bluuebunny/crossref_metadata_2025_split huggingface dataset:
A TetR family regulator of an RND efflux system that directs artemisinin resistance in
Vibrio cholerae
Authors: Chung In-Young , Choi Shin-Yae , Bae Hee-Won , Cho You-Hee 
Published: December 2023

ABSTRACT

Artemisinin (ARS) displayed bactericidal activity against
Vibrio cholerae
. To assess the mechanistic details of its antibacterial action, we have isolated
V. cholerae
mutants with enhanced ARS resistance and identified a gene (VCA0767) whose loss-of-function resulted in the ARS resistance phenotypes. This gene (
atrR
) encodes a TetR family transcriptional regulator, and its deletion mutant displayed the reduction in ARS-induced ROS formation and DNA damage. Transcriptomic analysis revealed that the genes encoding a
r
esistance-
n
odulation-cell
d
ivision (RND) efflux pump operon (
vexRAB
) and the outer membrane component (
tolC
) were highly upregulated in the
artR
mutant, suggesting that AtrR might act as a negative regulator of this operon and
tolC
. Gene deletion of
vexR
,
vexB
, or
tolC
abrogated the ARS resistance of the
atrR
mutant, and more importantly, the ectopic expression of VexAB-TolC was sufficient for the ARS resistance, indicating that the increased expression of the VexAB-TolC efflux system is necessary and sufficient for the ARS resistance of the
atrR
mutant. The cytoplasmic accumulation of ARS was compromised in the
vexBtolC
mutant, suggesting that the VexAB-TolC might be the primary efflux system exporting ARS to reduce its toxicity inside of the bacterial cells. The
atrR
mutant displayed resistance to erythromycin as well in a VexR-dependent manner. This result suggests that AtrR may act as a global regulator responsible for preventing intracellular accumulation of toxic chemicals by enhancing the RND efflux system.

IMPORTANCE

Drug efflux protein complexes or efflux pumps are considered as the major determinants of multiple antimicrobial resistance by exporting a wide range of structurally diverse antibiotics in bacterial pathogens. Despite the clinical significance of the increased expression of the efflux pumps, their substrate specificity and regulation mechanisms are poorly understood. Here, we demonstrated that VexAB-TolC, a
r
esistance-
n
odulation-cell
d
ivision (RND) efflux pump of
V. cholerae
, is responsible for the resistance to artemisinin (ARS), an antimalarial drug with bactericidal activity. Furthermore, we newly identified AtrR, a TetR family repressor, as a global regulator for VexRAB and the common outer membrane channel, TolC, where VexR functions as the pathway-specific regulator of the vexAB operon. Our findings will help improve our insight into a broad range of substrate specificity of the VexAB-TolC system and highlight the complex regulatory networks of the multiple RND efflux systems during
V. cholerae
pathogenesis.
Varying
Flavobacterium psychrophilum
shedding dynamics in three bacterial coldwater disease-susceptible salmonid (Family
Salmonidae
) species
Authors: Knupp Christopher , Soto Esteban , Loch Thomas P. 
Published: December 2023

ABSTRACT

Flavobacterium psychrophilum
causes bacterial coldwater disease (BCWD) and is responsible for substantial losses in farm and hatchery-reared salmonids (Family
Salmonidae
). Although
F. psychrophilum
infects multiple economically important salmonids and is transmitted horizontally, the extent of knowledge regarding
F. psychrophilum
shedding rates and duration is limited to rainbow trout (
Oncorhynchus mykiss
). Concurrently, hundreds of
F. psychrophilum
sequence types (STs) have been described using multilocus sequence typing (MLST), and evidence suggests that some variants have distinct phenotypes, including differences in host associations. Whether shedding dynamics differ among
F. psychrophilum
variants and/or salmonids remains unknown. Thus, three
F. psychrophilum
isolates (e.g., US19, US62, and US87) in three MLST STs (e.g., ST13, ST277, and ST275) with apparent host associations for coho salmon (
O. kisutch
), Atlantic salmon (
Salmo salar
), or rainbow trout were intramuscularly injected into each respective fish species. Shedding rates of live and dead fish were determined by quantifying
F. psychrophilum
loads in water via quantitative PCR. Both live and dead Atlantic and coho salmon shed
F. psychrophilum
, as did live and dead rainbow trout. Regardless of salmonid species, dead fish shed
F. psychrophilum
at higher rates (e.g., up to ~10
8
–10
10
cells/fish/hour) compared to live fish (up to ~10
7
–10
9
cells/fish/hour) and for a longer duration (5–35 days vs 98 days); however, shedding dynamics varied by
F. psychrophilum
variant and/or host species, a matter that may complicate BCWD management. Findings herein expand knowledge on
F. psychrophilum
shedding dynamics across multiple salmonid species and can be used to inform future BCWD management strategies.

IMPORTANCE

Flavobacterium psychrophilum
causes bacterial coldwater disease (BCWD) and rainbow trout fry syndrome, both of which cause substantial losses in farmed and hatchery-reared salmon and trout populations worldwide. This study provides insight into
F. psychrophilum
shedding dynamics in rainbow trout (
Oncorhynchus mykiss
) and, for the first time, coho salmon (
O. kisutch
) and Atlantic salmon (
Salmo salar
). Findings revealed that live and dead fish of all fish species shed the bacterium. However, dead fish shed
F. psychrophilum
at higher rates than living fish, emphasizing the importance of removing dead fish in farms and hatcheries. Furthermore, shedding dynamics may differ according to
F. psychrophilum
genetic variant and/or fish species, a matter that may complicate BCWD management. Overall, study results provide deeper insight into
F. psychrophilum
shedding dynamics and will guide future BCWD management strategies.
Pharmacokinetic/pharmacodynamic integration of amphenmulin: a novel pleuromutilin derivative against
Mycoplasma gallisepticum
Authors: Wang Wenxiang , Yu Jiao , Ji Xuan , Xia Xirui , Ding Huanzhong 
Published: December 2023

ABSTRACT

Amphenmulin is a novel pleuromutilin derivative with great anti-mycoplasma potential. The present study evaluated the action characteristics of amphenmulin against
Mycoplasma gallisepticum
using pharmacokinetic/pharmacodynamic (PK/PD) modeling approaches. Following intravenous administration, amphenmulin exhibited an elimination half-life of 2.13 h and an apparent volume of distribution of 3.64 L/kg in healthy broiler chickens, demonstrating PK profiles of extensive distribution and rapid elimination. The minimum inhibitory concentration (MIC) of amphenmulin against
M. gallisepticum
was determined to be 0.0039 µg/mL using the broth microdilution method, and the analysis of the static time–kill curves through the sigmoid
E
max
model showed a highly correlated relationship (R ≥ 0.9649) between the kill rate and drug concentrations (1–64 MIC). A one-compartment open model with first-order elimination was implemented to simulate the
in vivo
anti-mycoplasma effect of amphenmulin, and it was found that bactericidal levels were reached with continuous administration for 3 days at doses exceeding 0.8 µg/mL. Furthermore, the area under the concentration–time curve divided by MIC (AUC/MIC) correlated well with the anti-mycoplasma effect of amphenmulin within 24 h after each administration, with a target value of 904.05 h for predicting a reduction of
M. gallisepticum
by 1 Log
10
CFU/mL. These investigations broadened the antibacterial spectrum of amphenmulin and revealed its characteristics of action against
M. gallisepticum
, providing a theoretical basis for further clinical development.

IMPORTANCE

Mycoplasma
has long been recognized as a significant pathogen causing global livestock production losses and public health concerns, and the use of antimicrobial agents is currently one of the mainstream strategies for its prevention and control. Amphenmulin is a promising candidate pleuromutilin derivative that was designed, synthesized, and screened by our laboratory in previous studies. Moreover, this study further confirms the excellent antibacterial activity of amphenmulin against
Mycoplasma gallisepticum
and reveals its action characteristics and model targets on
M. gallisepticum
by establishing an
in vitro
pharmacokinetic/pharmacodynamic synchronization model. These findings can further broaden the pharmacological theoretical basis of amphenmulin and serve as data support for its clinical development, which is of great significance for the discovery of new antimicrobial drugs and the control of bacterial diseases in humans and animals.
Cost-effectiveness of camrelizumab combined with chemotherapy in the first-line treatment of recurrent or metastatic nasopharyngeal carcinoma in China
Authors: Zhao Ziying , Chen Tongfeng , Zhou Zhen , Guo Rui , Liu Qiao 
Published: December 2023

ObjectiveThis study aimed to investigate the cost-effectiveness of adding Chinese-developed anti-PD-1 antibody camrelizumab to first-line platinum-doublet chemotherapy in patients with recurrent or metastatic nasopharyngeal carcinoma (L/M NPC) from the perspective of Chinese healthcare system.DesignA Markov model consisting of four health states, progression-free survival, first progression survival, second progression survival and death, was built to simulate 3-week patient transitions over a 20-year horizon. A direct comparison between first-line camrelizumab in combination with gemcitabine plus cisplatin and gemcitabine plus cisplatin was performed by calculating transition probabilities from the CAPTAIN-1st trial. Costs and utilities were collected from the local public database and literature. One-way and probabilistic sensitivity analyses were employed to evaluate the robustness of the model.SettingThe Chinese healthcare system perspective.ParticipantsA hypothetical cohort of Chinese patients with pathologically diagnosed L/M NPC who had an Eastern Cooperative Oncology Group performance status of 0 or 1.InterventionsFirst-line camrelizumab in combination with camrelizumab and gemcitabine plus cisplatin (CGP) versus gemcitabine plus cisplatin (GP).Primary outcome measureCost, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER).ResultsThe baseline analysis demonstrated that, compared with first-line GP, first-line CGP yields an effectiveness increase of 0.26 QALY, accompanied by an increment of US$6137.59 in healthcare cost. This results in an ICER of US$23 482.32/QALY. With the willingness-to-pay (WTP) threshold for a QALY set at US$37 654.50, first-line CGP proves to be cost-effective in 97.20% of the iterations. Deterministic sensitivity analyses indicated that the uncertainty in model parameters had no substantial effect on our results. Probability sensitivity analysis indicated that CGP was cost-effective at the assumed WTP threshold.ConclusionFor Chinese patients with L/M NPC, adding Chinese-developed anti-PD-1 antibody camrelizumab to the first-line GP chemotherapy may be cost-effective.
Developing a model for decision-making around antibiotic prescribing for patients with COVID-19 pneumonia in acute NHS hospitals during the first wave of the COVID-19 pandemic: qualitative results from the Procalcitonin Evaluation of Antibiotic use in COVID-19 Hospitalised patients (PEACH Study)
Authors: Henley Josie , Brookes-Howell Lucy , Euden Joanne , Pallmann Philip , Llewelyn Martin , Howard Philip , Powell Neil , Dark Paul , Szakmany Tamas , Hellyer Thomas P , Albur Mahableshwar , Hamilton Ryan , Prestwich Graham , Ogden Margaret , Maboshe Wakunyambo , Sandoe Jonathan , Thomas-Jones Emma , Carrol Enitan 
Published: December 2023

ObjectiveTo explore and model factors affecting antibiotic prescribing decision-making early in the pandemic.DesignSemistructured qualitative interview study.SettingNational Health Service (NHS) trusts/health boards in England and Wales.ParticipantsClinicians from NHS trusts/health boards in England and Wales.MethodIndividual semistructured interviews were conducted with clinicians in six NHS trusts/health boards in England and Wales as part of the Procalcitonin Evaluation of Antibiotic use in COVID-19 Hospitalised patients study, a wider study that included statistical analysis of procalcitonin (PCT) use in hospitals during the first wave of the pandemic. Thematic analysis was used to identify key factors influencing antibiotic prescribing decisions for patients with COVID-19 pneumonia during the first wave of the pandemic (March to May 2020), including how much influence PCT test results had on these decisions.ResultsDuring the first wave of the pandemic, recommendations to prescribe antibiotics for patients with COVID-19 pneumonia were based on concerns about secondary bacterial infections. However, as clinicians gained more experience with COVID-19, they reported increasing confidence in their ability to distinguish between symptoms and signs caused by SARS-CoV-2 viral infection alone, and secondary bacterial infections. Antibiotic prescribing decisions were influenced by factors such as clinician experience, confidence, senior support, situational factors and organisational influences. A decision-making model was developed.ConclusionThis study provides insight into the decision-making process around antibiotic prescribing for patients with COVID-19 pneumonia during the first wave of the pandemic. The importance of clinician experience and of senior review of decisions as factors in optimising antibiotic stewardship is highlighted. In addition, situational and organisational factors were identified that could be optimised. The model presented in the study can be used as a tool to aid understanding of the complexity of the decision-making process around antibiotic prescribing and planning antimicrobial stewardship support in the context of a pandemic.Trial registration numberISRCTN66682918.
Childhood and adolescent factors shaping vulnerability to underage entry into sex work: a quantitative hierarchical analysis of female sex workers in Nairobi, Kenya
Authors: Shah Pooja , Kabuti Rhoda , Beksinska Alicja , Nyariki Emily , Babu Hellen , Kungu Mary , Jama Zaina , Ngurukiri Pauline ,   The Maisha Fiti Study Champions, Kaul Rupert , Kyegombe Nambusi , Medley Graham F , Devries Karen , Seeley Janet , Weiss Helen Anne , Beattie Tara S , Kimani Joshua 
Published: December 2023

ObjectiveTo explore factors associated with early age at entry into sex work, among a cohort of female sex workers (FSWs) in Nairobi, Kenya.BackgroundYounger age at sex work initiation increases the risk of HIV acquisition, condom non-use, violence victimisation and alcohol and/or substance use problems. This study aimed to understand factors in childhood and adolescence that shape the vulnerability to underage sex work initiation.DesignBuilding on previous qualitative research with this cohort, analysis of behavioural–biological cross-sectional data using hierarchical logistic regression.Participants and measuresFSWs aged 18–45 years were randomly selected from seven Sex Workers Outreach Programme clinics in Nairobi, and between June and December 2019, completed a baseline behavioural–biological survey. Measurement tools included WHO Adverse Childhood Experiences, Alcohol, Smoking and Substance Involvement Screening Test and questionnaires on sociodemographic information, sexual risk behaviours and gender-based violence. Descriptive statistics and logistic regression were conducted using hierarchical modelling.ResultsOf the 1003 FSWs who participated in the baseline survey (response rate 96%), 176 (17.5%) initiated sex work while underage (<18 years). In the multivariable analysis, factors associated with entering sex work while underage included incomplete secondary school education (aOR=2.82; 95% CI=1.69 to 4.73), experiencing homelessness as a child (aOR=2.20; 95% CI=1.39 to 3.48), experiencing childhood physical or sexual violence (aOR=1.85; 95% CI=1.09 to 3.15), young age of sexual debut (≤15 years) (aOR=5.03; 95% CI=1.83 to 13.79) and being childless at time of sex work initiation (aOR=9.80; 95% CI=3.60 to 26.66).ConclusionsLower education level and childhood homelessness, combined with sexual violence and sexual risk behaviours in childhood, create pathways to underage initiation into sex work. Interventions designed for girls and young women at these pivotal points in their lives could help prevent underage sex work initiation and their associated health, social and economic consequences.
Supporting High-impAct useRs in Emergency Departments (SHarED) quality improvement: a mixed-method evaluation
Authors: Sillero-Rejon Carlos , Kirbyshire Megan , Thorpe Rebecca , Myring Gareth , Evans Clare , Lloyd-Rees Johanna , Bezer Angela , McLeod Hugh 
Published: December 2023

BackgroundThe need to better manage frequent attenders or high-impact users (HIUs) in hospital emergency departments (EDs) is widely recognised. These patients often have complex medical needs and are also frequent users of other health and care services. The West of England Academic Health Science Network launched its Supporting High impAct useRs in Emergency Departments (SHarED) quality improvement programme to spread a local HIU intervention across six other EDs in five Trusts.AimSHarED aimed to reduce ED attendance and hospital admissions by 20% for enrolled HIUs. To evaluate the implementation of SHarED, we sought to learn about the experience of staff with HIU roles and their ED colleagues and assess the impact on HIU attendance and admissions.MethodsWe analysed a range of data including semistructured interviews with 10 HIU staff; the number of ED staff trained in HIU management; an ED staff experience survey; and ED attendances and hospital admissions for 148 HIUs enrolled in SHarED.ResultsStaff with HIU roles were unanimously positive about the benefits of SHarED for both staff and patients. SHarED contributed to supporting ED staff with patient-centred recommendations and provided the basis for more integrated case management across the health and care system. 55% of ED staff received training. There were improvements in staff views relating to confidence, support, training and HIUs receiving more appropriate care. The mean monthly ED attendance per HIU reduced over time. Follow-up data for 86% (127/148) of cases showed a mean monthly ED attendances per HIU reduced by 33%, from 2.1 to 1.4, between the 6 months pre-enrolment and post-enrolment (p<0.001).ConclusionSHarED illustrates the considerable potential for a quality improvement programme to promote more integrated case management by specialist teams across the health and care system for particularly vulnerable individuals and improve working arrangements for hard-pressed staff.
Factors associated with the response to postnatal dexamethasone use in very low birthweight infants: a nationwide cohort study
Authors: Baek Seung Hwan , Shin Jeong Eun , Han Jungho , Song In Gyu , Park Joonsik , Lee Su Min , Shim Sungbo , Eun Ho Seon , Lee Soon Min , Lim Joohee , Yoon So Jin , Chang Wook , Park Min Soo 
Published: December 2023

BackgroundDexamethasone is widely used as a systemic corticosteroid to treat and prevent bronchopulmonary dysplasia (BPD) in preterm infants. We evaluated the current epidemiology of dexamethasone use to prevent BPD and analyse the factors associated with the response to dexamethasone in very low birthweight infants using a nationwide database.MethodsWe included very low birthweight infants born between January 2013 and December 2020 with a gestational age of 23–31 weeks using data from the Korean Neonatal Network registry. Patients were grouped based on their dexamethasone use into ‘Dex’ or ‘No Dex’ groups. Clinical variables and data were collected, and the annual trends of dexamethasone use and the proportion of patients who received dexamethasone according to gestational age were analysed. Respiratory outcomes were compared between the groups. Univariate and multivariate analyses were performed to analyse factors associated with the response to dexamethasone in BPD.ResultsOf 11 261 eligible infants, 2313 (20.5%) received dexamethasone, and 1714 (74.1%) of them were diagnosed with moderate-to-severe BPD. The 8-year annual prevalence of dexamethasone use was 17.7–22.3%. The ‘Dex’ group had more moderate-to-severe BPD, more frequent invasive ventilation use at a postmenstrual age of 36 weeks and longer ventilator duration. Birth weight, 5-minute APGAR score, pulmonary hypertension within the first 28 days, surgical treatment of patent ductus arteriosus, medical treatment of patent ductus arteriosus, pathological chorioamnionitis, hydrocortisone or budesonide use, surgical management of necrotising enterocolitis and fungal sepsis were associated with BPD after dexamethasone use.ConclusionsApproximately 20.5% of preterm infants received dexamethasone, and the frequency increased as gestational age decreased. Poor response to dexamethasone was associated with antenatal and postnatal inflammation, low birth weight and early pulmonary hypertension.
Case series of anifrolumab for treatment of cutaneous lupus erythematosus and lupus-related mucocutaneous manifestations in patients with SLE
Authors: Bao Aaron , Petri Michelle A , Fava Andrea , Kang Jun 
Published: December 2023

ObjectiveTo assess the efficacy of anifrolumab, a type-1 interferon receptor subunit-1 monoclonal antibody, in treating refractory cutaneous lupus erythematosus (CLE) and lupus non-specific mucocutaneous manifestations in patients with systemic lupus erythematosus (SLE).MethodsA case series comprising four SLE patients with refractory CLE received anifrolumab (300mg) as add-on therapy. Medical history, serological markers and images were collected. Cutaneous Lupus Erythematosus Disease Area and Severity Index–Activity (CLASI-A) was assessed at baseline and post-treatment visits.ResultsPatient 1:Anifrolumab effectively treated refractory chronic cutaneous lupus erythematosus with lupus panniculitis and calcinosis cutis.Patient 2:Anifrolumab demonstrated rapid improvement in generalised discoid lupus, achieving a substantial reduction in CLASI-A from 40 to 8.Patient 3:Switching from belimumab to anifrolumab led to notable improvement in photosensitivity and tumid lupus.Patient 4:Anifrolumab effectively managed refractory subacute cutaneous lupus erythematosus, resulting in remarkable cutaneous improvement and successful tapering of prednisone and mycophenolate mofetil.ConclusionAnifrolumab demonstrates efficacy in treating refractory CLE subtypes and lupus non-specific mucocutaneous manifestations in SLE patients. Further studies are needed to establish response rates, optimal dosing, and long-term outcomes.