NSD2 drives t(4;14) myeloma cell dependence on adenylate kinase 2 by diverting one-carbon metabolism to the epigenome.

ABSTRACT: Chromosomal translocation (4;14), an adverse prognostic factor in multiple myeloma (MM), drives overexpression of the histone methyltransferase nuclear receptor binding SET domain protein 2 (NSD2). A genome-wide CRISPR screen in MM cells identified adenylate kinase 2 (AK2), an enzyme critical for high-energy phosphate transfer from the mitochondria, as an NSD2-driven vulnerability. AK2 suppression in t(4;14) MM cells decreased nicotinamide adenine dinucleotide phosphate (NADP[H]) critical for conversion of ribonucleotides to deoxyribonucleosides, leading to replication stress, DNA damage, and apoptosis. Driving a large genome-wide increase in chromatin methylation, NSD2 overexpression depletes S-adenosylmethionine, compromising the synthesis of creatine from its precursor, guanidinoacetate. Creatine supplementation restored NADP(H) levels, reduced DNA damage, and rescued AK2-deficient t(4;14) MM cells. As the creatine phosphate shuttle constitutes an alternative means for mitochondrial high-energy phosphate transport, these results indicate that NSD2-driven creatine depletion underlies the hypersensitivity of t(4;14) MM cells to AK2 loss. Furthermore, AK2 depletion in t(4;14) cells impaired protein folding in the endoplasmic reticulum, consistent with impaired use of mitochondrial adenosine triphosphate (ATP). Accordingly, AK2 suppression increased the sensitivity of MM cells to proteasome inhibition. These findings delineate a novel mechanism in which aberrant transfer of carbon to the epigenome creates a metabolic vulnerability, with direct therapeutic implications for t(4;14) MM.

Structural basis for a highly conserved RNA-mediated enteroviral genome replication.

Enteroviruses contain conserved RNA structures at the extreme 5' end of their genomes that recruit essential proteins 3CD and PCBP2 to promote genome replication. However, the high-resolution structures and mechanisms of these replication-linked RNAs (REPLRs) are limited. Here, we determined the crystal structures of the coxsackievirus B3 and rhinoviruses B14 and C15 REPLRs at 1.54, 2.2 and 2.54 Šresolution, revealing a highly conserved H-type four-way junction fold with co-axially stacked sA-sD and sB-sC helices that are stabilized by a long-range A•C•U base-triple. Such conserved features observed in the crystal structures also allowed us to predict the models of several other enteroviral REPLRs using homology modeling, which generated models almost identical to the experimentally determined structures. Moreover, our structure-guided binding studies with recombinantly purified full-length human PCBP2 showed that two previously proposed binding sites, the sB-loop and 3' spacer, reside proximally and bind a single PCBP2. Additionally, the DNA oligos complementary to the 3' spacer, the high-affinity PCBP2 binding site, abrogated its interactions with enteroviral REPLRs, suggesting the critical roles of this single-stranded region in recruiting PCBP2 for enteroviral genome replication and illuminating the promising prospects of developing therapeutics against enteroviral infections targeting this replication platform.

A systematic appraisal of the information, engagement, aesthetic and functional quality of nutrition-related smartphone apps for children and adolescents.

OBJECTIVE: Nutrition-related smartphone applications (apps) could improve children's nutrition knowledge and skills. However, little is known about the quality of nutrition-related apps for children. This study aimed to identify and evaluate the quality of nutrition-related smartphone apps designed for children ages 4-17. DESIGN: This systematic appraisal is guided by the Protocol for App Store Systematic Reviews. SETTING: Using Google's Advanced Search, we identified 1814 apps/1184 additional apps in an updated search on iOS, of which twenty-four were eligible. The apps' objective and subjective quality were evaluated using the twenty-three-item, five-point Mobile App Rating Scale. The objective quality scale consists of four subscales: engagement, functionality, aesthetics and information. RESULTS: Most of the apps (75 %) focussed solely on promoting nutrition skills, such as making food dishes, rather than nutrition knowledge. Of the twenty-four apps, 83 % targeted children 4-8 years old. The app objective quality mean score was 3·60 ± 0·41. The subscale mean scores were 3·20 ± 0·41 for engagement, 4·24 ± 0·47 for functionality, 4·03 ± 0·51 for aesthetics and 2·94 ± 0·62 for information. The app subjective quality mean score was 2·10 ± 0·90. CONCLUSIONS: More robust approaches to app development leveraging co-design approaches, including involving a multidisciplinary team of experts to provide evidence-based nutrition information, are warranted.

Lessons learned from implementing SNAP-Ed in a nursing/K-8 partnership school during the pandemic.

The COVID-19 pandemic had forced schools and school-based partnerships in the US to re-imagine extracurricular activities while schools were closed for in-person learning. We highlight lessons learned from implementing the Supplemental Nutrition Assistance Education Program (SNAP-Ed) virtually, a nutrition education program to improve nutrition literacy and skills among children, in a Maryland School of Nursing/K-8 Partnership school amid in-person school closures.

What can we learn from the last 20 years: A review of litigation trends in otolaryngology.

INTRODUCTION: Litigation in healthcare is a large financial burden to the NHS and can be a cause of great stress to clinicians. The overall number of claims across specialities, from the years 1995-2017 have increased. Despite being one of the smaller surgical specialities, litigation costs are still significant within Otolaryngology. In this piece we sought to analyse the available data to identify trends within litigation and therefore which areas of practise could be improved. METHODS: A freedom of information request was submitted to NHS Resolution for summarised data on claims coded under 'Otolaryngology' or 'ENT' between 1996 and 2017. Information was collected on the total number of claims, the number of successful claims and details on the reasons for making claims. RESULTS: The total number of claims made against Otolaryngology departments from 1996/97 to 2016/17 was 1952. The overall number of claims have increased during this time period. The total amount of money paid out between 1996 and 2017 was £108, 240, 323. The top causes of claim by injury were unnecessary pain and unnecessary operations. The highest number of claims by cause were for failure or delay in diagnosis and intraoperative problems. CONCLUSION: These results highlight areas that local units can focus on to reduce their litigation burden. Targeted initiatives aimed at improving patient-clinician communication, the consent process and improving local organisational efficiency will address a significant proportion of claims. Re-examination of this data on a regular basis can serve as a useful adjunct in assessing the impact of quality improvement initiatives and implementation of best practiseswithin the speciality.

Outcome of Primary Desmoid Tumors at All Anatomic Locations Initially Managed with Active Surveillance.

BACKGROUND: The behavior of desmoid tumors is unpredictable and varies from spontaneous remission to symptomatic and radiologic progression. This study aimed to evaluate the radiologic and symptomatic course of the disease in patients initially managed with active surveillance. METHODS: Patients with a primary desmoid tumor at any anatomic location diagnosed between 1998 and 2016 were identified in a prospectively maintained database from a single sarcoma reference center in the United Kingdom. Inverse univariate Cox proportional hazard regression analyses were conducted to evaluate the course of the disease and indications for initiating treatment. RESULTS: The study identified 168 patients with a primary desmoid tumor initially managed with active surveillance. The tumors were located in the abdominal wall (n = 61, 36%), an extremity (n = 51, 30%), chest wall (n = 30, 18%), intra-abdominal site (n = 15, 9%), or elsewhere (n = 11, 6%). Of all the patients, 36% experienced radiologic progressive disease, 36% had stable disease, and 27% regressed. The patients younger than 50 years were more likely to progress (p = 0.046), whereas the patients with chest wall or upper-extremity tumors reported significantly more pain (p = 0.01). Eventually, 46% of the patients proceeded to treatment. The median time to start of treatment after initial surveillance was 31 months, whereas the median follow-up time for the patients not receiving any treatment was 40.5 months. The indications for initiation of treatment were pain (32%), progression (31%), or both (13%). CONCLUSIONS: Patients with desmoid tumors can be managed with initial active surveillance, although almost half of patients may eventually need treatment. Pain, tumor progression, or both are the most common indications for the initiation of treatment.

Trans-epithelial migration is essential for neutrophil activation during RSV infection.

The recruitment of neutrophils to the infected airway occurs early following respiratory syncytial virus (RSV) infection, and high numbers of activated neutrophils in the airway and blood are associated with the development of severe disease. The aim of this study was to investigate whether trans-epithelial migration is sufficient and necessary for neutrophil activation during RSV infection. Here, we used flow cytometry and novel live-cell fluorescent microscopy to track neutrophil movement during trans-epithelial migration and measure the expression of key activation markers in a human model of RSV infection. We found that when migration occurred, neutrophil expression of CD11b, CD62L, CD64, NE, and MPO increased. However, the same increase did not occur on basolateral neutrophils when neutrophils were prevented from migrating, suggesting that activated neutrophils reverse migrate from the airway to the bloodstream side, as has been suggested by clinical observations. We then combined our findings with the temporal and spatial profiling and suggest 3 initial phases of neutrophil recruitment and behavior in the airways during RSV infection; (1) initial chemotaxis; (2) neutrophil activation and reverse migration; and (3) amplified chemotaxis and clustering, all of which occur within 20 min. This work and the novel outputs could be used to develop therapeutics and provide new insight into how neutrophil activation and a dysregulated neutrophil response to RSV mediates disease severity.

Initiation of a discharge pharmacy within a busy urban emergency department: The first year.

PURPOSE: Discharge prescriptions represent an important aspect of care for patients seen in the emergency department (ED) setting and are used by providers to continue therapy for acute illness once patients leave the ED or to prevent future exacerbations of chronic conditions. The success of an ED discharge and the medications prescribed rely on patient compliance. Compliance depends on patients' ability to obtain prescriptions, which can be hindered by limited access to pharmacies and cost. SUMMARY: In order to address issues traditionally associated with medication noncompliance, a discharge pharmacy was implemented within a busy urban ED. The pharmacy began processing prescriptions on December 18, 2019, using a formulary aimed towards providing commonly prescribed and high-risk medications. The pharmacy accepts insurance plans in addition to utilizing 340B Drug Pricing Program pricing to offer affordable medications to patients. During the first year of operation 10,230 prescriptions were filled for 5,703 patients, representing 13% of all patients discharged during that time. Of the prescriptions filled, 35.4% were for products considered high-risk medications, including epinephrine auto-injectors, insulin, and antibiotics. Over 50% of these high-risk medications were provided to patients through reduced cash pricing. Pharmacist interventions were made on 4.3% of prescriptions to address incorrect dosing, avoid use of inappropriate antibiotics, and recommend alternative therapies. CONCLUSION: The implementation of a discharge pharmacy within the ED allowed over 5,700 patients to be discharged with medications and represents a potential solution to issues surrounding medication noncompliance. Similar initiatives have the opportunity to improve medication access for a larger ED population.

Loss of cardiac myosin light chain kinase contributes to contractile dysfunction in right ventricular pressure overload.

Nearly 1 in every 100 children born have a congenital heart defect. Many of these defects primarily affect the right heart causing pressure overload of the right ventricle (RV). The RV maintains function by adapting to the increased pressure; however, many of these adaptations eventually lead to RV hypertrophy and failure. In this study, we aim to identify the cellular and molecular mechanisms of these adaptions. We utilized a surgical animal model of pulmonary artery banding (PAB) in juvenile rats that has been shown to accurately recapitulate the physiology of right ventricular pressure overload in young hearts. Using this model, we examined changes in cardiac myocyte protein expression as a result of pressure overload with mass spectrometry 4 weeks post-banding. We found pressure overload of the RV induced significant downregulation of cardiac myosin light chain kinase (cMLCK). Single myocyte calcium and contractility recordings showed impaired contraction and relaxation in PAB RV myocytes, consistent with the loss of cMLCK. In the PAB myocytes, calcium transients were of smaller amplitude and decayed at a slower rate compared to controls. We also identified miR-200c, which has been shown to regulate cMLCK expression, as upregulated in the RV in response to pressure overload. These results indicate the loss of cMLCK is a critical maladaptation of the RV to pressure overload and represents a novel target for therapeutic approaches to treat RV hypertrophy and failure associated with congenital heart defects.

Factors Influencing Emergency Department Utilization and Hospital Re-Admissions in a Predominantly Obese, Racially Diverse Urban Renal Transplant Population.

INTRODUCTION: Early emergency department and hospital re-admissions are common in renal transplant recipients, but data are lacking in unique populations. Study Aim: The purpose of this study was to identify patient risk factors for multiple acute care utilization events within the first year of renal transplantation. DESIGN: This was a single-center, retrospective cohort study of adult renal transplant recipients between 9/2013-9/2016. Patients were compared across number of emergency department visits and by hospital re-admissions. Diagnoses were categorized. Univariate and multivariate logistic regression was used to assess risk for multiple acute care utilization events within the first 12 months post-transplant. RESULTS: A total of 216 patients were analyzed and were on average 50.5 (SD 13.9) years old, redominantly Black (49.77%) with an average body mass index of 33.33 (9.8) and were recipients of deceased donor renal transplants (61.11%). A total of 105 (48.6%) patients visited the emergency epartment and 119 (55.1%) patients had a hospital readmission. Patients having a body mass index >35 kg/m2 did not differ across emergency department visit or hospitalization groups. Delayed graft function (OR 2.86, 95% CI 1.07-7.65) and previous renal transplant (OR 2.77, 95% CI 1.04-7.39) were significantly associated with multiple acute care utilizations. DISCUSSION: Acute care utilization following renal transplantation was similar to previously reported experiences. Obesity did not impact use of acute care resources or patient outcomes. Strategies addressing potential preventable emergency visits and hospital re-dmissions should be promoted.

Point-of-care naloxone distribution in the emergency department: A pilot study.

PURPOSE: Opioid overdose education and naloxone distribution (OEND) for use by laypersons has been shown to be safe and effective, but implementation in the emergency department (ED) setting is challenging. Recent literature has shown a discouragingly low rate of obtainment of naloxone that is prescribed in the ED setting. We conducted a study to evaluate the feasibility of point-of-care (POC) distribution of naloxone in an ED, hypothesizing a rate of obtainment higher than prescription fill rates reported in previous studies. SUMMARY: A multidisciplinary team of experts, including pharmacists, physicians, nurses, and case management professionals used an iterative process to develop a protocol for POC OEND in the ED. The protocol includes 5 steps: (1) patient screening, (2) order placement in the electronic health record (EHR), (3) a patient training video, (4) dispensing of naloxone kit, and (5) written discharge instructions. The naloxone kits were assembled, labeled to meet requirements for a prescription, and stored in an automated dispensing cabinet. Two pharmacists, 30 attending physicians, 65 resident physicians, and 108 nurses were trained. In 8 months, 134 orders for take-home naloxone were entered and 117 naloxone kits were dispensed, resulting in an obtainment rate of 87.3%. The indication for take-home naloxone kit was heroin use for 61 patients (92.4%). CONCLUSION: POC naloxone distribution is feasible and yielded a rate of obtainment significantly higher than previous studies in which naloxone was prescribed. POC distribution can be replicated at other hospitals with low rates of obtainment.

C/VDdb: A multi-omics expression profiling database for a knowledge-driven approach in cardiovascular disease (CVD).

The cardiovascular disease (C/VD) database is an integrated and clustered information resource that covers multi-omic studies (microRNA, genomics, proteomics and metabolomics) of cardiovascular-related traits with special emphasis on coronary artery disease (CAD). This resource was built by mining existing literature and public databases and thereafter manual biocuration was performed. To enable integration of omic data from distinct platforms and species, a specific ontology was applied to tie together and harmonise multi-level omic studies based on gene and protein clusters (CluSO) and mapping of orthologous genes (OMAP) across species. CAD continues to be a leading cause of death in the population worldwide, and it is generally thought to be an age-related disease. However, CAD incidence rates are now known to be highly influenced by environmental factors and interactions, in addition to genetic determinants. With the complexity of CAD aetiology, there is a difficulty in research studies to elucidate general elements compared to other cardiovascular diseases. Data from 92 studies, covering 13945 molecular entries (4353 unique molecules) is described, including data descriptors for experimental setup, study design, discovery-validation sample size and associated fold-changes of the differentially expressed molecular features (p-value<0.05). A dedicated interactive web interface, equipped with a multi-parametric search engine, data export and indexing menus are provided for a user-accessible browsing experience. The main aim of this work was the development of a data repository linking clinical information and molecular differential expression in several CVD-related traits from multi-omics studies (genomics, transcriptomics, proteomics and metabolomics). As an example case of how to query and identify data sets within the database framework and concomitantly demonstrate the database utility, we queried CAD-associated studies and performed a systems-level integrative analysis. URL: www.padb.org/cvd.

Primary-care-based social prescribing for mental health: an analysis of financial and environmental sustainability.

UNLABELLED: Aim To assess the effects of a social prescribing service development on healthcare use and the subsequent economic and environmental costs. BACKGROUND: Social prescribing services for mental healthcare create links with support in the community for people using primary care. Social prescribing services may reduce future healthcare use, and therefore reduce the financial and environmental costs of healthcare, by providing structured psychosocial support. The National Health Service (NHS) is required to reduce its carbon footprint by 80% by 2050 according to the Climate Change Act (2008). This study is the first of its kind to analyse both the financial and environmental impacts associated with healthcare use following social prescribing. The value of this observational study lies in its novel methodology of analysing the carbon footprint of a service at the primary-care level. METHOD: An observational study was carried out to assess the impact of the service on the financial and environmental impacts of healthcare use. GP appointments, psychotropic medications and secondary-care referrals were measured. Findings Results demonstrate no statistical difference in the financial and carbon costs of healthcare use between groups. Social prescribing showed a trend towards reduced healthcare use, mainly due to a reduction in secondary-care referrals compared with controls. The associations found did not achieve significance due to the small sample size leading to a large degree of uncertainty regarding differences. This study demonstrates that these services are potentially able to pay for themselves through reducing future healthcare costs and are effective, low-carbon interventions, when compared with cognitive behavioral therapy or antidepressants. This is an important finding in light of Government targets for the NHS to reduce its carbon footprint by 80% by 2050. Larger studies are required to investigate the potentials of social prescribing services further.

Improving the quality of discharge summaries: implementing updated Academy of Medical Royal Colleges standards at a district general hospital.

Quality of documentation is harder to quantify and incentivise, but it has a significant impact on patient care. Good discharge summaries facilitate continuity between secondary and primary care. The junior doctors' forum led this project to improve the quality of electronic discharge summaries (eDS). Baseline measurement revealed significant room for improvement. We measured the quality of 10 summaries per month (across all inpatient specialties), against 23 indicators from the revised Academy of Medical Royal Colleges (AoMRC) standards (2013) that were prioritised by GPs as a "minimum dataset". Junior doctors felt that the Trust's dual eDS systems were responsible for great variation in quality. This was confirmed by the results of a comparison audit of the systems in April 2014: one system greatly outperformed the other (57% mean compliance with iSoft clinical management (iCM) based system vs. 77% with InfoPath-based system). We recommended that the Trust move to a single eDS system, decommissioning the iCM-based system, and this proposal was approved by several Trust committees. We worked with information services, junior doctors, general practitioners and hospital physicians to develop and implement a generic template to further improve compliance with AoMRC standards. In August 2014, the iCM-based system was withdrawn, the new template went live, and training was delivered, coinciding with the changeover of junior doctors to minimise disruption. Median compliance increased from 66.7% to 77.8%. Quality of discharge summaries had improved across the specialties. There was a reduction in the number of complaints and positive qualitative feedback from general practitioners and junior doctors. Completion of discharge summaries within 24 hours was not affected by this change. There is still more to be done to improve quality; average compliance with the full AoMRC standards (39 indicators) is 59.5%. With the approval of the Trust executive committee further plan, do, study, act (PDSA) cycles are underway, working to improve the remaining specialty-specific templates.