bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preclinical characterization of a non-peptidomimetic HIV protease inhibitor with improved metabolic stability
Authors: Mulato Andrew , Lansdon Eric , Aoyama Ron , Voigt Johannes , Lee Michael , Liclican Albert , Lee Gary , Singer Eric , Stafford Brian , Gong Ruoyu , Murray Bernard , Chan Julie , Lee Johnny , Xu Yili , Ahmadyar Shekeba , Gonzalez Ana , Cho Aesop , Stepan George J. , Schmitz Uli , Schultz Brian , Marchand Bruno , Brumshtein Boris , Wang Ruth , Yu Helen , Cihlar Tomas , Xu Lianhong , Yant Stephen R. 
Published: February 2024

ABSTRACT

Protease inhibitors (PIs) remain an important component of antiretroviral therapy for the treatment of HIV-1 infection due to their high genetic barrier to resistance development. Nevertheless, the two most commonly prescribed HIV PIs, atazanavir and darunavir, still require co-administration with a pharmacokinetic boosting agent to maintain sufficient drug plasma levels which can lead to undesirable drug-drug interactions. Herein, we describe GS-9770, a novel investigational non-peptidomimetic HIV PI with unboosted once-daily oral dosing potential due to improvements in its metabolic stability and its pharmacokinetic properties in preclinical animal species. This compound demonstrates potent inhibitory activity and high on-target selectivity for recombinant HIV-1 protease versus other aspartic proteases tested. In cell culture, GS-9770 inhibits Gag polyprotein cleavage and shows nanomolar anti-HIV-1 potency in primary human cells permissive to HIV-1 infection and against a broad range of HIV subtypes. GS-9770 demonstrates an improved resistance profile against a panel of patient-derived HIV-1 isolates with resistance to atazanavir and darunavir. In resistance selection experiments, GS-9770 prevented the emergence of breakthrough HIV-1 variants at all fixed drug concentrations tested and required multiple protease substitutions to enable outgrowth of virus exposed to escalating concentrations of GS-9770. This compound also remained fully active against viruses resistant to drugs from other antiviral classes and showed no
in vitro
antagonism when combined pairwise with drugs from other antiretroviral classes. Collectively, these preclinical data identify GS-9770 as a potent, non-peptidomimetic once-daily oral HIV PI with potential to overcome the persistent requirement for pharmacological boosting with this class of antiretroviral agents.
Regional centromere configuration in the fungal pathogens of the
Pneumocystis
genus
Authors: Cissé Ousmane H. , Curran Shelly J. , Folco H. Diego , Liu Yueqin , Bishop Lisa , Wang Honghui , Fischer Elizabeth R. , Davis A. Sally , Combs Christian , Thapar Sabrina , Dekker John P. , Grewal Shiv , Cushion Melanie , Ma Liang , Kovacs Joseph A. 
Published: February 2024

ABSTRACT

Centromeres are constricted chromosomal regions that are essential for cell division. In eukaryotes, centromeres display a remarkable architectural and genetic diversity. The basis of centromere-accelerated evolution remains elusive. Here, we focused on
Pneumocystis
species, a group of mammalian-specific fungal pathogens that form a sister taxon with that of the
Schizosaccharomyces pombe
, an important genetic model for centromere biology research. Methods allowing reliable continuous culture of
Pneumocystis
species do not currently exist, precluding genetic manipulation. CENP-A, a variant of histone H3, is the epigenetic marker that defines centromeres in most eukaryotes. Using heterologous complementation, we show that the
Pneumocystis
CENP-A ortholog is functionally equivalent to CENP-A
Cnp1
of
S. pombe
. Using organisms from a short-term
in vitro
culture or infected animal models and chromatin immunoprecipitation (ChIP)-Seq, we identified CENP-A bound regions in two
Pneumocystis
species that diverged ~35 million years ago. Each species has a unique short regional centromere (<10 kb) flanked by heterochromatin in 16–17 monocentric chromosomes. They span active genes and lack conserved DNA sequence motifs and repeats. These features suggest an epigenetic specification of centromere function. Analysis of centromeric DNA across multiple
Pneumocystis
species suggests a vertical transmission at least 100 million years ago. The common ancestry of
Pneumocystis
and
S. pombe
centromeres is untraceable at the DNA level, but the overall architectural similarity could be the result of functional constraint for successful chromosomal segregation.

IMPORTANCE

Pneumocystis
species offer a suitable genetic system to study centromere evolution in pathogens because of their phylogenetic proximity with the non-pathogenic yeast
S. pombe
, a popular model for cell biology. We used this system to explore how centromeres have evolved after the divergence of the two clades ~ 460 million years ago. To address this question, we established a protocol combining short-term culture and ChIP-Seq to characterize centromeres in multiple
Pneumocystis
species. We show that
Pneumocystis
have short epigenetic centromeres that function differently from those in
S. pombe
.
Heme sequestration by hemophilin from
Haemophilus haemolyticus
reduces respiratory tract colonization and infection with non-typeable
Haemophilus influenzae
Authors: Fulte Sam , Atto Brianna , McCarty Arianna , Horn Kadi J. , Redzic Jasmina S. , Eisenmesser Elan , Yang Michael , Marsh Robyn L. , Tristram Stephen , Clark Sarah E. 
Published: February 2024

ABSTRACT

Iron acquisition is a key feature dictating the success of pathogen colonization and infection. Pathogens scavenging iron from the host must contend with other members of the microbiome similarly competing for the limited pool of bioavailable iron, often in the form of heme. In this study, we identify a beneficial role for the heme-binding protein hemophilin (Hpl) produced by the non-pathogenic bacterium
Haemophilus haemolyticus
against its close relative, the opportunistic respiratory tract pathogen non-typeable
Haemophilus influenzae
(NTHi). Using a mouse model, we found that pre-exposure to
H. haemolyticus
significantly reduced NTHi colonization of the upper airway and impaired NTHi infection of the lungs in an Hpl-dependent manner. Further, treatment with recombinant Hpl was sufficient to decrease airway burdens of NTHi without exacerbating lung immunopathology or systemic inflammation. Instead, mucosal production of the neutrophil chemokine CXCL2, lung myeloperoxidase, and serum pro-inflammatory cytokines IL-6 and TNFα were lower in Hpl-treated mice. Mechanistically,
H. haemolyticus
suppressed NTHi growth and adherence to human respiratory tract epithelial cells through the expression of Hpl, and recombinant Hpl could recapitulate these effects. Together, these findings indicate that heme sequestration by non-pathogenic, Hpl-producing
H. haemolyticus
is protective against NTHi colonization and infection.

IMPORTANCE

The microbiome provides a critical layer of protection against infection with bacterial pathogens. This protection is accomplished through a variety of mechanisms, including interference with pathogen growth and adherence to host cells. In terms of immune defense, another way to prevent pathogens from establishing infections is by limiting the availability of nutrients, referred to as nutritional immunity. Restricting pathogen access to iron is a central component of this approach. Here, we uncovered an example where these two strategies intersect to impede infection with the respiratory tract bacterial pathogen
Haemophilus influenzae
. Specifically, we find that a non-pathogenic (commensal) bacterium closely related to
H. influenzae
called
Haemophilus haemolyticus
improves protection against
H. influenzae
by limiting the ability of this pathogen to access iron. These findings suggest that beneficial members of the microbiome improve protection against pathogen infection by effectively contributing to host nutritional immunity.
Supplemental Material: Lithospheric mantle as a metal storage reservoir for orogenic gold deposits in active continental margins: Evidence from Hg isotopes
Authors: Zhang Jing-Yuan , Qiu Kun-Feng , Deng Jun , al. et 
Published: February 2024

<p>Geology of the Jiaodong gold province, analytical methods, supplementary notes, Figure S1, and Tables S1–S2. </p>
German primary care data collection projects: a scoping review
Authors: Moser Konstantin , Massag Janka , Frese Thomas , Mikolajczyk Rafael , Christoph Jan , Pushpa Joshi , Straube Johanna , Unverzagt Susanne 
Published: February 2024

BackgroundThe widespread use of electronic health records (EHRs) has led to a growing number of large routine primary care data collection projects globally, making these records a valuable resource for health services and epidemiological and clinical research. This scoping review aims to comprehensively assess and compare strengths and limitations of all German primary care data collection projects and relevant research publications that extract data directly from practice management systems (PMS).MethodsA literature search was conducted in the electronic databases in May 2021 and in June 2022. The search string included terms related to general practice, routine data, and Germany. The retrieved studies were classified as applied studies and methodological studies, and categorised by type of research, subject area, sample of publications, disease category, or main medication analysed.ResultsA total of 962 references were identified, with 241 studies included from six German projects in which databases are populated by EHRs from PMS. The projects exhibited significant heterogeneity in terms of size, data collection methods, and variables collected. The majority of the applied studies (n = 205, 85%) originated from one database with a primary focus on pharmacoepidemiological topics (n = 127, 52%) including prescription patterns (n = 68, 28%) and studies about treatment outcomes, compliance, and treatment effectiveness (n = 34, 14%). Epidemiological studies (n = 77, 32%) mainly focused on incidence and prevalence studies (n = 41, 17%) and risk and comorbidity analysis studies (n = 31, 12%). Only 10% (n = 23) of studies were in the field of health services research, such as hospitalisation.ConclusionThe development and durability of primary care data collection projects in Germany is hindered by insufficient public funding, technical issues of data extraction, and strict data protection regulations. There is a need for further research and collaboration to improve the usability of EHRs for health services and research.
Nursing students’ Health Literacy skills: a scoping review protocol for driving research
Authors: Bulfone Giampiera , Bressan Valentina , Zerilli Irene , Mazzotta Rocco , Favara Giuliana , Magnano San Lio Roberta , Barchitta Martina , Agodi Antonella 
Published: February 2024

IntroductionThe healthcare systems in Europe are changing rapidly due to the increased complexity of healthcare needs, specifically for the ageing population with chronic diseases. Nurses play a key role in providing care for patients with chronic diseases, encouraging patients to take care of their own health improving their Health Literacy (HL) too. Previous works have highlighted the paucity of HL content in nursing curricula, and the need to prioritise the development of HL skills in academic teaching and assessment methods. The aim of this study is to analyse HL skills nursing literature to further develop scientific knowledge in this area of research.Methods and analysisThis scoping review will be conducted following Arksey and O’Malley’s framework. This study is based on the Joanna Briggs Institute manual. A systematic search will be performed by four researchers using the electronic databases of MEDLINE (via PubMed), the Education Resources Information Centre, the Cumulative Index to Nursing and Allied Health Literature, Scopus, Web of Science and Google Scholar. We will include any paper that focuses on HL skills and undergraduate nursing students. We will select every primary study (quantitative, qualitative and mixed method design) published in peer-reviewed journals up until February 2023, in both Italian and English language, without any time limit.Ethics and disseminationThis scoping review is part of a large project of the University of Catania which aims at developing higher educational standards for nursing student. This project will not involve patients/public and does not require ethical committee approval. This scoping review will be submitted to international peer-reviewed journals.Registration detailsThe protocol was registered with the Open Science Framework on 20 April 2023 (https://osf.io/cn8d7).
Predictors at diagnosis for start of biologic disease-modifying antirheumatic drugs in patients with early rheumatoid arthritis: a cohort study
Authors: Hameed Mohaned , Exarchou Sofia , Eberhard Anna , Sharma Ankita , Bergström Ulf , Cagnotto Giovanni , Einarsson Jon Thorkell , Turesson Carl 
Published: February 2024

ObjectivesTo investigate the relation between patient characteristics at rheumatoid arthritis (RA) diagnosis and subsequent initiation of treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs).DesignA retrospective cohort study.Setting and participantsConsecutive patients (N=330) with early RA (symptom duration <12 months) diagnosed at Skåne University Hospital, Malmö/Lund, Sweden, from 2012 to 2016, were included. Data on demographics, education, comorbidities and treatment were obtained from national registers.OutcomeThe relation between patient characteristics at diagnosis and time to first bDMARD/tsDMARD initiation was analysed using Cox regression models. As a secondary outcome, the relation between characteristics at diagnosis and b/tsDMARD initiation within 3 years was analysed using logistic regression.ResultsA total of 330 patients (mean age 59.2 years; SD 16.4) were included. During follow-up, 41% received a bDMARD (never preceded by a tsDMARD). Higher age at diagnosis was associated with a lower probability of starting bDMARD treatment (multivariable-adjusted HR 0.66 per SD; 95% CI 0.56 to 0.78). Anticitrullinated protein antibody (ACPA) positivity and higher tender joint count at diagnosis were also associated with subsequent bDMARD treatment initiation in multivariable analysis. A higher level of formal education and absence of comorbidities predicted start of a bDMARD in crude, but not in age-adjusted, analyses.ConclusionsOlder patients with RA were less likely to start bDMARDs, whereas ACPA-positive patients, and those with extensive joint involvement at diagnosis, were more likely to receive early bDMARD treatment. The impact of age on the subsequent start of bDMARD therapy was not explained by level of education or comorbidities, suggesting that other aspects of age influence treatment decisions in early RA.
Computerised modified paramedian approach technique versus conventional midline approach technique of lumbar puncture: a randomised control trial protocol
Authors: Zhuang Yuan-Dong , Chen Yi-Ze , Lin Qi-Ying , Chen Yi-Xin , Zhong Si-Qi , Lei Ding , Chen Chun-Mei 
Published: February 2024

IntroductionThe lumbar puncture (LP) technique is widely used for diagnostic and therapeutic purposes. In recent years, the paramedian approach technique (PAT) has gained increasing interest due to its advantages over the conventional midline approach technique (MAT) that has been traditionally employed in clinical practice for LP. However, there have been inconsistent discussions regarding the efficacy of different LP techniques. Based on digital virtual human and computer simulation techniques, a new approach called computerised modified PAT (CMPAT) was proposed. Therefore, the aim of this study is to discuss a randomised controlled trial (RCT) protocol to investigate and compare the effects of CMPAT and MAT in patients undergoing LP.Methods and analysisWe will conduct a prospective, multicentre RCT. The study will recruit 84 patients aged 18–99 years who require LP. Participants will be randomly assigned to either the CMPAT treatment group (group A) or the MAT treatment group (group B). The primary outcome measure will be the number of needle insertion attempts required for a successful LP. Secondary outcomes will include the puncture success rate, pain assessment in the back, head, and legs, and the occurrence of complications. The measurement of these secondary outcomes will be taken during the procedure, as well as at specific time points: 30 min, 6 hours, 1 day, 3 days, 7 days, 2 weeks and 4 weeks after the procedure. Pain levels will be assessed using a Numerical Rating Scale.Ethics and disseminationEthical approval (2022YF052-01) has been obtained from the Ethics Committee of Fujian Medical University Union Hospital, Fuzhou, China. The research findings will be published in an international peer-reviewed scientific journal and presented at scientific conferences.Trial registration numberChiCTR2300067937.
Study protocol for a randomised open-label clinical trial examining the safety and efficacy of the Android Artificial Pancreas System (AAPS) with advanced bolus-free features in adults with type 1 diabetes: the ‘CLOSE IT’ (Closed Loop Open SourcE In Type 1 diabetes) trial
Authors: Wilkinson Tom , Tomic Dunya , Boyle Erin , Burren David , Elghattis Yasser , Jenkins Alicia , Keesing Celeste , Middleton Sonia , Nanayakkara Natalie , Williman Jonathan , de Bock Martin , Cohen Neale D 
Published: February 2024

IntroductionMultiple automated insulin delivery (AID) systems have become commercially available following randomised controlled trials demonstrating benefits in people with type 1 diabetes (T1D). However, their real-world utility may be undermined by user-associated burdens, including the need to carbohydrate count and deliver manual insulin boluses. There is an important need for a ‘fully automated closed loop’ (FCL) AID system, without manual mealtime boluses. The (Closed Loop Open SourcE In Type 1 diabetes) trial is a randomised trial comparing an FCL AID system to the same system used as a hybrid closed loop (HCL) in people with T1D, in an outpatient setting over an extended time frame.Methods and analysisRandomised, open-label, parallel, non-inferiority trial comparing the Android Artificial Pancreas System (AAPS) AID algorithm used as FCL to the same algorithm used as HCL. Seventy-five participants aged 18–70 will be randomised (1:1) to one of two treatment arms for 12 weeks: (a) FCL—participants will be advised not to bolus for meals and (b) HCL—participants will use the AAPS AID algorithm as HCL with announced meals. The primary outcome is the percentage of time in target sensor glucose range (3.9–10.0 mmol/L). Secondary outcomes include other glycaemic metrics, safety, psychosocial factors, platform performance and user dietary factors. Twenty FCL arm participants will participate in a 4-week extension phase comparing glycaemic and dietary outcomes using NovoRapid (insulin aspart) to Fiasp (insulin aspart and niacinamide).Ethics and disseminationApprovals are by the Alfred Health Ethics Committee (615/22) (Australia) and Health and Disability Ethics Committees (2022 FULL 13832) (New Zealand). Each participant will provide written informed consent. Data protection and confidentiality will be ensured. Study results will be disseminated by publications, conferences and patient advocacy groups.Trial registration numbersACTRN12622001400752 and ACTRN12622001401741.
Exploring the safety and quality of mobile X-ray imaging in a new infectious disease biocontainment unit: an in situ simulation and video-reflexive study
Authors: Wyer Mary , Hor Su-yin , Barratt Ruth , Garrahy Phillip , Moore Cameron , Williams Veazey Leah , Degeling Chris , Gilbert G L 
Published: February 2024

ObjectivesDuring a precommissioning inspection of a new biocontainment centre, radiographers noted structural features of quarantine rooms that could compromise staff and patient safety and the X-ray image quality, even after significant modifications had been made to an earlier radiography protocol. The aim of this study was to explore the safety and effectiveness of the modified protocol, in the new space, and identify improvements, if required.DesignA qualitative study using in situ simulation and video-reflexive methods.SettingA newly built biocontainment centre, prior to its commissioning in 2021, in a large, tertiary hospital in Sydney, Australia.ParticipantsFive radiographers, and a nurse and a physician from the biocontainment centre, consented to participate. All completed the study.InterventionsTwo simulated mobile X-ray examinations were conducted in the unit prior to its commissioning; simulations were videoed. Participants and other stakeholders analysed video footage, collaboratively, and sessions were audio recorded, transcribed and analysed thematically. Problems and potential solutions identified were collated and communicated to the hospital executive, for endorsement and actioning, if possible.ResultsFour themes were identified from the data: infection exposure risks, occupational health and exposure risks, communication and X-ray image quality. Facilitated group reviews of video footage identified several important issues, across these four areas of risk, which had not been identified previously.ConclusionsIn situ simulation is used, increasingly, to evaluate and improve healthcare practices. This study confirmed the added value of video-reflexive methods, which provided experienced participants with a richer view of a familiar protocol, in a new setting. Video footage can be examined immediately, or later if required, by a broader group of stakeholders, with diverse experience or expertise. Using video reflexivity, clinicians identified potential safety risks, which were collated and reported to the hospital executive, who agreed to implement modifications.
Worry perception and its association with work conditions among healthcare workers during the first wave of the COVID-19 pandemic: a web-based multimethod survey at a university hospital in Sweden
Authors: Alexiou Eirini , Wijk Helle , Åkerström Magnus , Jonsdottir Ingibjörg H , Degl’ Innocenti Alessio , Ahlstrom Linda 
Published: February 2024

ObjectivesIn this study, we explored healthcare workers’ (HCWs) worry perception and its association with their work situation during the first wave of the COVID-19 pandemic.DesignA web-based multimethods survey including multiple choice and open-ended questions was used.SettingThe study was conducted at a university hospital in Sweden.ParticipantsAll HCWs who were working during the first wave of the COVID-19 pandemic in March–June 2020 were eligible. HCWs (n=6484, response rate=41%) from 69 departments fulfilled the study inclusion criteria and responded to the survey. Of them, we analysed data from the 3532 participants who replied to the open-ended questions (54% of the respondents).Main outcomes measuresWorry perception and its association with work conditions among HCWs.Results29% (n=1822) and 35% (n=2235) of the responding HCWs experienced a daily or more than daily strong worry of being infected or infecting others with SARS-CoV-2. This finding could be further confirmed and explored with themes from the qualitative results: ‘ambiguity of feeling safe and secure’, ‘being obliged to adapt to a new reality’ and ‘into the unknown’. The themes consisted of 6 main categories and 15 subcategories. The findings revealed that the two main drivers of worry perceived by HCWs were lack of personal protective equipment and fear of bringing the virus home to their families and friends.ConclusionsWorries of getting infected are common among HCWs during crises such as the COVID-19 pandemic. Several factors are raised that plausibly could minimise the negative effects of worry among HCWs. Thus, effective preventive work plans should be created, promoted and communicated in order to minimise the effects of such crises and support HCWs. By focusing on effective communication and preparedness, including access to relevant protective equipment and providing general support to HCWs, the work environment and patient care could be sustained during a crisis such as the COVID-19 pandemic.