bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population pharmacokinetic modeling of ceftriaxone in cerebrospinal fluid in children: should we be using once- or twice-daily dosing for meningitis?
Authors: Boast A. , Zhang W. , Soeorg H. , Gonis G. , Di Carlo A. , Daley A. , Curtis N. , McWhinney B. , Ungerer J. P. J. , Lei A. , Standing J. F. , Gwee A. 
Published: October 2024

ABSTRACT

Guidelines for bacterial meningitis in children recommend intravenous ceftriaxone 50 mg/kg (max 2 g) twice daily (BD) or 100 mg/kg (max 4 g) once daily (OD), leaving the decision regarding the dose frequency to the prescriber. We investigated the cerebrospinal fluid (CSF) penetration of ceftriaxone to evaluate whether one dosing regimen is superior. Unbound ceftriaxone concentrations were measured in serum and CSF samples from children aged 0–18 years treated with ceftriaxone if there was a sample remaining after clinical tests were performed. A serum–CSF population pharmacokinetic model was developed using non-linear mixed-effects modeling. The once- and twice-daily dosing regimens were simulated, and the probability of target attainment (PTA) was determined for maintaining a CSF concentration above a minimum inhibitory concentration (MIC) of 1 mg/L for common meningitis pathogens and 4 mg/L for
Staphylococcus aureus
for 100% of the dosing interval. Sixteen serum and 87 CSF samples were collected from 98 children (age range 0.1–18.5 years). The final two-compartment serum–CSF model included a renal maturation function with weight scaling on clearance and volume of distribution. The estimated serum:CSF uptake was 20.1%. For MIC 1 mg/L, the 24 h PTA was higher for OD (88%) compared with BD (53%) dosing, although both achieved a 100% PTA at steady state. For
S. aureus
(MIC 4 mg/L), neither dosing regimen was sufficient. Our findings support the use of a 100 mg/kg once daily regimen for empirical treatment of bacterial meningitis due to earlier achievement of the pharmacodynamic target. Neither dosing regimen was adequate for
S. aureus
meningitis.
Complete genome sequence of
Rhodococcus qingshengii
phage Perlina
Authors: Jaryenneh James , Krishna Rohan , Schoeniger Joseph S. , Mageeney Catherine M. 
Published: October 2024

ABSTRACT

Rhodococcus
phage Perlina is a novel phage isolated on
Rhodococcus qingshengii
S10. Perlina encodes 112 open reading frames with typical phage structural genes identified and 3 tRNAs (tRNA-Ile, tRNA-Met, and tRNA-Asn). Few close relatives can be identified at the nucleotide level, suggesting a new phage species.
Metagenomic, metabolomic, and lipidomic shifts associated with fecal microbiota transplantation for recurrent
Clostridioides difficile
infection
Authors: McMillan Arthur S. , Zhang Guozhi , Dougherty Michael K. , McGill Sarah K. , Gulati Ajay S. , Baker Erin S. , Theriot Casey M. 
Published: October 2024

ABSTRACT

Recurrent
C. difficile
infection (rCDI) is an urgent public health threat, for which the last resort and lifesaving treatment is a fecal microbiota transplant (FMT). However, the exact mechanisms that mediate a successful FMT are not well-understood. Here, we use longitudinal stool samples collected from patients undergoing FMT to evaluate intra-individual changes in the microbiome, metabolome, and lipidome after successful FMTs relative to their baselines pre-FMT. We show changes in the abundance of many lipids, specifically a decrease in acylcarnitines post-FMT, and a shift from conjugated bile acids pre-FMT to deconjugated secondary bile acids post-FMT. These changes correlate with a decrease in Enterobacteriaceae, which encode carnitine metabolism genes, and an increase in Lachnospiraceae, which encode bile acid altering genes such as bile salt hydrolases (BSHs) and the bile acid-inducible (
bai
) operon, post-FMT. We also show changes in gut microbe-encoded amino acid biosynthesis genes, of which Enterobacteriaceae was the primary contributor to amino acids
C. difficile
is auxotrophic for. Liquid chromatography, ion mobility spectrometry, and mass spectrometry (LC-IMS-MS) revealed a shift from microbial conjugation of primary bile acids pre-FMT to secondary bile acids post-FMT. Here, we define the structural and functional changes associated with a successful FMT and generate hypotheses that require further experimental validation. This information is meant to help guide the development of new microbiota-focused therapeutics to treat rCDI.

IMPORTANCE

Recurrent
C. difficile
infection is an urgent public health threat, for which the last resort and lifesaving treatment is a fecal microbiota transplant. However, the exact mechanisms that mediate a successful FMT are not well-understood. Here, we show changes in the abundance of many lipids, specifically acylcarnitines and bile acids, in response to FMT. These changes correlate with Enterobacteriaceae pre-FMT, which encodes carnitine metabolism genes, and Lachnospiraceae post-FMT, which encodes bile salt hydrolases and
baiA
genes. There was also a shift from microbial conjugation of primary bile acids pre-FMT to secondary bile acids post-FMT. Here, we define the structural and functional changes associated with a successful FMT, which we hope will help aid in the development of new microbiota-focused therapeutics to treat rCDI.
Protein aggregation is a consequence of the dormancy-inducing membrane toxin TisB in
Escherichia coli
Authors: Leinberger Florian H. , Cassidy Liam , Edelmann Daniel , Schmid Nicole E. , Oberpaul Markus , Blumenkamp Patrick , Schmidt Sebastian , Natriashvili Ana , Ulbrich Maximilian H. , Tholey Andreas , Koch Hans-Georg , Berghoff Bork A. 
Published: October 2024

ABSTRACT

Bacterial dormancy is a valuable strategy to survive stressful conditions. Toxins from chromosomal toxin-antitoxin systems have the potential to halt cell growth, induce dormancy, and eventually promote a stress-tolerant persister state. Due to their potential toxicity when overexpressed, sophisticated expression systems are needed when studying toxin genes. Here, we present a moderate expression system for toxin genes based on an artificial 5′ untranslated region. We applied the system to induce expression of the toxin gene
tisB
from the chromosomal type I toxin-antitoxin system
tisB/istR-1
in
Escherichia coli
. TisB is a small hydrophobic protein that targets the inner membrane, resulting in depolarization and ATP depletion. We analyzed TisB-producing cells by RNA-sequencing and revealed several genes with a role in recovery from TisB-induced dormancy, including the chaperone genes
ibpAB
and
spy
. The importance of chaperone genes suggested that TisB-producing cells are prone to protein aggregation, which was validated by an
in vivo
fluorescent reporter system. We moved on to show that TisB is an essential factor for protein aggregation upon DNA damage mediated by the fluoroquinolone antibiotic ciprofloxacin in
E. coli
wild-type cells. The occurrence of protein aggregates correlates with an extended dormancy duration, which underscores their importance for the life cycle of TisB-dependent persister cells.

IMPORTANCE

Protein aggregates occur in all living cells due to misfolding of proteins. In bacteria, protein aggregation is associated with cellular inactivity, which is related to dormancy and tolerance to stressful conditions, including exposure to antibiotics. In
Escherichia coli
, the membrane toxin TisB is an important factor for dormancy and antibiotic tolerance upon DNA damage mediated by the fluoroquinolone antibiotic ciprofloxacin. Here, we show that TisB provokes protein aggregation, which, in turn, promotes an extended state of cellular dormancy. Our study suggests that protein aggregation is a consequence of membrane toxins with the potential to affect the duration of dormancy and the outcome of antibiotic therapy.
Development of an infant colon simulating
in vitro
model, I-TIM-2, to study the effects of modulation strategies on the infant gut microbiome composition and function
Authors: Colberg Olivia , Hermes Gerben D. A. , Licht Tine Rask , Wichmann Anita , Baker Adam , Laursen Martin Frederik , Wellejus Anja 
Published: October 2024

ABSTRACT

The early life stages are critical for the development of the gut microbiome. Variables such as antibiotics exposure, birth-mode via Cesarean section, and formula feeding are associated with disruptions in microbiome development and are related to adverse health effects later in life. Studying the effects of microbiome-modulating strategies in infants is challenged by appropriate ethical constraints. Therefore, we developed I-TIM-2, an infant
in vitro
colonic model based on the validated, computer-controlled, dynamic model of the colon, TIM-2. The system, consisting of four separate compartments, was inoculated with feces from four healthy, primarily breastfed infants, displaying distinctive microbiome profiles. For each infant’s fecal sample, a 96-h experiment was performed, with two compartments receiving an infant diet adapted medium and two compartments additionally receiving five human milk oligosaccharides (HMOs) in physiological concentrations and proportions. Bacterial composition was determined by shotgun metagenomics and qPCR. Concentrations of short-chain fatty acids (SCFAs) and HMOs were determined by LC-MS. Microbial diversity and high amounts of inoculum-derived species were preserved in the model throughout each experiment. Microbiome composition and SCFA concentrations were consistent with published data from infants. HMOs strongly modulated the microbiome composition by stimulating relative proportions of
Bifidobacterium
. This affected the metabolic output and resulted in an increased production of acetic and formic acid, characteristic of bifidobacterial HMO metabolism. In conclusion, these data demonstrate the development of a valid model to study the dynamics and modulations of the infant gut microbiome and metabolome.

IMPORTANCE

The infant gut microbiome is intricately linked to the health of its host. This is partly mediated through the bacterial production of metabolites that interact with the host cells. Human milk shapes the establishment of the infant gut microbiome as it contains human milk sugars that select for primarily bifidobacteria. The establishment can be disrupted by modern interventions such as formula feeding. This can alter the microbiome composition and metabolite production profile, which can affect the host. In this article, we set up an infant
in vitro
colonic model to study microbiome interactions and functions. In this model, we investigated the effects of human milk sugars and their promotion of bifidobacteria at the expense of other bacteria. The model is an ideal system to assess the effects of various modulating strategies on the infant gut microbiome and its interactions with its host.
Vitreoretinal lymphoma: the importance of cerebral spinal fluid evaluation at initial diagnosis
Authors: Silverman Rebecca F , Abramson David H , Canestraro Julia , Grommes Christian , Francis Jasmine H 
Published: October 2024

Background/aimsTo determine if patients with vitreoretinal lymphoma (VRL) and concomitant central nervous system lymphoma (CNSL) may present without brain MRI findings, but possess cerebrospinal fluid (CSF) suspicious for lymphoma.MethodsThis was a retrospective, single-centre, observational study evaluating patients with a diagnosis or suspicion of VRL seen at Memorial Sloan Kettering Cancer Center between 2006 and 2024. Patients were included if the final diagnosis was biopsy-proven CNSL and both MRI brain with and without contrast±CSF evaluation (obligatory for inclusion if MRI negative) were performed at the initial diagnostic workup. Patients were excluded if CNS disease treatment (brain, spine or CSF) preceded ocular disease. Patients with prior extra-CNS disease were included. Clinical records and radiographic imaging were retrospectively reviewed and relevant data were recorded for each patient. We evaluated the proportion of patients with MRI negative and CSF suspicious for lymphoma. Subgroup analysis included imaging features, pathology, treatment and disease course.ResultsWe identified 65 patients. Of the 65 patients at the presentation of VRL, 30 had negative MRI brain and CSF, 16 had positive brain MRI and negative CSF and 8 had both positive MRI brain and CSF. 11 (16.9%) had CSF suspicious for lymphoma without positive findings on MRI of the brain. In this subgroup, the median age was 66 years (range 49–82) and 36% were female. 86% of these patients were asymptomatic neurologically. 73% underwent systemic treatment. At a mean 3 years follow-up, 91% of patients were living.ConclusionIn patients with suspected VRL, it is possible to have CSF test positive for lymphoma in the context of negative brain MRI. This suggests, when evaluating VRL patients for concomitant CNS disease, CSF evaluation leads to earlier detection and systemic treatment, even when MRI brain findings are negative. In our cohort, an absence of CSF evaluation in the context of negative brain MRI could have missed 16.9% of patients with CNS lymphoma.
Low-volume combined aerobic and resistance high-intensity interval training in type 2 diabetes: a randomised controlled trial
Authors: Gajanand Trishan , Cox Emily R , Keating Shelley E , Brown Wendy J , Hordern Matthew D , Burton Nicola W , Chachay Veronique S , Gomersall Sjaan R , Fassett Robert G , Coombes Jeff S 
Published: October 2024

ObjectiveThe objective of this study was to compare the effects of novel, time-efficient, low-volume combined aerobic and resistance high-intensity interval training (C-HIIT), and current exercise guidelines (210 min/week of combined moderate-intensity continuous training (C-MICT)), with waitlist control (CON) on glycaemic control in people with type 2 diabetes mellitus (T2D).MethodsSixty-nine low-active people with T2D were randomised to 8 weeks of supervised C-HIIT (78 min/week), supervised C-MICT (210 min/week), or waitlist CON. Those in waitlist CON were re-randomised to supervised C-HIIT/C-MICT at week 8. Following 8 weeks of supervised training, participants completed 10 months of self-directed exercise. Outcomes were assessed at baseline, week 8 and month 12. Participants in waitlist CON were only included in the exercise groups for the month 12 analysis. Analyses were completed using intention-to-treat analysis of covariance (n=69; week 8) and linear mixed modelling (n=63; month 12).ResultsCompared with CON, at week 8, HbA1cdecreased in C-HIIT (adjusted mean difference: –0.7% (95% CI –1.3, –0.2%)) and C-MICT (–1.2% (–1.9, –0.6%)). There were also improvements in C-HIIT and C-MICT versus CON at week 8 for fat mass (–1.9 (–3.1, –0.6) and –1.5 (–2.6, –0.4) kg, respectively), lean mass (1.5 (0.8, 2.3) and 0.9 (0.1, 1.7) kg), and exercise capacity (124 (77, 171) and 49 (5, 93) s). At month 12, adherence was low, and most measures returned to baseline.ConclusionsLow-volume C-HIIT (78 min/week) and C-MICT (210 min/week) improved glycaemic control, body composition and exercise capacity similarly over 8 weeks in people with T2D. However, at month 12, improvements were not maintained following self-directed exercise. Regardless, these data suggest that supervised low-volume C-HIIT is a time-efficient and effective strategy for improving outcomes in T2D.
EASIX-guided risk stratification for complications and outcome after CAR T-cell therapy with ide-cel in relapsed/refractory multiple myeloma
Authors: Frenking Jan H , Zhou Xiang , Wagner Vivien , Hielscher Thomas , Kauer Joseph , Mai Elias K , Friedrich Mirco J , Michel Christian S , Hajiyianni Marina , Breitkreutz Iris , Costello Patrick , Nadeem Omar , Weinhold Niels , Goldschmidt Hartmut , Schmitt Anita , Luft Thomas , Schmitt Michael , Müller-Tidow Carsten , Topp Max , Einsele Hermann , Dreger Peter , Munshi Nikhil C , Sperling Adam S , Rasche Leo , Sauer Sandra , Raab Marc S 
Published: October 2024

BackgroundChimeric antigen receptor (CAR) T-cell therapy has demonstrated significant benefits in the treatment of relapsed/refractory multiple myeloma (RRMM). However, these outcomes can be compromised by severe complications, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS) and immune effector cell-associated hematotoxicity (ICAHT), predisposing for life-threatening infections.MethodsThis retrospective observational study examined a total of 129 patients with RRMM who had received idecabtagene vicleucel (ide-cel) at two major myeloma centers in Germany and one center in the USA to assess the Endothelial Activation and Stress Index (EASIX) as a risk marker for an unfavorable clinical course and outcome after CAR T-cell therapy. EASIX is calculated by lactate dehydrogenase (U/L) × creatinine (mg/dL) / platelets (109cells/L) and was determined before lymphodepletion (baseline) and at the day of CAR T-cell infusion (day 0). The analysis was extended to EASIX derivatives and the CAR-HEMATOTOX score.ResultsAn elevated baseline EASIX (>median) was identified as a risk marker for severe late ICAHT, manifesting with an impaired hematopoietic reconstitution and pronounced cytopenias during the late post-CAR-T period. Patients with high EASIX levels (>upper quartile) were particularly at risk, as evidenced by an increased rate of an aplastic phenotype of neutrophil recovery, severe late-onset infections and ICANS. Finally, we found associations between baseline EASIX and an inferior progression-free and overall survival. Moreover, the EASIX at day 0 also demonstrated potential to serve as a risk marker for post-CAR-T complications and adverse outcomes.ConclusionsIn conclusion, EASIX aids in risk stratification at clinically relevant time points prior to CAR T-cell therapy with ide-cel. Increased EASIX levels might help clinicians to identify vulnerable patients to adapt peri-CAR-T management at an early stage.
Prospects for detecting the couplings of axion-like particle with neutrinos at the CEPC
Authors: Yue Chong-Xing , Li Xin-Yang , Sun Xiao-Chen 
Published: October 2024

AbstractWe explore the possibility of detecting the couplings of axion-like particle (ALP) with leptons from their loop-level impact on the ALP couplings to electroweak (EW) gauge bosons via the signal process "Equation missing" at the circular electron positron collider (CEPC) and obtain prospective sensitivities to the ALP-lepton couplings. Our numerical results show that the CEPC with the center of mass energy $$\sqrt{s}=240~(91)$$

s

=
240

(
91
)

GeV and the integrated luminosity $$\mathcal {L}=5.6~(16)$$

L
=
5.6

(
16
)

$$\hbox {ab}^{-1}$$

ab

-
1

might be sensitive for probing the ALP-lepton couplings in the ALP mass range from 10 GeV to 130 (50) GeV, where the prospective sensitivities to the ALP-neutrino coupling $$Tr(g_{a\nu \nu })/f_a$$

T
r

(

g

a
ν
ν

)

/

f
a

can be as low as 0.016 (0.012) $$\hbox {GeV}^{-1}$$

GeV

-
1

and $$0.0031~(2.8 \times 10^{-4})$$

0.0031

(
2.8
×

10

-
4

)

$$\hbox {GeV}^{-1}$$

GeV

-
1

for $$c_{R}=0$$

c
R

=
0

and $$c_{R}=c_{L}$$

c
R

=

c
L

, and to the ALP-charged lepton coupling $$Tr(g_{a\ell \ell })/f_a$$

T
r

(

g

a
ℓ
ℓ

)

/

f
a

can be as low as 0.035 (0.07) $$\hbox {GeV}^{-1}$$

GeV

-
1

for $$c_{L}=0$$

c
L

=
0

. We find that the prospective sensitivities given by the CEPC are not covered by the current and expected exclusion regions in some ALP mass intervals. The CEPC has the potential for exploring the ALP-neutrino couplings via some promising processes induced by the ALP-EW gauge boson couplings in the future.
$$\phi $$ meson mass and decay width in magnetized strange hadronic matter
Authors: Chahal Nisha , Kumar Rajesh , Dutt Suneel , Kumar Arvind 
Published: October 2024

AbstractWe investigate the medium modifications in mass and decay width of $$\phi $$
ϕ
meson in the presence of an external magnetic field. The in-medium mass of $$\phi $$
ϕ
meson has been calculated using the decay process $$\phi $$
ϕ
$$\rightarrow $$
→
$$K {\bar{K}}$$

K

K

¯

at one-loop level. The medium modifications are introduced by using a chiral SU(3) model employing a mean-field effective approach. Due to the introduction of the magnetic field, masses of charged $$K^+$$

K
+

and $$K^-$$

K
-

increases with advancing magnetic field values. A negligible change in the value of neutral $$K^0$$

K
0

and $${\bar{K}}^0$$

K

¯

0

has been observed for varying magnetic fields. Due to electromagnetic interactions with charged K and $${\bar{K}}$$

K

¯

mesons, there is a gradual augmentation in the effective mass of $$\phi $$
ϕ
meson. The probability of the mentioned decay process ceases to be zero for low density and strangeness fraction values at higher magnetic field values. Investigating the decay width and effective mass of $$\phi $$
ϕ
meson under the influence of an external magnetic field is relevant to understanding the hadronic matter properties under extreme conditions achievable at heavy-ion collision experiments.
Mark–Scavenge: Waiting for Trash to Take Itself Out
Authors: Norlinder Jonas , Österlund Erik , Black-Schaffer David , Wrigstad Tobias 
Published: October 2024

Moving garbage collectors (GCs) typically free memory by evacuating live objects in order to reclaim contiguous
memory regions. Evacuation is typically done either during tracing (scavenging), or after tracing when
identification of live objects is complete (mark–evacuate). Scavenging typically requires more memory (memory
for all objects to be moved), but performs less work in sparse memory areas (single pass). This makes it
attractive for collecting young objects. Mark–evacuate typically requires less memory and performs less
work in memory areas with dense object clusters, by focusing relocation around sparse regions, making it
attractive for collecting old objects. Mark–evacuate also completes identification of live objects faster, making
it attractive for concurrent GCs that can reclaim memory immediately after identification of live objects
finishes (as opposed to when evacuation finishes), at the expense of more work compared to scavenging, for
young objects.
We propose an alternative approach for concurrent GCs to combine the benefits of scavenging with the
benefits of mark–evacuate, for young objects. The approach is based on the observation that by the time
young objects are relocated by a concurrent GC, they are likely to already be unreachable. By performing
relocation lazily, most of the relocations in the defragmentation phase of mark–evacuate can typically be
eliminated. Similar to scavenging, objects are relocated during tracing with the proposed approach. However,
instead of relocating all objects that are live in the current GC cycle, it lazily relocates profitable sparse object
clusters that survived from the previous GC cycle. This turns the memory headroom that concurrent GCs
typically “waste” in order to safely avoid running out of memory before GC finishes, into an asset used to
eliminate much of the relocation work, which constitutes a significant portion of the GC work.
We call this technique mark–scavenge and implement it on-top of ZGC in OpenJDK in a collector we call
MS-ZGC. We perform a performance evaluation that compares MS-ZGC against ZGC. The most striking result
is (up to) 91% reduction in relocation of dead objects (depending on machine-dependent factors).