STAT1 remains controversial. In this study, we used infectious clones of ZIKV MR766 as tools and found that ZIKV infection triggered caspase-dependent cleavage of STAT1 during late infection. Further studies identified that the cleavage site is the aspartic acid 694, and the D694A mutation rendered STAT1 resistant to ZIKV infection-induced cleavage. Murine STAT1 (mSTAT1) was resistant to cleavage in ZIKV-infected cells. Ectopically expressed STAT1.D694A and mSTAT1 exerted comparable anti-ZIKV activity upon IFN treatment, challenging the role of STAT1 cleavage in IFN antagonism. We further knocked out STAT1 in the mouse embryonic fibroblast NIH3T3 cells, and STAT1 knockout dramatically augmented ZIKV infection, suggesting a STAT1-mediated viral restriction. Intriguingly, in the STAT1-knockout NIH3T3 cells, complementation of mSTAT1.D695G, a cleavage-sensitive variant, and the wild-type mSTAT1 both restored comparable anti-viral activities. These data suggest that caspase-mediated STAT1 cleavage is dispensable for IFN antagonism in ZIKV-infected cells.

IMPORTANCE
Zika virus (ZIKV) is a re-emerging flavivirus. Similar to other flaviviruses, ZIKV antagonizes the host interferon (IFN) signaling pathway to establish infection. Understanding the molecular mechanism by which ZIKV antagonizes IFN-induced antiviral signaling may lead to a new antiviral strategy by cracking the IFN antagonism. Flaviviruses have been reported to employ NS5-dependent and -independent mechanisms to block STAT2-mediated signaling, whereas whether flaviviruses target STAT1 remains controversial. Herein, we found that ZIKV infection triggered caspase-dependent cleavage of STAT1 at the aspartic acid 694 during late infection, whereas murine STAT1 (mSTAT1) was resistant to cleavage. Intriguingly, ectopically expressed cleavage-resistant human STAT1.D694A or complementation of cleavable mSTAT1.D695G exerted comparable anti-ZIKV activity with their counterparts, challenging the role of caspase-mediated STAT1 cleavage in the IFN antagonism in ZIKV-infected cells. These data may also imply a dominant role of the antagonism of STAT2 but not STAT1 in ZIKV-infected cells.
Association between leisure sedentary behaviour and uterine fibroids in non-menopausal women: a population-based study
Authors: Sun Yunrui , Han Xiaoyu , Hou Zhongxin , Deng Haoyuan , Cheng Nan , Zhang Nishang , Zhang Jianghui , Li Yi , Wang Qian , Yin Jianzhong , Meng Qiong 
Published: November 2023

ObjectiveSedentary behaviour is associated with a variety of adverse health outcomes, including obesity, oestrogen metabolism and chronic inflammation, all of which are related to the pathogenesis of uterine fibroids (UFs). This study aimed to explore the relationship between leisure sedentary time (LST) and UFs.DesignCross-sectional.SettingWe conducted a cross-sectional analysis of data from patients from the Yunnan region in the China Multi-Ethnic Cohort Study.ParticipantsA total of 6623 non-menopausal women aged 30–55 years old were recruited. Menstrual status was self-reported. Participants who lacked a unique national identity card, suffered from serious mental illness, did not have a clear diagnosis of UFs, or provided incomplete information were excluded.Primary and secondary outcomeUFs were diagnosed by abdominal B-ultrasound. Leisure sedentary behaviour was assessed by using a face-to-face questionnaire interview. Logistic regression and restricted cubic spline were employed to explore the relationship between LST and UFs.ResultsA total of 562 participants had UFs, with a prevalence rate of 8.5% (7.8%, 9.2%). Multivariate adjusted logistic regression analysis showed that the risk of UFs in women with LST≥6 hour/day was 2.008 times that in women with LST<2 hour/day (95% CI 1.230 to 3.279). The restricted cubic spline results showed that there was a linear dose‒response relationship between LST and UFs (p for non-linearity>0.05). According to the results of the stratified analysis for menstrual status and body mass index (BMI), there was a correlation between LST and the prevalence of UFs only in women with a BMI<24 kg/m2or perimenopause.ConclusionLST was independently associated with the prevalence of UFs, and a linear dose‒response relationship was observed. Our study provides evidence on the factors influencing UFs, and further research is needed to propose feasible measures for UFs prevention.
Patient safety in remote primary care encounters: multimethod qualitative study combining Safety I and Safety II analysis
Authors: Payne Rebecca , Clarke Aileen , Swann Nadia , van Dael Jackie , Brenman Natassia , Rosen Rebecca , Mackridge Adam , Moore Lucy , Kalin Asli , Ladds Emma , Hemmings Nina , Rybczynska-Bunt Sarah , Faulkner Stuart , Hanson Isabel , Spitters Sophie , Wieringa Sietse , Dakin Francesca H , Shaw Sara E , Wherton Joseph , Byng Richard , Husain Laiba , Greenhalgh Trisha 
Published: November 2023

Background
Triage and clinical consultations increasingly occur remotely. We aimed to learn why safety incidents occur in remote encounters and how to prevent them.

Setting and sample
UK primary care. 95 safety incidents (complaints, settled indemnity claims and reports) involving remote interactions. Separately, 12 general practices followed 2021–2023.

Methods
Multimethod qualitative study. We explored causes of real safety incidents retrospectively (‘Safety I’ analysis). In a prospective longitudinal study, we used interviews and ethnographic observation to produce individual, organisational and system-level explanations for why safety and near-miss incidents (rarely) occurred and why they did not occur more often (‘Safety II’ analysis). Data were analysed thematically. An interpretive synthesis of why safety incidents occur, and why they do not occur more often, was refined following member checking with safety experts and lived experience experts.

Results
Safety incidents were characterised by inappropriate modality, poor rapport building, inadequate information gathering, limited clinical assessment, inappropriate pathway (eg, wrong algorithm) and inadequate attention to social circumstances. These resulted in missed, inaccurate or delayed diagnoses, underestimation of severity or urgency, delayed referral, incorrect or delayed treatment, poor safety netting and inadequate follow-up. Patients with complex pre-existing conditions, cardiac or abdominal emergencies, vague or generalised symptoms, safeguarding issues, failure to respond to previous treatment or difficulty communicating seemed especially vulnerable. General practices were facing resource constraints, understaffing and high demand. Triage and care pathways were complex, hard to navigate and involved multiple staff. In this context, patient safety often depended on individual staff taking initiative, speaking up or personalising solutions.

Conclusion
While safety incidents are extremely rare in remote primary care, deaths and serious harms have resulted. We offer suggestions for patient, staff and system-level mitigations.
Health services under pressure: a scoping review and development of a taxonomy of adaptive strategies
Authors: Page Bethan , Irving Dulcie , Amalberti Rene , Vincent Charles 
Published: November 2023

ObjectiveThe objective of this review was to develop a taxonomy of pressures experienced by health services and an accompanying taxonomy of strategies for adapting in response to these pressures. The taxonomies were developed from a review of observational studies directly assessing care delivered in a variety of clinical environments.DesignIn the first phase, a scoping review of the relevant literature was conducted. In the second phase, pressures and strategies were systematically coded from the included papers, and categorised.Data sourcesElectronic databases (MEDLINE, Embase, CINAHL, PsycInfo and Scopus) and reference lists from recent reviews of the resilient healthcare literature.Eligibility criteriaStudies were included from the resilient healthcare literature, which used descriptive methodologies to directly assess a clinical environment. The studies were required to contain strategies for managing under pressure.Results5402 potential articles were identified with 17 papers meeting the inclusion criteria. The principal source of pressure described in the studies was the demand for care exceeding capacity (ie, the resources available), which in turn led to difficult working conditions and problems with system functioning. Strategies for responding to pressures were categorised into anticipatory and on-the-day adaptations. Anticipatory strategies included strategies for increasing resources, controlling demand and plans for managing the workload (efficiency strategies, forward planning, monitoring and co-ordination strategies and staff support initiatives). On-the-day adaptations were categorised into: flexing the use of existing resources, prioritising demand and adapting ways of working (leadership, teamwork and communication strategies).ConclusionsThe review has culminated in an empirically based taxonomy of pressures and an accompanying taxonomy of strategies for adapting in response to these pressures. The taxonomies could help clinicians and managers to optimise how they respond to pressures and may be used as the basis for training programmes and future research evaluating the impact of different strategies.
Delayed vaccine-induced CD8+T cell expansion by topoisomerase I inhibition mediates enhanced CD70-dependent tumor eradication
Authors: van der Sluis Tetje C , van Haften Floortje J , van Duikeren Suzanne , Pardieck Iris N , de Graaf J Fréderique , Vleeshouwers Ward , van der Maaden Koen , Melief Cornelis J M , van der Burg Sjoerd H , Arens Ramon 
Published: November 2023

BackgroundThe survival of patients with cervical cancer who are treated with cisplatin in conjunction with the topoisomerase I inhibitor topotecan is enhanced when compared with patients treated with only one of these chemotherapeutics. Moreover, cisplatin-based and T cell-based immunotherapy have been shown to synergize, resulting in stronger antitumor responses. Here, we interrogated whether topotecan could further enhance the synergy of cisplatin with T cell-based cancer immunotherapy.MethodsMice bearing human papilloma virus 16 (HPV16) E6/E7-expressing TC-1 tumors were vaccinated with HPV16 E7 long peptides and additionally received chemotherapy consisting of cisplatin and topotecan. We performed an in-depth study of this combinatorial chemoimmunotherapy on the effector function and expansion/contraction kinetics of vaccine-induced CD8+T cells in the peripheral blood and tumor microenvironment (TME). In addition, we interrogated the particular role of chemotherapy-induced upregulation of costimulatory ligands by tumor-infiltrated myeloid cells on T cell proliferation and survival.ResultsWe show that E7 long peptide vaccination combined with cisplatin and topotecan, results in CD8+T cell-dependent durable rejection of established tumors and 94% long-term survival. Although topotecan initially repressed the expansion of vaccine-induced CD8+T cells, these cells eventually expanded vigorously, which was followed by delayed contraction. These effects associated with the induction of the proliferation marker Ki-67 and the antiapoptosis molecule Bcl-2 by intratumoral tumor-specific CD8+T cells, which was regulated by topotecan-mediated upregulation of the costimulatory ligand CD70 on myeloid cells in the TME.ConclusionsTaken together, our data show that although treatment with cisplatin, topotecan and vaccination initially delays T cell expansion, this combinatorial therapy results eventually in a more robust T cell-mediated tumor eradication due to enhancement of costimulatory molecules in the TME.
Supportive relationships between patients and family caregivers in specialist palliative care: a qualitative study of barriers and facilitators
Authors: McCauley Rachel , Ryan Karen , McQuillan Regina , Selman Lucy E , Foley Geraldine 
Published: November 2023

ObjectivesPatients with advanced illness and their family caregivers can be mutually supportive. However, what facilitates and/or restricts supportive relationships between patients and family caregivers in palliative care remains unclear. We aimed to identify key barriers to and facilitators of supportive relationships between people with advanced illness and family caregivers in specialist palliative care.MethodsA qualitative study using grounded theory methodology was conducted. Semistructured interviews were undertaken with 15 patients with advanced illness and 21 family caregivers purposively and theoretically sampled from a large regional specialist palliative care service. Verbatim transcripts were analysed in line with grounded theory coding procedures.ResultsMutual support was underpinned by mutual concern and understanding. Facilitators of supportive relationships included patients and family caregivers already having a close relationship, caregivers assuming caregiving duties by choice, caregivers feeling competent in a caregiving role, patients valuing caregiver efforts, availability of respite for the caregiver and direct support from healthcare professionals to help both patients and caregivers adjust to advanced illness. Barriers to supportive relationships included absence of support from the wider family, prior mutual conflict between the patient and caregiver, caregivers feeling constrained in their caregiving role and patient and caregiver distress induced by mutual loss.ConclusionsMultiple factors at both a micro (eg, relationship based) and mesolevel (eg, assistance from services) impact patient and family caregiver ability to support one another in specialist palliative care. Supportive relationships between patients and family caregivers are mediated by feelings pertaining to both control and loss.
Futile life-sustaining treatment in the intensive care unit – nurse and physician experiences: meta-synthesis
Authors: Choi Hye Ri , Ho Mu-Hsing , Lin Chia-Chin 
Published: November 2023

BackgroundContinuing futile life-sustaining treatment prolongs patients’ suffering and family members’ and medical staff’s psychological distress. Additionally, continuing futile treatment is inefficient in healthcare resource distribution. Although the withdrawal of futile life-sustaining treatment is ideal, the prevalence is variable.ObjectiveTo synthesise nurses’ and physicians’ experiences with continuing futile life-sustaining treatment in the intensive care unit.DesignThis meta-synthesis was conducted following the thematic synthesis. The Preferred Reporting Items for Systematic Review and Meta-Analyses and Enhancing transparency in reporting the synthesis of qualitative research statement were used in reporting the synthesis of qualitative research statements.Methods and data sourcesA systematic search was conducted following the inclusion and exclusion criteria in APA PsycINFO, CINAHL Plus, EMBASE, MEDLINE, PubMed and Web of Science in May 2023. Two reviewers independently screened and extracted the data. The extracted data were analysed using thematic analysis of qualitative research.FindingsA total of 16 studies were finally included, and 141 quotes were extracted and analysed. The main findings were categorised into four themes: (1) contextual and cultural diversity, (2) perceptions of futile treatment, (3) professional roles and responsibilities, and (4) emotional distress.ConclusionThe study highlights the influence of culture, religion and family members, as well as perceptions of futile treatment among clinicians, on continuing futile life-sustaining treatment. Also, nurses’ awareness of their roles and responsibilities in ensuring patients’ comfort at end of life was revealed. This study informs future research to explore the experiences of futile life-sustaining treatment across various contexts.
Mortality and Morbidity of Heart Failure Hospitalization in Adult Patients With Congenital Heart Disease
Authors: Agasthi Pradyumna , Van Houten Holly K. , Yao Xiaoxi , Jain C. Charles , Egbe Alexander , Warnes Carole A. , Miranda William R. , Dunlay Shannon M. , Stephens Elizabeth H. , Johnson Jonathan N. , Connolly Heidi M. , Burchill Luke J. 
Published: November 2023

Background
Little is known about outcomes following heart failure (HF) hospitalization among adults with congenital heart disease (CHD) in the United States. We aim to compare the outcomes of HF versus non‐HF hospitalizations in adults with CHD.

Methods and Results

Using a national deidentified administrative claims data set, patients with adult congenital heart disease (ACHD) hospitalized with and without HF (ACHDHF+, ACHDHF−) were characterized to determine the predictors of 90‐day and 1‐year mortality and quantify the risk of mortality, major adverse cardiac and cerebrovascular events, and health resource use. Cox proportional hazard regression was used to compare ACHDHF+ versus ACHDHF− for risk of events and health resource use. Of 26 454 unique ACHD admissions between January 1, 2010 and December 31, 2020, 5826 (22%) were ACHDHF+ and 20 628 (78%) were ACHDHF−. The ACHD HF+ hospitalizations increased from 6.6% to 14.0% (
P
<0.0001). Over a mean follow‐up period of 2.23 ± 2.19 years, patients with ACHDHF+ had a higher risk of mortality (hazard ratio [HR], 1.86 [95% CI, 1.67–2.07],
P
<0.001), major adverse cardiac and cerebrovascular events (HR, 1.73 [95% CI, 1.63–1.83],
P
<0.001) and health resource use including rehospitalization (HR, 1.09 [95% CI, 1.05–1.14],
P
<0.001) and increased postacute care service use (HR, 1.56 [95% CI, 1.32–1.85],
P
<0.001). Cardiology clinic visits within 30 days of hospital admission were associated with lower 90‐day and 1‐year all‐cause mortality (odds ratio [OR], 0.62 [95% CI, 0.49–0.78],
P
<0.001; OR, 0.69 [95% CI, 0.58–0.83],
P
<0.001, respectively).

Conclusions
HF hospitalization is associated with increased risk of mortality and morbidity with high health resource use in patients with ACHD. Recent cardiology clinic attendance appears to mitigate these risks.
Association Between Onset Age of Coronary Heart Disease and Incident Dementia: A Prospective Cohort Study
Authors: Liang Jie , Li Chenglong , Gao Darui , Ma Qian , Wang Yongqian , Pan Yang , Zhang Wenya , Xie Wuxiang , Zheng Fanfan 
Published: November 2023

Background
The association of age at coronary heart disease (CHD) onset with incident dementia remains unexplored. This study aimed to examine whether younger onset age of CHD is associated with a higher risk of incident dementia.

Methods and Results

Data were obtained from the UK Biobank. Information on the diagnosis of CHD and dementia was collected at baseline and follow‐ups. Propensity score matching method and Cox proportional hazards models were used to evaluate the association between different ages at CHD onset and incident dementia. A total of 432 667 adults (mean±SD age, 56.9±8.1 years) were included, of whom 11.7% had CHD. Compared with participants without CHD, participants with CHD exhibited higher risks of developing all‐cause dementia, Alzheimer's disease, and vascular dementia. More importantly, younger age at CHD onset (per 10‐year decrease) was significantly associated with elevated risks of all‐cause dementia (hazard ratio [HR], 1.25 [95% CI, 1.20–1.30];
P
<0.001), Alzheimer's disease (HR, 1.29 [95% CI, 1.20–1.38];
P
<0.001), and vascular dementia (HR, 1.22 [95% CI, 1.13–1.31];
P
<0.001). After propensity score matching, patients with CHD had significantly higher risks of all‐cause dementia, Alzheimer's disease, and vascular dementia than matched controls among all onset age groups, and the HRs gradually elevated with decreasing age at CHD onset.

Conclusions
Younger onset age of CHD is associated with higher risks of incident all‐cause dementia, Alzheimer's disease, and vascular dementia, underscoring the necessity to pay attention to the neurocognitive status of individuals diagnosed with CHD at younger age to conduct timely interventions to attenuate subsequent risk of incident dementia.