bluuebunny/crossref_metadata_2025_split huggingface dataset:
A dolabralexin-deficient mutant provides insight into specialized diterpenoid metabolism in maize
Authors: Murphy Katherine M , Dowd Tyler , Khalil Ahmed , Char Si Nian , Yang Bing , Endelman Benjamin J , Shih Patrick M , Topp Christopher , Schmelz Eric A , Zerbe Philipp 
Published: March 2023

Abstract
Two major groups of specialized metabolites in maize (Zea mays), termed kauralexins and dolabralexins, serve as known or predicted diterpenoid defenses against pathogens, herbivores, and other environmental stressors. To consider the physiological roles of the recently discovered dolabralexin pathway, we examined dolabralexin structural diversity, tissue-specificity, and stress-elicited production in a defined biosynthetic pathway mutant. Metabolomics analyses support a larger number of dolabralexin pathway products than previously known. We identified dolabradienol as a previously undetected pathway metabolite and characterized its enzymatic production. Transcript and metabolite profiling showed that dolabralexin biosynthesis and accumulation predominantly occur in primary roots and show quantitative variation across genetically diverse inbred lines. Generation and analysis of CRISPR-Cas9-derived loss-of-function Kaurene Synthase-Like 4 (Zmksl4) mutants demonstrated dolabralexin production deficiency, thus supporting ZmKSL4 as the diterpene synthase responsible for the conversion of geranylgeranyl pyrophosphate precursors into dolabradiene and downstream pathway products. Zmksl4 mutants further display altered root-to-shoot ratios and root architecture in response to water deficit. Collectively, these results demonstrate dolabralexin biosynthesis via ZmKSL4 as a committed pathway node biochemically separating kauralexin and dolabralexin metabolism, and suggest an interactive role of maize dolabralexins in plant vigor during abiotic stress.
AWARENESS OF PAEDIATRIC RADIOLOGICAL PROTECTION AND IMAGING PARAMETERS AMONG GROUP OF SRI LANKAN RADIOGRAPHERS
Authors: Satharasinghe Duminda , Niroshan Nithiyananthan , Jeyasugiththan Jeyasingam 
Published: March 2023

Abstract
The present survey evaluated the level of awareness of radiological protection concepts and imaging parameters among Sri Lankan radiographers for the first time. The data were collected using an electronic questionnaire of 22 questions on demographic data, awareness of radiation protection concepts and imaging parameters. Only 84 out of 122 (68.8%) requested radiographers to return the questionnaire. More than 85% had ≥3 years of experience in the radiography field. The average scores for questions on best practices, imaging parameters and radiation protection were 75, 75.8 and 70.2%, respectively, with an overall score of 73.4%. Significant confusion existed on protective shielding, paediatric consenting capability, use of grids and excess X-ray field during paediatric radiography. Although the overall knowledge and awareness of participants on studied concepts were satisfactory, a continuous professional development credit system and implementation of a code of practice are required to improve the quality of radiography practice.
Investigations into hydrogen sulfide-induced suppression of neuronal activityin vivoand calcium dysregulationin vitro
Authors: Kim Dong-Suk , Pessah Isaac N , Santana Cristina M , Purnell Benton S , Li Rui , Buchanan Gordon F , Rumbeiha Wilson K 
Published: March 2023

AbstractAcute exposure to high concentrations of hydrogen sulfide (H2S) leads to sudden death and, if survived, lingering neurological disorders. Clinical signs include seizures, loss of consciousness, and dyspnea. The proximate mechanisms underlying H2S-induced acute toxicity and death have not been clearly elucidated. We investigated electrocerebral, cardiac, and respiratory activity during H2S exposure using electroencephalogram (EEG), electrocardiogram, and plethysmography. H2S suppressed electrocerebral activity and disrupted breathing. Cardiac activity was comparatively less affected. To test whether Ca2+ dysregulation contributes to H2S-induced EEG suppression, we developed an in vitro real-time rapid throughput assay measuring patterns of spontaneous synchronized Ca2+ oscillations in cultured primary cortical neuronal networks loaded with the indicator Fluo-4 using the fluorescent imaging plate reader (FLIPR-Tetra®). Sulfide &gt;5 ppm dysregulated synchronous calcium oscillation (SCO) patterns in a dose-dependent manner. Inhibitors of NMDA and AMPA receptors magnified H2S-induced SCO suppression. Inhibitors of L-type voltage-gated Ca2+ channels and transient receptor potential (TRP) channels prevented H2S-induced SCO suppression. Inhibitors of T-type voltage-gated Ca2+ channels, ryanodine receptors, and sodium channels had no measurable influence on H2S-induced SCO suppression. Exposures to &gt;5 ppm sulfide also suppressed neuronal electrical activity in primary cortical neurons measured by multielectrode array (MEA), an effect alleviated by pretreatment with the nonselective TRP channel inhibitor, 2-aminoethoxydiphenylborate (2-APB). 2-APB also reduced primary cortical neuronal cell death from sulfide exposure. These results improve our understanding of the role of different Ca2+ channels in acute H2S-induced neurotoxicity and identify TRP channel modulators as novel structures with potential therapeutic benefits.
Prevalence of childhood obesity in Brazil: a systematic review
Authors: Santos Fabrício De Paula , Silva Eliane Aparecida Ferraz , Baêta Caroline Lana Veloso , Campos Felipe Sávio , Campos Helton Oliveira 
Published: March 2023

AbstractThe present study aimed to analyze the prevalence of childhood obesity in Brazil and compare it between boys and girls. This systematic review was conducted and reported according to the guidelines outlined in the PRISMA statement. A systematic search of electronic databases, including PubMed, LILACS, and SciELO, was performed in November 2021. Studies that met the following criteria were included: (i) original quantitative studies regardless of their design; (ii) childhood obesity was clearly defined; (iii) prevalence of childhood obesity was reported or it was possible to extract from tables or figures in the text; and (iv) eligible population included children under 12 years of age. A total of 112 articles were included in the systematic review. The prevalence of childhood obesity in Brazil was of 12.2%, being 10.8% in girls and 12.3% in boys. In addition, wide heterogeneity in the childhood obesity prevalence was observed between the states, since it was 2.6% in Pará, while it was 15.8% in Rondônia. Thus, the importance of urgently implementing measures to prevent and treat childhood obesity should be emphasized aiming to reduce obese children and adolescents and future health problems in adult life resulting from this cardiovascular risk factor.
Purifying selection decreases the potential for Bangui orthobunyavirus outbreaks in humans
Authors: Orf Gregory S , Perez Lester J , Meyer Todd V , Luk Ka-Cheung , Forberg Kenn , Rodgers Mary A , Hadji Abbas , James Linda , Mampunza Samuel , Achari Asmeeta , Yu Guixia , Federman Scot , Chiu Charles Y , McArthur Carole A , Cloherty Gavin A , Berg Michael G 
Published: March 2023

AbstractPathogens carried by insects, such as bunyaviruses, are frequently transmitted into human populations and cause diseases. Knowing which spillover events represent a public health threat remains a challenge. Metagenomic next-generation sequencing (mNGS) can support infectious disease diagnostics by enabling the detection of any pathogen from clinical specimens. mNGS was performed on blood samples to identify potential viral coinfections in human immunodeficiency virus (HIV)-positive individuals from Kinshasa, the Democratic Republic of the Congo (DRC), participating in an HIV diversity cohort study. Time-resolved phylogenetics and molecular assay development assisted in viral characterization. The nearly complete genome of a novel orthobunyavirus related to Nyangole virus, a virus previously identified in neighboring Uganda, was assembled from a hepatitis B virus–positive patient. A quantitative polymerase chain reaction assay was designed and used to screen &gt;2,500 plasma samples from Cameroon, the DRC, and Uganda, failing to identify any additional cases. The recent sequencing of a US Center for Disease Control Arbovirus Reference Collection revealed that this same virus, now named Bangui virus, was first isolated in 1970 from an individual in the Central African Republic. Time-scaled phylogenetic analyses of Bangui with the related Anopheles and Tanga serogroup complexes indicate that this virus emerged nearly 10,000 years ago. Pervasive and episodic models further suggest that this virus is under purifying selection and that only distant common ancestors were subject to positive selection events. This study represents only the second identification of a Bangui virus infection in over 50 years. The presumed rarity of Bangui virus infections in humans can be explained by its constraint to an avian host and insect vector, precluding efficient transmission into the human population. Our results demonstrate that molecular phylogenetic analyses can provide insights into the threat posed by novel or re-emergent viruses identified by mNGS.
CDK6 activity in a recurring convergent kinase network motif
Authors: Gangemi Christina G , Sabapathy Rahkesh T. , Janovjak Harald 
Published: March 2023

AbstractIn humans, more than 500 kinases phosphorylate ~15% of all proteins in an emerging phosphorylation network. Convergent local interaction motifs, in which ≥two kinases phosphorylate the same substrate, underlie feedback loops and signal amplification events but have not been systematically analyzed. Here, we first report a network‐wide computational analysis of convergent kinase‐substrate relationships (cKSRs). In experimentally validated phosphorylation sites, we find that cKSRs are common and involve >80% of all human kinases and >24% of all substrates. We show that cKSRs occur over a wide range of stoichiometries, in many instances harnessing co‐expressed kinases from family subgroups. We then experimentally demonstrate for the prototypical convergent CDK4/6 kinase pair how multiple inputs phosphorylate the tumor suppressor retinoblastoma protein (RB) and thereby hamper in situ analysis of the individual kinases. We hypothesize that overexpression of one kinase combined with a CDK4/6 inhibitor can dissect convergence. In breast cancer cells expressing high levels of CDK4, we confirm this hypothesis and develop a high‐throughput compatible assay that quantifies genetically modified CDK6 variants and inhibitors. Collectively, our work reveals the occurrence, topology, and experimental dissection of convergent interactions toward a deeper understanding of kinase networks and functions.
Safety of Fezolinetant for Vasomotor Symptoms Associated With Menopause
Authors: Neal-Perry Genevieve , Cano Antonio , Lederman Samuel , Nappi Rossella E. , Santoro Nanette , Wolfman Wendy , English Marci , Franklin Catherine , Valluri Udaya , Ottery Faith D. 
Published: March 2023

OBJECTIVE:
To evaluate the safety, tolerability, and effect of fezolinetant on endometrial health over 52 weeks.

METHODS:
We conducted a phase 3, randomized, double-blind, 52-week safety study (SKYLIGHT 4 [Study to Find Out How Safe Long-term Treatment With Fezolinetant is in Women With Hot Flashes Going Through Menopause]) of placebo, fezolinetant 30 mg, and fezolinetant 45 mg once daily (1:1:1). Participants were postmenopausal and seeking treatment for vasomotor symptoms associated with menopause. Primary endpoints were treatment-emergent adverse events, percentage of participants with endometrial hyperplasia, and percentage with endometrial malignancy. Endometrial hyperplasia or malignancy was evaluated according to U.S. Food and Drug Administration guidance (point estimate of 1% or less with an upper bound of one-sided 95% CI of 4% or less). Secondary endpoints included change in bone mineral density (BMD) and trabecular bone score. A sample size of 1,740 was calculated to enable observation of one or more events (≈80% probability for events with background rate of less than 1%).

RESULTS:
A total of 1,830 participants were randomized and took one or more medication dose (July 2019–January 2022). Treatment-emergent adverse events occurred in 64.1% (391/610) of the placebo group, 67.9% (415/611) of the fezolinetant 30-mg group, and 63.9% (389/609) of the fezolinetant 45-mg group. Treatment-emergent adverse events leading to discontinuation were similar across groups (placebo, 26/610 [4.3%]; fezolinetant 30 mg, 34/611 [5.6%]; fezolinetant 45 mg, 28/609 [4.6%]). Endometrial safety was assessed in 599 participants. In the fezolinetant 45-mg group, 1 of 203 participants had endometrial hyperplasia (0.5%; upper limit of one-sided 95% CI 2.3%); there were no cases in the placebo (0/186) or fezolinetant 30 mg (0/210) group. Endometrial malignancy occurred in 1 of 210 in the fezolinetant 30-mg group (0.5%; 95% CI 2.2%) with no cases in the other groups. Liver enzyme elevations more than three times the upper limit of normal occurred in 6 of 583 placebo, 8 of 590 fezolinetant 30 mg, and 12 of 589 fezolinetant 45 mg participants; no Hy's law cases were reported (ie, no severe drug-induced liver injury with alanine aminotransferase or aspartate aminotransferase more than three times the upper limit of normal and total bilirubin more than two times the upper limit of normal, with no elevation of alkaline phosphatase and no other reason to explain the combination). Changes in BMD and trabecular bone score were similar across groups.

CONCLUSION:
Results from SKYLIGHT 4 confirm the 52-week safety and tolerability of fezolinetant and support its continued development.

FUNDING SOURCE:
Astellas Pharma Inc.

CLINICAL TRIAL REGISTRATION:

ClinicalTrials.gov, NCT04003389.
Initiation and Treatment Discontinuation of Medications for Opioid Use Disorder in Pregnant People Compared With Nonpregnant People
Authors: Xu Kevin Y. , Jones Hendrée E. , Schiff Davida M. , Martin Caitlin E. , Kelly Jeannie C. , Carter Ebony B. , Bierut Laura J. , Grucza Richard A. 
Published: March 2023

OBJECTIVE:
To examine the association between pregnancy and medications for opioid use disorder (MOUD) initiation and discontinuation among reproductive-aged people receiving treatment for opioid use disorder (OUD) in the United States.

METHODS:
We conducted a retrospective cohort study of people with gender recorded as female, aged 18–45 years, in the MerativeTM MarketScan® Commercial and Multi-State Medicaid Databases (2006–2016). Opioid use disorder and pregnancy status were identified based on inpatient or outpatient claims for established International Classification of Diseases, Ninth and Tenth Revision diagnosis and procedure codes. The main outcomes were buprenorphine and methadone initiation and discontinuation, determined by using pharmacy and outpatient procedure claims. Analyses were conducted at the treatment episode level. Adjusting for insurance status, age, and co-occurring psychiatric and substance use disorders, we used logistic regression to estimate MOUD initiation and used Cox regression to estimate MOUD discontinuation.

RESULTS:
Our sample included 101,772 reproductive-aged people with OUD, encompassing 155,771 treatment episodes (mean age 30.8 years, 64.4% Medicaid insurance, 84.1% White), of whom 2,687 (3.2%, encompassing 3,325 episodes) were pregnant. In the pregnant group, 51.2% of treatment episodes (1,703/3,325) involved psychosocial treatment without MOUD, in comparison with 61.1% (93,156/152,446) in the nonpregnant comparator group. In adjusted analyses assessing likelihood of initiation for individual MOUD, pregnancy status was associated with an increase in buprenorphine (adjusted odds ratio [aOR] 1.57, 95% CI 1.44–1.70) and methadone initiation (aOR 2.04, 95% CI 1.82–2.27). Discontinuation rates of MOUD at 270 days were high for both buprenorphine (72.4% for nonpregnant episodes vs 59.9% for pregnant episodes) and methadone (65.7% for nonpregnant episodes vs 54.1% for pregnant episodes). Pregnancy was associated with a decreased likelihood of discontinuation at 270 days for both buprenorphine (adjusted hazard ratio [aHR] 0.71, 95% CI 0.67–0.76) and methadone (aHR 0.68, 95% CI 0.61–0.75), in comparison with nonpregnant status.

CONCLUSION:
Although a minority of reproductive-aged people with OUD in the United States are initiated on MOUD, pregnancy is associated with a significant increase in treatment initiation and a reduced risk of medication discontinuation.
Increased Scheduled Intravenous Ketorolac After Cesarean Delivery and Its Effect on Opioid Use
Authors: Hostage Jean , Kolettis Diana , Sverdlov Deanna , Ludgin Jennifer , Drzymalski Dan , Sweigart Benjamin , Mhatre Mohak , House Michael 
Published: March 2023

OBJECTIVE:
To evaluate the efficacy of scheduled ketorolac in reducing opioid use after cesarean delivery.

METHODS:
This was a single-center, randomized, double-blind, parallel-group trial to assess pain management after cesarean delivery with scheduled ketorolac compared with placebo. All patients undergoing cesarean delivery with neuraxial anesthesia received two doses of 30 mg intravenous ketorolac postoperatively and then were randomized to receive four doses of 30 mg of intravenous ketorolac or placebo every 6 hours. Additional nonsteroidal anti-inflammatory drugs were held until 6 hours after the last study dose. The primary outcome was total morphine milligram equivalents (MME) used in the first 72 postoperative hours. Secondary outcomes included the number of patients who used no opioid postoperatively, postoperative pain scores, postoperative change in hematocrit and serum creatinine, and postoperative satisfaction with inpatient care and pain management. A sample size of 74 per group (n=148) provided 80% power to detect a population mean difference in MME of 32.4, with an SD for both groups of 68.7 after accounting for protocol noncompliance.

RESULTS:
From May 2019 to January 2022, 245 patients were screened and 148 patients were randomized (74 per group). Patient characteristics were similar between groups. The median (quartile 1–3) MME from arrival in the recovery room until postoperative hour 72 was 30.0 (0.0–67.5) for the ketorolac group and 60.0 (30.0–112.5) for the placebo group (Hodges–Lehmann median difference −30.0, 95% CI −45.0 to −15.0, P<.001). In addition, participants who received placebo were more likely to have numeric rating scale pain scores higher than 3 out of 10 (P=.005). The mean±SD decrease from baseline hematocrit to postoperative day 1 was 5.5±2.6% for the ketorolac group and 5.4±3.5% for the placebo group (P=.94). The mean±SD postoperative day 2 creatinine was 0.61±0.06 mg/dL in the ketorolac group and 0.62±0.08 mg/dL in the placebo group (P=.26). Participant satisfaction with inpatient pain control and postoperative care was similar between groups.

CONCLUSION:
Compared with placebo, scheduled intravenous ketorolac significantly decreased opioid use after cesarean delivery.

CLINICAL TRIAL REGISTRATION:

ClinicalTrials.gov, NCT03678675.
Occurrence and prognosis of lung cancer metastasis to major organs: a population-based study
Authors: Wang Huyu , Shui Lili , Chen Rouqian , Chen Yuhao , Guo Jing , Chen Yajuan 
Published: March 2023

Background
Lung cancer metastasis to major organs is an important factor affecting survival. We analyzed the influence of patient characteristics on the incidence and survival of metastasis to major organs.

Methods
We collected data from the Surveillance, Epidemiology, and End Results database on 58 659 patients diagnosed with stage IV primary lung cancer, including age, sex, race, histological type of tumor, laterality, primary site, number of extrametastatic sites, and treatment.

Results
Multiple variables affected the incidence of metastasis to major organs and survival. According to histological type of tumor, the following were more common: bone metastasis from adenocarcinoma; brain metastasis from large-cell carcinoma and adenocarcinoma; liver metastasis from small-cell carcinoma; and intrapulmonary metastasis from squamous-cell carcinoma. A larger number of metastatic sites increased the risk of other metastases and shorter survival. Liver metastasis conferred the worst prognosis, followed by bone metastasis, and brain or intrapulmonary metastasis conferred better prognosis. The effect of radiotherapy alone was poorer than chemotherapy alone or combined chemotherapy and radiotherapy. In most cases, the effects of chemotherapy and combined chemotherapy and radiotherapy were equivalent.

Conclusion
Multiple variables affected the incidence of metastasis to major organs and survival. Compared with radiotherapy alone or combined chemotherapy and radiotherapy, chemotherapy alone may be the most cost-effective option for patients with stage IV lung cancer.
Correction of Rippling in Implant-based Breast Reconstruction with Serratus Fascia Flap
Authors: Faenza Mario , Lanzano Giuseppe , Grella Elisa , Izzo Sara , Ferraro Giuseppe Andrea 
Published: March 2023

Summary:
Implant-based breast reconstruction represents the most popular procedure for the treatment of women undergoing skin-sparing mastectomy. In selected patients, it allows for obtaining an excellent appearance of the reconstructed breast with great satisfaction to the patient. However, aesthetic and functional results can be affected by complications requiring reoperation. Among them, rippling is an undesired occurrence associated with implant-based reconstruction. It consists of a cutaneous manifestation, visible and/or palpable, of the implant wrinkles and edge which appear mostly when the patient leans forward. To treat this contour deformity, several techniques have been described such as acellular dermal matrices and autologous tissues. In this study, we intend to add the serratus anterior fascial flap within the autologous options in the treatment of implant rippling, reporting our experience.