bluuebunny/crossref_metadata_2025 huggingface dataset:
The significance of CD49f expression in pediatric B-cell acute lymphoblastic leukemia
Authors: Hunyadi Anna , Kriston Csilla , Szalóki Gábor , Péterffy Borbála , Egyed Bálint , Szepesi Ágota , Timár Botond , Erdélyi Dániel J , Csanádi Krisztina , Kutszegi Nóra , Márk Ágnes , Barna Gábor
Published: September 2024

Objectives

CD49f is an adhesion molecule present on malignant lymphoblasts in B-cell acute lymphoblastic leukemia; it is associated with a poor prognosis. CD49f expression has been proposed as a marker for measurable residual disease (MRD) marker, but this marker has yet to be implemented in clinical practice.

Methods

In this study, we used flow cytometry to detect CD49f expression by leukemic blasts in paired bone marrow and cerebrospinal fluid samples at diagnosis and bone marrow at day 15 of treatment.

Results

At diagnosis, 93% of bone marrow and 100% of cerebrospinal fluid lymphoblasts expressed CD49f. The intensity of CD49f expression statistically significantly increased during treatment (P < .001). In MRD-negative end-of-treatment samples, only a small population of hematogones expressed CD49f. Interestingly, the intensity of CD49f expression varied among the different groups of recurrent genetic abnormalities. The ETV6::RUNX1 fusion and ETV6::RUNX1 combined with the high hyperdiploid group were associated with increased expression, whereas the Philadelphia-like group showed low CD49f expression. The lower CD49f expression at diagnosis predicted a lower MRD rate at day 15 of treatment.

Conclusions

We concluded that CD49f can be used as an MRD marker and possible prognostic factor in B-cell acute lymphoblastic leukemia.
Examining Food-Specific and General Inhibitory Control and Working Memory as Moderators of Relations Between Emotion Regulation Difficulties and Eating Pathology in Adults With Overweight/Obesity: A Preregistered, Cross-Sectional Study
Authors: Barnhart Wesley R , Braden Abby L , Buelow Melissa T
Published: September 2024

Objective

Empirical research and theory support the interaction of executive functions (e.g., inhibitory control, working memory) and emotion regulation in guiding goal-oriented behavior; however, applications to eating pathology (e.g., binge eating) are limited. Such research is scant with adults with overweight/obesity (AwO/O), a population reporting high levels of binge eating, emotion regulation difficulties, and deficits in inhibitory control and working memory. We tested interactions between emotion regulation and executive functioning in relation to eating pathology in AwO/O while considering stimuli-specific deficits (e.g., food-specific deficits) in behavioral task performance.

Method

AwO/O (N = 204; MBMI = 32.11; Mage = 38.30 [SD = 12.16]) completed a preregistered, online study assessing demographics and emotion regulation difficulties (Difficulties in Emotional Regulation Scale), inhibitory control (go/no-go task, food and general stimuli), working memory (N-Back Task, food and general stimuli), binge eating (Binge Eating Scale), and disordered eating (Eating Disorder Examination-Questionnaire).

Results

There was limited evidence of moderation in models examining food-specific and general inhibitory control and working memory, emotion regulation difficulties, and binge eating. Preliminary support was found for emotion regulation difficulties to be more strongly associated with more disordered eating in AwO/O reporting more food-specific and general working memory deficits. Consistent, positive associations between emotion regulation difficulties and eating pathology were observed.

Conclusions

Among adults with AwO/O, emotion regulation difficulties are closely related to eating pathology, regardless of performance on working memory and inhibitory control tasks. Clinicians and researchers working with AwO/O may consider how emotion regulation difficulties and working memory deficits work together to influence disordered eating.
Variable calling of m6A and associated features in databases: a guide for end-users
Authors: Song Renhua , J Sutton Gavin , Li Fuyi , Liu Qian , Wong Justin J-L
Published: September 2024

N6-methyladenosine (m$^{6}$A) is a widely-studied methylation to messenger RNAs, which has been linked to diverse cellular processes and human diseases. Numerous databases that collate m$^{6}$A profiles of distinct cell types have been created to facilitate quick and easy mining of m$^{6}$A signatures associated with cell-specific phenotypes. However, these databases contain inherent complexities that have not been explicitly reported, which may lead to inaccurate identification and interpretation of m$^{6}$A-associated biology by end-users who are unaware of them. Here, we review various m$^{6}$A-related databases, and highlight several critical matters. In particular, differences in peak-calling pipelines across databases drive substantial variability in both peak number and coordinates with only moderate reproducibility, and the inclusion of peak calls from early m$^{6}$A sequencing protocols may lead to the reporting of false positives or negatives. The awareness of these matters will help end-users avoid the inclusion of potentially unreliable data in their studies and better utilize m$^{6}$A databases to derive biologically meaningful results.
Enhancing clinical genomic accuracy with panelGC: a novel metric and tool for quantifying and monitoring GC biases in hybridization capture panel sequencing
Authors: Cheng Xuanjin , Goktas Murathan T , Williamson Laura M , Krzywinski Martin , Mulder David T , Swanson Lucas , Slind Jill , Sihvonen Jelena , Chow Cynthia R , Carr Amy , Bosdet Ian , Tucker Tracy , Young Sean , Moore Richard , Mungall Karen L , Yip Stephen , Jones Steven J M
Published: September 2024

Accurate assessment of fragment abundance within a genome is crucial in clinical genomics applications such as the analysis of copy number variation (CNV). However, this task is often hindered by biased coverage in regions with varying guanine–cytosine (GC) content. These biases are particularly exacerbated in hybridization capture sequencing due to GC effects on probe hybridization and polymerase chain reaction (PCR) amplification efficiency. Such GC content–associated variations can exert a negative impact on the fidelity of CNV calling within hybridization capture panels. In this report, we present panelGC, a novel metric, to quantify and monitor GC biases in hybridization capture sequencing data. We establish the efficacy of panelGC, demonstrating its proficiency in identifying and flagging potential procedural anomalies, even in situations where instrument and experimental monitoring data may not be readily accessible. Validation using real-world datasets demonstrates that panelGC enhances the quality control and reliability of hybridization capture panel sequencing.
Longitudinal health-related quality of life in people with thoracic aortic aneurysms
Authors: Sharples Linda D , Anagnostopoulou Vasiliki , Pouncey Anna L , Freeman Carol , McCarthy Andrew , Gray Joanne , McMeekin Peter , Sastry Priya , Vale Luke , Bicknell Colin , Large Stephen R
Published: September 2024

Background

Surgical intervention for thoracic aortic aneurysms is high risk. Understanding changes in health-related quality of life before and after endovascular stent grafting and open surgical repair can aid treatment decision-making.

Methods

The Effective Treatments for Thoracic Aortic Aneurysms (‘ETTAA’) study (ISRCTN04044627) was a longitudinal, observational study. Adults with new/existing arch or descending thoracic aortic aneurysms greater than or equal to 4 cm in diameter were followed from 2014 to 2022. Five domains of health-related quality of life (Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression) were recorded using the EuroQoL, five dimensions, five levels (‘EQ-5D-5L’) questionnaire and analysed using a range of longitudinal mixed models.

Results

Of 886 thoracic aortic aneurysm participants, 824 completed at least 2 questionnaires. Patients had slightly worse health-related quality of life than age-matched norms. Without surgery, deterioration occurred over time in Mobility (0.072/year (95% c.i. 0.042 to 0.101), P < 0.001) and Self-Care (0.039/year (95% c.i. 0.018 to 0.061), P < 0.001) in both sexes and Pain/Discomfort in women (0.069/year (95% c.i. 0.020 to 0.118), P = 0.005). For 6 weeks after endovascular stent grafting, there was a significant impairment in Self-Care (0.214 (95% c.i. 0.112 to 0.316), P < 0.001) and (for women only) in Usual Activities (0.625 (95% c.i. 0.338 to 0.911), P < 0.001), which then returned to pre-endovascular stent grafting levels. Six weeks after open surgical repair, the impairment in health-related quality of life was greater (Mobility 0.492 (95% c.i. 0.314 to 0.669), Self-Care 0.474 (95% c.i. 0.364 to 0.583), Usual Activities 1.469 (95% c.i. 1.042 to 1.896), and Pain/Discomfort 0.561 (95% c.i. 0.363 to 0.760), all P < 0.001) and took longer to return to pre-open surgical repair levels, partly due to increased complications and longer hospitalization. Anxiety/Depression decreased after open surgical repair (−0.214 (95% c.i. −0.326 to −0.101), P < 0.001). Age, sex, frailty, smoking, New York Heart Association class, and chronic obstructive pulmonary disease were significantly associated with health-related quality of life.

Conclusion

Without intervention, health-related quality of life declines as age increases. Changes in health-related quality of life should contribute to surgical treatment decision-making.
3T sodium-MRI as predictor of neurocognition in nondemented older adults: a cross sectional study
Authors: Lui Elaine , Venkatraman Vijay K , Finch Sue , Chua Michelle , Li Tie-Qiang , Sutton Bradley P , Steward Christopher E , Moffat Bradford , Cyarto Elizabeth V , Ellis Kathryn A , Rowe Christopher C , Masters Colin L , Lautenschlager Nicola T , Desmond Patricia M
Published: September 2024

Dementia is a burgeoning global problem. Novel magnetic resonance imaging (MRI) metrics beyond volumetry may bring new insight and aid clinical trial evaluation of interventions early in the Alzheimer’s disease course to complement existing imaging and clinical metrics. To determine whether: (i) normalized regional sodium-MRI values (Na-SI) are better predictors of neurocognitive status than volumetry (ii) cerebral amyloid PET status improves modelling. Nondemented older adult (>60 years) volunteers of known Alzheimer's Disease Assessment Scale (ADAS-Cog11), Mini-Mental State Examination (MMSE) and Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neurocognitive test scores, ApolipoproteinE (APOE) e4 +/− cerebral amyloid PET status were prospectively recruited for 3T sodium-MRI brain scans. Left and right hippocampal, entorhinal and precuneus volumes and Na-SI (using the proportional intensity scaling normalization method with field inhomogeneity and partial volume corrections) were obtained after segmentation and co-registration of 3D-T1-weighted proton images. Descriptive statistics, correlation and best-subset regression analyses were performed. In our 76 nondemented participants (mean(standard deviation) age 75(5) years; woman 47(62%); cognitively unimpaired 54/76(71%), mildly cognitively impaired 22/76(29%)), left hippocampal Na-SI, not volume, was preferentially in the best models for predicting MMSE (Odds Ratio (OR) = 0.19(Confidence Interval (CI) = 0.07,0.53), P-value = 0.001) and ADAS-Cog11 (Beta(B) = 1.2(CI = 0.28,2.1), P-value = 0.01) scores. In the entorhinal analysis, right entorhinal Na-SI, not volume, was preferentially selected in the best model for predicting ADAS-Cog11 (B = 0.94(CI = 0.11,1.8), P-value = 0.03). While right entorhinal Na-SI and volume were both selected for MMSE modelling (Na-SI OR = 0.23(CI = 0.09,0.6), P-value = 0.003; volume OR = 2.6(CI = 1.0,6.6), P-value = 0.04), independently, Na-SI explained more of the variance (Na-SI R2 = 10.3; volume R2 = 7.5). No imaging variable was selected in the best CERAD models. Adding cerebral amyloid status improved model fit (Akaike Information Criterion increased 2.0 for all models, P-value < 0.001–0.045). Regional Na-SI were more predictive of MMSE and ADAS-Cog11 scores in our nondemented older adult cohort than volume, hippocampal more robust than entorhinal region of interest. Positive amyloid status slightly further improved model fit.
Regulating oxidation states of Cu nanowires for enhanced catalytic reduction of 4-nitrophenol
Authors: Li Zhong , Chao Yongchen , Sun Kaiyue , Cao Junyang , Sun Dan , Wu Dengfeng
Published: September 2024

The construction of highly efficient and low-cost catalysts is crucial for the reduction reaction of 4-nitrophenol (4-NP). Herein, we provide a simple processing method, including vacuum storage, natural oxidation, and heating oxidation, that effectively regulates the surface oxidation state of copper nanowires and produces copper nanowires with different oxidation states (such as Cu, Cu2O, and CuO). Research has found that CuNW-N (Cu nanowires for vacuum storage) catalysts with a surface composition of 67.9% Cu0, 20.6% Cu+, and 11.5% Cu2+ exhibit the best catalytic performance for the reduction of 4-nitrophenol (4-NP) and their reaction rate constant reaches 0.791 min−1. This work provides a feasible catalyst preparation strategy for the efficient catalytic reduction of 4-NP.
Surgical skill simulation training to proficiency reduces procedural errors among novice cardiac device implanters: a randomized study
Authors: Mascheroni Jorio , Stockburger Martin , Patwala Ashish , Mont Lluís , Rao Archana , Retzlaff Hartwig , Garweg Christophe , Gallagher Anthony G , Verbelen Tom
Published: September 2024

Aims

In cardiac device implantation, having both surgical skills and ability to manipulate catheter/lead/wire is crucial. Few cardiologists, however, receive formal surgical training prior to implanting. Skills are mostly acquired directly on-the-job and surgical technique varies across institutions; suboptimal approaches may increase complications. We investigated how novel proficiency-based progression (PBP) simulation training impacts the surgical quality of implantations, compared to traditional simulation (SIM) training.

Methods and results

In this international prospective study, novice implanters were randomized (blinded) 1:1 to participate in a simulation-based procedure training curriculum, with proficiency demonstration requirements for advancing (PBP approach) or without (SIM). Ultimately, trainees performed the surgical tasks of an implant on a porcine tissue that was video-recorded and then scored by two independent assessors (blinded to group), using previously validated performance metrics. Primary outcomes were the number of procedural Steps Completed, Critical Errors, Errors (non-critical), and All Errors Combined. Thirty novice implanters from 10 countries participated. Baseline experiences were similar between groups. Compared to SIM-trained, the PBP-trained group completed on average 11% more procedural Steps (P < 0.001) and made 61.2% fewer Critical Errors (P < 0.001), 57.1% fewer Errors (P = 0.140), and 60.7% fewer All Errors Combined (P = 0.001); 11/15 (73%) PBP trainees demonstrated the predefined target performance level vs. 3/15 SIM trainees (20%) in the video-recorded performance.

Conclusion

Proficiency-based progression training produces superior objectively assessed novice operators’ surgical performance in device implantation compared with traditional (simulation) training. Systematic PBP incorporation into formal academic surgical skills training is recommended before in vivo device practice. Future studies will quantify PBP training’s effect on surgery-related device complications.
Evolutionary innovation accelerates morphological diversification in pufferfishes and their relatives
Authors: Troyer Emily M , Evans Kory M , Goatley Christopher H R , Friedman Matt , Carnevale Giorgio , Nicholas Benjamin , Kolmann Matthew , Bemis Katherine E , Arcila Dahiana
Published: September 2024

Evolutionary innovations have played an important role in shaping the diversity of life on Earth. However, how these innovations arise and their downstream effects on patterns of morphological diversification remain poorly understood. Here, we examine the impact of evolutionary innovation on trait diversification in tetraodontiform fishes (pufferfishes, boxfishes, ocean sunfishes, and allies). This order provides an ideal model system for studying morphological diversification owing to their range of habitats and divergent morphologies, including the fusion of the teeth into a beak in several families. Using three-dimensional geometric morphometric data for 176 extant and fossil species, we examine the effect of skull integration and novel habitat association on the evolution of innovation. Strong integration may be a requirement for rapid trait evolution and facilitating the evolution of innovative structures, like the tetraodontiform beak. Our results show that the beak arose in the presence of highly conserved patterns of integration across the skull, suggesting that integration did not limit the range of available phenotypes to tetraodontiforms. Furthermore, we find that beaks have allowed tetraodontiforms to diversify into novel ecological niches, irrespective of habitat. Our results suggest that general rules pertaining to evolutionary innovation may be more nuanced than previously thought.
Becoming a Rescuer in the Pyrenees: Border Guides Who took Jews from France to Franco’s Spain (1940–1943)
Authors: Adams Jacqueline
Published: September 2024

During the Holocaust, thousands of Jews in France fled Europe via Franco’s Spain. When leaving France, refugees who lacked the required travel documents avoided police and customs officers at the Franco-Spanish border by walking over the Pyrenees. Guides (passeurs) led them through the mountains to the border, choosing trails and times that would make encounters with police patrols less likely. Most charged large sums of money, but some worked without payment. This article explores why the latter group engaged in this dangerous form of rescue, by examining how they became border guides. It focuses on two French farmers, a French Christian brother at a sanatorium, and an antifascist activist from Germany. The sources analyzed include the memoirs, unpublished accounts, diaries, letters and oral history interviews of the guides, their work associates, and the refugees; as well as official correspondence between French police and government officials in the Pyrenees region, and the archival records of the Brothers of the Christian Schools. The author’s primary research finding is that the border guides considered in this study undertook the dangerous task of guiding refugees because they had had a series of experiences and had engaged in a series of actions that made it more feasible for them to do so when asked. Their values and understanding of their work also help explain why they became guides. Reflections on the implications of this research for our comprehension of bystanders’ actions conclude the article.
Graft incompatibility between pepper and tomato elicits an immune response and triggers localized cell death
Authors: Thomas Hannah Rae , Gevorgyan Alice , Hermanson Alexandra , Yanders Samantha , Erndwein Lindsay , Norman-Ariztía Matthew , Sparks Erin E , Frank Margaret H
Published: September 2024

Graft compatibility is the capacity of two plants to form cohesive vascular connections. Tomato and pepper are incompatible graft partners; however, the underlying cause of graft rejection between these two species remains unknown. We diagnosed graft incompatibility between tomato and diverse pepper varieties based on weakened biophysical stability, decreased growth, and persistent cell death using viability stains. Transcriptomic analysis of the junction was performed using RNA sequencing, and molecular signatures for incompatible graft response were characterized based on meta-transcriptomic comparisons with other biotic processes. We show that tomato is broadly incompatible with diverse pepper cultivars. These incompatible graft partners activate prolonged transcriptional changes that are highly enriched for defense processes. Amongst these processes was broad nucleotide-binding and leucine-rich repeat receptors (NLR) upregulation and genetic signatures indicative of an immune response. Using transcriptomic datasets for a variety of biotic stress treatments, we identified a significant overlap in the genetic profile of incompatible grafting and plant parasitism. In addition, we found over 1000 genes that are uniquely upregulated in incompatible grafts. Based on NLR overactivity, DNA damage, and prolonged cell death, we hypothesize that tomato and pepper graft incompatibility is characterized by an immune response that triggers cell death which interferes with junction formation.
Mortality Trends in Inflammatory Bowel Disease by Age, Sex, and Race in the United States from 1999 to 2020
Authors: Aziz Saleha , Akhlaq Anum , Owings Anna , Gurz Sana , Zafar Yousaf , Ali Basim , Tang Shou-jiang
Published: September 2024

Background

The prevalence and disease course of inflammatory bowel disease (IBD) have evolved over the years. It is unknown how these factors have impacted all-cause mortality. Our study assesses IBD mortality trends in the United States over 20 years by age, sex, and race.

Methods

We used the Centers for Disease Control Wide-Ranging OnLine Data for Epidemiologic Research database for multiple causes of death in Crohn’s disease (CD) and ulcerative colitis (UC) from 1999 to 2020. Age-adjusted mortality rates (AAMR) and crude mortality rates per 100 000 population were obtained. Joinpoint Analysis Software was used for annual percentage change (APC) overall and by age, sex, and race (White and Black).

Results

Overall AAMR in CD and UC were 0.79 and 0.53, respectively. All-cause mortality was stable from 1999 to 2018. There was a significant rise in APC from 2018 to 2020 (CD vs. UC, +11.28 vs. +9.29). This rise was observed across both races, sexes, and ages ≥45 years in the last 2–4 years of the study. AAMR in females compared with males varied in CD (0.81 vs. 0.79) and UC (0.45 vs. 0.62). White adults had higher AAMR than Black adults in both CD (0.94 vs. 0.50) and UC (0.58 vs. 0.28). The crude mortality rate increased with age and was highest in those ≥85 years (CD vs. UC, 5.07 vs. 5.23).

Conclusions

All-cause mortality trends in IBD were stable until 2018 and rose between 2018 and 2020. Mortality rates were higher amongst the elderly and White adults. Females with CD and males with UC had higher mortality rates.
Risk of Paradoxical Rheumatoid Arthritis in Inflammatory Bowel Disease Patients Exposed to Tumor Necrosis Factor Inhibitors: A Propensity-Matched Multicenter Study
Authors: Keluth Chavan Akash , Jha Pankhuri , Perez Jaime Abraham , Harper Elleson , Sinh Preetika , Cooper Gregory , Katz Jeffry , Cominelli Fabio , Regueiro Miguel , Mansoor Emad
Published: September 2024

Lay Summary

Tumor necrosis factor (TNF) inhibitor therapy for inflammatory bowel disease (IBD) has been associated with an increased risk of rheumatoid arthritis and other inflammatory conditions. Our retrospective study did not show an increased risk when compared with non-anti-TNF therapy for IBD.
Half a Century of Global Invasion: How Global Trends Can Inform the Spread and Phenology of the Non-Native Kelp, Undaria Pinnatifida, in California, United States
Authors: McHaskell Danielle Alexis
Published: September 2024

Synopsis

The potential for non-native species to outcompete native species, change ecosystem dynamics, and decrease biodiversity necessitates an understanding of their ecological role. Non-native seaweed species (NNSS) can be particularly impactful due to their cryptic life cycles, high fecundity, and tolerance to stressors, which could allow rapid spread across coastlines. This literature review summarizes a few well-known NNSS in California with a focus on using global literature on Undaria pinnatifida to inform potential trends of habitat use, dispersal, and phenology in this region. Globally, we found that Undaria is widely documented in bays and harbors, but there are documented cases of it establishing populations in coastal habitats in exposed rocky reef ecosystems, including California. Using data on thermal tolerance for U. pinnatifida in its native range, I found the sea surface temperatures (SST) throughout the west coast of the USA during 2019 are within the thermal tolerance of Undaria with the best SST for gametophytes occurring most frequently in southern California. Using data from the literature, I estimated the potential for Undaria to disperse from known populations in San Diego, CA, USA. These data suggest that Undaria has the potential to disperse into open coastal habitats in this region. This study provides a case for further using pre-existing literature from other regions to guide research conducted in regions of interest that can inform management decisions.
The Role of Polycystic Kidney Disease-Like Homologs in Planarian Nervous System Regeneration and Function
Authors: Ross K G , Alvarez Zepeda S , Auwal M A , Garces A K , Roman S , Zayas R M
Published: September 2024

Synopsis

Planarians are an excellent model for investigating molecular mechanisms necessary for regenerating a functional nervous system. Numerous studies have led to the generation of extensive genomic resources, especially whole-animal single-cell RNA-seq resources. These have facilitated in silico predictions of neuronal subtypes, many of which have been anatomically mapped by in situ hybridization. However, our knowledge of the function of dozens of neuronal subtypes remains poorly understood. Previous investigations identified that polycystic kidney disease (pkd)-like genes in planarians are strongly expressed in sensory neurons and have roles in mechanosensation. Here, we examine the expression and function of all the pkd genes found in the Schmidtea mediterranea genome and map their expression in the asexual and hermaphroditic strains. Using custom behavioral assays, we test the function of pkd genes in response to mechanical stimulation and in food detection. Our work provides insight into the physiological function of sensory neuron populations and protocols for creating inexpensive automated setups for acquiring and analyzing mechanosensory stimulation in planarians.
Counter-Terrorism and Human Rights at the UN Security Council: Blurring Boundaries in a Social Space
Authors: Hoffmann Alvina
Published: September 2024

How do we study the UN Security Council, a bastion of sovereign nation-state politics, from the perspective of “outsiders” such as UN special rapporteurs? This article reimagines the relationship between security and human rights at the UN through a social space approach. By challenging institutional and geographical boundaries between the Security Council in New York and the Human Rights Council in Geneva, I follow actors in a social space in which transversal lines connecting security and human rights become visible. I uncover a social space that is animated by actors, their relations and social positions relative to each other as well as connections between institutions, geographical locations, practical competencies, and material infrastructures. On this basis, I theorize four distinct boundary-blurring practices of UN special rapporteurs: between the issue areas of human rights and security, between the geographical locations of New York and Geneva, between institutions such as the Security Council, Human Rights Council and the OHCHR, and between the domains of politics and law. While these practices help them enter into the social space of the Security Council in New York, special rapporteurs need to pay “entry costs” by accepting the basic premises of the counter-terrorism architecture in return for recognition as valid actors in this architecture. Taking this viewpoint from the outside, I argue, illuminates the extension of the Security Council beyond its institutional confines and uncovers “the human-rightisation” of global security policy.
Comparative evaluation of early treatment with ceftolozane/tazobactam versus ceftazidime/avibactam for non-COVID-19 patients with pneumonia due to multidrug-resistant Pseudomonas aeruginosa
Authors: Lodise Thomas P , Obi Engels N , Watanabe Alexandre H , Yucel Emre , Min Jae , Nathanson Brian H
Published: September 2024

Background

Ceftolozane/tazobactam and ceftazidime/avibactam are commonly used in patients with MDR-Pseudomonas aeruginosa (PSA) pneumonia (PNA). This study compared outcomes between non-COVID-19 hospitalized patients with MDR-PSA PNA who received ceftolozane/tazobactam or ceftazidime/avibactam.

Methods

The study included non-COVID-19 adult hospitalized patients with MDR-PSA PNA in the PINC AI Healthcare Database (2016–22) who received ceftolozane/tazobactam or ceftazidime/avibactam within 3 days of index culture for ≥2 days. Outcomes were mortality, recurrent MDR-PSA PNA, discharge destination, post-index culture day length of stay (LOS) and costs (in US dollars, USD), and hospital readmission.

Results

The final sample included 197 patients (117 ceftolozane/tazobactam, 80 ceftazidime/avibactam). No significant differences were observed in mortality and post-index culture LOS and costs between groups. In the multivariable analyses, patients who received ceftolozane/tazobactam versus ceftazidime/avibactam had lower recurrent MDR-PSA PNA (7.9% versus 18.0%, P = 0.03) and 60 day PNA-related readmissions (11.1% versus 28.5%, P = 0.03) and were more likely to be discharged home (25.8% versus 9.8%, P = 0.03). Compared with ceftazidime/avibactam patients, ceftolozane/tazobactam patients had lower adjusted median total antibiotic costs (5052 USD versus 8099 USD, P = 0.003) and lower adjusted median comparator (ceftolozane/tazobactam or ceftazidime/avibactam) antibiotic costs (3938 USD versus 6441 USD, P = 0.005). In the desirability of outcome ranking (DOOR) analysis, a ceftolozane/tazobactam-treated patient was more likely to have a more favourable outcome than a ceftazidime/avibactam-treated patient [DOOR probability: 59.6% (95% CI: 52.5%–66.8%)].

Conclusions

Early treatment with ceftolozane/tazobactam may offer some clinical and cost benefits over ceftazidime/avibactam in patients with MDR-PSA PNA. Further large-scale studies are necessary to comprehensively understand the outcomes associated with these treatments for MDR-PSA PNA.
Widespread geographic distribution of Aedes aegypti (Diptera: Culicidae) kdr variants in Panama
Authors: García Joel , Chong Mabelle , Rojas Ambar L , McMillan W Owen , Bennett Kelly L , Lenhart Audrey E , Chaves Luis F , Loaiza Jose R
Published: September 2024

We searched for evidence of knockdown resistance (kdr) mutations in the voltage-gated sodium channel gene of Aedes aegypti (Linnaeus) (Diptera: Culicidae) and Aedes albopictus (Skuse) (Diptera: Culicidae) mosquitoes from Panama. Conventional PCR was performed on 469 Ae. aegypti and 349 Ae. albopictus. We did not discover kdr mutations in Ae. albopictus, but 2 nonsynonymous kdr mutations, V1016I (found in 101 mosquitoes) and F1534C (found in 29 of the mosquitoes with the V1016I), were detected in Ae. aegypti. These kdr mutations were present in all specimens that were successfully sequenced for both IIS5-S6 and IIIS6 regions, which included samples collected from 8 of the 10 provinces of Panama. No other kdr mutations were found in Ae. aegypti, including V1016G, which has already been reported in Panama. Findings suggest that the V1016I-F1534C variant is prevalent in Panama, which might be related to the introduction and passive movement of mosquitoes as part of the used-tire trade. However, we cannot rule out the possibility that selection on de novo replacement of kdr mutations also partially explains the widespread distribution pattern of these mutations. These 2 ecological and evolutionary processes are not mutually exclusive, though, as they can occur in tandem. Research in Panama needs to calculate the genotypic and allelic frequencies of kdr alleles in local Ae. aegypti populations and to test whether some combinations confer phenotypic resistance or not. Finally, future studies will have to track the introduction and spreading of new kdr mutations in both Aedes species.
Forest encroachment in Eastern European forest-steppes at a decadal time scale
Authors: Erdős László , Ónodi Gábor , Tölgyesi Csaba , Kröel-Dulay György , Bátori Zoltán , Aradi Eszter , Török Péter , Ho Khanh Vu , Puspitasari Indri , Körmöczi László
Published: September 2024

In the Eurasian forest-steppe, with increasing aridity, the balance between naturally co-existing forest and grassland patches is expected to shift towards grassland dominance in the long run, although feedback mechanisms and changes in land-use may alter this process. In this study, we compared old and recent aerial photographs of Hungarian forest-steppes to find out whether and how the forest proportion and the number of forest patches change at the decadal time scale. The percentage area covered by forest significantly increased in all study sites. The observed forest encroachment may be a legacy from earlier land-use: due to ceased or reduced grazing pressure, forests are invading grasslands until the potential forest cover allowed by climate and soil is reached. The number of forest patches significantly increased at one site (Fülöpháza), while it decreased at two sites (Bugac and Orgovány) and showed no significant change at the fourth site (Tázlár). This indicates that forest encroachment can happen at least in two different ways: through the emergence of new forest patches in the grassland, and through the extension and coalescence of already existing forest patches. Though the present work revealed increasing tree cover at a decadal time scale, the dynamic process should be monitored in the future to see how the vegetation reacts to further aridification. This could help devise a conservation strategy, as the woody/non-woody balance has a profound influence on basic ecosystem properties.
Homoharringtonine promotes non-small-cell lung cancer cell death via modulating HIF-1α/ERβ/E2F1 feedforward loop
Authors: Su Qi , Ren Jiayan , Chen Kun , Leong Sze Wei , Han Xu , Li Na , Wu Jianlin , Zhang Yanmin
Published: September 2024

Objectives

Hypoxia conditions promote the adaptation and progression of non-small-cell lung cancer (NSCLC) via hypoxia-inducible factors (HIF). HIF-1α may regulate estrogen receptor β (ERβ) and promote the progression of NSCLC. The phytochemical homoharringtonine (HHT) exerts strong inhibitory potency on NSCLC, with molecular mechanism under hypoxia being elusive.

Methods

The effects of HHT on NSCLC growth were determined by cell viability assay, colony formation, flow cytometry, and H460 xenograft models. Western blotting, molecular docking program, site-directed mutagenesis assay, immunohistochemical assay, and immunofluorescence assay were performed to explore the underlying mechanisms of HHT-induced growth inhibition in NSCLC.

Key findings

HIF-1α/ERβ signaling-related E2F1 is highly expressed and contributes to unfavorable survival and tumor growth. The findings in hypoxic cells, HIF-1α overexpressing cells, as well as ERβ- or E2F1-overexpressed and knockdown cells suggest that the HIF-1α/ERβ/E2F1 feedforward loop promotes NSCLC cell growth. HHT suppresses HIF-1α/ERβ/E2F1 signaling via the ubiquitin-proteasome pathway, which is dependent on the inhibition of the protein expression of HIF-1α and ERβ. Molecular docking and site-directed mutagenesis revealed that HHT binds to the GLU305 site of ERβ. HHT inhibits cell proliferation and colony formation and promotes apoptosis in both NSCLC cells and xenograft models.

Conclusion

The formation of the HIF-1α/ERβ/E2F1 feedforward loop promotes NSCLC growth and reveals a novel molecular mechanism by which HHT induces cell death in NSCLC.
Administrative border effects in COVID-19 related mortality
Authors: Berta Paolo , Bratti Massimiliano , Fiorio Carlo V , Pisoni Enrico , Verzillo Stefano
Published: September 2024

Lombardy, the first region in Italy to be hit by COVID-19 and one of the first in Western countries, was in the spotlight during the first wave of the pandemic in 2020 due to its high mortality rates. Simple regional comparisons are, however, hampered by potentially unobservable variables affecting mortality, such as the virus spread. To address this ‘unobserved heterogeneity’ concern, we adopt a Difference in Geographic Regression Discontinuity Design (DiD-GRDD), which compares 2020 vs. 2017–2019 excess mortality in Lombardy’s municipalities close to the administrative borders with neighbouring municipalities in other regions. Our study documents a one to two percentage point higher excess mortality in Lombardy limited to the oldest age group (81+). An exploratory mediation analysis points to the management of nursing homes during the pandemic as a possible critical factor explaining higher mortality in Lombardy.
Nonparametric estimation via partial derivatives
Authors: Dai Xiaowu
Published: September 2024

Traditional nonparametric estimation methods often lead to a slow convergence rate in large dimensions and require unrealistically large dataset sizes for reliable conclusions. We develop an approach based on partial derivatives, either observed or estimated, to effectively estimate the function at near-parametric convergence rates. This novel approach and computational algorithm could lead to methods useful to practitioners in many areas of science and engineering. Our theoretical results reveal behaviour universal to this class of nonparametric estimation problems. We explore a general setting involving tensor product spaces and build upon the smoothing spline analysis of variance framework. For d-dimensional models under full interaction, the optimal rates with gradient information on p covariates are identical to those for the (d−p)-interaction models without gradients and, therefore, the models are immune to the curse of interaction. For additive models, the optimal rates using gradient information are n, thus achieving the parametric rate. We demonstrate aspects of the theoretical results through synthetic and real data applications.
Analyzing Potential Non-Ignorable Selection Bias in an Off-Wave Mail Survey Implemented in a Long-Standing Panel Study
Authors: Schroeder Heather M , West Brady T
Published: September 2024

Typical design-based methods for weighting probability samples rely on several assumptions, including the random selection of sampled units according to known probabilities of selection and ignorable unit nonresponse. If any of these assumptions are not met, weighting methods that account for the probabilities of selection, nonresponse, and calibration may not fully account for the potential selection bias in a given sample, which could produce misleading population estimates. This analysis investigates possible selection bias in the 2019 Health Survey Mailer (HSM), a sub-study of the longitudinal Health and Retirement Study (HRS). The primary HRS data collection has occurred in “even” years since 1992, but additional survey data collections take place in the “off-wave” odd years via mailed invitations sent to selected participants. While the HSM achieved a high response rate (83 percent), the assumption of ignorable probability-based selection of HRS panel members may not hold due to the eligibility criteria that were imposed. To investigate this possible non-ignorable selection bias, our analysis utilizes a novel analysis method for estimating measures of unadjusted bias for proportions (MUBP), introduced by Andridge et al. in 2019. This method incorporates aggregate information from the larger HRS target population, including means, variances, and covariances for key covariates related to the HSM variables, to inform estimates of proportions. We explore potential non-ignorable selection bias by comparing proportions calculated from the HSM under three conditions: ignoring HRS weights, weighting based on the usual design-based approach for HRS “off-wave” mail surveys, and using the MUBP adjustment. We find examples of differences between the weighted and MUBP-adjusted estimates in four out of ten outcomes we analyzed. However, these differences are modest, and while this result gives some evidence of non-ignorable selection bias, typical design-based weighting methods are sufficient for correcting for it and their use is appropriate in this case.
HIV-1 usurps mixed-charge domain-dependent CPSF6 phase separation for higher-order capsid binding, nuclear entry and viral DNA integration
Authors: Jang Sooin , Bedwell Gregory J , Singh Satya P , Yu Hyun Jae , Arnarson Bjarki , Singh Parmit K , Radhakrishnan Rajalingam , Douglas AidanDarian W , Ingram Zachary M , Freniere Christian , Akkermans Onno , Sarafianos Stefan G , Ambrose Zandrea , Xiong Yong , Anekal Praju V , Montero Llopis Paula , KewalRamani Vineet N , Francis Ashwanth C , Engelman Alan N
Published: September 2024

HIV-1 integration favors nuclear speckle (NS)-proximal chromatin and viral infection induces the formation of capsid-dependent CPSF6 condensates that colocalize with nuclear speckles (NSs). Although CPSF6 displays liquid-liquid phase separation (LLPS) activity in vitro, the contributions of its different intrinsically disordered regions, which includes a central prion-like domain (PrLD) with capsid binding FG motif and C-terminal mixed-charge domain (MCD), to LLPS activity and to HIV-1 infection remain unclear. Herein, we determined that the PrLD and MCD both contribute to CPSF6 LLPS activity in vitro. Akin to FG mutant CPSF6, infection of cells expressing MCD-deleted CPSF6 uncharacteristically arrested at the nuclear rim. While heterologous MCDs effectively substituted for CPSF6 MCD function during HIV-1 infection, Arg-Ser domains from related SR proteins were largely ineffective. While MCD-deleted and wildtype CPSF6 proteins displayed similar capsid binding affinities, the MCD imparted LLPS-dependent higher-order binding and co-aggregation with capsids in vitro and in cellulo. NS depletion reduced CPSF6 puncta formation without significantly affecting integration into NS-proximal chromatin, and appending the MCD onto a heterologous capsid binding protein partially restored virus nuclear penetration and integration targeting in CPSF6 knockout cells. We conclude that MCD-dependent CPSF6 condensation with capsids underlies post-nuclear incursion for viral DNA integration and HIV-1 pathogenesis.
A single rare σ70 variant establishes a unique gene expression pattern in the E. coli pathobiont LF82
Authors: Arroyo-Mendoza Melissa , Proctor Alexandra , Correa-Medina Abraham , DeWolf Sarah , Brand Meghan Wymore , Rosas Virginia , Lorenzi Hernan , Wannemuehler Michael J , Phillips Gregory J , Hinton Deborah M
Published: September 2024

LF82, an adherent-invasive Escherichia coli (AIEC) pathobiont, is associated with Crohn's disease, an inflammatory bowel disease of unknown etiology. Although AIEC phenotypes differ from those of ‘commensal’ or pathogenic E. coli, work has failed to identify genetic features accounting for these differences. We have investigated a natural, but rare, single nucleotide polymorphism (SNP) in LF82 present within the highly conserved rpoD gene, encoding σ70 [primary sigma factor, RNA polymerase (RNAP)]. We demonstrate that σ70 D445V results in transcriptomic and phenotypic changes consistent with LF82 phenotypes, including increased antibiotic resistance and biofilm formation and increased capacity for methionine biosynthesis. RNA-seq analyses comparing σ70 V445 versus σ70 D445 identified 24 genes upregulated by σ70 V445 in both LF82 and the laboratory E. coli K-12 strain MG1655. Using in vitro transcription, we demonstrate that σ70 D445V directly increases transcription from promoters for several of the up-regulated genes and that the presence of a 16 bp spacer and -14 G:C is associated with this increase. The position of D445V within RNAP suggests that it could affect RNAP/spacer interaction. Our work represents the first identification of a distinguishing SNP for this pathobiont and suggests an underrecognized mechanism by which pathobionts and strain variants can emerge.
Biology of calcium homeostasis regulation in intestine and kidney
Authors: Deluque Amanda Lima , Dimke Henrik , Alexander R Todd
Published: September 2024

Calcium (Ca2+) is an essential divalent cation involved in many bodily functions including bone composition, cell growth and division, blood clotting, and muscle contraction. The bone, intestine and kidneys are important for the maintenance of Ca2+ homeostasis. Ninety-nine percent of body Ca2+ is stored in the skeleton as hydroxyapatite. The small, and to a lesser extent the large intestine absorbs Ca2+ from the diet. Once in the circulation, Ca2+ is filtered by the glomerulus and the majority, >95%, is reabsorbed along the nephron. The remainder is excreted in the urine. Two general (re)absorptive pathways contribute to the vectorial transport of Ca2+ across renal and intestinal epithelia: (i) a paracellular pathway, which is reliant on claudins in the tight junction of epithelium and the electrochemical gradient, and (ii) a transcellular pathway, which requires different influx, intracellular buffering/shuttling and basolateral efflux mechanisms, to actively transport Ca2+ across the epithelial cell. Blood Ca2+ levels are maintained by hormones including parathyroid hormone, 1,25-dihydroxyvitamin D3 and fibroblast growth factor 23, and through effects of Ca2+-sensing receptor (CaSR) signaling. Disruption of Ca2+ homeostasis can result in altered blood Ca2+ levels and/or hypercalciuria, the latter is a phenomenon closely linked to the formation of kidney stones. Genetic alterations affecting renal Ca2+ handling can cause hypercalciuria, an area of expanding investigation. This review explores the molecular mechanisms governing Ca2+ homeostasis by the intestine and kidneys and discusses clinical aspects of genetic disorders associated with Ca2+-based kidney stone disease.