bluuebunny/crossref_metadata_2025_split huggingface dataset:
CRISPR/Cas9 gene editing uncovers the roles of CONSTITUTIVE TRIPLE RESPONSE 1 and REPRESSOR OF SILENCING 1 in melon fruit ripening and epigenetic regulation
Authors: Giordano Andrea , Santo Domingo Miguel , Quadrana Leandro , Pujol Marta , Martín-Hernández Ana Montserrat , Garcia-Mas Jordi 
Published: April 2022

Abstract
Melon (Cucumis melo) has emerged as an alternative model to tomato for studying fruit ripening due to the coexistence of climacteric and non-climacteric varieties. Previous characterization of a major quantitative trait locus (QTL), ETHQV8.1, that is able to trigger climacteric ripening in a non-climacteric background resulted in the identification of a negative regulator of ripening CTR1-like (MELO3C024518) and a putative DNA demethylase ROS1 (MELO3C024516) that is the orthologue of DML2, a DNA demethylase that regulates fruit ripening in tomato. To understand the role of these genes in climacteric ripening, in this study we generated homozygous CRISPR knockout mutants of CTR1-like and ROS1 in a climacteric genetic background. The climacteric behavior was altered in both loss-of-function mutants in two growing seasons with an earlier ethylene production profile being observed compared to the climacteric wild type, suggesting a role of both genes in climacteric ripening in melon. Single-cytosine methylome analyses of the ROS1-knockout mutant revealed changes in DNA methylation in the promoter regions of the key ripening genes such as ACS1, ETR1, and ACO1, and in transcription factors associated with ripening including NAC-NOR, RIN, and CNR, suggesting the importance of ROS1-mediated DNA demethylation for triggering fruit ripening in melon.
Major niche transitions in Pooideae correlate with variation in photoperiodic flowering and evolution of CCT domain genes
Authors: Fjellheim Siri , Young Darshan A , Paliocha Martin , Johnsen Sylvia Sagen , Schubert Marian , Preston Jill C 
Published: April 2022

AbstractThe external cues that trigger timely flowering vary greatly across tropical and temperate plant taxa, the latter relying on predictable seasonal fluctuations in temperature and photoperiod. In the grass family (Poaceae) for example, species of the subfamily Pooideae have become specialists of the northern temperate hemisphere, generating the hypothesis that their progenitor evolved a flowering response to long days from a short-day or day-neutral ancestor. Sampling across the Pooideae, we found support for this hypothesis, and identified several secondary shifts to day-neutral flowering and one to short-day flowering in a tropical highland clade. To explain the proximate mechanisms for the secondary transition back to short-day-regulated flowering, we investigated the expression of CCT domain genes, some of which are known to repress flowering in cereal grasses under specific photoperiods. We found a shift in CONSTANS 1 and CONSTANS 9 expression that coincides with the derived short-day photoperiodism of our exemplar species Nassella pubiflora. This sets up the testable hypothesis that trans- or cis-regulatory elements of these CCT domain genes were the targets of selection for major niche shifts in Pooideae grasses.
Multi-omics data integration analysis identifies the spliceosome as a key regulator of DNA double-strand break repair
Authors: Sherill-Rofe Dana , Raban Oded , Findlay Steven , Rahat Dolev , Unterman Irene , Samiei Arash , Yasmeen Amber , Kaiser Zafir , Kuasne Hellen , Park Morag , Foulkes William D , Bloch Idit , Zick Aviad , Gotlieb Walter H , Tabach Yuval , Orthwein Alexandre 
Published: April 2022

Abstract
DNA repair by homologous recombination (HR) is critical for the maintenance of genome stability. Germline and somatic mutations in HR genes have been associated with an increased risk of developing breast (BC) and ovarian cancers (OvC). However, the extent of factors and pathways that are functionally linked to HR with clinical relevance for BC and OvC remains unclear. To gain a broader understanding of this pathway, we used multi-omics datasets coupled with machine learning to identify genes that are associated with HR and to predict their sub-function. Specifically, we integrated our phylogenetic-based co-evolution approach (CladePP) with 23 distinct genetic and proteomic screens that monitored, directly or indirectly, DNA repair by HR. This omics data integration analysis yielded a new database (HRbase) that contains a list of 464 predictions, including 76 gold standard HR genes. Interestingly, the spliceosome machinery emerged as one major pathway with significant cross-platform interactions with the HR pathway. We functionally validated 6 spliceosome factors, including the RNA helicase SNRNP200 and its co-factor SNW1. Importantly, their RNA expression correlated with BC/OvC patient outcome. Altogether, we identified novel clinically relevant DNA repair factors and delineated their specific sub-function by machine learning. Our results, supported by evolutionary and multi-omics analyses, suggest that the spliceosome machinery plays an important role during the repair of DNA double-strand breaks (DSBs).
Prospective genomically guided identification of “early/evolving” and “undersampled” IDH-wildtype glioblastoma leads to improved clinical outcomes
Authors: Zhang Yalan , Lucas Calixto-Hope G , Young Jacob S , Morshed Ramin A , McCoy Lucie , Oberheim Bush Nancy Ann , Taylor Jennie W , Daras Mariza , Butowski Nicholas A , Villanueva-Meyer Javier E , Cha Soonmee , Wrensch Margaret , Wiencke John K , Lee Julieann C , Pekmezci Melike , Phillips Joanna J , Perry Arie , Bollen Andrew W , Aghi Manish K , Theodosopoulos Philip , Chang Edward F , Hervey-Jumper Shawn L , Berger Mitchel S , Clarke Jennifer L , Chang Susan M , Molinaro Annette M , Solomon David A 
Published: April 2022

Abstract

Background
Genomic profiling studies of diffuse gliomas have led to new improved classification schemes that better predict patient outcomes compared to conventional histomorphology alone. One example is the recognition that patients with IDH-wildtype diffuse astrocytic gliomas demonstrating lower-grade histologic features but genomic and/or epigenomic profile characteristic of glioblastoma typically have poor outcomes similar to patients with histologically diagnosed glioblastoma. Here we sought to determine the clinical impact of prospective genomic profiling for these IDH-wildtype diffuse astrocytic gliomas lacking high-grade histologic features but with molecular profile of glioblastoma.

Methods
Clinical management and outcomes were analyzed for 38 consecutive adult patients with IDH-wildtype diffuse astrocytic gliomas lacking necrosis or microvascular proliferation on histologic examination that were genomically profiled on a prospective clinical basis revealing criteria for an integrated diagnosis of “diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV” per cIMPACT-NOW criteria.

Results
We identified that this diagnosis consists of two divergent clinical scenarios based on integration of radiologic, histologic, and genomic features that we term “early/evolving” and “undersampled” glioblastoma, IDH-wildtype. We found that prospective genomically guided identification of early/evolving and undersampled IDH-wildtype glioblastoma resulted in more aggressive patient management and improved clinical outcomes compared to a biologically matched historical control patient cohort receiving standard-of-care therapy based on histomorphologic diagnosis alone.

Conclusions
These results support routine use of genomic and/or epigenomic profiling to accurately classify glial neoplasms, as these assays not only improve diagnostic classification but critically lead to more appropriate patient management that can improve clinical outcomes.
Silent Persistent Left Superior Vena Cava Right-to-Left Shunt as a Unique Cause of Recurrent Brain Abscesses
Authors: Spier Addie B , David Diana , Al Zoubi Moamen , Taylor Montoya , Evans Colin E 
Published: April 2022

Abstract
We present a novel case of recurrent brain abscesses found to be the result of a silent congenital right-to-left extracardiac shunt, a persistent left superior vena cava draining into the left atrium. The patient’s brain abscess was evacuated surgically and treated with antibiotics, and his shunt was subsequently repaired. The case suggests that attention should be paid to evaluation for shunt physiology allowing for bypass of the pulmonary circulation in those with recurrent brain abscesses.
Original Research: Combating the Opioid Epidemic Through Nurse Use of Multimodal Analgesia: An Integrative Literature Review
Authors: Tavernier Jennifer René 
Published: April 2022

ABSTRACT

Background:
Opioid misuse and addiction have become a national crisis. New pain management guidelines call for the use of multimodal analgesia to manage acute pain. In hospital settings, a clinical decision aid that emphasizes multimodal analgesia may improve nurses' use of this opioid-sparing strategy.

Purpose:
This integrative review was conducted to provide nurses with evidence-based information on the opioid-sparing benefits of multimodal analgesia.

Methods:
A literature search was conducted using several electronic databases and Google Scholar. These initial searches yielded 136 articles of interest. Twenty-eight were selected for retrieval and in-depth appraisal; of these, 13 met all inclusion criteria.

Results:
Of the 13 reviewed studies, six were randomized controlled trials, six were retrospective cohort or population-based studies, and one was a qualitative study. Overall, the findings provided strong evidence that multimodal analgesia is effective in managing acute pain in surgical patients while reducing opioid requirements. Several studies also found that multimodal analgesia was associated with shorter hospital lengths of stay.

Conclusions:
With the appropriate tools and education, nurses can make the transition from traditional opioids to multimodal analgesia strategies. In so doing, they can have a significant positive impact on the opioid epidemic. Hospital leaders must address nursing practice regarding the use of opioids alone versus multimodal analgesia for the management of acute pain. Clinical decision tools such as the Michigan Opioid Safety Score may help nurses adopt new acute pain management guidelines. Further research regarding nursing practice and the opioid epidemic is needed.
Clinical Effects of Inadvertent Increased Lipid Infusion in Neonates
Authors: Hulgan Christina Marie , Snow Timothy , Check Jennifer 
Published: April 2022

Background:
Utility of total parenteral nutrition (TPN) with an intravenous lipid emulsion (IVLE) component is common in the neonatal intensive care unit; however, there are inherent risks to TPN use. With IVLE administered separate from other TPN components, opportunities exist for additional error and subsequent potential harm.

Clinical Findings:
We present 2 cases in term infants where IVLE infusions were noted to be inadvertently administered at higher than prescribed rates, prompting concern for lipemia and end-organ damage due to hyperviscosity.

Primary Diagnosis:
Both infants developed iatrogenic hypertriglyceridemia and hyponatremia.

Intervention:
Upon recognition of the error, IVLE was immediately discontinued in each case. Triglyceride levels were serially monitored until they reached a normal level. Electrolyte panels and hepatic function panels were also drawn to assess for electrolyte derangements and function. Radiologic studies were performed for evaluation of end-organ effects of hyperviscosity.

Outcomes:
Triglyceride levels for both infants normalized within 7 hours. Both infants survived to discharge without any known effects related to the inadvertent excessive lipid infusion.

Conclusion:
It is helpful to perform a root-cause analysis for these types of events; have the exact amount of lipids in the bag needed and no overfill; consider having lipids in 4-hour dosage aliquots; require 2 nurses to verify infusion rates hourly; and educational sessions and unit protocols for any infusion may reduce the risk of administration error.
A Chitosan-Coated Chamomile Microparticles Formulation to Prevent Radiodermatitis in Breast
Authors: Garbuio Danielle C. , Ribeiro Vanessa dos Santos , Hamamura Ana C. , Faustino Alexandre , Freitas Luís Alexandre Pedro de , Viani Gustavo , Carvalho Emília Campos de 
Published: April 2022

Purpose:
The aim was to evaluate the effect of a topical formulation containing chitosan-coated Chamomilla recutita (L.) rauschert microparticles regarding the incidence, grade, and days for the appearance of radiodermatitis (RD) in women with breast cancer.

Methods:
A double-blinded, controlled, randomized, phase II clinical trial developed with women diagnosed with breast cancer who will receive radiation therapy. The participants were randomly divided into 2 groups: control and treatment. They were followed up until the end of the treatment or the appearance of grade III RD.

Results:
Fifty-four women were included in the study. There is no significant difference between the groups in the incidence (88.9% vs. 88.9%, P=1.0) or time to develop any grade of RD (3 days of difference, P=0.300). A significant reduction was observed in the incidence (P=0.03) and in the time to appearance (7 d of difference, P=0.01) grade 2 or >RD. In the follow-up evaluation (15 d after the end of treatment), the Chamomile group presented a superior skin recovery than the control group (P=0.0343). High-intensity local symptoms as pain, and pruritus were significantly reduced in the Chamomile group.

Conclusions:
Although no effect was observed with chamomile to reduce any grade of RD, it was effective to reduce grade 2 or >toxicity, to improve skin recovery and to diminish high-intensity local symptoms.

Trial Registration:
Brazilian Registry of Clinical Trials (ReBEC): RBR-9hnftg, April 29, 2019.
High Tacrolimus Intrapatient Variability and Subtherapeutic Immunosuppression are Associated With Adverse Kidney Transplant Outcomes
Authors: Mendoza Rojas Aleixandra , Hesselink Dennis A. , van Besouw Nicole M. , Dieterich Marjolein , de Kuiper Ronella , Baan Carla C. , van Gelder Teun 
Published: April 2022

Background:
Kidney transplant recipients with high intrapatient variability (IPV) in tacrolimus (Tac) exposure experience more rejection and reduced graft survival. To understand the underlying pathophysiology of this association, the authors investigated whether patients with high tacrolimus IPV have a more activated immune system than patients with low IPV. In addition, exposure to tacrolimus and mycophenolic acid (MPA) was studied in relation to rejection and graft survival.

Methods:
At the time of patient inclusion (5–7 years post-transplantation), the frequency of donor-reactive cells was determined by enzyme-linked immunosorbent assay, and the development of donor-specific anti-Human Leukocyte Antigen antibodies (DSA) was measured by Luminex Single Antigen assay. Tacrolimus IPV was retrospectively calculated between 6 and 12 months and the exposure to tacrolimus and MPA was determined between 1 and 5 years post-transplantation.

Results:
A total of 371 kidney transplant recipients were included in this study, of whom 56 developed a rejection episode after 12 months and 60 experienced graft failure after 5–7 years. No correlations were found between tacrolimus IPV or immunosuppression exposure and the number of donor-reactive cells after 5 years of transplantation. DSA were detected more often in patients with low exposure to both tacrolimus and MMF [4/21 (19%) versus 17/350 (4.9%), P = 0.04]. In this cohort, neither tacrolimus IPV nor low overall immunosuppression exposure was associated with a higher incidence of rejection. However, regression analysis showed that a higher tacrolimus IPV was associated with an increased incidence of graft failure (odds ratio = 1.03, P = 0.02).

Conclusions:
This study verifies the relationship between high tacrolimus IPV and impaired kidney allograft survival in long-term follow-up. DSA was also found to be more prevalent in patients with subtherapeutic concentrations of tacrolimus and MPA. An increased prevalence of donor-specific alloreactivity is yet to be demonstrated in patients with high IPV.
Accelerated Cranioplasty with Perforator-preserved Split Flap Sandwiched Plate for Treatment of Infected Cranial Defects
Authors: Okada Yoshimoto , Narushima Mitsunaga , Banda Chihena H. , Danno Kanako , Mitsui Kohei , Shiraishi Makoto , Shiba Masato , Suzuki Yume , Ishiura Ryohei 
Published: April 2022

Summary:
Large cranial vault defects are challenging to manage due to the need to balance infection control, skin coverage, and restoration of the protective mechanical rigidity of the skull while also ensuring good head and neck aesthetic results. Conventional-staged treatment requires a long time period that includes debridement and scalp skin defect coverage with flaps as a first step, followed by definitive plate reconstruction 3–9 months later after infection control and flap atrophy resolution. We report a case of successful early cranioplasty in a factory worker who developed a large full-thickness cranial skull defect following artificial dura infection. Reconstruction was performed in two stages using an anterolateral thigh (ALT) flap. In the first stage, the scalp defect was covered with an ALT flap to close the skin following debridement. In the second stage performed 6 weeks later, the ALT flap was split into adiposal and adipocutaneous flaps to sandwich a computer-aided design custom-made titanium plate with an opening for the perforator to complete the cranioplasty. The patient successfully returned to work without recurrence of infection with 1-year follow-up. We report this case to demonstrate the utility of adipocutaneous flap plate sandwiching techniques in providing well-vascularized cover for early definitive cranial reconstruction and accelerated patient recovery.
ASSOCIATED FACTORS AND SURGICAL OUTCOMES OF MICROCYSTOID MACULAR EDEMA AND CONE BOUQUET ABNORMALITIES IN EYES WITH EPIRETINAL MEMBRANE
Authors: Cicinelli Maria Vittoria , Post Michal , Brambati Maria , Rabiolo Alessandro , Pignatelli Francesco , Szaflik Jacek P. , Bandello Francesco , Coppola Michele 
Published: April 2022

Purpose:
To investigate the associated features and the surgical outcomes in eyes with microcystoid macular edema (MME) and cone bouquet abnormalities (CBA) undergoing epiretinal membrane peeling.

Methods:
Retrospective study including patients who underwent pars plana vitrectomy for idiopathic epiretinal membrane. Factors associated with MME and CBA at baseline and their regression were identified with logistic regression models. Postoperative visual acuity was evaluated with linear mixed models from baseline to 12 months. Risk factors for new or worsened macular edema were explored with a Cox regression model.

Results:
One hundred and eighty-seven eyes are included in this study; 30 eyes (16%) had MME and 53 eyes (28%) had CBA preoperatively. Microcystoid macular edema was associated with severe epiretinal membrane stage (odds ratio [95% confidence interval] = 3.6 [1.3–12.7], P = 0.02); CBA was inversely associated with ectopic inner foveal layer thickness (odds ratio [95% confidence interval] = 0.97 [0.97–0.99] for each 1-μm EIFL increase, P = 0.006). Eyes with MME had worse visual acuity after epiretinal membrane peeling (P = 0.01) and were at risk of macular edema worsening (hazard ratio [95% confidence interval] = 2.22 [1.01–5.16], P = 0.04). Older age was associated with MME persistence (odds ratio [95% confidence interval] = 2.46 [1.06–6.82] for each 10-year increase, P = 0.04). No significant associations were found for CBA.

Conclusion:
Although CBA had no prognostic consequences, MME was associated with suboptimal visual recovery and less efficient control of inflammation after surgery. Degeneration of Müller cells may have an alleged role, and further imaging and functional tests are warranted.
Home-Based Perimetry for Glaucoma: Where Are We Now?
Authors: Daka Qëndresë , Mustafa Rona , Neziri Burim , Virgili Gianni , Azuara-Blanco Augusto 
Published: April 2022

Purpose:
To systematically summarize the current literature on home-based perimeters for glaucoma.

Methods:
A systematic review was conducted in accordance with the PRISMA-DTA checklist. Studies reporting portable perimeters designed for home use were retrieved from electronic databases and handsearching of reference lists of relevant publications. Studies reporting diagnostic accuracy data were evaluated with the QUADAS-2 tool and using standard automated perimetry as the reference standard. Other aspects of the technology such as detection of disease progression and patient acceptability were also included. Data were reported in a narrative and tabular format.

Results:
Of 18 included studies, 10 evaluated tablet-based perimeters, 4 evaluated web-based perimeters, and 4 evaluated head-mounted displays. Most studies used a clinic or laboratory setting. All studies reporting diagnostic accuracy data had high risk of bias in at least one domain. Across studies, sensitivity ranged from 54% in detecting mild to 91% in detecting moderate/severe glaucoma patients from controls, while specificity was between 50% and 100% for any form of glaucoma. The reported acceptability was high but had high risk of bias.

Conclusion:
Several promising technologies designed for home-based perimetry have been reported. Current studies used a controlled setting in highly selected populations. There is uncertainty on the performance and value of home-based perimetry for glaucoma. Additional efforts are required to elucidate the ability of the home-based perimeters to detect glaucoma and disease progression in real life situations.
A Randomized, Controlled Comparison of NCX 470 (0.021%, 0.042%, and 0.065%) and Latanoprost 0.005% in Patients With Open-angle Glaucoma or Ocular Hypertension: The Dolomites Study
Authors: Walters Thomas R. , Kothe Angela C. , Boyer José L. , Usner Dale W. , Lopez Krisol , Duquesroix Brigitte , Fechtner Robert D. , Navratil Tomas 
Published: April 2022

Précis:
NCX 470 0.042% and 0.065% were statistically superior in intraocular pressure (IOP) lowering to latanoprost 0.005%, and NCX 470 0.021% was noninferior. All NCX 470 concentrations were safe and well tolerated.

Purpose:
The purpose of this study was to compare varying concentrations of NCX 470 (a nitric oxide–donating bimatoprost) to latanoprost in a dose-response safety and efficacy trial.

Patients and Methods:
Adult patients with bilateral open-angle glaucoma or ocular hypertension were randomized to NCX 470 0.021% (n=111), 0.042% (n=108), 0.065% (n=107), or latanoprost 0.005% (n=107) once daily in the evening. IOP was measured at 8:00 am, 10:00 am, and 4:00 pm at weeks 1, 2, and 4. The primary efficacy endpoint was the reduction from baseline in mean diurnal IOP at week 4. Secondary efficacy endpoints included reductions from baseline in mean diurnal IOP at weeks 1 and 2, and reductions from baseline in time-matched IOP at 8:00 am, 10:00 am, and 4:00 pm at weeks 1, 2, and 4. Adverse events were evaluated.

Results:
All concentrations of NCX 470 resulted in significant reductions of mean diurnal IOP. The 0.042% and 0.065% concentrations were statistically superior to latanoprost 0.005%, and 0.021% was noninferior to latanoprost for change from baseline in mean diurnal IOP at week 4. The 0.065% concentration was also superior to latanoprost by up to 1.4 mm Hg for reduction from baseline at 8:00 am, 10:00 am, and 4:00 pm at week 4. NCX 470 was safe and well tolerated; conjunctival hyperemia was the most frequently reported adverse event.

Conclusions:
NCX 470 demonstrated dose-dependent reductions in IOP. The 0.042% and 0.065% concentrations demonstrated significantly greater reductions from baseline in mean diurnal IOP than latanoprost 0.005% at week 4, suggesting that higher concentrations may show even greater efficacy.