bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergistic effects of polymyxin and vancomycin combinations on carbapenem- and polymyxin-resistant
Klebsiella pneumoniae
and their molecular characteristics
Authors: Nwabor Ozioma Forstinus , Chukamnerd Arnon , Terbtothakun Pawarisa , Nwabor Lois Chinwe , Surachat Komwit , Roytrakul Sittiruk , Voravuthikunchai Supayang Piyawan , Chusri Sarunyou 
Published: October 2023

ABSTRACT

The emergence and spread of polymyxin resistance, especially among
Klebsiella pneumoniae
isolates, threaten the effective management of infections. This study profiled for polymyxin resistance mechanisms and investigated the activity of polymyxins plus vancomycin against carbapenem- and polymyxin-resistant
K. pneumoniae
. The entire genome sequences of seven isolates were profiled for resistance and virulence determinants. The effects of combination therapy were evaluated using the checkerboard technique, time-kill assay, and population profile analysis. Protein profiles of the isolates treated with monotherapy were compared to that of combination therapy. The whole-genome sequencing data revealed that the isolates harbored β-lactams, carbapenems, aminoglycoside, fluoroquinolones, macrolides, and tetracycline resistance genes, with several virulence-associated genes. The plasmids including the
bla
OXA-232
-bearing ColKP3 plasmid were also identified in our isolates. Profiling for polymyxin resistance mechanism revealed a missense mutation in the
crrB
gene that resulted in a Q180L variant that conferred a deleterious effect on protein function. The combination assay indicated fractional inhibitory concentration index ranging from 0.31 to 1.13, whereas the time-kill assay demonstrated synergistic log reduction in colony-forming units per milliliter. Furthermore, population analysis profiling using dual antibiotics indicated enhancement in bacterial log reduction at lower antibiotics concentrations, compared to higher concentrations of single polymyxins. For protein profiling, 796 proteins were identified, and 56 and 94 of them were increased and decreased in the combined drug treatment groups, respectively, while other differentially produced proteins were detected in all treatment groups, except for the control group. The results demonstrated that the vancomycin combination might benefit the antimicrobial activities of polymyxins.

IMPORTANCE

This study provides insights into the mechanisms of polymyxin resistance in
K. pneumoniae
clinical isolates and demonstrates potential strategies of polymyxin and vancomycin combinations for combating this resistance. We also identified possible mechanisms that might be associated with the treatment of these combinations against carbapenem- and polymyxin-resistant
K. pneumoniae
clinical isolates. The findings have significant implications for the development of alternative therapies and the effective management of infections caused by these pathogens.
2% chlorhexidine gluconate aqueous versus 2% chlorhexidine gluconate in 70% isopropyl alcohol for skin disinfection prior to percutaneous central venous catheterisation: the ARCTIC randomised controlled feasibility trial
Authors: Clarke Paul , Soe Aung , Nichols Amy , Harizaj Helen , Webber Mark A , Linsell Louise , Bell Jennifer L , Tremlett Catherine , Muthukumar Priyadarsini , Pattnayak Santosh , Partlett Christopher , King Andrew , Juszczak Ed , Heath Paul T 
Published: October 2023

ObjectiveCatheter-related sepsis (CRS) is a major complication with significant morbidity and mortality. Evidence is lacking regarding the most appropriate antiseptic for skin disinfection before percutaneous central venous catheter (PCVC) insertion in preterm neonates. To inform the feasibility and design of a definitive randomised controlled trial (RCT) of two antiseptic formulations, we conducted the Antiseptic Randomised Controlled Trial for Insertion of Catheters (ARCTIC) feasibility study to assess catheter colonisation, sepsis, and skin morbidity.DesignFeasibility RCT.SettingTwo UK tertiary-level neonatal intensive care units.PatientsPreterm infants born <34 weeks’ gestation scheduled to undergo PCVC insertion.InterventionsSkin disinfection with either 2% chlorhexidine gluconate (CHG)-aqueous or 2% CHG-70% isopropyl alcohol (IPA) before PCVC insertion and at removal.Primary outcomeProportion in the 2% CHG-70% IPA arm with a colonised catheter at removal.Main feasibility outcomesRates of: (1) CRS, catheter-associated sepsis (CAS), and CRS/CAS per 1,000 PCVC days; (2) recruitment and retention; (3) data completeness.Safety outcomesDaily skin morbidity scores recorded from catheter insertion until 48 hours post-removal.Results116 babies were randomised. Primary outcome incidence was 4.1% (95% confidence interval: 0.9% to 11.5%). Overall catheter colonisation rate was 5.2% (5/97); CRS 2.3/1000 catheter days; CAS 14.8/1000 catheter days. Recruitment, retention and data completeness were good. No major antiseptic-related skin injury was reported.ConclusionsA definitive comparative efficacy trial is feasible, but the very low catheter colonisation rate would make a large-scale RCT challenging due to the very large sample size required. ARCTIC provides preliminary reassurance supporting potential safe use of 2% CHG-70% IPA and 2% CHG-aqueous in preterm neonates.Trial registration numberISRCTN82571474.
Measurements of in vivo skeletal muscle oxidative capacity are lower following sustained isometric compared with dynamic contractions
Authors: Bartlett Miles F. , Fitzgerald Liam F. , Nagarajan Rajakumar , Kent Jane A. 
Published: October 2023

Human skeletal muscle oxidative capacity can be quantified non-invasively using 31-phosphorus magnetic resonance spectroscopy (31P-MRS) to measure the rate constant of phosphocreatine (PCr) recovery ( kPCr) following contractions. In the quadricep muscles, several studies have quantified kPCr following 24–30 s of sustained maximal voluntary isometric contraction (MVIC). This approach has the advantage of simplicity but is potentially problematic because sustained MVICs inhibit perfusion, which may limit muscle oxygen availability or increase the intracellular metabolic perturbation, and thus affect kPCr. Alternatively, dynamic contractions allow reperfusion between contractions, which may avoid limitations in oxygen delivery. To determine whether dynamic contraction protocols elicit greater kPCr than sustained MVIC protocols, we used a cross-sectional design to compare quadriceps kPCr in 22 young and 11 older healthy adults following 24 s of maximal voluntary: (1) sustained MVIC and (2) dynamic (MVDC; 120°·s−1, 1 every 2 s) contractions. Muscle kPCr was ∼20% lower following the MVIC protocol compared with the MVDC protocol ( p ≤ 0.001), though this was less evident in older adults ( p = 0.073). Changes in skeletal muscle pH ( p ≤ 0.001) and PME accumulation ( p ≤ 0.001) were greater following the sustained MVIC protocol, and pH ( p ≤ 0.001) and PME ( p ≤ 0.001) recovery were slower. These results demonstrate that (i) a brief, sustained MVIC yields a lower value for skeletal muscle oxidative capacity than an MVDC protocol of similar duration and (ii) this difference may not be consistent across populations (e.g., young vs. old). Thus, the potential effect of contraction protocol on comparisons of kPCr in different study groups requires careful consideration in the future.
Multiple electron pumping
Authors: Blumenthal Mark D. , Mahony Declan , Ahmad Salahuddeen , Gouveia Dominique , Howe Hume , Beere Harvey E. , Mitchel Thomas , Ritchie Dave A. , Pepper Michael 
Published: October 2023

AbstractThe need to pump single electrons with a high degree of accuracy and fidelity has led to the development of a range of different pump and turnstile designs. Previous pumping mechanisms have all demonstrated that pumping more than one electron per cycle degrades the quantisation of the measured current. This unreliable delivery of multiple electrons per cycle has limited the use of on-demand single electron sources in electron quantum optic experiments. We present highly quantised current with multiple electrons pumped per cycle. We experimentally demonstrate that in our pumps an increase in electron throughput per cycle does not lead to an appreciable degradation in the accuracy of the produced current.Our pump is realised in an aluminium gallium arsenide two-dimensional electron gas, where electrons are pumped through a one-dimensional split-gate confinement potential under the influence of an applied source-drain voltage $V_{\text{SD}}$

V
SD

, and where the pump is driven by a trapezoidal arbitrary waveform. This combination of a split-gate potential, $V_{\text{SD}}$

V
SD

bias and trapezoidal wave form has led to the observation of robust quantised plateaus where not just a single electron, but a multiple integer number of electrons are pumped per cycle with a high degree of robustness and without the need of a magnetic field. For seven electrons per cycle, we report an increase of over two orders of magnitude in pumping accuracy from $2.72 \times 10^{-2}$
2.72
×

10

−
2

in devices operating in the conventional pumping regime, to $1.64 \times 10^{-4}$
1.64
×

10

−
4

in pumps operating in what we call the long plateau regime, a regime accessed under a change in a split-gate pumps applied $V_{\text{SD}}$

V
SD

voltage. This pump will find direct use in quantum transport measurements where the metrological accuracy of single electrons pumped per cycle is not required and the low throughput per cycle of electrons is limiting.
TAS0612, a Novel RSK, AKT, and S6K Inhibitor, Exhibits Antitumor Effects in Preclinical Tumor Models
Authors: Ichikawa Koji , Ito Satoshi , Kato Emi , Abe Naomi , Machida Takumitsu , Iwasaki Junya , Tanaka Gotaro , Araki Hikari , Wakayama Kentaro , Jona Hideki , Sugimoto Tetsuya , Miyadera Kazutaka , Ohkubo Shuichi 
Published: October 2023

Abstract
The MAPK and PI3K pathways are involved in cancer growth and survival; however, the clinical efficacy of single inhibitors of each pathway is limited or transient owing to resistance mechanisms, such as feedback signaling and/or reexpression of receptor-type tyrosine kinases (RTK). This study identified a potent and novel kinase inhibitor, TAS0612, and characterized its properties. We found that TAS0612 is a potent, orally available compound that can inhibit p90RSK (RSK), AKT, and p70S6K (S6K) as a single agent and showed a strong correlation with the growth inhibition of cancer cells with PTEN loss or mutations, regardless of the presence of KRAS and BRAF mutations. Additional RSK inhibitory activity may differentiate the sensitivity profile of TAS0612 from that of signaling inhibitors that target only the PI3K pathway. Moreover, TAS0612 demonstrated broad-spectrum activity against tumor models wherein inhibition of MAPK or PI3K pathways was insufficient to exert antitumor effects. TAS0612 exhibited a stronger growth-inhibitory activity against the cancer cell lines and tumor models with dysregulated signaling with the genetic abnormalities described above than treatment with inhibitors against AKT, PI3K, MEK, BRAF, and EGFR/HER2. In addition, TAS0612 demonstrated the persistence of blockade of downstream growth and antiapoptotic signals, despite activation of upstream effectors in the signaling pathway and FoxO-dependent reexpression of HER3. In conclusion, TAS0612 with RSK/AKT/S6K inhibitory activity may provide a novel therapeutic strategy for patients with cancer to improve clinical responses and overcome resistance mechanisms.
Stimulant or Depressant? Resource-Related Income Shocks and Conflict
Authors: Gehring Kai , Langlotz Sarah , Kienberger Stefan 
Published: October 2023

Abstract
We provide evidence on the mechanisms linking resource-related income shocks to conflict, focusing on illegal crops. We hypothesize that the degree of group competition over resources and the extent of law enforcement explain whether opportunity cost or contest effects dominate. Combining temporal variation in international drug prices with spatial variation in the suitability to produce opium, we show that higher prices increase household living standards and reduce conflict in Afghanistan. Analyzing shifts in conflict tactics and using geo-referenced data on drug production networks and territorial control highlight the importance of opportunity costs, and reveal heterogeneous effects consistent with our theory.
The Anatomy of a Hospital System Merger: The Patient Did Not Respond Well to Treatment
Authors: Gaynor Martin , Sacarny Adam , Sadun Raffaella , Syverson Chad , Venkatesh Shruthi 
Published: October 2023

Abstract
Despite the continuing US hospital merger wave, it remains unclear how mergers change, or fail to change, hospital behavior and performance. We open the “black box” of hospital practices through a mega-merger between two for-profit chains. Benchmarking the merger's effects against the acquirer's stated aims, we show they achieved some of their goals, harmonizing electronic medical records and sending managers to target hospitals. Post-acquisition managerial processes were similar across the merged chain. However, these interventions failed to drive detectable gains in performance. Our findings demonstrate the importance of organizations for merger research in health care and the economy more generally.
The Impact of Projected Changes in Hurricane Frequencies on U.S. Hurricane Wind and Surge Damage
Authors: Jewson Stephen 
Published: October 2023

Abstract
We use a simple risk model for U.S. hurricane wind and surge economic damage to investigate the impact of projected changes in the frequencies of hurricanes of different intensities due to climate change. For average annual damage, we find that changes in the frequency of category-4 storms dominate. For distributions of annual damage, we find that changes in the frequency of category-4 storms again dominate for all except the shortest return periods. Sensitivity tests show that accounting for landfall, uncertainties, and correlations leads to increases in damage estimates. When we propagate the distributions of uncertain frequency changes to give a best estimate of the changes in damage, the changes are moderate. When we pick individual scenarios from within the distributions of frequency changes, we find a significant probability of much larger changes in damage. The inputs on which our study depends are highly uncertain, and our methods are approximate, leading to high levels of uncertainty in our results. Also, the damage changes we consider are only part of the total possible change in hurricane damage due to climate change. Total damage change estimates would also need to include changes due to other factors, including possible changes in genesis, tracks, size, forward speed, sea level, rainfall, and exposure. Nevertheless, we believe that our results give important new insights into U.S. hurricane risk under climate change.

Significance Statement
We investigate how changes in the frequencies of hurricanes of different intensities as a result of climate change may contribute to changes in U.S. economic damage due to wind and surge. We find that economic damage will likely increase as a result of projected increases in the frequency of landfalling hurricanes. Analysis of our results shows that increases in the frequency of category-4 storms are the main driver of the changes. Our best estimate results, based on a multimodel ensemble, give modest increases in damage, but within the ensemble there are individual scenarios that give much larger increases in damage. The large range of individual damage estimates is a motivation for continuing efforts to reduce the uncertainty around hurricane projections under climate change.
A Novel Tumor Glycolysis Inhibitor: 4-Methylumbelliferone
Authors: Li Zi-Yao , Yang Qin , Cheng Xiao-Ge , Zhou Yan-Li , Piao Xiang-Ling , Qiu Li , Zhou Bo-Jun , Wu Song-Tao 
Published: October 2023

Background and Objectives 4-Methylumbelliferone (4-MU) is a coumarin compound that can be extracted from the medicinal plant with anti-cancer properties, Smilax china L. In recent years, studies have revealed its potential as an anti-tumor and anti-metastasis drug with promising effects in cancer treatment. Despite an increase in research on the metabolic patterns of tumor cells, no prior research has suggested that 4-MU inhibits tumor proliferation by blocking glycolysis. This thesis presents evidence that 4-MU binds to proteins involved in glycolysis, thus mediating its anti-tumor effects. Materials and Methods Network pharmacology, transcriptomics, and molecular docking were utilized to forecast the potential targets and probable pathways of 4-MU’s anti-cancer activity, and the affinity of 4-MU towards potential targets was discovered using microscale thermophoresis (MST) detection. Results The results of transcriptome analysis brought to light that the genes with differential expressions were primarily enriched in metabolic pathways, including glycolysis-related proteins. Using network pharmacology and molecular docking, our study identified Heat Shock Protein 90 Alpha Family Class A Member 1 (Hsp90AA1), mitochondria, phosphoglycerate kinase 2 (PGK2), glycerol-3-phosphate dehydrogenase (GPD2), and glucose-6-phosphate isomerase (GPI) as potential targets of 4-MU. The strong binding affinity between 4-MU and these proteins was confirmed by the MST assay. Conclusion The findings indicate that 4-MU can hinder glycolysis by binding to glycolysis-associated proteins such as Hsp90AA1, PGK2, GPD2, and GPI. This results in the prevention of the energy supply to the tumor tissue, which ultimately curbs tumor growth, thereby demonstrating its anti-tumor properties. These results conclude that 4-MU has the capacity to be a novel glycolysis inhibitor for cancer treatment. Moreover, the identification of these glycolysis-associated proteins as possible targets for cancer therapy offers new avenues for research in the field of cancer treatment, thus providing further valuable evidence for the anti-cancer mechanism of 4-MU.
Shockwave Treatment vs Surgery for Proximal Fifth Metatarsal Stress Fractures in Soccer Players: A Pilot Study
Authors: Ramon Silvia , Lucenteforte Giacomo , Alentorn-Geli Eduard , Steinbacher Gilbert , Unzurrunzaga Rocío , Álvarez-Díaz Pedro , Barastegui David , Grossi Sebastián , Sala Esther , Martinez-De la Torre Adrián , Mangano Giulia Rita Agata , Cuscó Xavier , Rius Marta , Ferré-Aniorte Alfred , Cugat Ramón 
Published: October 2023

Background To compare the clinical, radiologic, and functional outcomes between shockwave and operative treatments for proximal fifth metatarsal stress fractures in soccer players in a pilot study. Methods: Between 2017 and 2019, 18 soccer players with fifth metatarsal stress fractures attended at Mutualidad de Futbolistas Españoles–Delegación Catalana were included. Patients were randomly assigned into 2 groups receiving either surgery with an intramedullary screw (group 1) or high-energy focused extracorporeal shockwave treatment (group 2 performed once a week for 3 weeks using 2000 impulses at an energy flux density of 0.21 mJ/mm2 and 4 Hz frequency). Clinical (pain), radiologic (bone healing), and functional (Tegner Activity Scale and American Orthopaedic Foot & Ankle Society [AOFAS] ankle-hindfoot scales) outcomes before and after receiving the treatment were compared between both groups. In addition, ability and time to return to play was also compared between groups. Results: No patients were lost to follow-up. There were no statistically significant differences at last follow-up between surgery and extracorporeal shockwave treatment for bone healing, pain relief, AOFAS ankle-hindfoot score, Tegner score, and time return to play. No complications were reported in either of the 2 groups. Conclusion: In this pilot study, extracorporeal shockwave treatment and operative treatment were found to be equally effective at reducing pain, achieving bone healing, and allowing the soccer players to return to play after proximal fifth metatarsal stress fractures. This study suggests that ESWT may be a good option for the management of proximal fifth metatarsal stress fractures in soccer players. If this approach proves successful in larger trials, the shockwave approach might help avoid known complications of the surgical treatment like wound problems, nerve injury, and hardware intolerance. Further investigations with larger sample size should be conducted in order to confirm the present conclusions. Level of Evidence: Level II, therapeutic, pilot randomized controlled trial.
Uncovering the Spectrum of Hemophagocytic Lymphohistiocytosis: A Nephrology Department’s Analysis of 14 Cases
Authors: Hajji Meriam , Barbouch Samia , Kaaroud Hayet , Ben Abdelghani Khaoula , Ben Hamida Fethi , Harzallah Amel , Abderrahim Ezzeddine 
Published: October 2023

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a disease of multi-organ dysfunction due to excessive immune activation causing widespread inflammation and tissue destruction. It is a severe condition associated with high morbidity and mortality. Early identification is crucial for prompt treatment. The objective of this case series is to underscore the intricacy of managing HLH in individuals with renal dysfunction. Methods: This is a retrospective study of patients diagnosed with HLH in a nephrology department over a period of 30 years. We retrospectively reviewed the medical files by applying the Revised HLH-2004 criteria. Results: Among the 14 female patients included, the mean age was 45.2 years (range 23-78). Nine patients presented with sudden onset of fever and chills. Physical examination revealed purpura in 3 cases, hepatomegaly and splenomegaly in 6 and 5 cases respectively, and peripheral lymphadenopathy in 1 case. Hemorrhagic complications were observed in 5 cases, hypertriglyceridemia in 9 cases, and hyperferritinemia in all cases. Hypothyroidism was observed in all cases, and impaired renal function was detected in 11 of them, with 5 experiencing it as a result of lupus nephritis, and 1 case attributed to pre-eclampsia. Hemophagocytosis was confirmed through sternal puncture in 11 cases. Treatment involved etiological therapy with corticosteroids and immunosuppressants and/or anti-infectives. Intravenous immunoglobulins were administered in 6 cases, while 2 cases required coagulation factor transfusions. Unfortunately, 9 patients did not survive. Conclusion: The study highlights the need for increased awareness and prompt recognition of HLH, particularly in patients with associated renal complications.