bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of a new protocol for rapid identification of
Streptococcus pneumoniae
in blood cultures using the modified bile solubility test: Gram staining is still standing
Authors: Aupaix Antoine , Verroken Alexia , Rodriguez-Villalobos Hector 
Published: December 2024

ABSTRACT

This study aimed to evaluate a new protocol of the bile solubility test performed directly on the blood from positive blood culture bottles to identify
Streptococcus pneumoniae
rapidly. Seventy-five positive blood cultures (PBC) showing Gram-positive cocci in pairs or chains on Gram stain, including 32
S. pneumoniae
isolates and three reference American Type Culture Collection (ATCC) isolates were included to evaluate the performance of a modified bile solubility test (MBST). One milliliter of blood from the PBC bottle was mixed with 0.5 mL of 10% desoxycholate or a saline solution. Both suspensions were analyzed after 10 min of incubation through a Gram stain to detect solubilization. This technique was compared with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry identification, performed on PBC following extraction or on colonies after short or standard incubation, and the optochin susceptibility test on colonies. The capsular serotypes were determined for all
S. pneumoniae
, and the Belgian National Reference Center confirmed the identification. All 32 clinical isolates and the ATCC isolate of
S. pneumoniae
were solubilized on the desoxycholate-treated slides, while the other species tested remained visually unchanged on both, the test and control slides. The MBST test demonstrated a 100% sensitivity and specificity with a mean turnaround time (TAT) of just 39 min, making it 14 h and 56 min faster than the optochin susceptibility test. This rapid variant of the bile solubility test appears to be a reliable method to identify
S. pneumoniae
directly from positive blood culture bottles, with a TAT of 39 min. It is a cost-effective, easy-to-perform, and time-efficient technique. Negative results should be interpreted cautiously, as they may result from mixed infections with
S. pneumoniae
and other Gram-positive cocci.
Tannic acid reactivates HIV-1 latency by mediating CBX4 degradation
Authors: Chen Cancan , Zhong Zhihan , Zhang Wanying , Xia Baijin , Wu Liyang , Liang Liting , Zhang Yiwen , Zhang Hui , Zhang Xu , Pan Ting , Li Linghua , Liu Bingfeng 
Published: December 2024

ABSTRACT

HIV-1 can integrate viral DNA into host cell chromosomes and establish a long-term stable latent viral reservoir, a major obstacle in curing HIV-1 infection. The reactivation of latent proviruses with latency-reversing agents (LRAs) is a prerequisite for the eradication of viral reservoirs. Previous reports have shown that tannic acid (TA) exerts several biological functions, including antioxidant and antitumor activities. Here, we identified a novel function of TA as a reactivator of HIV-1 latency. TA showed similar features to the HIV-1 transactivator of transcription (Tat) and was able to reactivate a larger number of proviruses from various integration sites. TA also showed a strong synergistic effect with other LRAs acting on different signaling pathways. Further studies revealed that the polycomb repressive complex 1 component, chromobox protein homolog 4 (CBX4), is specifically degraded by TA through ubiquitination. CBX4 is associated with the tri-methylation at lysine 27 of histone H3 (H3K27me3) which was enriched on HIV-1 long terminal repeat regions. The TA-induced CBX4 degradation decreased the H3K27me3 enrichment and subsequently enhanced the transcriptional activity of the integrated proviruses. These results suggest that TA is an efficient LRA aiming to a new target for HIV-1 latency, which could be developed to eradicate latent proviruses.

IMPORTANCE
HIV-1 remains a global health challenge, with its ability to integrate into the host genome and evade the effects of drugs. To overcome this obstacle, the “shock and kill” strategy was proposed, targeting the reactivation of latent HIV-1 for subsequent eradication through antiretroviral medication and immune system reinforcement. Here, we found a new reactivator for HIV-1 latency, tannic acid (TA), which can reactivate HIV-1 latency widely and deeply. Moreover, we demonstrated that TA could promote the interaction between the polycomb repressive complex 1 component CBX4 and the E3 ubiquitin ligase cullin 4A (CUL4A), resulting in CBX4 degradation through the ubiquitin-proteasome system. These events reduce H3K27me3 enrichment in the HIV-1 long terminal repeat region, thereby promoting HIV-1 transcription and ultimately reactivating HIV-1 latent infection. Our work may facilitate the identification of new latency-reversing agents and provide more theoretical evidence for the molecular mechanism of HIV-1 latency.
Valine potentiates cefoperazone-sulbactam to kill methicillin-resistant
Staphylococcus aureus
Authors: Li Shao-hua , Tao Yuan , Yang Zhi-cheng , Fu Huan-zhe , Lin Hui-yin , Peng Xuan-xian , Li Hui 
Published: December 2024

ABSTRACT

Metabolic state-reprogramming approach was extended from Gram-negative bacteria to Gram-positive bacterium methicillin-resistant
Staphylococcus aureus
(MRSA) for identifying desired reprogramming metabolites to synergize existing antibiotic killing to MRSA. Metabolomics comparison between MRSA and methicillin-sensitive
Staphylococcus aureus
showed a depressed metabolic state in MRSA. Valine was identified as the most depressed metabolite/biomarker, and valine, leucine and isoleucine biosynthesis as the most enriched metabolic pathway. Thus, valine was used as a reprogramming metabolite to potentiate existing antibiotic killing to MRSA. Among the tested antibiotics, valine synergized cefoperazone-sulbactam (SCF) to produce the greatest killing effect. The combined effect of SCF and valine was demonstrated in clinical MRSA isolates and in mouse systemic and thigh infection models. Underlying mechanisms were attributed to valine-induced the activation of the pyruvate cycle/the TCA cycle and fatty acid biosynthesis. The activated pyruvate cycle/the TCA cycle elevated proton motive force by NADH and the activated fatty acid biosynthesis promoted membrane permeability by lauric acid. Both together increased cefoperazone uptake, which outpaces efflux action and thereby intracellular drug is elevated to effectively kill MRSA. These results provide the combination of valine and SCF to produce a new drug candidate effective against MRSA.

IMPORTANCE

Methicillin-resistant
Staphylococcus aureus
(MRSA) is possibly the most infamous example of antibiotic resistance and new antibiotics are urgently needed to control it. The present study used metabolic state-reprogramming approach to identify an ideal biomarker as an antibiotic adjuvant for reversing the metabolic state of MRSA. The most repressed valine was identified as the adjuvant. Exogenous valine most effectively potentiated cefoperazone-sulbactam (SCF) to kill MRSA
in vitro
and
in vivo
. Viability of 18 clinical MRSA isolates was reduced by the top 276.64-fold in the presence of valine and SCF. In mouse models, lower bacterial load in liver, spleen, kidney, thigh, and higher survival were determined in the SCF + valine than valine or SCF alone. Valine promoted MRSA to increase SCF uptake that overcomes the efflux and enzymatic hydrolysis. It also extended the PAE of SCF. These occur because valine activates the pyruvate cycle to elevate proton motive force by NADH and increases membrane permeability by lauric acid. Therefore, the combination of valine and SCF is a new drug candidate effective against MRSA.
An Escherichia coli Strain for Plasmid DNA Production with a Low Endotoxin Level
Authors: Kharlampieva D. D. , Bobrovsky P. A. , Grafskaia E. N. , Lazarev V. N. , Manuvera V. A. 
Published: December 2024

Abstract
Plasmid DNA (pDNA) is one of the possible types of vectors used in gene therapy. Escherichia coli is the most common bacterium for the production of pDNA. Lipopolysaccharides are the main component of the outer membrane of E. coli. Lipopolysaccharides are strong endotoxins, and their presence in pharmacological substances is highly undesirable. One of the approaches to eliminating endotoxin contamination of target substances is knocking out the genes of the lipopolysaccharide biosynthesis pathway. Using the CRISPR/Cas9 genome editing technology, we obtained a mutant form of the E. coli strain SCS110. We knocked out the genes kdsD, gutQ, lpxM, lpxL, lpxP, pagP, and eptA. As a result, lipopolysaccharide contamination of pDNA samples isolated by different methods from the mutant E. coli SCS 110 was significantly lower (19 to 295 times) than in pDNA samples from the original strain.
Should We Expect Further Acceleration of the Earth’s Rotation in the Coming Years?
Authors: Malkin Z. M. 
Published: December 2024

Abstract
Recently, it has been suggested in the literature that the difference between universal and coordinated time UT1–UTC could reach a large positive value in the coming years [1]. This would make it necessary to introduce a negative leap second into UTC for the first time in history, which in turn will cause serious problems in time keeping and synchronization systems around the world. Based on the latest Earth’s rotation and universal time data published by the international Earth rotation and reference systems service (IERS) and their prediction, in this paper, we have shown that the acceleration trend observed over the past four years is likely to return to slowing down soon. Therefore, fears about the possible need to introduce a negative leap second into the UTC time scale in the next few years in the light of recent observational data have seen unfounded.
Postnatal betamethasone treatment in extremely preterm infants and risk of neurodevelopmental impairment: a cohort study
Authors: Löfberg Linn , Serenius Fredrik , Hellstrom-Westas Lena , Olhager Elisabeth , Ley David , Farooqi Aijaz , Stephansson Olof , Abrahamsson Thomas 
Published: December 2024

ObjectiveTo evaluate if postnatal treatment with betamethasone in extremely preterm infants was associated with neurodevelopmental impairment (NDI) at 6.5 years of age.DesignProspective cohort study.SettingExtremely Preterm Infants in Sweden Study (gestational age <27 weeks, born 2004–2007).Patients428 children born extremely preterm were assessed at 6.5 years of age, 115 treated with betamethasone and 313 not treated.Main outcome measuresNDI at 6.5 years of age. Evaluation at 6.5 years included cognitive testing with the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV), neurological examination and a medical record review.ExposureTreatment with postnatal betamethasone.Main outcomeModerate to severe NDI at 6.5 years of age, defined as a composite including cerebral palsy, and/or impairment in cognition, hearing and vision.ResultsModerate to severe NDI was more prevalent in children treated with postnatal betamethasone (49% treated vs 26% not treated, p<0.001). Betamethasone-treated children had worse cognitive development with mean WISC-IV score of 75 (SD 13.7) vs 87 (SD 14.0, p<0.001). The effect was dose dependent: 1.35 mg/kg vs 1.0 mg/kg (p=0.01) in betamethasone-treated children with moderate to severe versus no or mild NDI, respectively. The differences remained after adjustment for potential confounders with logistic regression (adjusted OR (aOR) 1.80, 95% CI 1.14 to 3.21). The difference in NDI also remained after propensity score matching, with crude OR 2.82 (95% CI 1.42 to 5.61, p=0.003) and aOR 2.17 (95% CI 1.07 to 4.69, p=0.04).ConclusionPostnatal treatment with betamethasone is associated with increased risk of NDI at 6.5 years.
Prognostic value of macular neovascularisation characteristics for photoreceptor integrity in nAMD: a prospective observational study
Authors: Pu Jiaxin , Zhuang Xuenan , Li Miaoling , Hao Xinlei , He Guiqin , Su Yongyue , Gan Yuhong , Zhang Xiongze , Ji Yuying , Mi Lan , Zhang Yining , Yang Ruijun , Chen Xuelin , Wen Feng 
Published: December 2024

PurposeTo explore the relationship between characteristics of macular neovascularisation (MNV) and photoreceptor integrity in patients with neovascular age-related macular degeneration (nAMD).MethodsThis prospective study enrolled treatment-naïve nAMD eyes and conducted a 3-month follow-up. 16 quantitative MNV features were evaluated using optical coherence tomography angiography, and the impaired areas of ellipsoid zone (EZ), external limiting membrane (ELM) and outer nuclear layer (ONL) were obtained using optical coherence tomography. Correlation and regression analyses assessed the relationships between MNV features and photoreceptor integrity.Results110 nAMD eyes from 110 patients (73.64% men) were included. Baseline MNV characteristics, including MNV perimeter, maxFeret, minFeret, vessel area, total vessel length, total number of junctions and endpoints, and mean E lacunarity, were positively correlated with photoreceptor damage areas (r ranging from 0.227 to 0.558, p<0.05 for all). Meanwhile, vessel density negatively correlated with photoreceptor damage (r=−0.468 for EZ, −0.394 for ELM and −0.538 for ONL, all p<0.05). After the loading phase, the EZ prognosis was independently associated with baseline MNV minFeret (Std β=0.362, p=0.011) and mean E lacunarity (Std β=0.130, p=0.041). The prognosis for ELM was independently linked to baseline MNV minFeret (Std β=0.373, p=0.014), while no significant factors were found to influence ONL prognosis (p>0.05 for all).ConclusionA strong correlation was observed between MNV features and photoreceptor integrity, with larger and more complex vascular networks associated with greater photoreceptor damage.
Optic nerve sheath enhancement on orbital MRI in giant cell arteritis
Authors: Ephrem Rebka K , Mohan Suyash , Rebello Ryan , Liang Rui , Kurtz Robert , Song Jae W , Tamhankar Madhura A , Rhee Rennie L 
Published: December 2024

BackgroundDifferentiating arteritic anterior ischaemic optic neuropathy (A-AION) due to giant cell arteritis (GCA) from non-arteritic anterior ischaemic optic neuropathy (NA-AION) may pose a diagnostic challenge. Our study aimed to assess the use of standard orbital MRI in distinguishing ocular manifestations of GCA from NA-AION.MethodsThis study included 25 consecutive patients (11 GCA, 14 NA-AION) who underwent contrast-enhanced orbital MRIs within 3 months of symptom onset. Two radiologists blinded to clinical data independently evaluated MRIs for the enhancement of the optic nerve sheath (ONS) and other orbital structures.ResultsOn orbital MRI, ONS enhancement of at least one eye was more common in patients with GCA than NA-AION (64% vs 14%, p=0.02). ONS enhancement on MRI was seen in patients with typical ophthalmologic exam findings of A-AION as well as in GCA patients with other features of ocular ischaemia (eg, retinal artery occlusion). Among patients with GCA, ONS enhancement was bilateral in six of seven cases even when visual symptoms and signs were unilateral.ConclusionPatients with ocular GCA are more likely to have ONS enhancement on MRI compared with NA-AION. ONS enhancement was observed in (i) A-AION and other forms of ocular ischaemia, demonstrating the potential value of MRI in multiple orbital pathologies in GCA, and (ii) both the affected and unaffected eye, suggesting MRI may detect early subclinical ocular disease in GCA. These results highlight the potential value of adding orbital MRI to the diagnostic workup of ocular GCA.
Concurrent symptom domains and associations with recovery timelines among collegiate athletes with sport-related concussion
Authors: D'Alonzo Bernadette A , Schneider Andrea LC , Barnett Ian J , Master Christina L , Hamilton Roy H , Wiebe Douglas J 
Published: December 2024

ObjectiveConcussion symptoms can be clustered into domains and understanding how multiple symptom domains present clinically may guide more accurate interventions. We investigate the associations between concurrent symptom domains and clinical recovery outcomes, as well as the role of sex in these relationships.MethodsWe analysed data from the Ivy League–Big Ten Epidemiology of Concussion Study and included sport-related concussions (SRC) across five academic years 2015–2016/2019–2020 with complete data (n=1160). We used symptoms from the Sport Concussion Assessment Tool 22-symptom evaluation, previously categorised into symptom domains. Symptom profiles characterise how athletes endorse concurrent symptom domains. Outcomes are time (in days) from SRC to symptom resolution, return to academics, and full play.ResultsFemales more commonly endorsed headache, sensory, and affective symptom domains. Four classes/symptom profiles emerged: (1) ‘low’ on all domains, (2) ‘high’ on headache and sensory domains, (3) ‘high’ on vestibulo-ocular, cognitive, and sleep domains, and (4) ‘high’ on all domains. Time to symptom resolution, return to academics, and return to play were consistently shorter among class/symptom profile 1 compared with other classes/profiles. Compared with class/profile 1, the chance of having symptoms resolve was lower among classes/profiles 2, 3, and 4 (HR 0.74, 95% CI 0.63 to 0.88; HR 0.74, 95% CI 0.60 to 0.92; HR 0.50, 95% CI 0.43 to 0.57, respectively). Results were similar for return to academics and full play outcomes. Interactions with sex were not statistically significant.ConclusionsFour symptom profiles characterised how concussion symptom domains co-occur. We found differences in recovery timelines among these groups, but not by sex. Findings inform and support targeted, symptom domain-specific interventions in concussion management.
Association of cardiorespiratory fitness with the incidence and progression trajectory of cardiometabolic multimorbidity
Authors: Chen Yanchun , Yang Hongxi , Li Dun , Zhou Lihui , Lin Jing , Yin Xin , Yang Weiling , Gao Ying , Zhang Qing , Leng Sean X , Wang Yaogang 
Published: December 2024

ObjectivesThis study examined the relationship of cardiorespiratory fitness (CRF) in the transition from healthy status to first cardiometabolic disease, subsequent cardiometabolic multimorbidity and further to death.MethodsWe used data from the UK Biobank of 47 484 participants without cardiometabolic diseases at baseline. CRF was assessed via a 6 min incremental ramp cycle ergometer test and expressed in metabolic equivalent of tasks (METs, 1 MET=3.5 mL/kg/min). Cardiometabolic multimorbidity was defined as at least two diseases among diabetes, hypertension, coronary heart disease and stroke.ResultsOver 12.5 years median follow-up, 8123 participants developed first cardiometabolic disease, 1958 developed cardiometabolic multimorbidity and 2177 died. CRF was associated with different transition stages in cardiometabolic multimorbidity development. The HRs (95% CIs) per MET increase in CRF were 0.94 (0.93 to 0.95) and 0.97 (0.96 to 0.99) for transitions from healthy baseline to first cardiometabolic disease and subsequent cardiometabolic multimorbidity. Per MET increase in CRF was associated with reduced risk of transition from healthy baseline to death (HR: 0.97, 95% CI 0.95 to 0.99), but not for the transition from first cardiometabolic disease and cardiometabolic multimorbidity to death. When first cardiometabolic disease was divided into specific cardiometabolic diseases, there were comparable trends of CRF on the disease-specific transitions from healthy baseline to first cardiometabolic disease and subsequent cardiometabolic multimorbidity.ConclusionHigher CRF was associated with a lower risk of progression from a healthy state to first cardiometabolic disease and subsequently to cardiometabolic multimorbidity. These findings suggest that improving CRF is a potential strategy for preventing cardiometabolic multimorbidity development.
Clinical outcomes and severity of laboratory-confirmed RSV compared with influenza, parainfluenza and human metapneumovirus in Australian children attending secondary care
Authors: Sarna Mohinder , Le Huong , Taye Belaynew Wasie , Glass Kathryn , Levy Avram , Richmond Peter , Moore Hannah C 
Published: December 2024

IntroductionAcute lower respiratory infections (ALRIs) are a major contributor to the global infectious disease burden and a common cause of hospitalisation for children under 2 years. We compared clinical severity in children hospitalised with respiratory syncytial virus (RSV), parainfluenza virus (PIV), human metapneumovirus (hMPV) and influenza virus (IFV).MethodsWe used a probabilistically linked population cohort born in Western Australia between 2010 and 2020 and hospitalised before the age of 2 years. Outcomes compared included length of hospital stay (LOS), admission to intensive care unit (ICU), need for respiratory support (RS), complex hospital course (RS, death, ICU admission or LOS >75th percentile), 7-day and 30-day mortality, hospital-in-the-home care, 30-day all-cause and ALRI-specific readmissions and emergency department presentations 14 days prior to hospitalisation. Logistic regression was used for binary outcomes, and negative binomial regression was used for discrete count variables. Incidence rates, time to RS and time to readmissions were calculated using survival analysis techniques.ResultsThe final cohort included 210 997 hospitalised children under 24 months of age for a total of 315 769 admissions. Infants hospitalised before 6 months had the highest rates for all virus-specific hospitalisations, particularly RSV hospitalisations (50.4 per 1000 child-years (95% CI 48.7 to 52.1)). Infants <6 months had higher odds of an ICU admission (adjusted OR (aOR) 2.39, 95% CI 1.36 to 4.19) and RS (aOR 4.68, 95% CI 2.95 to 7.44) and a complex hospital course (aOR 2.69, 95% CI 2.13 to 3.42) with RSV and four times higher hazards of requiring RS earlier (adjusted HR (aHR) 4.06, 95% CI 2.59 to 6.36). An ALRI-coded 30-day readmission was recorded in 10%–24% of virus-specific hospitalisations.DiscussionYoung infants have a more severe and complex hospital course with RSV hospitalisation compared with hospitalisation with other respiratory viruses and should be prioritised for prevention measures such as the single-dose monoclonal antibody, nirsevimab.
Early detection of colorectal cancer using aberrant circulating cell-free mitochondrial DNA fragmentomics
Authors: Wang Siyuan , Peng Fan , Dang Miao , Jiao Huanmin , Zhang Huanqin , Zhou Kaixiang , Guo Wenjie , Gong Zhiyun , Guo Lin , Lu Renquan , Li Deliang , Liu Bingrong , Guo Xu , Xing Jinliang , Liu Yang 
Published: December 2024

BackgroundEarly detection of colorectal cancer (CRC) is crucial for improving the survival rates of patients.ObjectiveWe aimed to develop a novel strategy for early CRC detection using the fragmentomic features of circulating cell-free mitochondrial DNA (ccf-mtDNA).DesignHere, a total of 1147 participants, including 478 healthy controls (HCs), 112 patients with advanced adenomas (AAs) and 557 patients with CRC, were enrolled from five hospitals and plasma samples were collected for capture-based ccf-mtDNA sequencing.ResultsOur data analysis revealed significantly aberrant ccf-mtDNA fragmentomic features in patients with CRC and AA when compared with HCs. Then, a CRC detection (CD) model was constructed based on the fragmentomic features of ccf-mtDNA from 246 patients with CRC and 168 HC in the training cohort, showing area under the curve of 0.9863, sensitivity of 92.68% and specificity of 93.45%. Both internal and two external validation cohorts demonstrated the excellent capacity of CD model in distinguishing patients with early-stage CRC from HCs, greatly surpassing the performance of serum biomarkers. Furthermore, our CD model can also detect patients with AA with a sensitivity of 79.35% in AA cohort 1 and 85.00% in AA cohort 2.ConclusionIn conclusion, based on aberrant ccf-mtDNA fragmentomic features, a novel and non-invasive approach was established for the detection of patients with early-stage CRC or AA, with high performance.