bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural polymorphism driven by a register shift in a CGAG-rich region found in the promoter of the neurodevelopmental regulatorAUTS2gene
Authors: Novotný Aleš , Plavec Janez , Kocman Vojč
Published: March 2023

The AUTS2 gene has been shown to influence brain development by controlling the number of neurons, promoting the growth of axons and dendrites and regulating neuronal migration. The expression of two isoforms of AUTS2 protein is precisely regulated and misregulation of their expression has been correlated with neurodevelopmental delay and autism spectrum disorder. A CGAG-rich region, which includes a putative protein binding site (PPBS), d(AGCGAAAGCACGAA), was found in the promoter region of AUTS2 gene. We show that oligonucleotides from this region adopt thermally stable non-canonical hairpin structures stabilized by G:C and sheared G:A base pairs arranged in a repeating structural motif we termed CGAG block. These motifs are formed consecutively, in a way that exploits a shift in register throughout the whole CGAG repeat to maximize the number of consecutive G:C and G:A base pairs. The differences in CGAG repeat shifting affect the structure of the loop region, where PPBS residues are predominantly located, specifically the loop length, types of base pairs and the pattern of base-base stacking. Finally, we propose a previously unexplored mechanism, by which different folds in the CGAG-rich region could cause a switch in expression between the full-length and C-terminal isoforms of AUTS2.
RNAJP: enhanced RNA 3D structure predictions with non-canonical interactions and global topology sampling
Authors: Li Jun , Chen Shi-Jie
Published: March 2023

RNA 3D structures are critical for understanding their functions. However, only a limited number of RNA structures have been experimentally solved, so computational prediction methods are highly desirable. Nevertheless, accurate prediction of RNA 3D structures, especially those containing multiway junctions, remains a significant challenge, mainly due to the complicated non-canonical base pairing and stacking interactions in the junction loops and the possible long-range interactions between loop structures. Here we present RNAJP (‘RNA Junction Prediction’), a nucleotide- and helix-level coarse-grained model for the prediction of RNA 3D structures, particularly junction structures, from a given 2D structure. Through global sampling of the 3D arrangements of the helices in junctions using molecular dynamics simulations and in explicit consideration of non-canonical base pairing and base stacking interactions as well as long-range loop–loop interactions, the model can provide significantly improved predictions for multibranched junction structures than existing methods. Moreover, integrated with additional restraints from experiments, such as junction topology and long-range interactions, the model may serve as a useful structure generator for various applications.
A virus-borne DNA damage signaling pathway controls the lysogeny-induction switch in a group of temperate pleolipoviruses
Authors: Chen Zhao , Liu Ying , Wang Yixuan , Du Xincheng , Deng Xiaoyuan , Xiang Jialin , Wang Yangyang , Wang Jiao , Krupovic Mart , Du Shishen , Chen Xiangdong
Published: March 2023

Many prokaryotic viruses are temperate and their reactivation is tightly regulated. However, except for a few bacterial model systems, the regulatory circuits underlying the exit from lysogeny are poorly understood, especially in archaea. Here, we report a three-gene module which regulates the switch between lysogeny and replicative cycle in a haloarchaeal virus SNJ2 (family Pleolipoviridae). The SNJ2 orf4 encodes a winged helix-turn-helix DNA binding protein which maintains lysogeny through repressing the expression of the viral integrase gene intSNJ2. To switch to the induced state, two other SNJ2-encoded proteins, Orf7 and Orf8, are required. Orf8 is a homolog of cellular AAA+ ATPase Orc1/Cdc6, which is activated upon mitomycin C-induced DNA damage, possibly through posttranslational modification. Activated Orf8 initiates the expression of Orf7 which, in turn, antagonizes the function of Orf4, leading to the transcription of intSNJ2, thereby switching SNJ2 to the induced state. Comparative genomics analysis revealed that the SNJ2-like Orc1/Cdc6-centered three-gene module is common in haloarchaeal genomes, always present in the context of integrated proviruses. Collectively, our results uncover the first DNA damage signaling pathway encoded by a temperate archaeal virus and reveal an unexpected role of the widely distributed virus-encoded Orc1/Cdc6 homologs.
YbiB: a novel interactor of the GTPase ObgE
Authors: Deckers Babette , Vercauteren Silke , De Kock Veerke , Martin Charlotte , Lazar Tamas , Herpels Pauline , Dewachter Liselot , Verstraeten Natalie , Peeters Eveline , Ballet Steven , Michiels Jan , Galicia Christian , Versées Wim
Published: March 2023

Obg is a widely conserved and essential GTPase in bacteria, which plays a central role in a large range of important cellular processes, such as ribosome biogenesis, DNA replication, cell division and bacterial persistence. Nevertheless, the exact function of Obg in these processes and the interactions it makes within the associated pathways remain largely unknown. Here, we identify the DNA-binding TrpD2 protein YbiB as an interactor of the Escherichia coli Obg (ObgE). We show that both proteins interact with high affinity in a peculiar biphasic fashion, and pinpoint the intrinsically disordered and highly negatively charged C-terminal domain of ObgE as a main driver for this interaction. Molecular docking and X-ray crystallography, together with site-directed mutagenesis, are used to map the binding site of this ObgE C-terminal domain within a highly positively charged groove on the surface of the YbiB homodimer. Correspondingly, ObgE efficiently inhibits the binding of DNA to YbiB, indicating that ObgE competes with DNA for binding in the positive clefts of YbiB. This study thus forms an important step for the further elucidation of the interactome and cellular role of the essential bacterial protein Obg.
Atypical neurofibromas reveal distinct epigenetic features with proximity to benign peripheral nerve sheath tumor entities
Authors: Kresbach Catena , Dottermusch Matthias , Eckhardt Alicia , Ristow Inka , Paplomatas Petros , Altendorf Lea , Wefers Annika K , Bockmayr Michael , Belakhoua Sarra , Tran Ivy , Pohl Lara , Neyazi Sina , Bode Helena , Farschtschi Said , Well Lennart , Friedrich Reinhard E , Reuss David , Snuderl Matija , Hagel Christian , Mautner Victor-Felix , Schüller Ulrich
Published: March 2023

Background

Plexiform neurofibromas can transform into atypical neurofibromas (ANF) and then further progress to aggressive malignant peripheral nerve sheath tumors (MPNST). ANF have been described to harbor distinct histological features and frequent loss of CDKN2A/B. However, histological evaluation may be rater-dependent, and detailed knowledge about the molecular mechanisms of malignant transformation is scarce. In general, malignant transformation can be accompanied by significant epigenetic changes, and global DNA methylation profiling is able to differentiate relevant tumor subgroups. Therefore, epigenetic profiling might provide a valuable tool to distinguish and characterize ANF with differing extent of histopathological atypia from neurofibromas and MPNST.

Methods

We investigated 40 tumors histologically diagnosed as ANF and compared their global methylation profile to other peripheral nerve sheath tumors.

Results

Unsupervised class discovery and t-SNE analysis indicated that 36/40 ANF cluster with benign peripheral nerve sheath tumors with clear separation from MPNST. 21 ANF formed a molecularly distinct cluster in proximity to schwannomas. Tumors in this cluster had a frequent heterozygous or homozygous loss of CDKN2A/B and significantly more lymphocyte infiltration than MPNST, schwannomas, and NF. Few ANF clustered closely with neurofibromas, schwannomas, or MPNST, raising the question, whether diagnosis based on histological features alone might pose a risk to both over- and underestimate the aggressiveness of these lesions.

Conclusions

Our data suggest that ANF with varying histological morphology show distinct epigenetic similarities and cluster in proximity to benign peripheral nerve sheath tumor entities. Future investigations should pay special respect to correlating this methylation pattern to clinical outcomes.
Characterization and Management of Adverse Reactions From the CLEAR Study in Advanced Renal Cell Carcinoma Treated With Lenvatinib Plus Pembrolizumab
Authors: Motzer Robert , George Saby , Merchan Jaime R , Hutson Thomas E , Song Xun , Perini Rodolfo F , Xie Ran , Bapat Urmi , Puente Javier
Published: March 2023

Background

Lenvatinib plus pembrolizumab showed significantly improved progression-free and overall survival outcomes compared with sunitinib in patients with advanced renal cell carcinoma in the CLEAR study (NCT02811861). Here, we used CLEAR data to characterize common adverse reactions (ARs; adverse-event preferred terms grouped in accordance with regulatory authority review) associated with lenvatinib plus pembrolizumab and review management strategies for select ARs.

Materials and Methods

Safety data from the 352 patients who received lenvatinib plus pembrolizumab in the CLEAR study were analyzed. Key ARs were chosen based on frequency of occurrence (≥30%). Time to first onset and management strategies for key ARs were detailed.

Results

The most frequent ARs were fatigue (63.1%), diarrhea (61.9%), musculoskeletal pain (58.0%), hypothyroidism (56.8%), and hypertension (56.3%); grade ≥3 severity ARs that occurred in ≥5% of patients were hypertension (28.7%), diarrhea (9.9%), fatigue (9.4%), weight decreased (8.0%), and proteinuria (7.7%). Median times to first onset of all key ARs were within approximately 5 months (approximately 20 weeks) of starting treatment. Strategies for effectively managing ARs included baseline monitoring, drug–dose modifications, and/or concomitant medications.

Conclusion

The safety profile of lenvatinib plus pembrolizumab was consistent with the known profile of each monotherapy; ARs were considered manageable with strategies including monitoring, dose modifications, and supportive medications. Proactive and prompt identification and management of ARs are important for patient safety and to support continued treatment.

Clinicaltrials.gov ID

NCT02811861
The influence of traffic stop policy changes on assaults against officers: A quasi-experimental approach
Authors: Boehme Hunter M
Published: March 2023

This study investigates whether the Fayetteville (NC) Police Department’s (FPD) prioritization of safety traffic stops and de-prioritization of investigatory stops from 2013 to 2016 impacted assaults on the police officers. Time series models found a statistically significant decrease in assaults on officers within the FPD following their traffic stop policy changes. The comparison police departments did not experience a significant effect of assaults on police officers during the same timeframe. Although the FPD increased the aggregate number of traffic stops from 2013 to 2016, their prioritization of safety stops, and subsequent de-prioritization of investigatory traffic stops resulted in a reduction in assaults on police officers. Since investigatory traffic stops are agued to be more confrontational and have relatively low ‘hit rates,’ de-prioritizing (yet not completely withdrawing from) such type of stops may impact assaults on officers in the aggregate. Several policy implications are discussed.
An observational study of domestic violence in Greece during COVID-19 through police records: The profile of heinous crimes between nuclear and extended family relationships
Authors: Chatzisymeonidis Stavros , Kioskli Kitty
Published: March 2023

In Greece, the frequency of serious crimes within families has been alarmingly high during COVID-19; nonetheless, no study has systematically investigated this subject at a national level. The current study aims to estimate the crime rates of family violence across the country and explore the profile of perpetrators and victims based on their sociodemographic characteristics and relationship status. Out of 372 crime cases reported to the Hellenic Police during 2020–2021, the highest crime rate is observed in the geographical area of the Ionian Sea with 13.45 per 100,000 population. Overall, there were 372 perpetrators with 89.5% of them being males and 386 victims with 83.6% of them being females. The majority of both groups (perpetrators and victims) were Greek, whereas the prevalent age group for perpetrators was 46–60 (31.2%), and for victims was 36–45 (28.5%). Nuclear relatives outnumbered the extended ones regarding all groups of family violence crimes; however, there were no statistically significant differences. Lastly, our multivariate regression model indicated that the likelihood for Greeks to commit sexual abuse instead of rape was 3.27 times greater than immigrants. Younger perpetrators were 0.30 times less likely than elders to murder a relative rather than rape them, whereas they were 10,833,846.63 times more likely than elders to severely injure a victim as opposed to rape them.
Controllable electron self-injection in laser wakefield acceleration with asymmetric gas-jet nozzle
Authors: Lei Zhenzhe , Jin Zhan , Zhidkov Alexei , Pathak Naveen , Mizuta Yoshio , Huang Kai , Nakanii Nobuhiki , Daito Izuru , Kando Masaki , Hosokai Tomonao
Published: March 2023

Beam charge control in the staging of laser wakefield acceleration (LWFA) is a crucial technique for developing full-optical jitter-free high-energy electron accelerators. Precise control of total charge in pre-accelerated electron bunches is necessary to achieve practical electron beam characteristics in the final acceleration stage(s). In contrast to the well-known cathode techniques in conventional accelerators, in LWFA the electron injection results from non-linear processes originating from plasma wave breaking. Therefore, the development of charge control requires a deep understanding of the electron self-injection processes and applications of non-trivial tools. The use of asymmetric gas-jet nozzles seems to be a promising way in developing charge control via tuning the target parameters such as plasma density, density slope, and acceleration length. Here, we demonstrate and characterize controllable electron self-injection, owing to a parametric resonance in slantwise density gas jets irradiated by 50 TW femtosecond laser pulses. The measured characteristics of the electron bunches, in which charge and energy distribution depend on the gas density and gas density gradient, agree well with those obtained by multidimensional particle-in-cell simulation and confirm the possibility of charge control.
A Systematic Appraisal of Conflicts of Interest and Researcher Allegiance in Clinical Studies of Dry Needling for Musculoskeletal Pain Disorders
Authors: Ware John W , Venere Kenny , Miller Stephanie A , Freeman Heather , Scalzitti David A , Hoogeboom Thomas
Published: March 2023

Objective

The purpose of this study was to determine the frequency and methods of conflicts of interest (COI) reporting in published dry needling (DN) studies and to determine the frequency of researcher allegiance (RA).

Methods

A pragmatic systematic search was undertaken to identify DN studies that were included in systematic reviews. Information regarding COI and RA were extracted from the full text of the published DN reports, and study authors were sent a survey inquiring about the presence of RA. A secondary analysis also was undertaken based on study quality/risk of bias scores that were extracted from the corresponding systematic reviews and study funding extracted from each DN study.

Results

Sixteen systematic reviews were identified, containing 60 studies of DN for musculoskeletal pain disorders, 58 of which were randomized controlled trials. Of the DN studies, 53% had a COI statement. None of these studies disclosed a COI. Nineteen (32%) authors of DN studies responded to the survey. According to the RA survey, 100% of DN studies included at least 1 RA criterion. According to the data extraction, 1 RA criterion was met in 45% of the DN studies. The magnitude of RA per study was 7 times higher according to the surveys than in the published reports.

Conclusion

These results suggest that COI and RA might be underreported in studies of DN. In addition, authors of DN studies might be unaware of the potential influence of RA on study results and conclusions.

Impact

Improved reporting of COI/RA might improve credibility of results and help identify the various factors involved in complex interventions provided by physical therapists. Doing so could help optimize treatments for musculoskeletal pain disorders provided by physical therapists.
Secret and Overt Information Acquisition in Financial Markets
Authors: Xiong Yan , Yang Liyan
Published: March 2023

We study the observability of investors’ information-acquisition activities in financial markets. Improving observability leads to two strategic effects on information acquisition: (1) the pricing effect, which arises from interactions between investors and the market maker and can encourage or discourage information acquisition, and (2) the competition effect, which concerns interactions among investors and always encourages information acquisition. We apply our theory to study voluntary and mandatory disclosures of corporate site visits. When the competition effect dominates, investors voluntarily disclose their visits. When the pricing effect dominates, mandatory disclosure is effective. Our analysis sheds novel light on Regulation Fair Disclosure.

Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Sympathetic dysregulation induced by postnatal intermittent hypoxia
Authors: Karlen-Amarante Marlusa , Leirão Isabela P , Katayama Pedro L , Colombari Eduardo , Bittencourt-Silva Paloma G , Menezes Miguel F , Zoccal Daniel B
Published: March 2023

Study Objectives

Exposure to postnatal chronic intermittent hypoxia (pCIH), as experienced in sleep-disordered breathing, is a risk factor for developing cardiorespiratory diseases in adulthood. pCIH causes respiratory instability and motor dysfunction that persist until adult life. In this study, we investigated the impact of pCIH on the sympathetic control of arterial pressure in rats.

Methods and Results

Neonate male Holtzman rats (P0–1) were exposed to pCIH (6% O2 for 30 seconds, every 10 minutes, 8 h/day) during their first 10–15 days of life, while control animals were maintained under normoxia. In early adult life (P25–40), freely behaving pCIH animals (n = 13) showed higher baseline arterial pressure levels linked to augmented sympathetic-mediated variability than control animals (n = 12, p < 0.05). Using decerebrated in situ preparations, we found that juvenile pCIH rats exhibited a twofold increase in thoracic sympathetic nerve activity (n = 14) and elevated firing frequency of ventromedullary presympathetic neurons (n = 7) compared to control rats (n = 6–7, p < 0.05). This pCIH-induced sympathetic dysregulation was associated with increased HIF-1α (hypoxia-inducible factor 1 alpha) mRNA expression in catecholaminergic presympathetic neurons (n = 5, p < 0.05). At older age (P90–99), pCIH rats displayed higher arterial pressure levels and larger depressor responses to ganglionic blockade (n = 6–8, p < 0.05), confirming the sympathetic overactivity state.

Conclusions

pCIH facilitates the vasoconstrictor sympathetic drive by mechanisms associated with enhanced firing activity and HIF-1α expression in ventromedullary presympathetic neurons. This excessive sympathetic activity persists until adulthood resulting in high blood pressure levels and variability, which contribute to developing cardiovascular diseases.
Solriamfetol improves chronic sleep fragmentation-induced increases in sleep propensity and ameliorates explicit memory in male mice
Authors: Puech Clementine , Badran Mohammad , Barrow Max B , Runion Alexandra R , Gozal David
Published: March 2023

Obstructive sleep apnea (OSA) is a highly prevalent condition characterized by episodes of partial or complete breath cessation during sleep that induces sleep fragmentation (SF). One of the frequent manifestations of OSA is the presence of excessive daytime sleepiness (EDS) associated with cognitive deficits. Solriamfetol (SOL) and modafinil (MOD) are wake-promoting agents commonly prescribed to improve wakefulness in OSA patients with EDS. This study aimed to assess the effects of SOL and MOD in a murine model of OSA characterized by periodic SF. Male C57Bl/6J mice were exposed to either control sleep (SC) or SF (mimicking OSA) during the light period (06:00 h to 18:00 h) for 4 weeks, which consistently induces sustained excessive sleepiness during the dark phase. Both groups were then randomly assigned to receive once-daily intraperitoneal injections of SOL (200 mg/kg), MOD (200 mg/kg), or vehicle for 1 week while continuing exposures to SF or SC. Sleep/wake activity and sleep propensity were assessed during the dark phase. Novel Object Recognition test, Elevated-Plus Maze Test, and Forced Swim Test were performed before and after treatment. SOL or MOD decreased sleep propensity in SF, but only SOL induced improvements in explicit memory, while MOD exhibited increased anxiety behaviors. Chronic SF, a major hallmark of OSA, induces EDS in young adult mice that is mitigated by both SOL and MOD. SOL, but not MOD, significantly improves SF-induced cognitive deficits. Increased anxiety behaviors are apparent in MOD-treated mice. Further studies aiming to elucidate the beneficial cognitive effects of SOL are warranted.
Zika virus knowledge, attitudes and prevention behaviors among pregnant women in the ZEN cohort study, Colombia, 2017–2018
Authors: Burkel Veronica K , Newton Suzanne M , Acosta Jacqueline , Valencia Diana , Benavides Monica , Tong Van T , Daza Marcela , Sancken Christina , Gonzalez Maritza , Polen Kara , Rodriguez Helena , Borbón Milena , Rao Carol Y , Gilboa Suzanne M , Honein Margaret A , Ospina Marta L , Johnson Candice Y
Published: March 2023

Background

Zika virus (ZIKV) infection during pregnancy can cause severe birth defects in the fetus and is associated with neurodevelopmental abnormalities in childhood. Our objective was to describe ZIKV knowledge and attitudes among pregnant women in Colombia while ZIKV was circulating and whether they predicted the adoption of behaviors to prevent ZIKV mosquito-borne and sexual transmission.

Methods

We used self-reported data from Zika en Embarazadas y Niños (ZEN), a cohort study of women in early pregnancy across three regions of Colombia during 2017–2018. We used Poisson regression to estimate associations between knowledge, attitudes and previous experience with mosquito-borne infection and preventative behaviors.

Results

Among 1519 women, knowledge of mosquito-borne transmission was high (1480; 97.8%) and 1275 (85.5%) participants were worried about ZIKV infection during pregnancy. The most common preventive behavior was wearing long pants (1355; 89.4%). Regular mosquito repellent use was uncommon (257; 17.0%). While ZIKV knowledge and attitudes were not associated with the adoption of ZIKV prevention behaviors, previous mosquito-borne infection was associated with increased condom use (prevalence ratio 1.4, 95% CI 1.1 to 1.7).

Conclusions

Participants were well informed about ZIKV transmission and its health consequences. However, whether this knowledge resulted in behavior change is less certain.
Altering Specificity and Autoactivity of Plant Immune Receptors Sr33 and Sr50 Via a Rational Engineering Approach
Authors: Tamborski Janina , Seong Kyungyong , Liu Furong , Staskawicz Brian J. , Krasileva Ksenia V.
Published: March 2023

Many resistance genes deployed against pathogens in crops are intracellular nucleotide-binding (NB) leucine-rich repeat (LRR) receptors (NLRs). The ability to rationally engineer the specificity of NLRs will be crucial in the response to newly emerging crop diseases. Successful attempts to modify NLR recognition have been limited to untargeted approaches or depended on previously available structural information or knowledge of pathogen-effector targets. However, this information is not available for most NLR-effector pairs. Here, we demonstrate the precise prediction and subsequent transfer of residues involved in effector recognition between two closely related NLRs without their experimentally determined structure or detailed knowledge about their pathogen effector targets. By combining phylogenetics, allele diversity analysis, and structural modeling, we successfully predicted residues mediating interaction of Sr50 with its cognate effector AvrSr50 and transferred recognition specificity of Sr50 to the closely related NLR Sr33. We created synthetic versions of Sr33 that contain amino acids from Sr50, including Sr33syn, which gained the ability to recognize AvrSr50 with 12 amino-acid substitutions. Furthermore, we discovered that sites in the LRR domain needed to transfer recognition specificity to Sr33 also influence autoactivity in Sr50. Structural modeling suggests these residues interact with a part of the NB-ARC domain, which we named the NB-ARC latch, to possibly maintain the inactive state of the receptor. Our approach demonstrates rational modifications of NLRs, which could be useful to enhance existing elite crop germplasm.

[Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
A LAMP Assay for Rapid Detection of the Pitch Canker Pathogen Fusarium circinatum
Authors: Meinecke Colton D. , Vos Lieschen De , Yilmaz Neriman , Steenkamp Emma T. , Wingfield Michael J. , Wingfield Brenda D. , Villari Caterina
Published: March 2023

The pine pitch canker pathogen Fusarium circinatum is endemic in the southeastern United States and Central America and represents an invasive threat globally. This ecologically adaptable fungus readily infects all parts of its pine hosts, leading to widespread mortality of nursery seedlings and decline in the health and productivity of forest stands. Because trees infected by F. circinatum can remain asymptomatic for long periods of time, accurate and rapid tools are needed for real-time diagnostics and surveillance at ports, in nurseries, and in plantations. To meet this need and to limit the spread and impact of the pathogen, we developed a molecular test using loop-mediated isothermal amplification (LAMP), a technology that allows for the rapid detection of pathogen DNA on portable, field-capable devices. LAMP primers were designed and validated to amplify a gene region unique to F. circinatum. Using a globally representative collection of F. circinatum isolates and other closely related species, we have demonstrated that the assay can be used to identify F. circinatum across its genetic diversity and that it is sensitive to as few as 10 cells from purified DNA extracts. The assay can also be used with a simple, pipette-free DNA extraction method and is compatible with testing symptomatic pine tissues in the field. This assay has the potential to facilitate diagnostic and surveillance efforts both in the laboratory and in the field and, thus, to reduce the spread and impact of pitch canker worldwide.
Identification and Characterization of Neocosmospora silvicola Causing Canker Disease on Pinus armandii in China
Authors: Chen Wenyan , Fan Xinlei , Tian Chengming , Li Feng , Chou Guifang
Published: March 2023

Chinese white pine, Pinus armandii, is a source of high-quality timber and an afforestation tree in China, which plays an important ecological and social role in water and soil conservation. Recently, a new canker disease has been reported in Longnan City, Gansu Province, where P. armandii is mainly distributed. In this study, the causal agent was isolated from diseased samples and identified as a fungal pathogen, Neocosmospora silvicola, based on morphological characteristics and molecular analyses (internal transcribed spacer, large subunit, RNA polymerase II, and translation elongation factor-1α). Pathogenicity tests on P. armandii revealed that N. silvicola isolates caused a 60% average mortality rate in artificially inoculated 2-year-old seedlings. The pathogenicity of these isolates was also observed on the branches of 10-year-old P. armandii trees with a 100% mortality rate. These results agree with the isolation of N. silvicola from diseased plants, suggesting the possible role of this fungus in the decline of P. armandii plants. Mycelial growth of N. silvicola was fastest on potato dextrose agar medium, and growth occurred at pH values ranging from 4.0 to 11.0 with temperatures between 5 and 40°C. The fungus also grew rapidly in complete darkness compared with other light conditions. Of the eight carbon and seven nitrogen sources tested, starch and sodium nitrate, respectively, were highly efficient in supporting the mycelial growth of N. silvicola. The ability of N. silvicola to grow at low temperatures (5°C) may explain its occurrence in the Longnan area of Gansu Province. This article is the first report of N. silvicola as an important fungal pathogen causing branch and stem cankers on Pinus tree species, which remains a threat to the forests.
Low-dose Initiation of Buprenorphine in Hospitalized Patients Using Buccal Buprenorphine: A Case Series
Authors: Adams Kathleen K. , Cohen Shawn M. , Guerra Michael E. , Weimer Melissa B.
Published: March 2023

Objective

To describe a low-dose buprenorphine initiation strategy with buccal buprenorphine.

Methods

This is a case series of hospitalized patients with opioid use disorder (OUD) and/or chronic pain who underwent low-dose buprenorphine initiation with buccal buprenorphine to sublingual buprenorphine. Results are descriptively reported.

Results

Forty-five patients underwent low-dose buprenorphine initiation from January 2020 to July 2021. Twenty-two (49%) patients had OUD only, 5 (11%) patients had chronic pain only, and 18 (40%) patients had both OUD and chronic pain. Thirty-six (80%) patients had documented history of heroin or non-prescribed fentanyl use before admission. Acute pain in 34 (76%) patients was the most commonly documented rationale for low-dose buprenorphine initiation. Methadone was the most common outpatient opioid utilized before admission (53%). The addiction medicine service consulted on 44 (98%) cases and median length of stay was approximately 2 weeks. Thirty-six (80%) patients completed the transition to sublingual buprenorphine with a median completion dose of 16 mg daily. Of the 24 patients (53%) with consistently documented Clinical Opiate Withdrawal Scale scores, no patients experienced severe opioid withdrawal. Fifteen (62.5%) experienced mild or moderate withdrawal and 9 (37.5%) experienced no withdrawal (Clinical Opiate Withdrawal Scale score <5) during the entire process. Continuity of postdischarge prescription refills ranged from 0 to 37 weeks and the median number of buprenorphine refills was 7 weeks.

Conclusions

Low-dose buprenorphine initiation with buccal buprenorphine to sublingual buprenorphine was well tolerated and can be safely and effectively utilized for patients whose clinical scenario precludes traditional buprenorphine initiation strategies.
Operative Fractures of the Phalangeal Head and Neck in Children—Does Open Reduction Affect Outcomes?
Authors: Vaslow Aaron S. , Deal James Banks , Ho Christine A.
Published: March 2023

Background:

Closed reduction percutaneous pinning of displaced pediatric phalangeal head and neck fractures is preferred to prevent malunion and loss of motion and function. However, open reduction is required for irreducible fractures and open injuries. We hypothesize that osteonecrosis is more common in open injuries than closed injuries that require either open reduction or closed reduction percutaneous pinning.

Methods:

Retrospective chart review of 165 phalangeal head and neck fractures treated surgically with pin fixation at a single tertiary pediatric trauma center from 2007 to 2017. Fractures were stratified as open injuries (OI), closed injuries undergoing open reduction (COR), or closed injuries treated with closed reduction (CCR). The groups were compared using Pearson χ2 tests and ANOVA. Two group comparisons were made with Student t test.

Results:

There were 17 OI fractures, 14 COR fractures, and 136 CCR fractures. Crush injury was the predominant mechanism in OI versus COR and CCR groups. The average time from injury to surgery was 1.6 days for OI, 20.4 days for COR, and 10.4 days for CCR. The average follow-up was 86.5 days (range, 0 to 1204). The osteonecrosis rate differed between the OI versus COR and OI versus CCR groups (71% for OI, 7.1% for COR, and 1.5% for CCR). Rates of coronal malangulation >15 degrees differed between the OI and COR or CCR groups, but the 2 closed groups did not differ. Outcomes were defined using Al-Qattan’s system; CCR had the most excellent and fewest poor outcomes. One OI patient underwent partial finger amputation. One CCR patient had rotational malunion but declined derotational osteotomy.

Conclusions:

Open phalangeal head and neck fractures have more concomitant digital injuries and postoperative complications compared with injuries closed on presentation, regardless of whether the fracture underwent open or closed reduction. Although osteonecrosis occurred in all 3 cohorts, it was most frequent in open injuries. This study allows surgeons to discuss rates of osteonecrosis and resultant complications with families whose child presents with phalangeal head and neck fractures that are indicated for surgical treatment.

Level of Evidence:

Therapeutic, Level III.
Prognosis of polypoid melanoma: a comparative study with non-polypoid melanomas
Authors: Jasso-Sosa Velma Y. , Lino-Silva Leonardo S. , Escobar-Jiménez Marín G. , Galván-Bustillos Joab R. , García-Ortega Dorian Y. , Salcedo-Hernández Rosa A. , Zepeda-Najar César , Frías-Fernández Pedro
Published: March 2023

Polypoid melanoma is considered an exophytic and frequently non-pigmented variant of nodular melanoma with an adverse prognosis; however, very few studies have been published about it with contradictory results. Therefore, our objective was to determine the prognostic value of this configuration in melanomas. A transversal retrospective study of 724 cases was analyzed according to the main configuration (polypoid vs. non-polypoid) regarding their clinicopathologic characteristics and survival analysis. Of the 724 cases, 35 (4.8%) met the definition of polypoid melanoma; such cases, compared with non-polypoid melanomas, were associated with a high Breslow thickness (7 mm vs. 3 mm), 68.6% had a Breslow >4 mm; showed different clinical stages of presentation, and presented more ulceration (77.1 vs. 51.4%). In the 5-year overall survival (OS) analysis, polypoid melanoma is associated with a lower 5-year OS, together with lymph node metastasis, Breslow thickness, clinical stage, mitoses per mm2, vertical growth phase, ulceration, and state of the surgical margins; however, in the multivariate analysis, the factors that remained independent predictors of death were the Breslow thickness groups, the clinical stage, the presence of ulceration, and the state of the surgical margins. Polypoid melanoma was not an independent predictor of OS. We found a prevalence of 4.8% of polypoid melanomas, which showed a worse prognosis than non-polypoid melanomas, explained by a higher proportion of ulcerated cases, greater Breslow thickness, and ulceration. However, polypoid melanoma was not an independent predictor of death.
Update on Chemoresistance Mechanisms to First-Line Chemotherapy for Gallbladder Cancer and Potential Reversal Strategies
Authors: Lai Jinbao , Yang Songlin , Lin Zhuying , Huang Wenwen , Li Xiao , Li Ruhong , Tan Jing , Wang Wenju
Published: March 2023

Objective:

Gallbladder cancer (GBC) mortality remains high and chemoresistance is increasing. This review consolidates what is known about the mechanisms of chemoresistance to inform and accelerate the development of novel GBC-specific chemotherapies.

Methods:

Studies related to GBC-related chemoresistance were systematically screened in PubMed using the advanced search function. Search terms included GBC, chemotherapy, and signaling pathway.

Results:

Analysis of existing studies showed that GBC has poor sensitivity to cisplatin, gemcitabine (GEM), and 5-fluorouracil. DNA damage repair-related proteins, including CHK1, V-SCR, and H2AX, are involved in tumor adaptation to drugs. GBC-specific chemoresistance is often accompanied by changes in the apoptosis and autophagy-related molecules, BCL-2, CRT, and GBCDRlnc1. CD44+ and CD133+ GBC cells are less resistant to GEM, indicating that tumor stem cells are also involved in chemoresistance. In addition, glucose metabolism, fat synthesis, and glutathione metabolism can influence the development of drug resistance. Finally, chemosensitizers such as lovastatin, tamoxifen, chloroquine, and verapamil are able improve the therapeutic effect of cisplatin or GEM in GBC.

Conclusions:

This review summarizes recent experimental and clinical studies of the molecular mechanisms of chemoresistance, including autophagy, DNA damage, tumor stem cells, mitochondrial function, and metabolism, in GBC. Information on potential chemosensitizers is also discussed. The proposed strategies to reverse chemoresistance should inform the clinical use of chemosensitizers and gene-based targeted therapy for this disease.
Gut microbiome-brain-cirrhosis axis
Authors: Smith Maren L. , Wade James B. , Wolstenholme Jennifer , Bajaj Jasmohan S.
Published: March 2023

Cirrhosis is characterized by inflammation, degeneration, and fibrosis of liver tissue. Along with being the most common cause of liver failure and liver transplant, cirrhosis is a significant risk factor for several neuropsychiatric conditions. The most common of these is HE, which is characterized by cognitive and ataxic symptoms, resulting from the buildup of metabolic toxins with liver failure. However, cirrhosis patients also show a significantly increased risk for neurodegenerative diseases such as Alzheimer and Parkinson diseases, and for mood disorders such as anxiety and depression. In recent years, more attention has been played to communication between the ways the gut and liver communicate with each other and with the central nervous system, and the way these organs influence each other’s function. This bidirectional communication has come to be known as the gut-liver-brain axis. The gut microbiome has emerged as a key mechanism affecting gut-liver, gut-brain, and brain-liver communication. Clinical studies and animal models have demonstrated the significant patterns of gut dysbiosis when cirrhosis is present, both with or without concomitant alcohol use disorder, and have provided compelling evidence that this dysbiosis also influences the cognitive and mood-related behaviors. In this review, we have summarized the pathophysiological and cognitive effects associated with cirrhosis, links to cirrhosis-associated disruption of the gut microbiome, and the current evidence from clinical and preclinical studies for the modulation of the gut microbiome as a treatment for cirrhosis and associated neuropsychiatric conditions.
Do published trial results influence physician prescribing patterns? Intravitreal antivascular endothelial growth factor usage by the United States Ophthalmologists before and after Protocol T study
Authors: Shah Serena , Markatia Zahra , Watane Arjun , Feldman Alexandra , Shah Lea , Sridhar Jayanth
Published: March 2023

Purpose of review

Clinical trial publications may influence physician prescribing patterns. The Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol T study, published in 2015, examined outcomes of intravitreal antivascular endothelial growth factor (VEGF) medications for treatment of diabetic macular oedema (DME). This study investigates if the Protocol T 1-year results were associated with changes in prescribing patterns.

Recent findings

Anti-VEGF agents have revolutionized treatment of DME by blocking angiogenesis signalled by VEGF. Three commonly used anti-VEGF agents are on-label aflibercept (Eylea, Regeneron) and ranibizumab (Lucentis, Genentech) and off-label bevacizumab (Avastin, Genentech).

From 2013 to 2018, there was a significant positive trend in the average number of aflibercept injections for any indication (P < 0.002). There was no significant trend in the average number of bevacizumab (P = 0.09) and ranibizumab (P = 0.43) for any indication. The mean proportion of aflibercept injections per provider per year was 0.181, 0.217, 0.311, 0.403, 0.419 and 0.427; each year-by-year comparison was significant (all P < 0.001), and the largest increase was in 2015, the year of publication of Protocol T 1-year results. These results imply and reinforce that clinical trial publications may have significant effects on ophthalmologist prescribing patterns.
Advancing Health Equity Through Graduate Forensic Nursing Education
Authors: Berishaj Kelly
Published: March 2023

Social justice is a core value of nursing and is deeply rooted within forensic nursing. Forensic nurses are uniquely positioned to examine and address social determinants of health that contribute to victimization, lack of access to forensic nursing services, and inability to utilize resources and services aimed at restoring health after an injury or illness related to trauma or violence. To achieve this, forensic nursing capacity and expertise must be strengthened through robust education. A graduate, forensic nursing, program sought to address this educational need by integrating content related to social justice, health equity, health disparity, and social determinants of health throughout its specialty curriculum.
Evidence on postbiotics in infants and children
Authors: Szajewska Hania , Salminen Seppo
Published: March 2023

Purpose of review

The aim is to provide updated information on the concept of postbiotics and recent data on the efficacy of postbiotics for the prevention and treatment of childhood diseases.

Recent findings

In line with a recently proposed consensus definition, a postbiotic is ‘a preparation of inanimate microorganisms and/or their components that confers a health benefit on the host’. Although inanimate, postbiotics may exert health benefits. There are only limited data on infant formulas containing postbiotics, but they are well tolerated, support adequate growth and demonstrate no potential identifiable risks, although clinical benefits remain limited. Currently, there is only limited support for postbiotic use for treating diarrhoea and preventing common paediatric infectious diseases in young children. Given the limited evidence, sometimes with a high risk of bias, caution is justified. No data in older children and adolescents are available.

The consensus definition of postbiotics facilitates further research. As not all postbiotics are the same, the type of disease and specific postbiotic studied should be considered when choosing postbiotics for the prevention or treatment of childhood diseases. Additional studies are needed to assess disease conditions responsive to postbiotics. Mechanisms of action of postbiotics need to be evaluated and characterized.
Community acquired and hospital acquired AKI - two diseases divided by a common definition
Authors: Kumar Vivek , Jha Vivekanand
Published: March 2023

Purpose of review

Acute kidney injury (AKI) is common across the world. AKI that is acquired in the community (community acquired AKI, CA-AKI) has different risk factors, epidemiological profile, presentation and impact as compared to hospital acquired AKI (HA-AKI). Hence, similar approaches to tackle CA-AKI and HA-AKI might not work. This review highlights the important differences between the two entities that have a bearing on the overall approach to the conditions and how CA-AKI has been overshadowed by HA-AKI in research, diagnosis and treatment recommendations and clinical practice guidelines.

Recent findings

The overall burden of AKI is disproportionately more in low and low-middle income countries. The Global Snapshot study of International Society of Nephrology's (ISN) AKI 0by25 program has shown that CA-AKI is the dominant form in these settings. Its profile and outcomes vary with geographical and socio-economic characteristics of the regions where it develops. The current clinical practice guidelines for AKI align more with HA-AKI than CA-AKI, and fail to capture the complete spectrum of CA-AKI as well as its impact. The ISN AKI 0by25 studies have uncovered the circumstantial compulsions in defining and assessing AKI in these settings and shown feasibility of community-based interventions.

Efforts are needed to better understand CA-AKI in low-resource settings and develop context specific guidance and interventions. A multidisciplinary, collaborative approach with representation from community would be required.
Approach to Endoscopic Balloon Dilatation in Pediatric Stricturing Crohn Disease: A Position Paper of the Endoscopy Special Interest Group of ESPGHAN
Authors: Ledder Oren , Homan Matjaž , Furlano Raoul , Papadopoulou Alexandra , Oliva Salvatore , Dias Jorge Amil , Dall’oglio Luigi , Faraci Simona , Narula Priya , Schluckebier Dominique , Hauser Bruno , Nita Andreia , Romano Claudio , Tzivinikos Christos , Bontems Patrick , Thomson Mike
Published: March 2023

Crohn disease (CD) is often complicated by bowel strictures that can lead to obstructive symptoms, resistant inflammation, and penetrating complications. Endoscopic balloon dilatation of CD strictures has emerged as a safe and effective technique for relieving these strictures, which may obviate the need for surgical intervention in the short and medium term. This technique appears to be underutilized in pediatric CD. This position paper of the Endoscopy Special Interest Group of European Society for Pediatric Gastroenterology, Hepatology and Nutrition describes the potential applications, appropriate evaluation, practical technique, and management of complications of this important procedure. The aim being to better integrate this therapeutic strategy in pediatric CD management.
The SARS-CoV-2 responsible for phlegmasia cerulea dolens: a case report
Authors: Banana Youssef , Bashir Husam , Boukabous Sara , Haddiya Intissar , Bentata Yassamine , Rezziki Abdellah , Benzirar Adnane , El Mahi Omar
Published: March 2023

Introduction:

Coronavirus disease 2019 (COVID-19) is a worldwide pandemic systemic infection that is responsible for serious coagulopathies similar to disseminated intravascular coagulation.

Case Presentation:

The authors report the case of a COVID-19 patient who presented with phlegmasia cerulea dolens (PCD) of the left lower limb, so he benefited from aponeurotomies of the internal and anterolateral muscular compartments.

Clinical Discussion:

The severe acute respiratory syndrome coronavirus 2 involves an inflammatory process in thrombotic events in COVID-19 patients, including a cytokine storm. PCD evolves in three semiological phases: venous stasis, weakening of the pulses, and the constitution of major ischemia. In the literature, the authors find many reports that have been published regarding increased thrombus formation in COVID-19 patients; these include DVT formation, pulmonary embolism, and stroke. Nevertheless, publications concerning PCD in COVID-19 patients remain rare.

Conclusion:

Although the severe acute respiratory syndrome coronavirus 2 remains a thrombogenic pathology, systematic anticoagulation is the subject of hypothesis. Hence the importance of regular monitoring of markers of vascular thrombosis.