bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deciphering the regulatory mechanisms of the cAMP/protein kinase A pathway and their roles in the pathogenicity of
Candida auris
Authors: Kim Ji-Seok , Lee Kyung-Tae , Bahn Yong-Sun 
Published: September 2023

ABSTRACT

The emergence of multidrug-resistant fungal pathogens is a significant concern for global public health.
Candida auris
poses a considerable threat as a multidrug-resistant fungal pathogen. Our recent study revealed that the adenylyl cyclase Cyr1 and protein kinase A (PKA) pathways play distinct and redundant roles in drug resistance and pathogenicity of
C. auris
. However, the upstream and negative feedback regulatory mechanisms of
C. auris
are not yet fully understood. In this study, we discovered that the small GTPase Ras1, along with its nucleotide exchange factor Cdc25 and GTPase-activating protein Ira2, plays a major role in regulating cAMP/PKA-dependent traits, while G-protein-coupled receptor Gpr1 and heterotrimeric G-protein α subunit Gpa2 play a minor role. Pde2 plays a major role in negative feedback regulation of the cAMP/PKA pathway, while Pde1 plays a minor role. Hyperactivation of the Ras/cAMP/PKA pathway by deleting
PDE2
or
BCY1
renders
C. auris
cells thermosensitive and susceptible to nutrient deficiency, which leads to attenuated virulence. Our study demonstrates the distinct contributions of hyperactivation of the Ras/cAMP/PKA signaling pathway to
C. auris
pathogenesis and suggests potential therapeutic targets for
C. auris-
mediated candidiasis.

IMPORTANCE

Candida auris
is a major concern as a multidrug-resistant fungal pathogen. While our previous studies highlighted the crucial roles of the cAMP/protein kinase A (PKA) pathway in regulating drug resistance, stress responses, morphogenesis, ploidy change, biofilm formation, and pathogenicity in this pathogen, their regulatory mechanism remains unclear. In our study, we provided evidence that the cAMP/PKA signaling pathway in
C. auris
is primarily governed by the small GTPase RAS rather than a G-protein-coupled receptor. Additionally, we discovered that the negative feedback regulation of cAMP, controlled by phosphodiesterases, is vital for
C. auris
virulence by promoting resistance to high temperatures and nutrient deficiencies. These findings underscore the diverse pathobiological significance of the Ras/cAMP/PKA signaling pathway in
C. auris
, shedding light on potential therapeutic targets and strategies for combating this multidrug-resistant fungal pathogen.
Structural geometry and kinematic evolution of the central Canadian Rocky Mountain Foothills fold-and-thrust belt: Complex kinematic relationships controlled by detachment utilization
Authors: McMechan M.E. 
Published: September 2023

AbstractBalanced regional cross sections based on surface, seismic, and subsurface data show that the thin-skinned fold-and-thrust belt in the Rocky Mountain Foothills of the Kakwa area of the central Canadian Rockies consists of a lower buried thrust belt developed in Paleozoic and Triassic strata and an upper exposed faulted fold belt of Jurassic to Cretaceous strata. Changes in fold wavelength, amplitude, and geometry with stratigraphic level indicate that multiple detachments were utilized in the upper faulted fold belt. Exposed folds are chevron or box shaped. Most appear to be detachment or fault propagation folds formed by fault-to-fold displacement transfer. Geometric and kinematic relationships in the upper faulted fold belt vary from thrust faults congruently folded by underlying folds (early fault) to folds abruptly truncated by thrust faults (late fault). In contrast, folding of thrust sheets in the buried thrust belt is consistent with in-sequence deformation for all faults except one. A sequential restoration of the balanced regional cross section shows that the variable kinematic relationships observed in the upper faulted fold belt can be explained by changes in the detachment level utilized by successive faults as they climbed out of the buried thrust belt. Chevron-folded thrust faults indicate a younger fault with associated fault displacement transfer folds formed in the footwall of an older fault. These folded thrusts formed by in-sequence faulting and utilization of successively higher detachment levels. Late faults that truncate preexisting folds required out-of-sequence (hinterlandward) utilization of a higher detachment level, and they illustrate another mechanism by which critical taper is maintained in a fold-and-thrust belt.
Association of baseline fasting plasma glucose with 1-year mortality in non-diabetic patients with acute cerebral infarction: a multicentre observational cohort study
Authors: Zhang Dandan , Liu Zhongzhong , Liu Pei , Zhang Huan , Guo Weiyan , Lu Qingli , Huang Congli , Wang Jing , Chang Qiaoqiao , Zhang Mi , Huo Yan , Wang Yan , Lin Xuemei , Wang Fang , Wu Songdi 
Published: September 2023

ObjectivesEvidence on the association between fasting blood glucose and mortality in non-diabetic patients who had a stroke is limited. We aimed to investigate the association of baseline fasting plasma glucose (FPG) with 1 year all-cause mortality in non-diabetic patients with acute cerebral infarction (ACI).DesignA multicentre prospective cohort study.SettingFour grade A tertiary hospitals in the Xi'an district of China.ParticipantsA total of 1496 non-diabetic patients within 7 days of ACI were included.Main outcome measuresThe outcome was 1 year all-cause mortality. Baseline FPG was analysed as a continuous variable and was divided into four quartiles (group Q1–group Q4). We used multivariable Cox regression analyses, curve fitting and Kaplan–Meier (K-M) analyses to explore the association of baseline FPG with 1 year all-cause mortality in non-diabetic patients with ACI.ResultsAfter controlling for confounders, multivariable Cox regression analyses indicated a 17% increase in 1 year all-cause mortality for every 1 mmol/L of baseline FPG increase (HR=1.17, 95% CI 1.02 to 1.35, p=0.030). Patients from the Q4 group had 2.08 times increased hazard of 1 year all-cause mortality compared with the Q1 group (HR=2.08, 95% CI 1.13 to 3.82, p=0.019), while the survival rate of patients in group Q4 was decreased compared with that in other groups (p<0.001). The curve fitting revealed a positive but non-linear association of baseline FPG with 1-year all-cause mortality in non-diabetic patients with ACI.ConclusionIn non-diabetic patients with ACI, elevated baseline FPG is an independent risk factor for 1-year all-cause mortality, and the two are positively and non-linearly associated. These results suggest that high FPG should be seen as a concern in non-diabetic patients with ACI.
Sequential multiple assignment randomised controlled trial protocol for developing an adaptive intervention to improve depressive symptoms among family caregivers of people with dementia
Authors: Kor Patrick Pui Kin , Chou Kee Lee , Zarit Steven H , Gallagher Dolores , Galante Julieta , Wong Samuel Y S , Cheung Daphne Sze Ki , Leung Angela Y M , Chu Leung-Wing 
Published: September 2023

ObjectivesFamily caregivers of people with dementia (FC-of-PWD) suffer from a high level of stress and depressive symptoms, which usually require different interventions at different stages. Although some standalone interventions such as behavioural activation (BA) and mindfulness practice (MP) have been shown to be potentially effective at reducing depressive symptoms, the best sequence and combination of these interventions for caregivers are unknown. This study aims to develop and identify a two-stage adaptive intervention with prespecified rules guiding whether, how or when to offer different interventions initially/over time to reduce depressive symptoms in FG-of-PWD.MethodsA sequential multiple assignment randomised trial design will be adopted. 272 FG-of-PWD with mild to moderate depressive symptoms will be recruited from the community. Four two-stage, embedded adaptive interventions involving BA and MP of different sequences and dosages (eg, 8 weeks of BA followed by booster sessions for responders and 8 weeks of MP for non-responders) will be assigned to the participants following a set of decision rules. The primary outcomes will be depressive symptoms (measured using the Patient Health Questionnaire-9), assessed after the second stage of the intervention. Other outcomes, such as positive aspects of caregiving (measured using the Positive Aspects of Caregiving Scale), sleep quality (measured using the Pittsburgh Sleep Quality Index) and time points will also be assessed. The analyses will follow the intention-to-treat principle. Several process indicators (eg, engagement in meaningful activities and level of mindfulness) will also be assessed. The findings will have strong implications for the further development of psychosocial adaptive interventions to reduce depressive symptoms among FC-of-PWD.Ethics and disseminationThis study has received ethical approval from the Human Research Ethics Committee at The Hong Kong Polytechnic University (HSEARS20211223001). The findings will be presented at academic conferences and submitted to peer-reviewed journals for publication.Trial registration numberNCT05634317.
What matters most? A qualitative study exploring priorities for supportive interventions for people with tuberculosis in urban Viet Nam
Authors: Smith Isabel , Forse Rachel , Sidney Annerstedt Kristi , Thanh Nguyen Thi , Nguyen Lan , Phan Thi Hoang Yen , Nguyen Han , Codlin Andrew , Vo Luan Nguyen Quang , Nguyen Nga Thi Thuy , Khan Amera , Creswell Jacob , Pham Huy Minh , Basu Lopa , Lönnroth Knut , Nguyen Binh Hoa , Nguyen Viet Nhung , Atkins Salla 
Published: September 2023

IntroductionThe health and economic burden of tuberculosis (TB) in urban Viet Nam is high. Social protection and support interventions can improve treatment outcomes and reduce costs. However, evidence regarding optimal strategies in this context is lacking. This study aimed to increase understanding of what people with TB and healthcare providers (HCPs) perceive as important to improve TB treatment outcomes and reduce costs.MethodsWe conducted qualitative focus group discussions (seven groups, n=30) and key informant interviews (n=4) with people with drug-susceptible and multidrug-resistant TB and HCPs in Ha Noi and Ho Chi Minh City. Topic guides covered perspectives on and prioritisation of different forms of social protection and support. Data were analysed using reflexive thematic analysis and interpreted using a Framework for Transformative Social Protection.ResultsWe identified three themes and seven subthemes. The first theme, ‘Existing financial safety nets are essential, but could go further to support people affected by TB’, highlights that support to meet the medical costs of TB treatment and flexible cash transfers are a priority for people with TB and HCPs. The second, ‘It is important to promote “physical and spiritual health” during TB treatment’, demonstrates that extended psychosocial and nutritional support would encourage people with TB during their treatment. The third, ‘Accessibility and acceptability are critical in designing social support interventions for people with TB’, shows the importance of ensuring that support is accessible and proportional to the needs of people with TB and their families.ConclusionsAccessible interventions that incorporate financial risk protection, nutritional and psychosocial support matter most to people with TB and HCPs in urban Viet Nam to improve their treatment outcomes and reduce catastrophic costs. This study can inform the design of stronger person-centred interventions to advance progress towards the goals of the WHO’s End TB Strategy.
Modelling NHS England 111 demand for primary care services: a discrete event simulation
Authors: Pilbery Richard , Smith Madeleine , Green Jonathan , Chalk Daniel , O'Keeffe Colin A 
Published: September 2023

ObjectivesThis feasibility study aimed to model in silico the current healthcare system for patients triaged to a primary care disposition following a call to National Health Service (NHS) 111 and determine the effect of reconfiguring the healthcare system to ensure a timely primary care service contact.DesignDiscrete event simulation.SettingSingle English NHS 111 call centre in Yorkshire.ParticipantsCallers registered with a Bradford general practitioner who contacted the NHS 111 service in 2021 and were triaged to a primary care disposition.Primary and secondary outcome measuresFace validity of conceptual model. Comparison between real and simulated data for quarterly counts (and 95% CIs) for patient contact with emergency ambulance (999), 111, and primary and secondary care services. Mean difference and 95% CIs in healthcare system usage between simulations and difference in mean proportion of avoidable admissions for callers who presented to an emergency department (ED).ResultsThe simulation of the current system estimated that there would be 39 283 (95% CI 39 237 to 39 328) primary care contacts, 2042 (95% CI 2032 to 2051) 999 calls and 1120 (95% CI 1114 to 1127) avoidable ED attendances. Modifying the model to ensure a timely primary care response resulted in a mean percentage increase of 196.1% (95% CI 192.2% to 199.9%) in primary care contacts, and a mean percentage decrease of 78.0% (95% CI 69.8% to 86.2%) in 999 calls and 88.1% (95% CI 81.7% to 94.5%) in ED attendances. Avoidable ED attendances reduced by a mean of −26 (95% CI −35 to −17).ConclusionIn this simulated study, ensuring timely contact with a primary care service would lead to a significant reduction in 999 and 111 calls, and ED attendances (although not avoidable ED attendance). However, this is likely to be impractical given the need to almost double current primary care service provision. Further economic and qualitative research is needed to determine whether this intervention would be cost-effective and acceptable to both patients and primary care clinicians.
Unintended consequences of the 18-week referral to treatment standard in NHS England: a threshold analysis
Authors: Quinn Laura , Bird Paul , Remsing Sandra , Reeves Katharine , Lilford Richard 
Published: September 2023

ObjectiveIn 2012, an ‘18-week referral to treatment standard’ was introduced in England. Among people on the list of those waiting for hospital treatment at a point in time, the standard states that at least ‘92% of patients should have been waiting for less than 18 weeks’. Targets can have unintended consequences, where patients are prioritised based on the target rather than clinical need. Such an effect will be evident as a spike in the number of hospital trusts at the target threshold, referred to as a threshold effect. This study examines for threshold effects across all non-specialist acute NHS England hospital trusts by financial year.MethodsA retrospective observational study of publicly available data examined waiting times for patients on the waiting list. We examined trust performance against the 92% target by financial year, from 2015/16 to 2021/22, using Cattaneoet al’s manipulation density test (test for discontinuity/spike in data around target threshold) for all patients and by type of treatment.ResultsThe proportion of NHS hospital trusts meeting the 92% target deteriorated over time. From 2015/16 to 2019/20, there was strong evidence of a threshold effect at the 92% target (p<0.001). There was no evidence of a threshold effect in 2020/21 (p=0.063) or 2021/22 (p=0.090). Threshold effects were present across most types of treatment in 2016/17 and fewer types from 2017/18 onwards.ConclusionWe observed striking evidence of a threshold effect suggesting that while targets change behaviour, they do so in a selective way, focusing on the threshold rather than a pervasive improvement in practice. However, at the height of the pandemic, as almost no trusts could reach the target, the threshold effect disappeared.
Associations between air pollution and the risk of first admission and multiple readmissions for cardiovascular diseases
Authors: Zhang Shiyu , Chen Lan , Qian Zhengmin (Min) , Li Dan , Cai Miao , Wang Chongjian , Zhang Zilong , Vaughn Michael G. , Keith Amy E. , Li Haitao , Lin Hualiang 
Published: September 2023

ObjectivesWe aimed to investigate the associations between air pollutants and the risk of admission and multiple readmission events for cardiovascular disease (CVD).MethodsA total of 285 009 participants free of CVD at baseline from the UK Biobank were included in this analysis. Four major cardiovascular admission events were identified during the follow-up: chronic ischaemic heart disease (CIHD), cerebrovascular disease, atrial fibrillation and heart failure. We used Prentice, Williams and Peterson-Total Time model to examine the association between ambient air pollution and first admission, as well as multiple readmissions for these CVDs.ResultsDuring a median follow-up of 12 years, 17 176 (6.03%) participants were hospitalised with CVDs, and 6203 (36.11%) patients with CVD had subsequent readmission events for CVDs. We observed significant associations between air pollution and both first admission and readmission for CVDs, with generally stronger associations on readmission for cardiovascular events. For example, the adjusted HRs for the first admission and subsequent readmission for cerebrovascular disease were 1.130 (95% CI 1.070 to 1.194) and 1.270 (95% CI 1.137 to 1.418) for each IQR increase of particulate matter with a diameter ≤2.5 µm. The corresponding HRs for CIHD were 1.060 (95% CI 1.008 to 1.114) and 1.120 (95% CI 1.070 to 1.171). Sex stratified analyses showed that the associations were generally more pronounced among females than males.ConclusionThis study provides evidence that ambient air pollutants might play an important role in both first admission and readmission for cardiovascular events. In addition, patients with pre-existing CVDs may be more vulnerable to air pollution compared with healthy population.
Unilateral focused ultrasound subthalamotomy in early Parkinson’s disease: a pilot study
Authors: Martínez Fernández Raúl , Natera Villalba Elena , Rodriguez-Rojas Rafael , del Álamo Marta , Pineda-Pardo Jose A , Obeso Ignacio , Mata-Marín David , Guida Pasqualina , Jimenez-Castellanos Tamara , Pérez-Bueno Diana , Duque Alicia , Máñez Miró Jorge U , Gasca-Salas Carmen , Matarazzo Michele , Obeso Jose A 
Published: September 2023

BackgroundUnilateral focused ultrasound subthalamotomy (FUS-STN) improves motor features of Parkinson’s disease (PD) in moderately advanced patients. The less invasive nature of FUS makes its early application in PD feasible. We aim to assess the safety and efficacy of unilateral FUS-STN in patients with PD of less than 5 years from diagnosis (early PD).MethodsProspective, open-label study. Eligible patients with early PD had highly asymmetrical cardinal features. The primary outcome was safety, defined as treatment-related adverse events at 6 months. Secondary outcomes included efficacy, assessed as motor improvement in the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), motor fluctuations, non-motor symptoms, daily living activities, quality of life, medication and patients’ impression of change.ResultsTwelve patients with PD (median age 52.0 (IQR 49.8–55.3) years, median time from diagnosis 3.0 (2.1–3.9) years) underwent unilateral FUS-STN. Within 2 weeks after treatment, five patients developed dyskinesia on the treated side, all resolved after levodopa dose adjustment. One patient developed mild contralateral motor weakness which fully resolved in 4 weeks. One patient developed dystonic foot and another hand and foot dystonia. The latter impaired gait and became functionally disabling initially. Both cases were well controlled with botulinum toxin injections. The off-medication motor MDS-UPDRS score for the treated side improved at 12 months by 68.7% (from 14.5 to 4.0, p=0.002), and the total motor MDS-UPDRS improved by 49.0% (from 26.5 to 13.0, p=0.002). Eleven patients (92%) reported global improvement 12 months after treatment.ConclusionUnilateral FUS-STN may be safe and effective to treat motor manifestations in patients with early PD. A larger confirmatory trial is warranted.Trial registration numberNCT04692116
Rituximab for the treatment of acute exacerbation of interstitial lung disease associated with connective tissue disease
Authors: León Román Francisco , Pintado-Cort Beatriz , García-Casado Diana , Muñiz-González Francisco , López García-Asenjo José Antonio , Díaz-Rodríguez Cristina , Montoro-López María Nieves , Loucel-Bellino Mauricio , Recio-Moreno Beatriz , Rebollo-Garrido Sara , Martínez-Hernández Yaiza , Cusacovich Ivan 
Published: September 2023

BackgroundAcute exacerbation of interstitial lung disease (AE-ILD) is a severe complication with a poor prognosis. No clinical trials have supported the use of rituximab in AE-ILD associated with connective tissue disease.MethodsWe present a series of four cases in which administration of rituximab was associated with appropriate clinical, radiological and functional progress.ResultsThe four patients were alive 30 days after discharge following their exacerbation.ConclusionsGiven the speed of action, safety and efficacy profile observed for rituximab, we believe that this agent should be further investigated in clinical trials so that it could be included in the daily clinical management of this severe condition.
Music therapy, quality of life and efficacy of immunotherapy for NSCLC
Authors: Duan Xu , Jia Yingxue , Chai Jiaying , Li Wen , Tang Lingxue , Li Anlong , Ge Han , Huang Runze , Cheng Huaidong 
Published: September 2023

ObjectiveOur study examines how non-small cell lung cancer (NSCLC) survivors undergoing immunotherapy can experience reduced anxiety and psychological distress, improved quality of life (QOL) and increased immunotherapy efficacy.Methods133 men and 20 women with NSCLCs were enrolled. In a randomised controlled trial involving a care as usual group (CG) and a music therapy group (MTG), the researchers employed various tools such as the Self-Rating Anxiety Scale, Symptom Distress Thermometer, Functional Assessment of Cancer Therapy-General version 4 and Response Evaluation Criteria in Solid Tumours. These measures were used to evaluate anxiety, psychological distress, QOL and immunotherapy efficacy in patients undergoing immunotherapy before and after patients’ completion.ResultsAfter the intervention, patients in the MTG demonstrated a noteworthy reduction in anxiety (t=6.272, p≤0.001) and distress (t=10.111, p≤0.001), as well as an increase in QOL (t=−7.649, p≤0.001). Moreover, compared with patients in the CG, those in the MTG demonstrated a remarkable drop in anxiety (t=−4.72, p≤0.001) and distress (t=−7.29, p≤0.001), a significant increase in QOL (t=5.363, p≤0.001) and a significant improvement in immunotherapy efficacy (z=−2.18, p≤0.05) after the intervention.ConclusionsThe use of individual music therapy sessions appears to be effective in reducing anxiety and distress, while also increasing QOL and immunotherapy efficacy in patients with NSCLCs undergoing immunotherapy.