bluuebunny/crossref_metadata_2025 huggingface dataset:
RARE-02. POLYAMINE PATHWAY INHIBITION IS A POTENT NOVEL THERAPEUTIC STRATEGY AGAINST DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Khan Aaminah , Gamble Laura , Upton Dannielle , Yu Denise , Pandher Ruby , Mayoh Chelsea , Burns Mark R , Norris Murray D , Haber Michelle , Tsoli Maria , Ziegler David S
Published: June 2021

Diffuse intrinsic pontine glioma (DIPG) is an aggressive paediatric brainstem tumour, with a median survival of less than 1 year. Polyamines are intracellular polycations that control important aspects of cell growth and are often upregulated in cancer. Difluoromethylornithine (DFMO) is an FDA-approved inhibitor of the enzyme ornithine decarboxylase (ODC1) which is a key driver of polyamine synthesis. We investigated the efficacy of polyamine pathway inhibitors as a therapeutic strategy against DIPG. We found that there were high over-expression levels of polyamine synthetic enzymes from DIPG primary patient samples and neurosphere cultures. Using alamar blue cytotoxicity and soft-agar clonogenic assays, we found that DFMO inhibited the proliferation of DIPG neurospheres. However, DIPG cells compensated for DFMO inhibition by increasing expression of the polyamine transporter SLC3A2 and subsequently uptake of polyamines. Addition of polyamine transporter inhibitor AMXT 1501 to DFMO led to synergistic inhibition of DIPG proliferation in vitro. Consistent with the in vitro results, the combination of DFMO and AMXT 1501 significantly prolonged the survival of mice bearing 3 different DIPG orthografts with at least 2/3 of the animals surviving up to 160 days. Addition of irradiation further improved the survival of mice treated with DFMO and AMXT 1501. Differential expression analysis showed that the polyamine transporter, SLC3A2, was significantly overexpressed in DIPG and other paediatric brain tumours including high grade gliomas compared with normal brain tissue. Our results suggest that DIPG tumours are exquisitely sensitive to polyamine inhibitors, and that dual blockade of polyamine synthesis and transport is a promising novel therapeutic strategy. AMXT 1501 is currently in clinical development, and following completion of an adult Phase 1 trial, a clinical trial of AMXT 1501 + DFMO for DIPG patients is planned through the CONNECT consortium.
RARE-03 CENTRAL NERVOUS SYSTEM TUMORS IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1, A COHORT FROM A NATIONAL PEDIATRIC ONCOLOGY CENTER
Authors: Vandenput Kim , Meijer Lisethe , Schouten-van Meeteren Netteke
Published: June 2021

Approximately 15% of the children with Neurofibromatosis type 1 (NF1) develop a central nervous system (CNS) tumor, predominantly optic pathway glioma. However, other brain tumor types are also frequent, resulting in a heterogenous population regarding tumor type, symptoms and treatment. Even though many tumors are indolent, clinical deterioration or radiological progression requires surveillance and treatment. Pediatric oncology care in the Netherlands has been centralized into the Princess Máxima Center since June 2018, providing care for the majority of Dutch NF1 CNS tumor patients. This retrospective cohort study describes the course of disease in NF1 patients with a CNS tumor diagnosed between 2005–2020, based on data from patient files. The population consisted of 95 patients (48 males), median age at diagnosis 4.3 (range 0.8–17.2) and 12.6 (range 2.9–19.9) years at follow up, 27% familiar NF1, mostly nonsense or frameshift mutations. Neurological and/or visual symptoms were present in 64 (67.4%) patients. 63.6% of the tumors was in the optic pathway, 9.1% in the cerebellum. Biopsy in 19/95 revealed 1 ependymoma and 18 low grade glioma, with rarely additional molecular changes besides NF1. Kaplan Meier median PFS was 24 months (range 3–174.5, n=65) in symptomatic presenting patients, 34 months (range 5–165, n=20) in asymptomatic patients with abnormal ophthalmological and/or neurological exam and 67.3 months (range 7–130, n=10) in asymptomatic patients without abnormalities at exam. Treatment was indicated in 53 (55.8%), predominantly chemotherapy (n=49), with substantial toxicity. Carboplatin allergy was seen in 29/44 (65.9%) patients, peripheral neuropathy in 21/46 (45.7%) patients receiving vincristine, and 5/10 patients receiving irinotecan and bevacizumab ended treatment early due to toxicity. In conclusion: analysis of our extensive cohort of NF1 patients with a CNS tumor indicates the relevance of regular screening of NF1 patients without complaints and critical surveillance and systematical documentation of treatment toxicity.
RARE-09. POORLY DIFFERENTIATED CLIVAL CHORDOMA IN EXTREME YOUNG AGE; CASE ILLUSTRATION AND REVIEW OF LITERATURE
Authors: Altewerki Malak , AlRamadan Abdullah , AlHindi Hindi , AlShail Essam
Published: June 2021

Chordomas are rare tumors believed to be originated from notochordal remnants. Of all intracranial neoplasms, the incidence of cranial chordomas is less than 1%1. The youngest patient with an intracranial chordoma reported in the literature was a newborn in the first few days after birth9. Intracranial chondroma are more predominant in males compared to females1. The clinical features of intracranial chondroma in the pediatric age group commonly include increased Intracranial pressure, lower cranial nerves palsy, and torticollis2. There is no optimum treatment, however, surgical resection of the tumor followed by radiation therapy reported successful outcome3. This is a case of a poorly differentiated clival chordoma of a 23-month old boy. The clinical features, pathological, radiological findings, and surgical technique are discussed with an elaboration of the current review of the literature of clival chordoma in the extreme young age group. To the best of our knowledge, this is the youngest age of clivus chordoma reported in Saudi Arabia.
RARE-22. THERAPEUTIC TARGETING OF PURINE METABOLISM IN DIPG
Authors: Mersich Ian , Dasgupta Biplab
Published: June 2021

Diffuse intrinsic pontine glioma is a universally lethal disease primarily impacting pediatric patients. There are currently no targeted therapies increasing overall for patients with these tumors; therefore, our lab set out to elucidate metabolic dependencies in DIPG patient-derived cell lines with the ultimate goal of identifying novel therapeutic targets. Through untargeted metabolomics and gene expression analyses, we have identified the purine metabolism gene ATIC to be important for DIPG tumor cell survival and proliferation. Anti-folate drugs such as methotrexate target de novo purine biosynthesis and are used to treat other pediatric cancers; however, we have identified a small molecule inhibitor of ATIC that may offer clinical benefits over other inhibitors of this pathway. In vitro cell viability experiments have demonstrated DIPG cell lines are much more sensitive to the ATIC inhibitor relative to normal neural stem cells and glial cell lines. Furthermore, we have started in vivo studies on pre-clinical mouse models of DIPG with promising results. Treatment with the ATIC inhibitor has significantly increased overall survival relative to control and vehicle treated mice. The dosage we started at was well tolerated in these mice so we are following up on this in vivo work through dose-escalation studies as well as combination treatment strategies. Mechanistically, the ATIC inhibitor works differently than anti-folate compounds such as methotrexate; therefore we are also elucidating why cancer cells are much more sensitive to this compound.
RARE-23. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR: A CASE SERIES
Authors: Aaroe Ashley , Ou Alexander , McGovern Susan , Paulino Arnold , Johnson Jason , Huse Jason , Fuller Gregory , de Groot John , Walter Andrew , Zaky Wafik
Published: June 2021

Introduction

Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare diagnosis first incorporated into the WHO Classification of Tumors of the Central Nervous System in 2016. Though historically considered indolent, emerging evidence suggests that the biological behavior of these tumors may be further classified by molecular features of prognostic significance.

Methods

A retrospective review was conducted in accordance with IRB approval of patients with the histologic diagnosis of DLGNT. Demographic, clinical, and molecular data where abstracted from the medical record when available.

Results

10 patients were identified (M = 8, F = 2). Median age at diagnosis was 6 years (range 0.3–21 years), and the most common symptoms at diagnosis were related to obstructive hydrocephalus, for which 3 patients required CSF diversion. MRI findings included diffuse leptomeningeal thickening, nodularity, or coating of the subarachnoid or ependymal surfaces. Histologically, these tumors expressed variable features of neuronal and/or glial differentiation. Four patients (40%) were treated with radiation therapy (all craniospinal), which was upfront for 2 patients. Chemotherapy regimens used included temozolomide, carboplatin and vincristine and vinblastine. NTRK or BRAF-targeted therapy were used upon progression. At follow-up, 6/10 had stable disease (4/6 of whom were on second line therapy), 1 had partial response, 1 passed away from sepsis and 2 were lost to follow-up. The median progression-free survival for the four patients who developed disease progression was 26 months (range 12–34 months). Next generation sequencing of the tumor tissue performed using a high-multiplex PCR-based NGS panel detected BRAF-KIAA1549 (4 patients) and NTRK (1 patient) fusions.

Conclusions

DLGNT are rare tumors with scarce data about imaging characteristic and standard of care treatment. Our case series reinforces current literature that although these tumors appear low-grade, they can be clinically aggressive. Further study is needed regarding molecular diagnosis and profiling treatment strategies.
EPCT-06. PRECISION ONCOLOGY IN THE PEDIATRIC TARGETED THERAPY 2.0 PROGRAM
Authors: Ecker Jonas , Selt Florian , Korshunov Andrey , Capper David , Dikow Nicola , Hirsch Steffen , Sutter Christian , van Tilburg Cornelis , von Deimling Andreas , Jones David T W , Pfister Stefan M , Sahm Felix , Witt Olaf , Milde Till
Published: June 2021

Introduction

Precise diagnoses and robust detection of actionable alterations is required for individualized treatments. By using extended molecular diagnostics, the Pediatric Targeted Therapy (PTT) 2.0 program aims at the improvement of diagnostic accuracy and detection of actionable alterations for pediatric high-risk patients. The impact of these analyses on clinical management is reported.

Methods

Pediatric patients with relapsed or progressive tumors after standard of care treatment were included, independent of histological diagnosis. Formalin fixed paraffin embedded material and a blood sample for germline correction were requested. DNA methylation array, targeted gene panel sequencing (130 genes), RNA and Sanger sequencing in selected cases, and immunohistochemistry (IHC) of selected markers (pERK, pAKT, pS6, PD-L1) were performed. A questionnaire-based follow-up was used to determine the clinical impact of the analysis.

Results

We enrolled n=263 patients from February 2017 to February 2019. Complete molecular analysis was possible for n=260 cases (99%). The most common entities were brain tumors (n=172/260, 65%). In brain tumors, DNA methylation array alone allowed robust diagnostic classification (score of >=0.9) in n=104/172 cases (60%). Actionable targets as detected by copy number calculation, gene panel sequencing, RNA sequencing and IHC were found in n=94/172 (55%) brain tumor cases. The most common actionable targets in brain tumors were MAPK (pERK, BRAF fusions, BRAF V600E), mTOR (pS6), PI3K (pAKT), CDK4/6 (CDKN2A/B loss), and immune checkpoints (PD-L1). Pathogenic germline alterations with clinical relevance were identified in n=12/172 brain tumor cases (6.9%) and were confirmed by Sanger sequencing, 5/12 (41%) of which were previously unknown. Clinical follow-up of subsequent treatment and outcome are ongoing.

Conclusion

The combination of next-generation diagnostics such as methylation arrays and targeted sequencing in addition to selected IHC markers added robust information with regard to diagnosis and actionable alterations. The impact on clinical decision-making and on outcome is currently being evaluated.
EPCT-15. RAPID EPIGENOMIC CLASSIFICATION OF BRAIN TUMORS ENABLES INTRAOPERATIVE NEUROSURGICAL RISK MODULATION
Authors: Djirackor Luna , Halldorsson Skarphedinn , Niehusmann Pitt , Leske Henning , Kuschel Luis P , Pahnke Jens , Due-Tønnessen Bernt J , Langmoen Iver A , Sandberg Cecilie J , Euskirchen Philipp , Vik-Mo Einar O
Published: June 2021

Background

Clear identification of tumor subtype is the main predictor of patient outcome and ultimately what is considered an adequate level of surgical risk. At brain tumor resection, imaging modalities and intraoperative histology often give an ambigious diagnosis, complicating intraoperative surgical decision-making. Here, we report a nanopore DNA methylation analysis (NDMA) sequencing approach combined with machine learning for classification of tumor entities that could be used intraoperatively.

Methods

We analyzed 50 biopsies obtained from biobanked tissue (43, prospective) or sampled at surgery (7, intraoperative) from 20 female and 30 male patients with a median age of 8 years. DNA was extracted using spin columns, quantified on a Qubit fluorometer and assessed for purity using NanoDrop spectrophotometer. DNA was then barcoded with the Rapid Barcoding kit from Oxford Nanopore technologies and loaded onto a MinION flow cell. Sequencing was performed for 3 hours (intraoperative) and 24 hours (prospective). Raw reads were basecalled using the Guppy algorithm, then fed into a snakemake workflow (nanoDx pipeline). This generated a report showing the copy number profile, genome-wide methylation status and subclassification of the tumor according to the Heidelberg reference cohort.

Results

Twelve different tumor classes were discovered within our cohort spanning from WHO Grade I to Grade IV. The results generated by NDMA were concordant with standard neuropathological diagnosis in 43 out of 50 cases (86%). Of the discordant cases, six were due to the biological complexity of the tumor and one case was misclassified by the pipeline. NDMA enabled correct subclassification of 6/7 intraop cases within a mean of 129 minutes.

Conclusion

NDMA can accurately subclassify tumor entities intraoperatively and guide surgical procedures when preoperative imaging and frozen section evaluation are unclear.
EPCT-17. DEVELOPING EYA PHOSPHATASE INHIBITORS WITH ON-TARGET EFFECTS IN SHH-MEDULLOBLASTOMA
Authors: H. Hwang Grace , Scott David A , Segal Rosalind A
Published: June 2021

Medulloblastoma, one of the most frequent malignant pediatric brain tumors, encompasses four molecularly and clinically distinct cancers. Sonic hedgehog (SHH)-subtype medulloblastoma constitutes about 30% of medulloblastomas, and therapies targeting the SHH pathway can lead to new highly selective treatment. The haloacid dehalogenase (HAD) phosphatase Eyes Absent 1 (EYA1) is critically involved in the development and progression of SHH-medulloblastoma: Eya1 is highly expressed in SHH-medulloblastomas, and single cell sequencing indicates that Eya1 is a consistent feature that can be detected in every individual cancer cell. Inhibition of EYA1 interrupts SHH pathway signaling. During normal development, EYA1 promotes symmetric division of cerebellar granule cell precursors (GCPs), the cells of origin for SHH-subtype medulloblastoma, and reduced levels of EYA1 decrease medulloblastoma mortality rates in mouse models. Therefore, targeting EYA1 may be a novel therapeutic avenue for these pediatric cancers. Benzarone derivatives have been suggested as allosteric EYA-inhibitors, and benzarone provides a promising platform for chemical derivatives. Here, we develop 60 novel benzarone derivatives and assess their efficacy in inhibiting SHH-medulloblastoma growth through the inhibition of EYA1. Several of the new compounds inhibit EYA1 phosphotyrosine phosphatase activity in a cell-based assay, interrupt SHH pathway, and prevent SHH-medulloblastoma growth in vitro. Our results show that these novel benzarone derivatives are a new promising avenue for developing therapeutics for pediatric SHH-medulloblastoma via inhibition of EYA phosphatases.
Humoral Immune Response to Clostridioides difficile Toxins A and B in Hospitalized Immunocompromised Patients With C difficile Infection
Authors: Alonso Carolyn D , Papamichael Konstantinos , Sprague Rebecca , Barrett Caitlin , Gonzales-Luna Anne J , Daugherty Kaitlyn , Garey Kevin W , Villafuerte-Gálvez Javier , Xu Hua , Lin Qianyun , Wang Lamei , Chen Xinhua , Pollock Nira R , Kelly Ciarán P
Published: June 2021

Background

The humoral immune response to Clostridioides difficile toxins in C difficile infection (CDI) is incompletely characterized in immunocompromised hosts (ICHs).

Methods

We conducted a prospective study of hospitalized adults with CDI, with and without immunosuppression (hematologic malignancy, active solid tumor, solid organ or stem cell transplant, inflammatory bowel disease, autoimmune disease, congenital or acquired immunodeficiency, asplenia, chronic receipt of high-dose steroids, or receipt of immunosuppressing medications within 12 months). Serum and stool antibody concentrations of immunoglobulin (Ig)M, IgG, and IgA to C difficile toxins A and B at treatment days 0, 3, and 10–14 were compared.

Results

Ninety-eight subjects (47 ICH; 51 non-ICH) were enrolled. Baseline serum antitoxin A and B antibody levels were similar. At day 3, ICHs demonstrated lower serum levels of antitoxin A IgG, antitoxin A IgA, and antitoxin B IgA (all P < .05). At day 10–14, lower antitoxin A IgG concentrations were observed in ICHs (ICH, 21 enzyme-linked immunosorbent assay [ELISA] units; interquartile range [IQR], 16.4–44.6) compared with non-ICH subjects (49.0 ELISA units; IQR, 21.5–103; P = .045). In stool, we observed lower concentrations of antitoxin B IgA antibodies at baseline and at day 3 for ICH subjects, with a notable difference in concentrations of antitoxin B IgA at day 3 (ICH, 6.7 ELISA units [IQR, 1.9–13.9] compared with non-ICH, 18.1 ELISA units [IQR, 4.9–31.7]; P = .003).

Conclusions

The ICHs with CDI demonstrated lower levels of C difficile antitoxin antibodies in serum and stool during early CDI therapy compared with non-ICHs. These data provide insight into the humoral response to CDI in ICHs.
Reciprocal adaptation of rice and Xanthomonas oryzae pv. oryzae: cross-species 2D GWAS reveals the underlying genetics
Authors: Zhang Fan , Hu Zhiqiang , Wu Zhichao , Lu Jialing , Shi Yingyao , Xu Jianlong , Wang Xiyin , Wang Jinpeng , Zhang Fan , Wang Mingming , Shi Xiaorong , Cui Yanru , Vera Cruz Casiana , Zhuo Dalong , Hu Dandan , Li Min , Wang Wensheng , Zhao Xiuqin , Zheng Tianqing , Fu Binying , Ali Jauhar , Zhou Yongli , Li Zhikang
Published: June 2021

A 1D/2D genome-wide association study strategy was adopted to investigate the genetic systems underlying the reciprocal adaptation of rice (Oryza sativa) and its bacterial pathogen, Xanthomonas oryzae pv. oryzae (Xoo) using the whole-genome sequencing and large-scale phenotyping data of 701 rice accessions and 23 diverse Xoo strains. Forty-seven Xoo virulence-related genes and 318 rice quantitative resistance genes (QR-genes) mainly located in 41 genomic regions, and genome-wide interactions between the detected virulence-related genes and QR genes were identified, including well-known resistance genes/virulence genes plus many previously uncharacterized ones. The relationship between rice and Xoo was characterized by strong differentiation among Xoo races corresponding to the subspecific differentiation of rice, by strong shifts toward increased resistance/virulence of rice/Xoo populations and by rich genetic diversity at the detected rice QR-genes and Xoo virulence genes, and by genome-wide interactions between many rice QR-genes and Xoo virulence genes in a multiple-to-multiple manner, presumably resulting either from direct protein–protein interactions or from genetic epistasis. The observed complex genetic interaction system between rice and Xoo likely exists in other crop–pathogen systems that would maintain high levels of diversity at their QR-loci/virulence-loci, resulting in dynamic coevolutionary consequences during their reciprocal adaptation.
A plant-specific syntaxin-6 protein contributes to the intracytoplasmic route for the begomovirus CabLCV
Authors: Gouveia-Mageste Bianca Castro , Martins Laura Gonçalves Costa , Dal-Bianco Maximiller , Machado João Paulo Batista , da Silva José Cleydson Ferreira , Kim Alice Y. , Yazaki Junshi , dos Santos Anésia Aparecida , Ecker Joseph R. , Fontes Elizabeth Pacheco Batista
Published: June 2021

Because of limited free diffusion in the cytoplasm, viruses must use active transport mechanisms to move intracellularly. Nevertheless, how the plant single-stranded DNA begomoviruses hijack the host intracytoplasmic transport machinery to move from the nucleus to the plasmodesmata remains enigmatic. Here, we identified nuclear shuttle protein (NSP)-interacting proteins from Arabidopsis (Arabidopsis thaliana) by probing a protein microarray and demonstrated that the cabbage leaf curl virus NSP, a facilitator of the nucleocytoplasmic trafficking of viral (v)DNA, interacts in planta with an endosomal vesicle-localized, plant-specific syntaxin-6 protein, designated NSP-interacting syntaxin domain-containing protein (NISP). NISP displays a proviral function, unlike the syntaxin-6 paralog AT2G18860 that failed to interact with NSP. Consistent with these findings, nisp-1 mutant plants were less susceptible to begomovirus infection, a phenotype reversed by NISP complementation. NISP-overexpressing lines accumulated higher levels of vDNA than wild-type. Furthermore, NISP interacted with an NSP-interacting GTPase (NIG) involved in NSP–vDNA nucleocytoplasmic translocation. The NISP–NIG interaction was enhanced by NSP. We also showed that endosomal NISP associates with vDNA. NISP may function as a docking site for recruiting NIG and NSP into endosomes, providing a mechanism for the intracytoplasmic translocation of the NSP–vDNA complex toward and from the cell periphery.
Histologic analysis of horses afflicted with idiopathic laryngeal hemiplegia: nerve and muscular properties
Authors: Hermanson John W , Svoboda Sarah M. , Cheetham Jonathan , Ducharme Normand G.
Published: June 2021

Equine idiopathic laryngeal hemiplegia (ILH), is characterized by respiratory distress at exercise due to paralysis of a muscle, the cricoarytenoideus dorsalis (CAD), that abducts the vocal folds during inspiration. Degeneration of the left recurrent laryngeal nerve (RLN) has been linked to paralysis in affected horses. Histology of this nerve and the CAD muscle in 18 horses was evaluated after endoscopic grading. Samples were evaluated for signs of degeneration, including differences in myelinated axons in the RLN or its laryngeal branches, as well as for fiber type grouping and muscle fiber hypertrophy and muscle atrophy in CAD muscles. There were more (p≤0.05) myelinated axons in the right RLN (601±29)than in the left (426±29). There was no significant difference in fiber type percentages (type I vs. II) in left vs. right CAD. However, there was more fiber type grouping in the left vs. the right CAD. In grade 1 horses, those without any functional deficit in movement of the vocal folds (subclinical disease), there were regions of fiber type grouping, suggesting reinnervation of those regions. In grade 4 horses (the worst cases) there was nearly total atrophy of the CAD, while nerves showed loss of myelinated axons. Results demonstrate that the RLN and CAD degenerate concomitantly in horses with both mild and severe laryngeal dysfunction. Funding was provided in part by the Zweig Fund and by Med‐El.
HIV persistence in lymph nodes
Authors: Banga Riddhima , Munoz Olivia , Perreau Matthieu
Published: June 2021

Purpose of review

HIV persists in distinct cellular and anatomical compartments in the body including blood, Central nervous system, and lymphoid tissues (spleen, lymph nodes [LNs], gut-associated lymphoid tissue) by diverse mechanisms despite antiretroviral therapy. Within LNs, human and animal studies have highlighted that a specific CD4 T cell subset - called T follicular helper cells locating in B cell follicles is enriched in cells containing replication-competent HIV as compared to extra-follicular CD4 T cells. Therefore, the objective of the present review is to focus on the potential mechanisms allowing HIV to persist within LN microenvironment.

Recent findings

The combination of factors that might be involved in the regulation of HIV persistence within LNs remain to be fully identified but may include - the level of activation, antiretroviral drug concentrations, presence of cytolytic mechanisms and/or regulatory cells, in addition to cell survival and proliferation propensity which would ultimately determine the fate of HIV-infected cells within LN tissue areas.

HIV persistence in blood and distinct body compartments despite long-standing and potent therapy is one of the major barriers to a cure. Given that the HIV reservoir is established early and is highly complex based on composition, viral diversity, distribution, replication competence, migration dynamics across the human body and possible compartmentalization in specific tissues, combinatorial therapeutic approaches are needed that may synergize to target multiple viral reservoirs to achieve a cure for HIV infection.
New findings bearing on the prevention, detection and management of high blood pressure
Authors: Carey Robert M. , Whelton Paul K.
Published: June 2021

Purpose of review

Hypertension is the foremost risk factor for cardiovascular disease (CVD) and death. This review highlights recent findings that apply to the prevention, detection, and management of high blood pressure (BP), in the context of the 2017 American College of Cardiology/American Heart Association BP guideline.

Recent findings

Several new findings on the association of BP measurement with CVD outcomes are now available. (1) Beginning with a systolic BP (SBP) as low as 90 mm Hg, coronary artery calcium deposition and the risk of incident atherosclerotic CVD (ASCVD) increased in stepwise fashion with increasing SBP levels within the normal range in adults at low risk for ASCVD. (2) Isolated diastolic hypertension was not associated with ASCVD, heart failure, or chronic kidney disease. (3) Nocturnal BP appeared to be better associated with CVD outcomes than office or daytime BP. (4) In a head-to-head comparison, home BP monitoring had higher reliability and predictive value than office or ambulatory BP to detect left ventricular hypertrophy, an intermediate form of hypertension-related target organ damage. In addition, new information indicates that autonomous aldosterone production is present in a substantially larger percentage of adults with hypertension than previously recognized. Finally, intensive BP lowering is associated with a significant reduction in the incidence of mild cognitive impairment, a precursor of dementia.

Ongoing research has made significant progress in the prevention, detection, and management of high BP, clarifying, amplifying, and/or supporting the 2017 ACC/AHA BP guideline recommendations.
Medical management of resistant hypertension: the role of sodium-glucose cotransporter 2 inhibitors (SGLT2i)
Authors: Alqudsi Muhannad , Velez Juan Carlos Q. , Navarrete Jose
Published: June 2021

Purpose of review

Controlling hypertension to the desired target is commonly unsuccessful and requires multi-drug regimen, which can lead to undesirable side effects. Resistant hypertension (RH) is more cumbersome to deal with and has robust morbidity and mortality burden even with current multiple medical options. Herein, we review the literature for the potential role of sodium-glucose cotransporter 2 inhibitors (SGLT2i) as a treatment option for hypertension and RH.

Recent findings

With more recent randomized controlled trials (RCTs), SGLT2i have gained more recognition for their renal and cardiovascular protection as well as mortality benefit that are believed to be medication class-related effects. Multiple RCTs have evaluated blood pressure (BP) lowering properties of SGLT2i, as a primary or secondary end point, in diabetic and nondiabetic patients, yet trials are scarce in studying SGLT2i as first-line antihypertensives, or as add-on agents for treating RH.

Finding the right medical therapy in treating hypertension, especially RH, is commonly onerous when it comes to achieving BP targets, avoiding medication side effects, and aiming for the best outcomes. Utilizing existing drugs like SGLT2i or exploring other novel agents with more RCTs for these purposes will be beneficial. The addition of SGLT2i to the therapeutic armamentarium in patients with RH should be considered as a target for upcoming RCTs.
New targets in inflammatory bowel disease therapy: 2021
Authors: Cohen Nathaniel A. , Rubin David T.
Published: June 2021

Purpose of review

In the rapidly progressing world of inflammatory bowel disease, this review discusses and summarizes new drug targets and results from major clinical trials in order to provide an update to physicians treating patients with inflammatory bowel diseases (IBD).

Recent findings

Multiple new mechanisms in the treatment of IBD are being developed and many are showing promising results in both ulcerative colitis and Crohn's disease patients. In addition to efficacy, some of these treatments may provide safety benefits over existing therapies.

The IBD physicians’ therapeutic armamentarium is rapidly expanding and keeping abreast of these developments is required in order to provide patients with optimized individualized care.
The role of the allergist in the management of eosinophilic esophagitis
Authors: Woo Wonhee , Aceves Seema S.
Published: June 2021

Purpose of review

The purpose of this review is to provide the current understanding of the role of allergens/antigens, the use of allergy testing, and to elucidate the role of the allergist in the management of eosinophilic esophagitis (EoE).

Recent findings

EoE is a T2 immune disorder that is part of the atopic march. EoE patients commonly have multiple concurrent allergic disorders. Recent studies demonstrate that, like other allergic diseases, epithelial barrier dysfunction plays a key role in EoE pathogenesis. Aero- and food allergens have been identified as EoE triggers. EoE management includes the assessment and avoidance of its instigating antigens. Due to the integrated T2 immune response in an allergic individual, proper EoE care should include the control of underlying atopic disorders. EoE is a complex disease that is optimally managed by a multidisciplinary approach.

This review provides an update on the role of the allergist in the clinical management of EoE.
Value-Based Payment
Authors: Pittman Patricia , Rambur Betty , Birch Susan , Chan Garrett K. , Cooke Cindy , Cummins Mollie , Leners Colleen , Low Lisa Kane , Meadows-Oliver Mikki , Shattell Mona , Taylor Cheryl , Trautman Deborah
Published: June 2021

Among the many lessons that have been reinforced by the SARS-COVID-19 pandemic is the failure of our current fee-for-service health care system to either adequately respond to patient needs or offer financial sustainability. This has enhanced bipartisan interest in moving forward with value-based payment reforms. Nurses have a rich history of innovative care models that speak to their potential centrality in delivery system reforms. However, deficits in terms of educational preparation, and in some cases resistance, to considering cost alongside quality, has hindered the profession's contribution to the conversation about value-based payments and their implications for system change. Addressing this deficit will allow nurses to more fully engage in redesigning health care to better serve the physical, emotional, and economic well-being of this nation. It also has the potential to unleash nurses from the tethers of a fee-for-service system where they have been relegated to a labor cost and firmly locate nurses in a value-generating role. Nurse administrators and educators bear the responsibility for preparing nurses for this next chapter of nursing.
Incorporating a Civility Program Into a Healthcare System
Authors: Garcia Mayra G. , Allen Stephanie , Griffis Leigh , Tidwell Jerithea , Watt Jennifer
Published: June 2021

Purpose/Objectives

Incivility contributes to employee dissatisfaction, turnover, patient errors, and a disrespectful culture. Turnover rates and employee exit interviews alerted hospital leaders to uncivil behaviors exhibited by staff. A clinical nurse specialist (CNS) team captured this as an opportunity to create a civility program to develop team cohesiveness and improve patient safety. The purpose of this process improvement project was to identify uncivil behaviors in a pediatric hospital.

Description of the Project/Program

Using the Plan-Do-Study-Act model, an interprofessional team led by CNSs collaborated on a program to assess, intervene, and evaluate a program to improve civility. A preprogram survey, the Negative Acts Questionnaire-Revised, was used to assess staff perceptions of their work environment. Staff attended an education program on ways to recognize and intervene in situations involving less than standard civil behavior. Classes included communication application in uncivil situations using scenarios paired with evidence-based practice articles. Unit leaders reset behavioral expectations learned from a leader-specific class on managing unproductive behaviors.

Outcome

Staff completed a postprogram Negative Acts Questionnaire-Revised survey 6 months after conclusion of classes. Survey results indicated the civility program effected a reduction in frequency of negative behaviors indicating an overall positive shift in workplace civility.

Conclusion

The program provided staff with tools to recognize and intervene for improving civility, which impacted the overall work environment and patient safety.
Establishing Performance Evaluation for Quality Inspection of Specialty Nurses
Authors: Cai Xinying , Zheng Shaoyan , Huang Jiajia , Zheng Zeli , Xu Manqing , Wu Xiaoying , Zhou Yuhua
Published: June 2021

Purpose

The present study aimed to establish an index system for the performance evaluation of specialty nurses (SNs) in tertiary hospitals.

Background

An objective index system for performance evaluation of SN has not yet been established in China.

Design

A 2-round Delphi survey sought opinions from experts about the index system for SNs' performance evaluation in tertiary hospitals in China.

Methods

Delphi survey was used to inquire approximately 20 experts from the fields of nursing management, nursing education, and clinical nursing. We determined the weight coefficient of each index of performance evaluation based on the opinion. Finally, the index of the quality evaluation was established for SN.

Results

A total of 20 experts from 10 provinces in China reached a consensus on the tertiary indexes of the assessment model. The indexes contained first-level (4), second-level (16), and third-level (24) indicators. The 4 aspects of the performance evaluation, including clinical specialist practice assessment, nursing research, education assessment, medical cooperation recognition, and personal comprehensive ability assessment, reached consensus.

Conclusion

Establishing the performance evaluation for SNs aided the SNs in achieving the best clinical practice after training. The performance evaluation still needed to be continuously improved.
A Tool Adaptation Workshop for Moral Distress in Military Critical Care Nurses
Authors: Wilson Melissa A.
Published: June 2021

Purpose

The US military healthcare services provide the highest level of trusted medical care to its members and to the world population during catastrophic events. These services can be difficult, making moral and ethical situations commonplace. Moral distress results when actions are inconsistent with personal or professional beliefs, resulting in a loss of moral integrity. Moral distress research is well established in the civilian literature and results in poor outcomes and increased expenses. There is little research studying moral distress in military providers.

Description of the Project

A clinical nurse specialist–led workshop was conducted with military and civilian experts. The expert panel reviewed the literature, examined instruments, and reviewed tool items for applicability to military healthcare providers.

Outcome

The team determined the existing civilian moral distress tool was applicable to military providers. Twelve additional items were added to the modified tool. A tool testing plan was developed to test the tool in military critical care nurses on the last day of the workshop for the next phase of this project.

Conclusion

The civilian moral distress tool was adapted for a military version and will be tested in the next phase of the project.
Epidemiological profiles and associated risk factors of SARS-CoV-2 positive patients based on a high-throughput testing facility in India
Authors: Malhotra Sumit , Rahi Manju , Das Payal , Chaturvedi Rini , Chhibber-Goel Jyoti , Anvikar Anup , Shankar Hari , Yadav C. P. , Meena Jaipal , Tewari Shalini , Gopinath Sudha V. , Chhabra Reba , Sharma Amit
Published: June 2021

We describe the epidemiological characteristics and associated risk factors of those presenting at a large testing centre for SARS-CoV-2 infection. This is a retrospective record review of individuals who underwent SARS-CoV-2 testing by reverse transcription–polymerase chain reaction (RT-PCR) at a high-throughput national-level government facility located in the north of India. Samples collected from 6 April to 31 December 2020 are included in this work and represent four highly populous regions. Additionally, there was a prospective follow-up of 1729 cases through telephone interviews from 25 May 2020 to 20 June 2020. Descriptive analysis has been performed for profiling clinic-epidemiological aspects of suspect cases. Multivariable logistic regression analysis was undertaken to determine risk factors that are associated with SARS-CoV-2 test positivity and symptom status. A total of 125 600 participants' details have been included in this report. The mean (s.d.) age of the participants was 33.1 (±15.3) years and 66% were male. Among these tested, 9515 (7.6%) were positive for COVID-19. A large proportion of positive cases were asymptomatic. In symptomatic positive cases, the commonest symptoms were cough and fever. Increasing age (groups 20–59 and ≥60 years compared to age group less than 5 years), male sex, history of international travel, symptoms for SARS-CoV-2, and participants from Delhi and Madhya Pradesh were positively associated with SARS-CoV-2 test positivity. Having co-morbidity, risk behaviours and intra-familial positivity were associated with a positive odds ratio for exhibiting SARS-CoV-2 symptoms. Intensified testing and isolation of cases, identification of both asymptomatic and symptomatic individuals and additional care of those with co-morbidities and risk behaviours will all be collectively important for disease containment in India. Reasons for differentials in testing between men and women remain an important area for in-depth study. The increased deployment of vaccines is likely to impact the trajectory of COVID-19 in the coming time, and therefore our data will serve as a comparative resource as India experiences the second wave of infection in light of newer variants that are likely to accelerate disease spread.
Replication of an open-access deep learning system for screening mammography: Reduced performance mitigated by retraining on local data
Authors: Condon J.J.J. , Oakden-Rayner L. , Hall K.A. , Reintals M. , Holmes A. , Carneiro G. , Palmer L.J.
Published: June 2021

Aim

To assess the generalisability of a deep learning (DL) system for screening mammography developed at New York University (NYU), USA (1, 2) in a South Australian (SA) dataset.

Methods and Materials

Clients with pathology-proven lesions (n=3,160) and age-matched controls (n=3,240) were selected from women screened at BreastScreen SA from January 2010 to December 2016 (n clients=207,691) and split into training, validation and test subsets (70%, 15%, 15% respectively). The primary outcome was area under the curve (AUC), in the SA Test Set 1 (SATS1), differentiating invasive breast cancer or ductal carcinoma in situ (n=469) from age-matched controls (n=490) and benign lesions (n=44). The NYU system was tested statically, after training without transfer learning (TL), after retraining with TL and without (NYU1) and with (NYU2) heatmaps.

Results

The static NYU1 model AUCs in the NYU test set (NYTS) and SATS1 were 83.0%(95%CI=82.4%-83.6%)(2) and 75.8%(95%CI=72.6%-78.8%), respectively. Static NYU2 AUCs in the NYTS and SATS1 were 88.6%(95%CI=88.3%-88.9%)(2) and 84.5%(95%CI=81.9%-86.8%), respectively. Training of NYU1 and NYU2 without TL achieved AUCs in the SATS1 of 65.8% (95%CI=62.2%-69.1%) and 85.9%(95%CI=83.5%-88.2%), respectively. Retraining of NYU1 and NYU2 with TL resulted in AUCs of 82.4%(95%CI=79.7-84.9%) and 86.3%(95%CI=84.0-88.5%) respectively.

Conclusion

We did not fully reproduce the reported performance of NYU on a local dataset; local retraining with TL approximated this level of performance. Optimising models for local clinical environments may improve performance. The generalisation of DL systems to new environments may be challenging.

Key Contributions

In this study, the original performance of deep learning models for screening mammography was reduced in an independent clinical population.

Deep learning (DL) systems for mammography require local testing and may benefit from local retraining.

An openly available DL system approximates human performance in an independent dataset.

There are multiple potential sources of reduced deep learning system performance when deployed to a new dataset and population.
Detection of Human Papillomaviruses DNA in paired peripheral blood and cervix samples patients with cervical lesions and healthy individuals
Authors: do Nascimento Kamylla Conceição Gomes , de Lima Elyda Gonçalves , da Mota Nunes Zhilbelly , Barros Júnior Marconi Rêgo , de Aragão Batista Marcus Vinícius , Lucena Antônio Roberto , da Costa Silva Neto Jacinto , Chagas Barbara Simas , Gurgel Ana Pavla Almeida Diniz , de Freitas Antonio Carlos
Published: June 2021

This study evaluated the presence of HPV DNA in the cervix and peripheral blood of women with cervical intraepithelial neoplasia (CIN I, II, and III) and healthy individuals. Overall, 139 paired peripheral blood and cervix samples of healthy women and women with CIN I, II, and III (n= 68) were tested for HPV DNA by using standard procedures. PCR-sequencing determined HPV types. Quantification of HPV16 E6 and E2 genes was performed to determine viral load and physical state. HPV DNA was detected in the cervix (21.1% in healthy individuals; 48.8-55.5% in CIN patients), blood (46.4% in healthy individuals; 44.1-77.7% in CIN patients), and paired peripheral blood and cervix samples (24% in healthy individuals; 32.5-44.4% in CIN patients). The most frequent types found in the cervix were HPV16, 18, 31, 33, 58, and 70, while HPV16, 18, 33, 58, and 66 were the most frequent types found in the blood. HPV DNA in the cervix was associated with previous sexually transmitted infections (STIs) (P=0.023; OR: 2.978; CI:1.34-7.821), HPV DNA in the blood (P=0.000; OR: 8.283; CI:3.700-18.540), and cervical lesions (CIN I/II or III) (P=0.007). Binomial logistic regression showed that HPV DNA in the blood (P=0.000; OR: 9.324; CI:3.612-24.072) and cervical lesions (P=0.011; OR: 3.622; CI:1.338-9.806) were associated with HPV DNA in the cervix. However, we did not find an association between HPV DNA in the blood and cervical lesions (P=0.385). Our results showed that only HPV DNA found in the cervix was associated with cervical lesions.
Overexpression of long non coding RNA OR3A4 is associated with altered p38 signalling, morphological and phenotypic changes, and reduced immunogenicity in Barrett’s Oesophagus
Authors: Nieto Tom , Sinha Yash , Zhuang Qin Qin , Coleman Mathew , Stockton Joanne , Whalley Celina , Hejmadi Rahul , Dilworth Mark , Stoldona Agata , Pestinger Valerie , Tucker Olga , Beggs Andrew D
Published: June 2021

Background

Barrett’s Oesophagus (BO) presents a particular pathological dilemma, in that patients who have no dysplasia within their BO experience a small but significant risk of malignant progression each year. Screening programmes have attempted to reduce the mortality from BO associated oesophageal adenocarcinoma but cannot predict which BO patients will progress to invasive malignancy. We have previously identified the long non coding RNA, OR3A4, is differentially hypomethylated in progressive BO. We aimed to understand its role in BO pathogenicity

Methods

The stable BO cell line CP-A, as well as the oesophageal adenocarcinoma cells line OE-33 was transfected with a lentiviral OR3A4 over-expression vector, and underwent high resolution microscopy, immunofluorescence, RT-qPCR, RNA sequencing, and targeted drug screening with the p38-MAPK inhibitor domipramod to understand the effects of OR3A4 expression on progression. We then compared progressive vs. non-progressive BO samples using quantitative multi-fluorophore (Vectra) immunohistochemistry.

Results

Over-expression of OR3A4 in CP-A lines resulted in a hyperproliferative, dysplastic cellular phenotype, with strong over-expression of MAPK and anti-apoptotic pathways at the RNA and protein level, which was sensitive to the p38-MAPK inhibitor domipramod. Vectra immunohistochemistry demonstrated that progressive BO had reduced visibility associated with a reduction in CD8+ T-cells and CD68+ macrophages and reduced CD4+ T-cells in the stomal compartment.

Conclusion

The overexpression of OR3A4, which we have previously shown is associated with progressive BO leads to a proliferative dysplastic cellular phenotype associated with increased, reversible MAPK signalling and loss of immune visibility.