bluuebunny/crossref_metadata_2025_split huggingface dataset:
The primary pharmacology of ceftazidime/avibactam: in vitro translational biology
Authors: Nichols Wright W , Bradford Patricia A , Lahiri Sushmita D , Stone Gregory G 
Published: June 2022

Abstract
Previous reviews of ceftazidime/avibactam have focused on in vitro molecular enzymology and microbiology or the clinically associated properties of the combination. Here we take a different approach. We initiate a series of linked reviews that analyse research on the combination that built the primary pharmacology data required to support the clinical and business risk decisions to perform randomized controlled Phase 3 clinical trials, and the additional microbiological research that was added to the above, and the safety and chemical manufacturing and controls data, that constituted successful regulatory licensing applications for ceftazidime/avibactam in multiple countries, including the USA and the EU. The aim of the series is to provide both a source of reference for clinicians and microbiologists to be able to use ceftazidime/avibactam to its best advantage for patients, but also a case study of bringing a novel β-lactamase inhibitor (in combination with an established β-lactam) through the microbiological aspects of clinical development and regulatory applications, updated finally with a review of resistance occurring in patients under treatment. This first article reviews the biochemistry, structural biology and basic microbiology of the combination, showing that avibactam inhibits the great majority of serine-dependent β-lactamases in Enterobacterales and Pseudomonas aeruginosa to restore the in vitro antibacterial activity of ceftazidime. Translation to efficacy against infections in vivo is reviewed in the second co-published article, Nichols et al. (J Antimicrob Chemother 2022; 77: 2341–52).
The primary pharmacology of ceftazidime/avibactam: in vivo translational biology and pharmacokinetics/pharmacodynamics (PK/PD)
Authors: Nichols Wright W , Bradford Patricia A , Stone Gregory G 
Published: June 2022

Abstract
This review describes the translational in vivo and non-clinical pharmacokinetics/pharmacodynamics (PK/PD) research that supported clinical trialling and subsequently licensing approval of ceftazidime/avibactam, a new β-lactam/β-lactamase inhibitor combination aimed at the treatment of infections by Enterobacterales and Pseudomonas aeruginosa. The review thematically follows on from the co-published article, Nichols et al. (J Antimicrob Chemother 2022; 77: 2321–40). Avibactam protected ceftazidime in animal models of infection with ceftazidime-resistant, β-lactamase-producing bacteria. For example, a single subcutaneous dose of ceftazidime at 1024 mg/kg yielded little effect on the growth of ceftazidime-resistant, blaKPC-2-carrying Klebsiella pneumoniae in the thighs of neutropenic mice (final counts of 4 × 108 to 8 × 108 cfu/thigh). In contrast, co-administration of avibactam in a 4:1 ratio (ceftazidime:avibactam) was bactericidal in the same model (final counts of 2 × 104 to 3 × 104 cfu/thigh). In a rat abdominal abscess model, therapy with ceftazidime or ceftazidime/avibactam (4:1 w/w) against blaKPC-2-positive K. pneumoniae resulted in 9.3 versus 3.3 log cfu/abscess, respectively, after 52 h. With respect to PK/PD, in Monte Carlo simulations, attainment of unbound drug exposure targets (ceftazidime fT&gt;8 mg/L and avibactam fT&gt;1 mg/L, each for 50% of the dosing interval) for the labelled dose of ceftazidime/avibactam (2 and 0.5 g, respectively, q8h by 2 h IV infusion), including dose adjustments for patients with impaired renal function, ranged between 94.8% and 99.6% of patients, depending on the infection modelled.
Population pharmacokinetics and dosing optimization of mezlocillin in neonates and young infants
Authors: Zhou Jing , Jiang Li , Zhang Zhi Ling , Wang Zhao Rui , Zhang Yan Xiu , Lin Xu , Tang Bo Hao , Yao Bu Fan , Guo Zi Xuan , Yang Jing Jing , Van Den Anker John , Wu Yue E , Zhao Wei 
Published: June 2022

Abstract

Objectives
Mezlocillin is used in the treatment of neonatal infectious diseases. However, due to the absence of population pharmacokinetic studies in neonates and young infants, dosing regimens differ considerably in clinical practice. Hence, this study aimed to describe the pharmacokinetic characteristics of mezlocillin in neonates and young infants, and propose the optimal dosing regimen based on the population pharmacokinetic model of mezlocillin.

Methods
A prospective, open-label pharmacokinetic study of mezlocillin was carried out in newborns. Blood samples were collected using an opportunistic sampling method. HPLC was used to measure the plasma drug concentrations. A population pharmacokinetic model was developed using NONMEM software.

Results
Ninety-five blood samples from 48 neonates and young infants were included. The ranges of postmenstrual age and birth weight were 29–40 weeks and 1200–4000 g, respectively, including term and preterm infants. A two-compartment model with first-order elimination was developed to describe the population pharmacokinetics of mezlocillin. Postmenstrual age, current weight and serum creatinine concentration were the most important covariates. Monte Carlo simulation results indicated that the current dose of 50 mg/kg q12h resulted in 89.2% of patients achieving the therapeutic target, when the MIC of 4 mg/L was used as the breakpoint. When increasing the dosing frequency to q8h, a dose of 20 mg/kg resulted in 74.3% of patients achieving the therapeutic target.

Conclusions
A population pharmacokinetic model of mezlocillin in neonates and young infants was established. Optimal dosing regimens based on this model were provided for use in neonatal infections.
Manufacturer Signal-to-Cutoff Threshold Underestimates Cumulative Incidence of SARS-CoV-2 Infection: Evidence from the Los Angeles Firefighters Study
Authors: Toubat Omar , Berg Anders H , Sobhani Kimia , Mulligan Karen , Hori Acacia M , Bhattacharya Jay , Sood Neeraj 
Published: June 2022

Abstract

Background
The objective of this analysis was to compare the performance sensitivity and specificity of manufacturer-recommended signal-to-cutoff (S/Co) thresholds with modified S/Co values to estimate the prevalence of SARS-CoV-2-specific antibodies in a cohort of firefighters with a known infection history.

Methods
Plasma venipuncture samples were used for serologic analysis of firefighters in Los Angeles, CA, USA, in October 2020. Seropositivity was assessed using the manufacturer’s recommended S/Co (≥1.4 IgG) and modified S/Co thresholds based on measured antibody levels in 178 negative control patients who had blood drawn prior to the emergence of COVID-19. Optimal S/Co threshold was determined by receiver operating characteristic (ROC) curve analysis.

Results
Of 585 firefighters included in the study, 52 (8.9%) reported having a PCR-positive test history prior to antibody testing. Thirty-five (67.3%) firefighters with a previous PCR-positive test were seropositive based on the manufacturer S/Co thresholds, consistent with an estimated 67.3% sensitivity and 100% specificity. After evaluating multiple modified S/Co thresholds based on pre-pandemic negative samples, a modified S/Co of 0.36 was found to yield optimal sensitivity (88.5%) and specificity (99.4%) by ROC curve analysis. This modified threshold improved serostatus classification accuracy by 21.2%.

Conclusions
S/Co thresholds based on known negative samples significantly increase seropositivity and more accurately estimate cumulative incidence of disease compared to manufacturer-based thresholds.
TT-pocket/HIRAN: binding to 3′-terminus of DNA for recognition and processing of stalled replication forks
Authors: Masai Hisao 
Published: June 2022

Abstract
Stalled replication forks need to be swiftly detected and protected from collapse and the cause for fork stall be removed to restore the active replication fork. In bacteria, stalled forks are recognized and stabilized by PriA, a DEXH-type helicase, which also facilitates reassembly of an active replication fork. A TT-pocket (three-prime terminus binding pocket) present in the N-terminal segment of PriA plays a crucial role in stabilization of the stalled forks by specifically binding to the 3$^\prime$-terminus of the nascent leading strand. Eukaryotic proteins, Rad5/HLTF, contain a TT-pocket related domain, HIRAN, that specifically binds to 3′-terminus of DNA and play a role in stalled fork processing. While the TT-pocket of PriA facilitates the formation of an apparently stable and immobile complex on a fork with a 3′-terminus at the fork junction, HIRAN of Rad5/HLTF facilitates fork regression by itself. A recent report shows that HIRAN can displace 3 nucleotides at the end of the duplex DNA, providing mechanistic insight into how stalled forks are reversed in eukaryotes. In this article, I will compare the roles of 3′-terminus binding domains in stalled fork processing in prokaryotes and in eukaryotes.
Parenting Stress over the First Year of Inflammatory Bowel Disease Diagnosis
Authors: Rea Kelly E , Cushman Grace K , Westbrook Adrianna L , Reed Bonney 
Published: June 2022

Abstract

Objective
A diagnosis of inflammatory bowel disease (IBD) in children can disrupt the family, including altered routines and increased medical responsibilities. This may increase parenting stress; however, little is known about parenting stress changes over the first year following an IBD diagnosis, including what demographic, disease, or psychosocial factors may be associated with parenting stress over time.

Methods
Fifty-three caregivers of children newly diagnosed with IBD (Mage = 14.17 years; Mdays since diagnosis = 26.15) completed parenting stress (Pediatric Inventory for Parents), child anxiety (Screen for Child Anxiety-Related Disorders), and child health-related quality of life (HRQOL; IMPACT) measures within 1 month of diagnosis and 6-month and 1-year follow-ups. Multilevel longitudinal models assessed change and predictors of parenting stress.

Results
Parenting stress was significantly associated with greater child anxiety and lower HRQOL at diagnosis (rs = 0.27 to −0.53). Caregivers of color and caregivers of female youth reported higher parenting stress at diagnosis (ts = 2.02–3.01). Significant variability and declines in parenting stress were observed across time (ts = −2.28 and −3.50). In final models, caregiver race/ethnicity and child HRQOL were significantly related to parenting stress over the first year of diagnosis (ts = −2.98 and −5.97).

Conclusion
Caregivers’ parenting stress decreases across 1 year of diagnosis. However, caregivers of color and those rating their child’s HRQOL as lower may be at risk for greater parenting stress. More research is needed to understand why caregivers of color reported greater parenting stress compared to White caregivers. Results highlight the importance of providing whole-family care when a child is diagnosed with IBD.
The therapeutic efficacy and safety of intravenous immunoglobulin in dermatomyositis and polymyositis: A systematic review and meta-analysis
Authors: Xiong Anji , Qiang Yiying , Cao Yuzi , Shuai Yu , Chen Huini , Xiang Qilang , Hu Ziyi , Song Zhuoyao , Zhou Shifeng , Zhang Yan , Cui Hongxu , Wang Ye , Luo Jie , Shuai Shiquan , Yang Yuan 
Published: June 2022

ABSTRACT

Objectives
To evaluate the efficacy and safety of intravenous immunoglobulin (IVIG) in the treatment of dermatomyositis (DM) and polymyositis (PM).

Methods
We searched PubMed, Embase, and the China National Knowledge Infrastructure for relevant studies from July 1919 to May 2021.

Results
Seventeen papers pertinent to our questions were found: In a meta-analysis, we found that IVIG significantly improved the level of CK (SMD (STD. Mean Difference) = −0.69; 95%CI −0.93, −0.46; P &lt; 0.0001), Manual Muscle Test (SMD = 1.12; 95%CI 0.77, 1.47; P &lt; 0.00001), Medical Research Council (SMD = 1.59; 95%CI 0.86, 2.33; P &lt; 0.00001), Activities of Daily Living (SMD = 1.07; 95%CI 0.59, 1.56; P &lt; 0.0001). The CK levels in DM and PM were also significantly improved after IVIG (SMD = −0.73; 95%CI −1.12, −0.34; P = 0.0002 and SMD = −3.29; 95%CI −5.82, −0.76; P &lt; 0.0001, respectively). The meta-analysis of three RCTs showed that there was a statistically significant improvement after IVIG (SMD = 0.63; 95%CI 0.22, 1.03; P = 0.002). In a random effects model, pooled muscle power improvement rate was 77% (95% CI: 66.0–87.0%). Meta-analyses of IVIG as first-line therapy showed a significant improvement of the CK level (SMD = −0.71; 95%CI −1.12, −0.30; P = 0.0007). The polled improvement rate of oesophageal disorders was 88% (95% CI: 80.0–95.0%). There was no statistically significant difference in the rate of improvement between the number of courses &lt;2 and ≥2 (0.80% vs. 0.80%, P = 0.9). The proportion of corticosteroid-sparing success reached 81.8%. Adverse reactions following IVIG administration are usually mild and transient. Seven patients developed serious adverse events.

Conclusion
IVIG seems to be an effective drug for DM/PM, improving muscle strength, CK levels, and oesophageal involvement, and it is well tolerated by patients.
The role of ultrasound and FDG-PET/CT to detect extracranial artery involvement in patients with suspected large vessel vasculitis
Authors: Molina-Collada Juan , Castrejón Isabel , Rivera Javier , Martínez-Barrio Julia , Nieto-González Juan Carlos , López Katerine , Montero Fernando , Trives Laura , González Carlos , Álvaro-Gracia José María 
Published: June 2022

ABSTRACT

Objective
To assess the accuracy of ultrasound (US) versus fluorodeoxyglucose—positron emission tomography/computed tomography (FDG-PET/CT) to identify extracranial involvement in large vessel vasculitis (LVV).

Methods
A retrospective observational study of patients with suspected LVV. All patients underwent US exam within 24 h per protocol. FDG-PET/CT was performed according to clinician criteria. The gold standard for LVV diagnosis was clinical confirmation after 6 months.

Results
Of the 113 patients included (74.3% female, mean age 74 years), 37 (32.7%) were diagnosed with LVV after 6 months. The sensitivity and specificity of US were 86.5% and 96.1%, respectively. Only 12 (42.9%) of 28 patients undergoing a FDG-PET/CT per clinician criteria showed positive findings. The sensitivity and specificity of FDG-PET/CT for LVV were 61.1% and 90%, respectively. Taking FDG-PET/CT as the reference, US showed extracranial inflammation in 10/12 (83.3%) and detected 2 (12.5%) additional cases of extracranial involvement with negative FDG-PET/CT. Conversely, FDG-PET/CT was positive in two patients with negative US (one isolated aortitis and one aortoiliac involvement).

Conclusions
US and FDG-PET/CT are both valid tools to detect extracranial involvement. The presence of US extracranial artery inflammation is consistent with FDG-PET/CT examination, although a negative US scan does not rule out extracranial involvement.
Stemness and clinical features in relation to the subventricular zone in diffuse lower-grade glioma: an exploratory study
Authors: Corell Alba , Gómez Vecchio Tomás , Ferreyra Vega Sandra , Dénes Anna , Neimantaite Alice , Hagerius Alexander , Barchéus Hanna , Solheim Ole , Lindskog Cecilia , Bontell Thomas Olsson , Carén Helena , Jakola Asgeir S , Smits Anja 
Published: June 2022

Abstract

Background
The subventricular zone (SVZ) of the human brain is a site of adult stem cell proliferation and a microenvironment for neural stem cells (NSCs). It has been suggested that NSCs in the SVZ are potential cells of origin containing driver mutations of glioblastoma, but their role in the origin of diffuse lower-grade gliomas (dLGGs) is not much studied.

Methods
We included 188 patients ≥18 years with IDH-mutated dLGG (WHO grades 2–3) histologically diagnosed between 2007 and 2020. Tissue microarrays of tumor samples for patients between 2007 and 2016 were used for immunodetection of Nestin, SOX2, SOX9, KLF4, NANOG, CD133 cMYC, and Ki67. DNA methylation profile was used for stemness index (mDNAsi). Tumor contact with the SVZ was assessed and the distance was computed.

Results
Overall, 70.2% of the dLGG had SVZ contact. Tumors with SVZ contact were larger (102.4 vs 30.9 mL, P &lt; .01), the patients were older (44.3 vs 40.4 years, P = .04) and more often had symptoms related to increased intracranial pressure (31.8% vs 7.1%, P &lt; .01). The expression of SOX2, SOX9, Nestin, and Ki67 showed intersample variability, but no difference was found between tumors with or without SVZ contact, nor with the actual distance to the SVZ. mDNAsi was similar between groups (P = .42).

Conclusions
We found no statistical relationship between proximity with the SVZ and mDNAsi or expression of SOX2, SOX9, Nestin, and Ki67 in IDH-mutated dLGG. Our data suggest that the potential impact of SVZ on IDH-mutated dLGG is probably not associated with a more stemness-like tumor profile.
Root Cap to Soil Interface: A Driving Force Toward Plant Adaptation and Development
Authors: Ganesh Alagarasan , Shukla Vishnu , Mohapatra Ankita , George Abin Panackal , Bhukya Durga Prasad Naik , Das Krishna Kodappully , Kola Vijaya Sudhakara Rao , Suresh Aparna , Ramireddy Eswarayya 
Published: June 2022

Abstract
Land plants have developed robust roots to grow in diverse soil ecosystems. The distal end of the root tip has a specialized organ called the ‘root cap’. The root cap assists the roots in penetrating the ground, absorbing water and minerals, avoiding heavy metals and regulating the rhizosphere microbiota. Furthermore, root-cap-derived auxin governs the lateral root patterning and directs root growth under varying soil conditions. The root cap formation is hypothesized as one of the key innovations during root evolution. Morphologically diversified root caps in early land plant lineage and later in angiosperms aid in improving the adaptation of roots and, thereby, plants in diverse soil environments. This review article presents a retrospective view of the root cap’s important morphological and physiological characteristics for the root–soil interaction and their response toward various abiotic and biotic stimuli. Recent single-cell RNAseq data shed light on root cap cell-type-enriched genes. We compiled root cap cell-type-enriched genes from Arabidopsis, rice, maize and tomato and analyzed their transcription factor (TF) binding site enrichment. Further, the putative gene regulatory networks derived from root-cap-enriched genes and their TF regulators highlight the species-specific biological functions of root cap genes across the four plant species.
Monitoring Corporate Compliance through Cooperative Federalism: Trends in Multistate Settlements by State Attorneys General
Authors: Provost Colin , Dishman Elysa , Nolette Paul 
Published: June 2022

AbstractRecent scholarship on U.S. regulatory federalism has tended to focus on conflict between the states and state resistance to federal initiatives. Less attention has been given to federal–state cooperation and how it affects regulatory enforcement. In this article, we examine intergovernmental cooperation in multistate lawsuits filed by state attorneys general to ascertain trends in multistate regulatory enforcement through litigation over time. We pay particular attention to the increasing use of compliance monitoring by both state and federal regulators, including through monitors independent of the regulated industries. Relying upon a dataset of legal settlements, scoping interviews, and two case studies of recent multistate litigation, we find that federal–state cooperation in multistate lawsuits has become more institutionalized over time. This increased cooperation has created a two-way street in which state and federal regulators often combine resources and learn from each other through the process of compliance monitoring.
Enforcing Hopelessness: Complicity, Dependence, and Organizing in Frontline Oil and Gas Communities
Authors: Malin Stephanie A , Kallman Meghan Elizabeth 
Published: June 2022

Abstract
Fossil fuel companies hold enormous political, economic, and knowledge production power. Recently, industry operators have pivoted from pushing climate denialism to campaigns aimed at individualizing responsibility for climate crisis. In this paper, we focus on one related outcome of such efforts – people’s experiences of complicity – here in the context of unconventional oil and gas (UOG) production. We ask: How do mobilized activists experience fossil fuel scapegoating, and what does it mean for their goals as they organize against UOG production? We show that even activists fighting UOG production feel complicit in fossil fuel production, and these feelings of complicity diminish their demands for UOG accountability. We argue that these outcomes have been especially pernicious in cultural contexts like that of the United States, where neoliberal ideologies are normalized, centering personal responsibility, individualization, and identification as consumers rather than citizens. We marshal an extensive qualitative dataset and advance a theory of complicity as a way to understand: a) how social movements intersect with neoliberalized patterns of life; b) how experiences of complicity affect activism; and c) how this may contribute to fossil fuel firms’ goals of undercutting organizing. We end by examining how a sub-set of activists works to dismantle this complicity narrative.
Risk of hypertension and treatment on out-of-hospital cardiac arrest incidence
Authors: Kim Jooyeong , Cho Sung-il , Park Jong-Hak , Song Juhyun , Ahn Sejoong , Cho Hanjin , Moon Sungwoo 
Published: June 2022

Abstract
Hypertension (HTN) is a high risk factor for major cardiovascular adverse events. This study aimed to investigate the effect of HTN risk on out-of-hospital cardiac arrest (OHCA) incidence and determine whether the effect of HTN on OHCA incidence differs according to antihypertensive medication.
This case-control study used the Korean Cardiac Arrest Resuscitation Consortium and Korean Community Health Survey (CHS). Cases were defined as emergency medical service-treated adult OHCA patients presumed to have a cardiac etiology from 2015 to 2017. Patients without information on HTN diagnosis were excluded from the study. The Korean CHS database's controls were matched at a 1:2 ratio with strata, including age, gender, and county of residence. Multivariable conditional logistic regression analysis was conducted to estimate HTN risk and antihypertensive treatment on OHCA incidence,
A total of 2633 OHCA patients and 5266 community-based controls were enrolled in this study. Among them, 1176 (44.7%) patients and 2049 (38.9%) controls were diagnosed with HTN. HTN was associated with an increased risk of OHCA (adjusted odds ratio [AOR]: 1.19 [1.07–1.32]). On comparing HTN with or without the antihypertensive treatment group with the non-HTN-diagnosed group (as a reference), the HTN without treatment group had the highest AOR (95% confidence interval) (3.41 [2.74–4.24]). The AOR in the HTN treatment group was reduced to that in the non-HTN-diagnosed group (0.96 [0.86–1.08]).
HTN increased OHCA risk, and the HTN without treatment group had the highest OHCA risk. Conversely, OHCA risk decreased to the non-HTN-diagnosed group level with HTN treatment.