bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic models of fibrillinopathies
Authors: Summers Kim M
Published: November 2023

The fibrillinopathies represent a group of diseases in which the 10–12 nm extracellular microfibrils are disrupted by genetic variants in one of the genes encoding fibrillin molecules, large glycoproteins of the extracellular matrix. The best-known fibrillinopathy is Marfan syndrome, an autosomal dominant condition affecting the cardiovascular, ocular, skeletal, and other systems, with a prevalence of around 1 in 3,000 across all ethnic groups. It is caused by variants of the FBN1 gene, encoding fibrillin-1, which interacts with elastin to provide strength and elasticity to connective tissues. A number of mouse models have been created in an attempt to replicate the human phenotype, although all have limitations. There are also natural bovine models and engineered models in pig and rabbit. Variants in FBN2 encoding fibrillin-2 cause congenital contractural arachnodactyly and mouse models for this condition have also been produced. In most animals, including birds, reptiles, and amphibians, there is a third fibrillin, fibrillin-3 (FBN3 gene) for which the creation of models has been difficult as the gene is degenerate and nonfunctional in mice and rats. Other eukaryotes such as the nematode C. elegans and zebrafish D. rerio have a gene with some homology to fibrillins and models have been used to discover more about the function of this family of proteins. This review looks at the phenotype, inheritance, and relevance of the various animal models for the different fibrillinopathies.
“A Soft Death”: Perceptions and Attitudes Toward Palliative Care in Senegal
Authors: Silverstein Hannah I , Sahawneh Fursan , Carpenter Brian D
Published: November 2023

Background and Objectives

Palliative care (PC) is a specialty medical service that aims to address the bio-psycho-social–spiritual needs of patients with serious illnesses and their care partners. Despite the value of PC, its expansion in Sub-Saharan Africa has been uneven and particularly underdeveloped in Senegal due to variability in access to training resources and funding. This study sought to understand the current landscape of PC services in Senegal and the barriers and opportunities in its growth.

Research Design and Methods

Semistructured interviews were conducted with six PC clinicians, four caregivers of people with serious illnesses, one driver for a PC service, and one public health professor, all native to Senegal. Questions addressed their experience delivering or receiving PC, perceptions of barriers to implementation and access, and recommendations for additional resources and initiatives. Interviews were translated and transcribed from French into English. Transcripts were qualitatively coded for concepts during open and focused coding to identify themes.

Results

Five themes were identified: (1) the current landscape of PC, (2) barriers to implementing PC, (3) strategies and philosophies in care, (4) unique features of Senegalese culture, and (5) the future of PC.

Discussion and Implications

Our findings demonstrate that PC in Senegal remains an underresourced and underutilized specialty medical service, but work is being done by personally committed clinicians. Results can inform PC expansion by highlighting important cultural factors influencing care in Senegal, as well as the need to expand training opportunities for clinicians, increase education of other medical providers and the public about the nature of PC, integrate PC into the healthcare system, and expand research to evaluate the impact of these resources. PC has the potential to be an important force for improving the quality of life for Senegalese patients and their care partners.
HIV Prevention Among Men Who Have Sex With Men: Tenofovir Alafenamide Combination Preexposure Prophylaxis Versus Placebo
Authors: Zivich Paul N , Cole Stephen R , Edwards Jessie K , Glidden David V , Das Moupali , Shook-Sa Bonnie E , Shao Yongwu , Mehrotra Megha L , Adimora Adaora A , Eron Joseph J
Published: November 2023

Background

While noninferiority of tenofovir alafenamide and emtricitabine (TAF/FTC) as preexposure prophylaxis (PrEP) for the prevention of human immunodeficiency virus (HIV) has been shown, interest remains in its efficacy relative to placebo. We estimate the efficacy of TAF/FTC PrEP versus placebo for the prevention of HIV infection.

Methods

We used data from the DISCOVER and iPrEx trials to compare TAF/FTC to placebo. DISCOVER was a noninferiority trial conducted from 2016 to 2017. iPrEx was a placebo-controlled trial conducted from 2007 to 2009. Inverse probability weights were used to standardize the iPrEx participants to the distribution of demographics and risk factors in the DISCOVER trial. To check the comparison, we evaluated whether risk of HIV infection in the shared tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) arms was similar.

Results

Notable differences in demographics and risk factors occurred between trials. After standardization, the difference in risk of HIV infection between the TDF/FTC arms was near zero. The risk of HIV with TAF/FTC was 5.8 percentage points lower (95% confidence interval [CI], −2.0% to −9.6%) or 12.5-fold lower (95% CI, .02 to .31) than placebo standardized to the DISCOVER population.

Conclusions

There was a reduction in HIV infection with TAF/FTC versus placebo across 96 weeks of follow-up.

Clinical Trials Registration

NCT02842086 and NCT00458393.
Prospective Assessment of Humoral and Cellular Immune Responses to a Third COVID-19 mRNA Vaccine Dose Among Immunocompromised Individuals
Authors: Haidar Ghady , Hodges Jacob C , Bilderback Andrew , Lukanski Amy , Linstrum Kelsey , Postol Barbara , Troyan Rachel , Wisniewski Mary K , Coughenour Lindsay , Heaps Amy , Jacobs Jana L , Hughes Kramer Kailey , Klamar-Blain Cynthia , Kohl Joshua , Liang Wendy , Morris Benjamin , Macatangay Bernard J C , Parikh Urvi M , Sobolewksi Michele D , Musgrove Christopher , Crandall Melissa D , Mahon John , Mulvey Katie , Collins Kevin , King Adam C , Wells Alan , Zapf Rachel , Agha Mounzer , Minnier Tami , Angus Derek C , Mellors John W
Published: November 2023

Background

Improved coronavirus disease 2019 (COVID-19) prevention is needed for immunocompromised individuals.

Methods

A prospective study was performed of health care workers (HCW) and immunocompromised participants with baseline serology following 2 mRNA vaccine doses and who were retested after dose 3 (D3); multivariable regression was used to identify predictors of serological responses. IFN-γ/TNF-α T-cell responses were assessed in a subset.

Results

In total, 536 participants were included: 492 immunocompromised (206 solid organ transplant [SOT], 128 autoimmune, 80 hematologic malignancy [HM], 48 solid tumor, 25 HIV), and 44 HCW. D3 significantly increased spike IgG levels among all, but SOT and HM participants had the lowest median antibody levels post-D3 (increase from 0.09 to 0.83 and 0.27 to 1.92, respectively), versus HCW and persons with HIV, autoimmune conditions, and solid tumors (increases from 4.44 to 19.79, 2.9 to 15.75, 3.82 to 16.32, and 4.1 to 25.54, respectively). Seropositivity post-D3 was lowest for SOT (49.0%) and HM (57.8%), versus others (>90%). Neutralization post-D3 was lowest among SOT and HM. Predictors of lower antibody levels included low baseline levels and shorter intervals between vaccines. T-cell responses against spike increased significantly among HCW and nonsignificantly among immunocompromised individuals.

Conclusions

D3 significantly improves serological but not T-cell responses among immunocompromised individuals. SOT and HM patients have suboptimal responses to D3.
Financial cooperation in the Asia-Pacific as regime complex: explaining patterns of coverage, membership, and rules
Authors: Grimes William W , Lee Yaechan , Kring William N
Published: November 2023

Since the 1997 Asian Financial Crisis, East Asia has gone from having virtually no regional financial cooperation to having multiple cooperative arrangements. This article focuses on the issue area of emergency liquidity provision, where global (International Monetary Fund), regional (Chiang Mai Initiative Multilateralization), and bilateral arrangements co-exist and overlap in complicated ways, forming a regime complex. While the overall system offers more options and greater funding than were available in 1997, it also raises questions about how those levels will operate in a crisis. This article shows how national preferences of likely creditor and likely borrower countries have interacted to create the current regime complex, as well as the political compromises and remaining uncertainties about how they will work together. It argues that the evolution and current shape of the regime complex have been driven by the efforts of key states to take advantage of or thwart power asymmetries.
UK clinicians’ attitudes towards the application of molecular diagnostics to guide antibiotic use in ICU patients with pneumonias: a quantitative study
Authors: Stewart Sarah-Jane F , Pandolfo Alyssa M , Moon Zoe , Jani Yogini , Brett Stephen J , Brealey David , Singh Suveer , Enne Virve I , Livermore David M , Gant Vanya , Horne Robert
Published: November 2023

Background

Molecular diagnostic tests may improve antibiotic prescribing by enabling earlier tailoring of antimicrobial therapy. However, clinicians’ trust and acceptance of these tests will determine their application in practice.

Objectives

To examine ICU prescribers’ views on the application of molecular diagnostics in patients with suspected hospital-acquired and ventilator-associated pneumonia (HAP/VAP).

Methods

Sixty-three ICU clinicians from five UK hospitals completed a cross-sectional questionnaire between May 2020 and July 2020 assessing attitudes towards using molecular diagnostics to inform initial agent choice and to help stop broad-spectrum antibiotics early.

Results

Attitudes towards using molecular diagnostics to inform initial treatment choices and to stop broad-spectrum antibiotics early were nuanced. Most (83%) were positive about molecular diagnostics, agreeing that using results to inform broad-spectrum antibiotic prescribing is good practice. However, many (58%) believed sick patients are often too unstable to risk stopping broad-spectrum antibiotics based on a negative result.

Conclusions

Positive attitudes towards the application of molecular diagnostics to improve antibiotic stewardship were juxtapositioned against the perceived need to initiate and maintain broad-spectrum antibiotics to protect unstable patients.
Cartel leniency programme in India—why no race here?
Authors: T.S. Somashekar , Tripathi Praveen
Published: November 2023

This article evaluates the implementation of the cartel leniency programme by the Competition Commission of India (CCI) using comprehensive data covering all related decisions of the CCI from 2009 to 2021. All other things remaining the same prima facie discoveries of cartels should have resulted in a ‘shock’ to ex ante expected returns of cartels, thereby encouraging more leniency applications. But, we find no such results or rather no ‘race’ to the agency. A successful leniency programme requires a transparent and deterrent penalty, plus consistency in applying leniency provisions. However, inconsistencies in the choice of penalty base and uncertainties in determining final penalties while using mitigating and aggravating factors have led to a poor correlation of penalties with cartel gain or harm. Strategic or otherwise, this has encouraged appeals to the appellate authority, thereby reducing the effective penalty to levels below deterrence. Many acts of bid rigging have been penalized using less stringent criteria and, in a few circumstances, also provided the benefit of leniency. Further, while individuals concerned in leniency cases have always been penalized, the CCI has not been so consistent in non-leniency cartel cases. These asymmetries and ‘other’ costs create disincentives for exercising the leniency option. We offer suggestions for enhancing the possibility of a race to the agency.
Fungal composition, quantification of mycotoxins, and enzyme activity in processed Solanum tuberosum Linn (potato) products stored at different relative humidity
Authors: Danladi Margaret M A , Ogbonna Chike I C , Ogbonna Abigail I , Giles Cindy , Fletcher Mary T , Akinsanmi Olufemi A
Published: November 2023

Aim

Postharvest loss of potatoes at the peak of harvest is of global concern. This study aimed to determine the quality of stored processed potato products based on fungal composition, mycotoxin contamination, and fungal enzyme activity.

Materials and methods

Potato products from three cultivars (Caruso, Marabel, and Nicola) were grouped as peeled or unpeeled, oven- or sun-dried, and all samples were in flour form. Samples were incubated separately for 6 weeks at 25%, 74%, and 87% relative humidities (RH) at 25°C. The pH, moisture content (MC), visible deterioration, mycotoxin, fungal identity by DNA sequencing, and enzyme activity were determined.

Results

Results of grouped products (based on variety, drying, and peeling method) revealed that MC increased in the oven-dried samples and the pH value reduced after incubation. About 26% of the products at 87% RH showed visible deterioration, low amounts of fumonisin were detected in fermented potato product and nine fungal genera were identified across the three RH levels. Enzyme activities by Aspergillus niger, Fusarium circinatum, and Rhizopus stolonifer isolates were confirmed.

Conclusion

RH influenced deterioration and fungal activities in some stored processed potato products. Low levels of fumonisin were detected.
Dietary supplementation with lysine (protein) in late pregnancy does not enhance mammary development in multiparous sows
Authors: Farmer Chantal , Gillies Caroline , Johannsen Jakob C , Hovey Russell C , Huber Lee-Anne
Published: November 2023

This project was conducted to determine if providing standardized ileal digestible (SID) Lys at 40% above estimated requirements (NRC, 2012), with the concomitant increased protein intake, from days 90 to 110 of gestation stimulates mammary development in multiparous sows. From day 90 of gestation, Yorkshire × Landrace multiparous sows (parities 2 and 3) were fed 2.6 kg/d of either a conventional diet (CTL, control, n = 17) providing 14.8 g/d of SID Lys or a diet providing 20.8 g/d of SID Lys via additional soybean meal (HILYS, n = 16). The diets were isoenergetic. Concentrations of IGF-1, glucose, free fatty acids (FFA), urea, and amino acids (AA) were measured in jugular blood samples obtained on days 90 and 110 of gestation. Sows were necropsied on day 110 ± 1 of gestation to obtain mammary glands for compositional and histological analyses. Backfat or BW changes of sows during late gestation were unaffected by treatment (P > 0.10), as was the case for fetal BW (P > 0.10). None of the variables measured in mammary tissue were altered by supplementary Lys (P > 0.10). Circulating IGF-1, glucose, and FFA did not differ (P > 0.10) between HILYS and CTL sows on day 110 of gestation, whereas concentrations of urea were greater (P < 0.01) in HILYS versus CTL gilts. Concentrations of Ile and Thr in plasma were also greater (P < 0.05), and those of Glu were lower (P < 0.01) in HILYS than CTL sows. These results demonstrate that feeding Lys (via protein) above current NRC recommendations during late gestation does not improve mammary development of multiparous sows. Hence, the use of a two-phase feeding strategy to provide more Lys (protein) to multiparous sows during this period is not necessary.
Impact of ACCELERATE Paediatric Strategy Forums: a review of the value of multi-stakeholder meetings in oncology drug development
Authors: Pearson Andrew D J , de Rojas Teresa , Karres Dominik , Reaman Gregory , Scobie Nicole , Fox Elizabeth , Lesa Giovanni , Ligas Franca , Norga Koen , Nysom Karsten , Pappo Alberto , Weigel Brenda , Weiner Susan L , Vassal Gilles
Published: November 2023

In a landscape of an increasing number of products and histology and age agnostic trials for rare patient cancer, prioritization of products is required. Paediatric Strategy Forums, organized by ACCELERATE and the European Medicines Agency with participation of the US Food and Drug Administration, are multi-stakeholder meetings that share information to best inform pediatric drug development strategies and subsequent clinical trial decisions. Academia, industry, regulators, and patient advocates are equal members, with patient advocates highlighting unmet needs of children and adolescents with cancer. The 11 Paediatric Strategy Forums since 2017 have made specific and general conclusions to accelerate drug development. Conclusions on product prioritization meetings, as well as global master protocols, have been outputs of these meetings. Forums have provided information for regulatory discussions and decisions by industry to facilitate development of high-priority products; for example, 62% of high-priority assets (agreed at a Forum) in contrast to 5% of those assets not considered high priority have been the subject of a Paediatric Investigational Plan or Written Request. Where there are multiple products of the same class, Forums have recommended a focused and sequential approach. Class prioritization resulted in an increase in waivers for non-prioritized B-cell products (44% to 75%) and a decrease in monotherapy trials, proposed in Paediatric Investigation Plans (PIP) submissions of checkpoint inhibitors from 53% to 19%. Strategy Forums could play a role in defining unmet medical needs. Multi-stakeholder forums, such as the Paediatric Strategy Forum, serve as a model to improve collaboration in the oncology drug development paradigm.
Opioid tapering in older cancer survivors does not increase psychiatric or drug hospitalization rates
Authors: Riviere Paul , Morgan Kylie M , Deshler Leah N , Huang Xinyi , Marienfeld Carla , Coyne Christopher J , Rose Brent S , Murphy James D
Published: November 2023

Background

Opioid tapering in the general population is linked to increases in hospitalizations or emergency department visits related to psychiatric or drug-related diagnoses. Cancer survivors represent a unique population with different opioid indications, prescription patterns, and more frequent follow-up care. This study sought to describe patterns of opioid tapering among older cancer survivors and to test the hypothesis of whether older cancer survivors face increased risks of adverse events with opioid tapering.

Methods

Using the Surveillance, Epidemiology and End Results Medicare–linked database, we identified 15 002 Medicare-beneficiary cancer survivors diagnosed between 2010 and 2017 prescribed opioids consistently for at least 6 months after their cancer diagnosis. Tapering was defined as a binary time-varying event occurring with any monthly oral morphine equivalent reduction of 15% or more from the previous month. Primary diagnostic billing codes associated with emergency room or hospital admissions were used for the composite endpoint of psychiatric- or drug-related event(s).

Results

There were 3.86 events per 100 patient-months, with 97.8% events being mental health emergencies, 1.91% events being overdose emergencies, and 0.25% involving both. Using a generalized estimating equation for repeated measure time-based analysis, opioid tapering was not statistically associated with acute events in the 3-month posttaper period (odds ratio [OR] = 1.02; P = .62) or at any point in the future (OR = 0.96; P = .46).

Conclusions

Opioid tapering in older cancer survivors does not appear to be linked to a higher risk of acute psychiatric- or drug-related events, in contrast to prior research in the general population.
Comprehensive causes of death in uveal melanoma: mortality in 1530 consecutively diagnosed patients followed until death
Authors: Stålhammar Gustav
Published: November 2023

Background

Uveal melanoma has a high propensity for metastatic spread. Yet, the comprehensive causes of death in a large consecutive cohort followed from diagnosis to death remain unknown.

Methods

All Swedish patients diagnosed with melanoma involving the iris, choroid, and/or ciliary body after January 1, 1960, were assessed for this study. Sequential inclusion was halted upon encountering the first surviving patient during data collection. Causes of death were collected from the National Cause of Death Registry and audited by analysis of up to 15 causative diagnoses.

Results

A total of 1530 patients were included, each histopathologically verified with primary uveal melanoma. Mortality from metastatic uveal melanoma was 31% at 5 years, 40% at 10 years, 45% at 20 years, 47% at 30 years, and 48% between 40 and 60 years post-diagnosis. Notably, the longest period between diagnosis and metastatic fatality was 49.6 years. Additionally, 186 other causes of death were recorded, with cardiovascular diseases constituting 26%, other cancers 10%, stroke 6%, dementias 2%, and lower respiratory infections 2% of total mortalities. Mortality from colorectal, lung, prostate, and stomach carcinomas over 60 years were 1.4%, 1.4%, 1.2%, and 0.9%, with metastatic uveal melanoma being the leading cumulative and annual cause of death for the initial 41 and 5 years post-diagnosis, respectively.

Conclusions

In this large consecutive cohort, half of the included patients ultimately succumbed to metastatic uveal melanoma, with deaths occurring up to 50 years after diagnosis. One-quarter and one-tenth of patients died from cardiovascular diseases and other cancers, respectively.
A catalogue of planetary nebulae chemical abundances in the Galactic bulge
Authors: Tan Shuyu , Parker Quentin A , Zijlstra Albert A , Rees Bryan
Published: November 2023

In this paper, the third of a series of papers, we present well-determined chemical abundances for 124 planetary nebulae (PNe) in the Galactic bulge from deep, long-slit FORS2 spectra from the 8.2 m ESO Very Large telescope (VLT). Prior to this work there were only ∼240 bulge PNe with chemical abundances previously determined over a ∼50 yr period and of highly variable quality. For 34 of these PNe we are presenting their abundances for the first time, which adds ∼14 per cent to the available sample of bulge PNe abundances. The interstellar reddening, physical conditions (electron densities, ne, temperatures, Te), and chemical compositions are derived as single values for each PN but also using different line diagnostics. Selected comparisons with the best literature fluxes for 75 PNe in common reveal that these significant new data are robust, reliable, and internally self-consistent forming the largest independent, high-quality, and well-understood derivation of PNe abundances currently available for study.
Evidence for a black hole in the historical X-ray transient A 1524-61 (= KY TrA)
Authors: Yanes-Rizo I V , Torres M A P , Casares J , Monelli M , Jonker P G , Abbot T , Armas Padilla M , Muñoz-Darias T
Published: November 2023

We present Very Large Telescope spectroscopy, high-resolution imaging, and time-resolved photometry of KY TrA, the optical counterpart to the X-ray binary A 1524-61. We perform a refined astrometry of the field, yielding improved coordinates for KY TrA and the field star interloper of similar optical brightness that we locate 0.64 ± 0.04 arcsec SE. From the spectroscopy, we refine the radial velocity semi-amplitude of the donor star to K2 = 501 ± 52 km s−1 by employing the correlation between this parameter and the full width at half-maximum of the H α emission line. The r-band light curve shows an ellipsoidal-like modulation with a likely orbital period of 0.26 ± 0.01 d (6.24 ± 0.24 h). These numbers imply a mass function f(M1) = 3.2 ± 1.0 M⊙. The KY TrA de-reddened quiescent colour (r − i)0 = 0.27 ± 0.08 is consistent with a donor star of spectral type K2 or later, in case of significant accretion disc light contribution to the optical continuum. The colour allows us to place a very conservative upper limit on the companion star mass, M2 ≤ 0.94 M⊙, and, in turn, on the binary mass ratio, q = M2/M1 ≤ 0.31. By exploiting the correlation between the binary inclination and the depth of the H α line trough, we establish i = 57 ± 13 deg. All these values lead to a compact object and donor mass of $M_1 = 5.8^{+3.0}_{-2.4}$$\, M_\odot$ and M2 = 0.5 ± 0.3 M⊙, thus confirming the black hole nature of the accreting object. In addition, we estimate a distance towards the system of 8.0 ± 0.9 kpc.
Shedding light on a species complex within the genus Goniodoridella Pruvot-Fol, 1933 (Nudibranchia: Goniodorididae), with the description of three new species
Authors: Paz-Sedano Sofía , Ekimova Irina , Smirnoff Dimitri , Gosliner Terrence M , Pola Marta
Published: November 2023

Goniodoridella Pruvot-Fol, 1933 is a genus of small nudibranchs found in the Indo-Pacific Ocean. Currently, the genus includes only two described species, the widely distributed type species Goniodoridella savignyi Pruvot-Fol, 1933 and G. borealis Martynov, Sanamyan & Korshunova, 2015, which is found in the northern Sea of Japan. However, because of the presence of a group of cryptic species, the known geographic range of G. savignyi may have been overestimated, while the species richness of the genus may be underestimated. In the current study, we examined specimens from Australia, the Philippines and Russia that were identified as G. savignyi, G. borealis and an undescribed species. Detailed analyses of the external morphology and internal anatomy of the specimens were carried out, as well as scanning electron micrography of the radula and the labial cuticle. Photographs of the penial spines were taken under a light microscope. DNA sequence data for selected mitochondrial and nuclear markers were obtained, allowing the inclusion of the genus Goniodoridella in molecular phylogenetic analyses for the first time. Our results support the monophyly of the genus Goniodoridella and confirm the existence of a species complex of which the type is G. savignyi. The new species G. geminae n. sp., G. serrata n. sp. and G. unidonta n. sp. are described.
Long or short? Telomere length and pancreatic cancer and its precursor lesions, a narrative review
Authors: Campa Daniele , Felici Alessio , Corradi Chiara , Peduzzi Giulia , Gentiluomo Manuel , Farinella Riccardo , Rizzato Cosmeri
Published: November 2023

Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal form of pancreatic cancer, with a survival approaching only 11% at 5 years after diagnosis. In the last 15 years, telomere length (TL) measured in leukocyte (LTL) has been studied in relation to PDAC risk. The majority of the studies reported an association between short LTL and increased PDAC risk, but the results are heterogeneous. Genome-wide association studies have identified several single-nucleotide polymorphisms (SNPs) in the telomerase reverse transcriptase (TERT) gene as susceptibility loci for PDAC. Polygenic risk scores computed using SNPs associated with LTL have been tested in relation to PDAC susceptibility with various methods and giving contrasting results. The aim of this review is to analyze all publications carried out specifically on LTL, considering LTL measured with qPCR and with genetic proxies, and PDAC risk. Additionally, we will give an overview of the most relevant associations between SNPs in telomere-associated genes and PDAC, to answer the question shorter or longer? Which one of the two is associated with PDAC risk?
RegulonDB v12.0: a comprehensive resource of transcriptional regulation inE. coliK-12
Authors: Salgado Heladia , Gama-Castro Socorro , Lara Paloma , Mejia-Almonte Citlalli , Alarcón-Carranza Gabriel , López-Almazo Andrés G , Betancourt-Figueroa Felipe , Peña-Loredo Pablo , Alquicira-Hernández Shirley , Ledezma-Tejeida Daniela , Arizmendi-Zagal Lizeth , Mendez-Hernandez Francisco , Diaz-Gomez Ana K , Ochoa-Praxedis Elizabeth , Muñiz-Rascado Luis J , García-Sotelo Jair S , Flores-Gallegos Fanny A , Gómez Laura , Bonavides-Martínez César , del Moral-Chávez Víctor M , Hernández-Alvarez Alfredo J , Santos-Zavaleta Alberto , Capella-Gutierrez Salvador , Gelpi Josep Lluis , Collado-Vides Julio
Published: November 2023

RegulonDB is a database that contains the most comprehensive corpus of knowledge of the regulation of transcription initiation of Escherichia coli K-12, including data from both classical molecular biology and high-throughput methodologies. Here, we describe biological advances since our last NAR paper of 2019. We explain the changes to satisfy FAIR requirements. We also present a full reconstruction of the RegulonDB computational infrastructure, which has significantly improved data storage, retrieval and accessibility and thus supports a more intuitive and user-friendly experience. The integration of graphical tools provides clear visual representations of genetic regulation data, facilitating data interpretation and knowledge integration. RegulonDB version 12.0 can be accessed at https://regulondb.ccg.unam.mx.
Endothelial to mesenchymal transition in kidney fibrosis
Authors: Jacobs Marleen E , de Vries Dorottya K , Engelse Marten A , Dumas Sébastien J , Rabelink Ton J
Published: November 2023

Fibrotic diseases are characterized by the uncontrolled accumulation of extracellular matrix (ECM) components leading to disruption of tissue homeostasis. Myofibroblasts as the main ECM-producing cells can originate from various differentiated cell types after injury. Particularly, the process of endothelial-to-mesenchymal transition (endMT), describing phenotypic shifts of endothelial cells to adopt a fully mesenchymal identity, may contribute to the pool of myofibroblasts in fibrosis, while leading to capillary rarefaction and exacerbation of tissue hypoxia. In renal disease, incomplete recovery from acute kidney injury (AKI) and the ensuing fibrotic reaction stand out as major contributors to chronic kidney disease (CKD) development. While the focus has largely been on impaired tubular epithelial repair as a potential fibrosis-driving mechanism, alterations in the renal microcirculation post-AKI, and in particular endMT as a maladaptive response, could hold equal significance. Dysfunctional interplays among various cell types in the kidney microenvironment can instigate endMT. Transforming growth factor beta (TGF-β) signaling, with its downstream activation of canonical/Smad-mediated and non-canonical pathways, has been identified as primary driver of this process. However, non-TGF-β-mediated pathways involving inflammatory agents and metabolic shifts in intercellular communication within the tissue microenvironment can also trigger endMT. These harmful, maladaptive cell–cell interactions and signaling pathways offer potential targets for therapeutic intervention to impede endMT and decelerate fibrogenesis such as in AKI–CKD progression. Presently, partial reduction of TGF-β signaling using anti-diabetic drugs or statins may hold therapeutic potential in renal context. Nevertheless, further investigation is warranted to validate underlying mechanisms and assess positive effects within a clinical framework.
Development of a Prognostic Model for Early Breast Cancer Integrating Neutrophil to Lymphocyte Ratio and Clinical-Pathological Characteristics
Authors: Faria Sara Socorro , Giannarelli Diana , Cordeiro de Lima Vladmir Claudio , Anwar Sumadi Luckman , Casadei Chiara , De Giorgi Ugo , Madonna Gabriele , Ascierto Paolo Antonio , Mendoza López Rossana Veronica , Chammas Roger , Capone Mariaelena
Published: November 2023

Background

Breast cancer-related inflammation is critical in tumorigenesis, cancer progression, and patient prognosis. Several inflammatory markers derived from peripheral blood cells count, such as the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), and systemic immune-inflammation index (SII) are considered as prognostic markers in several types of malignancy.

Methods

We investigate and validate a prognostic model in early patients with breast cancer to predict disease-free survival (DFS) based on readily available baseline clinicopathological prognostic factors and preoperative peripheral blood-derived indexes.

Results

We analyzed a training cohort of 710 patients and 2 external validation cohorts of 980 and 157 patients with breast cancer, respectively, with different demographic origins. An elevated preoperative NLR is a better DFS predictor than others scores. The prognostic model generated in this study was able to classify patients into 3 groups with different risks of relapse based on ECOG-PS, presence of comorbidities, T and N stage, PgR status, and NLR.

Conclusion

Prognostic models derived from the combination of clinicopathological features and peripheral blood indices, such as NLR, represent attractive markers mainly because they are easily detectable and applicable in daily clinical practice. More comprehensive prospective studies are needed to unveil their actual effectiveness.
Risk of attention deficit hyperactivity disorder diagnosis following multiple exposures to general anesthesia in the paediatric population: A systematic review and meta-analysis
Authors: Skakum Megan , Katako Audrey , Mitchell-Dueck Jenna , Ricci M Florencia , Russell Kelly
Published: November 2023

Objectives

The risk of attention deficit hyperactivity disorder (ADHD) following multiple exposures to anesthesia has been debated. Our objective was to systematically review the literature to examine the association between multiple exposures to general anesthesia before age 5 and subsequent diagnosis of ADHD.

Methods

A systematic search of EMBASE, PubMed, and SCOPUS was performed using key search terms in February 2022. We included studies that: were published after 1980, included only otherwise healthy children who experienced two or more exposures to general anesthetic before age 5, diagnosed ADHD by a medical professional before age 19 years after exposure to general anesthetic, were cross-sectional, case–control, or cohort study, and were published in English. The results (expressed as hazard ratios [HR] and associated 95% confidence intervals [CI]) were pooled using meta-analytic techniques. Studies which did not present their results as HR and 95% CI were analyzed separately. GRADE was used to determine the certainty of the findings. PRISMA guidelines were followed at each stage of the review.

Results

Eight studies (196,749 children) were included. Five reported HR and 95% CI and were subsequently pooled for meta-analysis. Multiple exposures to anesthesia were associated with diagnosis of ADHD before the 19th year of life (HR: 1.71; 95% CI: 1.59, 1.84). Two of the three studies not used in the meta-analysis also found an increased risk of ADHD diagnosis following multiple anesthetic exposures.

Conclusions

There was an association between multiple early exposures to general anesthesia and later diagnosis of ADHD.
Variety of Plant Oils: Species-Specific Lipid Biosynthesis
Authors: Clews Alyssa C , Ulch Brandon A , Jesionowska Monika , Hong Jun , Mullen Robert T , Xu Yang
Published: November 2023

Plant oils represent a large group of neutral lipids with important applications in food, feed and oleochemical industries. Most plants accumulate oils in the form of triacylglycerol within seeds and their surrounding tissues, which comprises three fatty acids attached to a glycerol backbone. Different plant species accumulate unique fatty acids in their oils, serving a range of applications in pharmaceuticals and oleochemicals. To enable the production of these distinctive oils, select plant species have adapted specialized oil metabolism pathways, involving differential gene co-expression networks and structurally divergent enzymes/proteins. Here, we summarize some of the recent advances in our understanding of oil biosynthesis in plants. We compare expression patterns of oil metabolism genes from representative species, including Arabidopsis thaliana, Ricinus communis (castor bean), Linum usitatissimum L. (flax) and Elaeis guineensis (oil palm) to showcase the co-expression networks of relevant genes for acyl metabolism. We also review several divergent enzymes/proteins associated with key catalytic steps of unique oil accumulation, including fatty acid desaturases, diacylglycerol acyltransferases and oleosins, highlighting their structural features and preference toward unique lipid substrates. Lastly, we briefly discuss protein interactomes and substrate channeling for oil biosynthesis and the complex regulation of these processes.
A proxitome-RNA-capture approach reveals that processing bodies repress coregulated hub genes
Authors: Liu Chen , Mentzelopoulou Andriani , Hatzianestis Ioannis H , Tzagkarakis Epameinondas , Skaltsogiannis Vasileios , Ma Xuemin , Michalopoulou Vassiliki A , Romero-Campero Francisco J , Romero-Losada Ana B , Sarris Panagiotis F , Marhavy Peter , Bölter Bettina , Kanterakis Alexandros , Gutierrez-Beltran Emilio , Moschou Panagiotis N
Published: November 2023

Cellular condensates are usually ribonucleoprotein assemblies with liquid- or solid-like properties. Because these subcellular structures lack a delineating membrane, determining their compositions is difficult. Here we describe a proximity-biotinylation approach for capturing the RNAs of the condensates known as processing bodies (PBs) in Arabidopsis (Arabidopsis thaliana). By combining this approach with RNA detection, in silico, and high-resolution imaging approaches, we studied PBs under normal conditions and heat stress. PBs showed a much more dynamic RNA composition than the total transcriptome. RNAs involved in cell wall development and regeneration, plant hormonal signaling, secondary metabolism/defense, and RNA metabolism were enriched in PBs. RNA-binding proteins and the liquidity of PBs modulated RNA recruitment, while RNAs were frequently recruited together with their encoded proteins. In PBs, RNAs follow distinct fates: in small liquid-like PBs, RNAs get degraded while in more solid-like larger ones, they are stored. PB properties can be regulated by the actin-polymerizing SCAR (suppressor of the cyclic AMP)-WAVE (WASP family verprolin homologous) complex. SCAR/WAVE modulates the shuttling of RNAs between PBs and the translational machinery, thereby adjusting ethylene signaling. In summary, we provide an approach to identify RNAs in condensates that allowed us to reveal a mechanism for regulating RNA fate.
Birinapant selectively enhances immunotoxin‐mediated killing of cancer cells conditional on the IAP protein levels within target cells
Authors: Antignani Antonella , Bilotta Maria Teresa , Roth Jacob S. , Urban Daniel J. , Shen Min , Hall Matthew D. , FitzGerald David
Published: November 2023

Immunotoxins (ITs) target cancer cells via antibody binding to surface antigens followed by internalization and toxin‐mediated inhibition of protein synthesis. The fate of cells responding to IT treatment depends on the amount and stability of specific pro‐apoptotic and pro‐survival proteins. When treated with a pseudomonas exotoxin‐based immunotoxin (HB21PE40), the triple‐negative breast cancer (TNBC) cell line MDA‐MB‐468 displayed a notable resistance to toxin‐mediated killing compared to the epidermoid carcinoma cell line, A431, despite succumbing to the same level of protein synthesis inhibition. In a combination screen of ~1912 clinically relevant and mechanistically annotated compounds, we identified several agents that greatly enhanced IT‐mediated killing of MDA‐MB‐468 cells while exhibiting only a modest enhancement for A431 cells. Of interest, two Smac mimetics, birinapant and SM164, exhibited this kind of differential enhancement. To investigate the basis for this, we probed cells for the presence of inhibitor of apoptosis (IAP) proteins and monitored their stability after the addition of immunotoxin. We found that high levels of IAPs inhibited immunotoxin‐mediated cell death. Further, TNFα levels were not relevant for the combination's efficacy. In tumor xenograft studies, combinations of immunotoxin and birinapant caused complete regressions in MDA‐MB‐468tumor‐bearing mice but not in mice with A431 tumors. We propose that IAPs constitute a barrier to immunotoxin efficacy which can be overcome with combination treatments that include Smac mimetics.
Extracorporeal Membrane Oxygenation Without Invasive Ventilation for Respiratory Failure in Adults: A Systematic Review*
Authors: Belletti Alessandro , Sofia Rosaria , Cicero Perla , Nardelli Pasquale , Franco Annalisa , Calabrò Maria Grazia , Fominskiy Evgeny V. , Triulzi Margherita , Landoni Giovanni , Scandroglio Anna Mara , Zangrillo Alberto
Published: November 2023

OBJECTIVES:

Extracorporeal membrane oxygenation (ECMO) is an advanced treatment for acute severe respiratory failure. Patients on ECMO are frequently maintained sedated and immobilized until weaning from ECMO, first, and then from mechanical ventilation. Avoidance of sedation and invasive ventilation during ECMO may have potential advantages. We performed a systematic literature review to assess efficacy and safety of awake ECMO without invasive ventilation in patients with respiratory failure.

DATA SOURCES:

PubMed, Web of Science, and Scopus were searched for studies reporting outcome of awake ECMO for adult patients with respiratory failure.

STUDY SELECTION:

We included all studies reporting outcome of awake ECMO in patients with respiratory failure. Studies on ECMO for cardiovascular failure, cardiac arrest, or perioperative support and studies on pediatric patients were excluded. Two investigators independently screened and selected studies for inclusion.

DATA EXTRACTION:

Two investigators abstracted data on study characteristics, rate of awake ECMO failure, and mortality. Primary outcome was rate of awake ECMO failure (need for intubation). Pooled estimates with corresponding 95% CIs were calculated. Subgroup analyses by setting were performed.

DATA SYNTHESIS:

A total of 57 studies (28 case reports) included data from 467 awake ECMO patients. The subgroup of patients with acute respiratory distress syndrome showed a pooled estimate for awake ECMO failure of 39.3% (95% CI, 24.0–54.7%), while in patients bridged to lung transplantation, pooled estimate was 23.4% (95% CI, 13.3–33.5%). Longest follow-up mortality was 121 of 439 (pooled estimate, 28%; 95% CI, 22.3–33.6%). Mortality in patients who failed awake ECMO strategy was 43 of 74 (pooled estimate, 57.2%; 95% CI, 40.2–74.3%). Two cases of cannula self-removal were reported.

CONCLUSIONS:

Awake ECMO is feasible in selected patients, although the effect on outcome remains to be demonstrated. Mortality is almost 60% in patients who failed awake ECMO strategy.
Risk Factors Associated With Development of Multiple-Organ Dysfunction Syndrome After Pediatric Drowning
Authors: Southard-Goebel Colton , Pike Francis , Rowan Courtney M. , Cater Daniel T.
Published: November 2023

Objective

This study aimed to describe a single-center experience of pediatric drowning and to investigate risk factors associated with the development of pediatric multiple-organ dysfunction syndrome (MODS) after drowning events.

Methods

A single-center retrospective case-control study was performed at a tertiary children's hospital examining patients aged 1 month to 25 years who were admitted to the pediatric intensive care unit after a drowning event. The study period was June 2016 to June 2021. Patients who developed MODS at day 1 of intensive care admission were compared with those who did not.

Results

A total of 48 patients with a median age of 2.3 years were included. Twenty-nine (60%) had MODS at 24 hours. Those with MODS at 24 hours were more likely to require cardiopulmonary resuscitation (CPR), required longer duration of CPR, and had longer submersion times; otherwise, there were no differences in baseline characteristics. Those who developed MODS at 24 hours had longer lengths of stays, longer lengths of mechanical ventilation, and higher mortality. Multiple admission parameters were evaluated based on MODS-free survival at 24 hours. On univariable analysis, patients without MODS-free survival at 24 hours had higher rates of CPR, higher blood glucose on admission, higher illness severity scores, higher lactates, and lower Glasgow Coma Scale scores. A multivariable model was constructed using risk factors at presentation that were significant on univariable analysis; blood glucose greater than 200 mg/dL was associated with decreased odds of MODS-free survival at 24 hours after controlling for CPR administration of greater than 5 minutes and body temperature.

Conclusions

Development of MODS in pediatric drowning is associated with worse patient outcomes. Hyperglycemia was identified as a potentially modifiable risk factor for the development of MODS at 24 hours and could serve as a useful prognostic parameter in this unique patient population.
Use of Antipseudomonal Antibiotics is not Associated with Lower Rates of Postoperative Drainage Procedures or More Favorable Culture Profiles in Children with Complicated Appendicitis
Authors: Cramm Shannon L. , Graham Dionne A. , Feng Christina , Allukian Myron , Blakely Martin L. , Chandler Nicole M. , Cowles Robert A. , Kunisaki Shaun M. , Lipskar Aaron M. , Russell Robert T. , Santore Matthew T. , Campbell Brendan T. , Commander Sarah J. , DeFazio Jennifer R. , Dukleska Katerina , Echols Justice C. , Esparaz Joseph R. , Gerall Claire , Griggs Cornelia L. , Hanna David N. , He Katherine , Keane Olivia A. , McLean Sean E. , Pace Elizabeth , Scholz Stefan , Sferra Shelby R. , Tracy Elisabeth T. , Zhang Lucy , Rangel Shawn J. ,   On behalf of the Eastern Pediatric Surgery Network
Published: November 2023

Objective:

To compare rates of postoperative drainage and culture profiles in children with complicated appendicitis treated with the two most common antibiotic regimens with and without antipseudomonal activity (piperacillin-tazobactam [PT] and ceftriaxone with metronidazole [CM]).

Summary of Background Data:

Variation in use of antipseudomonal antibiotics has been driven by a paucity of multicenter data reporting clinically relevant, culture-based outcomes.

Methods:

Retrospective cohort study of patients with complicated appendicitis (7/2015-6/2020) using NSQIP-Pediatric data from 15 hospitals participating in a regional research consortium. Operative report details, antibiotic utilization, and culture data were obtained through supplemental chart review. Rates of 30-day postoperative drainage and organism-specific culture positivity were compared between groups using mixed effects regression to adjust for clustering after propensity matching on measures of disease severity.

Results:

1002 children met criteria for matching (58.9% received CM and 41.1% received PT). In the matched sample of 778 patients, children treated with PT had similar rates of drainage overall (PT: 11.8%, CM: 12.1%; OR 1.44 [OR:0.71-2.94]) and higher rates of drainage associated with growth of any organism (PT: 7.7%, CM: 4.6%; OR 2.41 [95%CI:1.08-5.39]) and Escherichia coli (PT: 4.6%, CM: 1.8%; OR 3.42 [95%CI:1.07-10.92]) compared to treatment with CM. Rates were similar between groups for drainage associated with multiple organisms (PT: 2.6%, CM: 1.5%; OR 3.81 [95%CI:0.96-15.08]) and Pseudomonas (PT: 1.0%, CM: 1.3%; OR 3.42 [95%CI:0.55-21.28]).

Conclusions and Relevance:

Use of antipseudomonal antibiotics is not associated with lower rates of postoperative drainage procedures or more favorable culture profiles in children with complicated appendicitis.