bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Safety and Efficacy of Dalbavancin and Active Comparator in Pediatric Patients With Acute Bacterial Skin and Skin Structure Infections
Authors: Giorgobiani Manana , Burroughs Margaret H. , Antadze Tinatin , Carrothers Timothy J. , Riccobene Todd A. , Patel Rinal , Lin Tao , Stefanova Penka 
Published: December 2022

Background:
Acute bacterial skin and skin structure infections (ABSSSIs) are a significant source of morbidity in children. Dalbavancin, approved for the treatment of adults and children with ABSSSI, has a well-established safety profile in adults. We report safety and descriptive efficacy data for the treatment of ABSSSI in children.

Methods:
Children with ABSSSI (birth–<18 years old) or sepsis (<3 months old) known/suspected to be caused by susceptible Gram-positive organisms were enrolled in this phase 3, multicenter, open-label, comparator-controlled study (NCT02814916). Children ≥3 months old were randomized 3:3:1 to receive single-dose dalbavancin, 2-dose dalbavancin, or a comparator antibiotic in 4 age cohorts; those <3 months old received single-dose dalbavancin. Clinical response and microbiologic efficacy were evaluated 48–72 hours and 14, 28 and 54 days posttreatment. Bowel flora testing and audiology were collected in a subset of patients at baseline and day 28. Adverse events (AEs) were collected throughout the study.

Results:
Treatment-emergent AEs occurred in 7.2%, 9.0% and 3.3% of patients in dalbavancin single-dose, dalbavancin 2-dose and comparator arms, respectively. Three serious AEs occurred in the dalbavancin single-dose arm; no treatment-related AEs, serious AEs, or AEs leading to study discontinuation were reported. Favorable clinical response at 48–72 hours was documented in 97.4%, 98.6% and 89.7% of patients. Safety and efficacy were comparable across age cohorts. The microbiologic intent-to-treat population had comparable clinical response for all baseline pathogens, including methicillin-resistant Staphylococcus aureus.

Conclusion:
The safety profile of dalbavancin was consistent in children and adults with ABSSSI. No new safety signals were identified.
Addressing health equity through a telehealth maternal–newborn home visit for nurse practitioner students
Authors: Doucette Julianne A. , Rousseau Jennifer , Vondracek Hugh 
Published: December 2022

ABSTRACT
This educational innovation describes the implementation and evaluation of a telehealth maternal–newborn home visit clinical experience for nurse practitioner students at an urban, private research university in the Midwest. The visits were conducted using the Family Connects evidence-based universal support program for families with newborns to evaluate each family's unique risks and to align their needs with available community resources. Students were prepared for the clinical experience through advanced practice didactic modules and simulation and then participated in the visits over a 2-week period. After the clinical opportunity, both students and community health nurse collaborators completed a survey about their experiences. The students reported feeling prepared to participate in the visits, that they were able to meet clinical objectives using telehealth, and learned about the community resources available for families with newborns. The nurses reported feeling prepared to collaborate with nurse practitioner students and that they benefitted from having a student participate in the visits. The experience prepared the students to meet the needs of a diverse patient population during the early postpartum/newborn period by providing newborn care advice, addressing access to health, assessing social determinants of health, and considering community resource referrals to reduce disparities and improve health equity. This article describes how a telehealth clinical experience addresses the American Association of Colleges of Nursing Essentials for advanced-level nursing students and provides recommendations for incorporating and evaluating telehealth clinical experiences in pediatric advanced practice education.
Patient Falls in Seclusion Rooms in Psychiatric Inpatient Care
Authors: Varpula Jaakko , Välimäki Maritta , Pulkkinen Johanna , Lantta Tella 
Published: December 2022

Background:
Patient falls are a major adverse event in psychiatric inpatient care.

Purpose:
To model the risk for patient falls in seclusion rooms in psychiatric inpatient care.

Methods:
Sociotechnical probabilistic risk assessment (ST-PRA) was used to model the risk for falls. Data sources were the research team, literature review, and exploration groups of psychiatric nurses. Data were analyzed with fault tree analysis.

Results:
The risk for a patient fall in a seclusion room was 1.8%. Critical paths included diagnosis of a psychiatric disorder, the mechanism of falls, failure to assess and prevent falls, and psychological or physical reason. The most significant individual risk factor for falls was diagnosis of schizophrenia.

Conclusions:
Falls that occur in seclusion events are associated with physical and psychological risk factors. Therefore, risk assessment methods and fall prevention interventions considering patient behavioral disturbance and physiological risk factors in seclusion are warranted.
Nursing Home Patient Safety Culture Perceptions Among Licensed Practical Nurses
Authors: Weaver Susan H. , de Cordova Pamela B. , Ravichandran Arun , Cadmus Edna 
Published: December 2022

Background:
Licensed practical nurses (LPNs) working in nursing homes are the primary licensed nurses providing care and ensuring patient safety in New Jersey. As such, it is important to understand LPNs' perception of patient safety culture (PSC) and job satisfaction, which may impact resident safety.

Purpose:
To describe the relationship between LPNs' perception of PSC in nursing homes and job satisfaction.

Methods:
A cross-sectional study design was used to survey LPNs in New Jersey.

Results:
LPNs working in nursing homes were less satisfied than LPNs working in other settings, and their perception of PSC was lower than that in 2019 national data report.

Conclusion:
LPNs in nursing homes indicated that PSC needs improvement. Now is an opportune time to implement initiatives to foster a culture of safety in nursing homes.
Carbonic Anhydrase IX (CAIX) Expressing Hypoxic Micro-environment Hampers CD8+ Immune Cell Infiltrate in Breast Carcinoma
Authors: Juhász Péter , Hasulyó Dóra , Bedekovics Judit , Beke Lívia , Kacsala Norbert , Török Miklós , Méhes Gábor 
Published: December 2022

Background:
Hypoxia and necrosis are common features of invasive cancer. The dynamic upregulation of carbonic anhydrase IX (CAIX), triggered by hypoxia-inducible factor 1 (HIF-1) is 1 of the mechanisms supporting cellular adaptation to hypoxia in solid tumors, including breast carcinoma. CAIX activity results in extracellular acidosis and in a profound reorganization of the tumor micro-environment, influencing biological behavior and prognosis. The main focus of our study was to evaluate the mass and distribution of the immune infiltrate, more specifically of CD8+ effector T-cells, in relation with tumoral CAIX expression.

Materials and Methods:
Formalin-fixed and paraffin-embedded breast carcinoma sections were analyzed following double immunohistochemical staining for CAIX and CD8. Scanned digital slides were evaluated for both labelings, and CD8-related signal was determined within and outside CAIX-positive tumor areas using the HistoQuant (3DHistech) image analysis software. Statistical analysis was performed using GraphPad Prism software.

Results:
Of the 34 breast carcinomas, 18 tested partially positive for CAIX. The remaining 16 cases were used as the CAIX-negative control group. Necrotic foci were generally associated with CAIX overexpression, and tumors exhibiting signs of necrosis had a significantly higher rate of relative CAIX expression compared with samples without necrosis (11.47±5.505 vs. without necrosis 3.765±3.5 P-value=0.0216). On the other hand, no statistically significant difference was found when comparing relative CD8+ lymphocyte counts in cases with necrosis as opposed to those where necrosis was absent (134.7±55.7 vs. 97.70±57.25; P value=0.1579). No difference in gross CD8+ T-lymphocyte infiltrate could be measured between CAIX positive and negative samples (98.48±37.32 vs. 95.99±50 P value=0.5928). However, in CAIX-expressing tumors a statistical correlation between the CD8+ T-lymphocyte infiltrate and the extent of CAIX-positive areas was observed. Within the same tumor, CD8+ T-lymphocyte counts showed a significant difference betweeen CAIX+ and CAIX- areas (13.06±9.4 vs. 135.6±62.2 P value <0.0001).

Conclusion:
Our measurements demonstrate for the first time that tumor areas with CAIX expression potentially hamper CD8+ T-lymphocyte infiltration in breast carcinoma. The hypoxia-driven adaptive micro-environment likely interferes with the specific response to biological and immune therapies requiring intact effector T-cell response.
Real-time Lung Weight Measurement During Cellular Ex Vivo Lung Perfusion: An Early Predictor of Transplant Suitability
Authors: Kosaka Ryo , Sakota Daisuke , Sakanoue Ichiro , Niikawa Hiromichi , Ohuchi Katsuhiro , Arai Hirokuni , McCurry Kenneth R. , Okamoto Toshihiro 
Published: December 2022

Background.
Increased extravascular lung water during ex vivo lung perfusion (EVLP) is associated with ischemia reperfusion injury and poor pulmonary function. A non-invasive technique for evaluating extravascular lung water during EVLP is desired to assess the transplant suitability of lungs. We investigated real-time lung weight measurements as a reliable method for assessing pulmonary functions in cellular EVLP using a porcine lung model.

Methods.
Fifteen pigs were randomly divided into 3 groups: control (no warm ischemia) or donation after circulatory death groups with 60 or 90 min of warm ischemia (n = 5, each). Real-time lung weight gain was measured by load cells positioned at the bottom of the organ chamber.

Results.
Real-time lung weight gain at 2 h was significantly correlated with lung weight gain as measured on a back table (R = 0.979, P < 0.01). Lung weight gain in non-suitable cases (n = 6) was significantly higher than in suitable cases (n = 9) at 40 min (51.6 ± 46.0 versus −8.8 ± 25.7 g; P < 0.01, cutoff = +12 g, area under the curve = 0.907). Lung weight gain at 40 min was significantly correlated with PaO2/FiO2, peak inspiratory pressure, shunt ratio, wet/dry ratio, and transplant suitability at 2 h (P < 0.05, each). In non-suitable cases, lung weight gain at 66% and 100% of cardiac output was significantly higher than at 33% (P < 0.05).

Conclusions.
Real-time lung weight measurement could potentially be an early predictor of pulmonary function in cellular EVLP.
Molecular Dynamics Simulation as a Promising Approach for Computational Study of Liquid Crystal-based Aptasensors
Authors: Zahraee Hamed , Arab Seyed Shahriar , Khoshbin Zahra , Taghdisi Seyed Mohammad , Abnous Khalil 
Published: December 2022

AbstractAs a potent computational methodology, molecular dynamics (MD) simulation provides advantageous knowledge about biological compounds from the molecular viewpoint. In particular, MD simulation gives exact information about aptamer strands, such as the short synthetic oligomers, their orientation, binding sites, folding-unfolding state, and conformational re-arrangement. Also, the effect of the different chemicals and biochemicals as the components of aptamer-based sensors (aptasensors) on the aptamer-target interaction can be investigated by MD simulation. Liquid crystals (LCs) as soft substances with characteristics of both solid anisotropy and liquid fluidity are new candidates for designing label-free aptasensors. To now, diverse aptasensors have been developed experimentally based on the optical anisotropy, fluidity, and long-range orientational order of LCs. Here, we represent a computational model of an LC-based aptasensor through a detailed MD simulation study. The different parameters are defined and studied to achieve a comprehensive understanding of the computational design of the LC-based aptasensor, including the density of LCs, their orientation angle, and lognormal distribution in the absence and presence of aptamer strands, both aptamer and target molecules with various concentrations, and interfering substance. As a case study, the tobramycin antibiotic is considered the target molecule for the computational model of the LC-based aptasensor.
Rewiring Cancer Drivers to Activate Apoptosis
Authors: Gourisankar Sai , Krokhotin Andrey , Ji Wenzhi , Liu Xiaofan , Chang Chiung-ying , Kim Samuel H. , Li Zhengnian , Wenderski Wendy , Simanauskaite Juste M. , Zhang Tinghu , Gray Nathanael S. , Crabtree Gerald R. 
Published: December 2022

ABSTRACTGenes that drive the proliferation, survival, invasion and metastasis of malignant cells have been identified for many human cancers1–6. Independent studies have identified cell death pathways that eliminate cells for the good of the organism7–10. The coexistence of the cell death pathways with the driver mutations suggest that the cancer driver could be rewired to activate cell death. We have invented a new class of molecules: TCIPs (Transcriptional/Epigenetic Chemical Inducers of Proximity) that recruit the endogenous cancer driver, or a downstream transcription factor, to the promoters of cell death genes thereby activating their expression. To develop this concept, we have focused on diffuse large B cell lymphoma (DLBCL), in which BCL6 is amplified or mutated11. BCL6 binds to the promoters of cell death genes and epigenetically suppresses their expression12. We produced the first TCIPs by chemically linking BCL6 inhibitors to small molecules that bind transcriptional activators. Several of these molecules robustly kill DLBCL at single-digit nanomolar concentrations, including chemotherapy-resistant, TP53-mutant lines. The dominant gain-of-function approach provided by TCIPs captures the combinatorial specificity inherit to transcription and can thereby accesses new therapeutic space. TCIPs are relatively non-toxic to normal cells and mice, apparently reflecting their need for coincident expression of both target proteins for effective killing. The general TCIP concept has applications in elimination of senescent cells, enhancing expression of therapeutic genes, treatment of diseases produced by haploinsufficiency, and activation of immunogens for immunotherapy.
Constraining the global niche suitability of the Eusuchia clade across the Cretaceous-Paleogene boundary
Authors: Harper Morgan , Farnsworth Alexander , Valdes Paul J. , Markwick Paul J. , Stockdale Maximilian T. 
Published: December 2022

AbstractThe crocodiles and their close relatives, the alligators and gharials, have a compelling evolutionary history. They are a clade of great antiquity, with their most recent common ancestor emerging within the Mesozoic. However, unlike many groups of such a great age, the crocodilians have an extensive crown-group, with around two dozen extant examples. They have a limited ecomorphology, which has varied little since their inception, and their biogeography has been shown to interact closely with climate. The biogeography of crocodilians in deep time remains an outstanding question, which is complicated further by the limitations of the fossil record. The fossil record is fundamentally incomplete yet represents the most common method used to infer biogeography of organisms. The scarcity of fossil remains makes apparent absences difficult to confirm. Preservation bias will promote fossil occurrences in areas with a high sedimentation rate, which may not be the true ecological niche for a given taxon. This study uses species distribution models of extant crocodilians to infer the ecological niche of related taxa in the Maastrichtian and Danian. Models indicate a much wider latitudinal range than is observed among extant examples, and the invasion of new ecospace following the end-Cretaceous mass extinction. In addition, we find that while temperature is of significance to crocodilian biogeography, it is precipitation that is the most influential climatic variable.
Efficacy of a bivalent (D614 + B.1.351) SARS-CoV-2 Protein Vaccine
Authors: Dayan Gustavo H. , Rouphael Nadine , Walsh Stephen R. , Chen Aiying , Grunenberg Nicole , Allen Mary , Antony Johannes , Asante Kwaku Poku , Suresh Bhate Amit , Beresnev Tatiana , Bonaparte Matthew I , Angeles Ceregido Maria , Dobrianskyi Dmytro , Fu Bo , Grillet Marie-Helene , Keshtkar-Jahromi Maryam , Juraska Michal , Jin Kee Jia , Kibuuka Hannah , Koutsoukos Marguerite , Masotti Roger , Michael Nelson L. , Reynales Humberto , Robb Merlin L. , Villagómez Martínez Sandra M. , Sawe Fredrick , Schuerman Lode , Tong Tina , Treanor John , Wartel T. Anh , Diazgranados Carlos A. , Chicz Roman M. , Gurunathan Sanjay , Savarino Stephen , Sridhar Saranya ,   the VAT00008 study team
Published: December 2022

AbstractBackgroundCOVID-19 vaccines with alternative strain compositions are needed to provide broad protection against newly emergent SARS-CoV-2 variants of concern.MethodsWe conducted a global Phase 3, multi-stage efficacy study (NCT04904549) among adults aged ≥18 years. Participants were randomized 1:1 to receive two intramuscular injections 21 days apart of a bivalent SARS-CoV-2 recombinant protein vaccine with AS03-adjuvant (5 μg of ancestral (D614) and 5 μg of B.1.351 [beta] variant spike protein) or placebo. Symptomatic COVID-19 was defined as laboratory-confirmed COVID-19 with COVID-19-like illness (CLI) symptoms. The primary efficacy endpoint was the prevention of symptomatic COVID-19 ≥14 days after the second injection (post-dose 2 [PD2]).ResultsBetween 19 Oct 2021 and 15 Feb 2022, 12,924 participants received ≥1 study injection. 75% of participants were SARS-CoV-2 non-naïve. 11,416 participants received both study injections (efficacy-evaluable population [vaccine, n=5,736; placebo, n=5,680]). Up to 15 March 2022, 121 symptomatic COVID-19 cases were reported (32 in the vaccine group and 89 in the placebo group) ≥14 days PD2 with a vaccine efficacy (VE) of 64.7% (95% confidence interval [CI] 46.6; 77.2%). VE was 75.1% (95% CI 56.3; 86.6%) in non-naïve and 30.9% (95% CI -39.3; 66.7%) in naïve participants. Viral genome sequencing identified the infecting strain in 68 cases (Omicron [BA.1 and BA.2 subvariants]: 63; Delta: 4; Omicron and Delta: 1). The vaccine was well-tolerated and had an acceptable safety profile.ConclusionsA bivalent vaccine conferred heterologous protection against symptomatic infection with newly emergent Omicron (BA.1 and BA.2) in non-naïve adults 18–59 years of age.ClinicalTrials.govNCT04904549
The large GTPase Sey1/atlastin mediates lipid droplet- and FadL-dependent intracellular fatty acid metabolism ofLegionella pneumophila
Authors: Hüsler Dario , Stauffer Pia , Keller Bernhard , Böck Desirée , Steiner Thomas , Ostrzinski Anne , Striednig Bianca , Swart A. Leoni , Letourneur François , Maaß Sandra , Becher Dörte , Eisenreich Wolfgang , Pilhofer Martin , Hilbi Hubert 
Published: December 2022

AbstractThe facultative intracellular bacteriumLegionella pneumophilaemploys the Icm/Dot type IV secretion system (T4SS) to replicate in a unique membrane-bound compartment, theLegionella-containing vacuole (LCV). The endoplasmic reticulum (ER)-resident large fusion GTPase Sey1/atlastin promotes remodeling and expansion of LCVs, and the GTPase is also implicated in the formation of ER-derived lipid droplets (LDs). Here we show that LCVs intimately interact with palmitate-induced LDs inDictyostelium discoideumamoeba. Comparative proteomics of LDs isolated from theD. discoideumparental strain Ax3 or ⊗sey1revealed 144 differentially produced proteins, of which 7 or 22 were exclusively detected in LDs isolated from strain Ax3 or ⊗sey1, respectively. Using dually fluorescence-labeled amoeba producing the LCV marker P4C-GFP or AmtA-GFP and the LD marker mCherry-perilipin, we discovered that Sey1 and theL. pneumophilaIcm/Dot T4SS as well as the effector LegG1 promote LCV-LD interactions.In vitroreconstitution of the LCV-LD interactions using purified LCVs and LDs fromD. discoideumAx3 or ⊗sey1revealed that Sey1 and GTP promote this process. The LCV-LD interactions were impaired for ⊗sey1-derived LDs, suggesting that Sey1 regulates LD composition. Palmitate promoted the growth of (i)L. pneumophilawild-type inD. discoideumAx3 but not in ⊗sey1mutant amoeba and (ii)L. pneumophilawild-type but not ⊗fadLmutant bacteria lacking a homologue of theE. colifatty acid transporter FadL. Finally, isotopologue profiling indicated that intracellularL. pneumophilametabolizes13C-palmitate, and its catabolism was reduced inD. discoideum⊗sey1andL. pneumophila⊗fadL. Taken together, our results reveal that Sey1 mediates LD- and FadL-dependent fatty acid metabolism of intracellularL. pneumophila.
The establishment of locally adaptive inversions in structured populations
Authors: Mackintosh Carl , Scott Michael F , Reuter Max , Pomiankowski Andrew 
Published: December 2022

AbstractInversions have been proposed to facilitate local adaptation, by linking together locally coadapted alleles at different loci. Classic prior work addressing this question theoretically has considered the spread of inversions in “continent-island” models in which there is a unidirectional flow of maladapted migrants into the island population. In this setting, inversions are most likely to establish when selection is weak, because stronger local selection more effectively purges maladaptive alleles, thus lessening the advantage of inversions. Here, we show this finding only holds under limited conditions. We study the establishment of inversions in a “two-deme” model, which explicitly considers the dynamics of allele frequencies in both populations linked by bidirectional migration. For symmetric selection and migration, we find that stronger local selection increases the flow of maladaptive alleles and favours inversions, the opposite of the pattern seen in the asymmetric continent-island model. Furthermore, we show that the strength and symmetry of selection also change the likelihood that an inversion captures an adaptive haplotype in the first place. Considering the combined process of invasion and capture shows that inversions are most likely to be found when locally adaptive loci experience strong selection. In addition, inversions that establish in one deme also protect adaptive allele combinations in the other, leading to differentiation between demes. Stronger selection in either deme once again makes differentiation between populations more likely. In contrast, differentiation is less likely when migration rates are high because adaptive haplotypes become less common. Overall, this analysis of evolutionary dynamics across a structured population shows that established inversions are most likely to have captured strongly selected local adaptation alleles.
The Axin scaffold protects the kinase GSK3β from cross-pathway inhibition
Authors: Gavagan Maire , Jameson Noel , Zalatan Jesse G. 
Published: December 2022

AbstractMultiple signaling pathways regulate the kinase GSK3β by inhibitory phosphorylation at Ser9, which then occupies the GSK3β priming pocket and blocks substrate binding. Since this mechanism should affect GSK3β activity towards all primed substrates, it is unclear why Ser9 phosphorylation does not affect other GSK3β-dependent pathways, such as Wnt signaling. We used biochemical reconstitution and cell culture assays to evaluate how Wnt-associated GSK3β is insulated from cross-activation by other signals. We found that the Wnt-specific scaffold protein Axin allosterically protects GSK3β from phosphorylation at Ser9 by upstream kinases, which prevents accumulation of pS9-GSK3β in the Axin-GSK3β complex. Scaffold proteins that protect bound proteins from alternative pathway reactions could provide a general mechanism to insulate signaling pathways from improper crosstalk.