Imprinted Maternally Expressed microRNAs Antagonize Paternally Driven Gene Programs in Neurons.

Imprinted genes with parental-biased allelic expression are frequently co-regulated and enriched in common biological pathways. Here, we functionally characterize a large cluster of microRNAs (miRNAs) expressed from the maternally inherited allele ("maternally expressed") to explore the molecular and cellular consequences of imprinted miRNA activity. Using an induced neuron (iN) culture system, we show that maternally expressed miRNAs from the miR-379/410 cluster direct the RNA-induced silencing complex (RISC) to transcriptional and developmental regulators, including paternally expressed transcripts like Plagl1. Maternal deletion of this imprinted miRNA cluster resulted in increased protein levels of several targets and upregulation of a broader transcriptional program regulating synaptic transmission and neuronal function. A subset of the transcriptional changes resulting from miR-379/410 deletion can be attributed to de-repression of Plagl1. These data suggest maternally expressed miRNAs antagonize paternally driven gene programs in neurons.

BET bromodomain inhibition as a therapeutic strategy to target c-Myc.

MYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective, we have targeted MYC transcription by interfering with chromatin-dependent signal transduction to RNA polymerase, specifically by inhibiting the acetyl-lysine recognition domains (bromodomains) of putative coactivator proteins implicated in transcriptional initiation and elongation. Using a selective small-molecule bromodomain inhibitor, JQ1, we identify BET bromodomain proteins as regulatory factors for c-Myc. BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of Myc-dependent target genes. In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell-cycle arrest and cellular senescence. Efficacy of JQ1 in three murine models of multiple myeloma establishes the therapeutic rationale for BET bromodomain inhibition in this disease and other malignancies characterized by pathologic activation of c-Myc.

Complications after transesophageal echocardiogram in pediatric patients with gastrostomy tube and/or Nissen fundoplication.

INTRODUCTION: Transesophageal echocardiography (TEE) is frequently used in children with and without congenital heart disease when transthoracic echocardiography is inadequate for visualizing cardiac structures. Recent guidelines state relative contraindications of TEE include post-gastrostomy tube (GT) or Nissen fundoplication surgery. No data exist documenting the incidence of complications in this population after a TEE. Aim of this study was to document the incidence of abdominal complications after TEE in pediatric patients who previously had a GT or Nissen fundoplication. METHODS: Single institution retrospective study was performed evaluating patients from 2013 through 2020. Patients were included if they had previously undergone a GT or Nissen procedure and subsequently underwent a TEE procedure. Baseline demographics were obtained. Major (esophageal/gastric perforation, oropharyngeal dysphagia, GT displacement, and Nissen breakdown) and minor (abdominal pain, feeding intolerance, and GT leakage) complications were recorded. RESULTS: Total of 34 patients underwent 48 TEE procedures. Age was 6.2 ± 6.6 years (median 3.0 years, .4 - 23.0 years) and weight was 18.5 ± 14.8 kgs (median 12.4 kgs, 4.2 - 57.5 kg) at time of TEE. Twenty-nine patients had congenital heart disease. Five patients had a Nissen fundoplication, 14 patients had a GT, and 15 patients had both procedures prior to the TEE. No patient had a major abdominal complication after the TEE. One patient had abdominal pain (2.1%), one patient had feeding intolerance and leakage around the GT site (2.1%), and two patients had leakage around the GT site (4.2%) after the TEE. Patients that experienced complications were significantly younger (1.7 ± 1.1 years vs. 6.6 ± 6.7 years, P < .01) and weighed less (8.7 ± 3.5 kg vs. 20.1 ± 15.5 kg, P < .01) than those that had no complications. All minor complications resolved with minimal interventions required. CONCLUSION: In this study, major abdominal complications did not occur after a TEE procedure in pediatric patients that had previous abdominal surgeries. The incidence of minor complications was relatively low and was easily remedied in this patient population. Though a relative contraindication by guidelines, TEE imaging, including transgastric views, can be performed relatively safely in pediatric patients with prior abdominal surgeries if needed.

Improving the end-of-life for people with dementia living in a care home: an intervention study.

BACKGROUND: One in three adults, most of whom are living in a care home at the time, dies with dementia. Their end-of-life is often in hospital, where they may experience uncomfortable interventions without known benefit and die rapidly with uncontrolled pain and comfort needs. This study aimed to improve end-of-life care for people with dementia in a care home by increasing the number and implementation of advanced care wishes. METHODS: We recruited staff, residents with dementia, and their relatives from a 120-bed nursing home in London, UK. The intervention was a ten-session manualized, interactive staff training program. We compared advance care wishes documentation and implementation, place of death for residents who died, and themes from staff and family carers' after-death interviews pre- and post-intervention. RESULTS: Post-intervention there were significant increases in documented advance care wishes arising from residents' and relatives' discussions with staff about end-of-life. These included do not resuscitate orders (16/22, 73% vs. 4/28, 14%; p < 0.001); and dying in the care homes as opposed to hospital (22/29, 76% vs. 14/30, 47%; p < 0.02). Bereaved relatives overall satisfaction increased from 7.5 (SD = 1.3) pre-intervention to 9.1 (SD = 2.4) post-intervention; t = 17.6, p = 0.06. Relatives reported increased consultation and satisfaction about decisions. Staff members were more confident about end-of-life planning and implementing advanced wishes. CONCLUSION: This small non-randomized study is the first end-of-life care in dementia intervention to report an increase in family satisfaction with a reduction in hospital deaths. This is promising but requires further evaluation in diverse care homes.

Pediatric Myocarditis.

Myocarditis is a condition caused by acute or chronic inflammation of the cardiac myocytes, resulting in associated myocardial edema and myocardial injury or necrosis. The exact incidence is unknown, but is likely underestimated, with more mild cases going unreported. Diagnosis and appropriate management are paramount in pediatric myocarditis, as it remains a recognized cause of sudden cardiac death in children and athletes. Myocarditis in children is most often caused by a viral or infectious etiology. In addition, there are now two highly recognized etiologies related to Coronavirus disease of 2019 (COVID-19) infection and the COVID-19 mRNA vaccine. The clinic presentation of children with myocarditis can range from asymptomatic to critically ill. Related to severe acute respiratory syndrome-Coronavirus 2 (SARs-CoV-2), children are at greater risk of developing myocarditis secondary to COVID-19 compared to the mRNA COVID-19 vaccine. Diagnosis of myocarditis typically includes laboratory testing, electrocardiography (ECG), chest X-ray, and additional non-invasive imaging studies with echocardiogram typically being the first-line imaging modality. While the reference standard for diagnosing myocarditis was previously endomyocardial biopsy, with the new revised Lake Louise Criteria, cardiac magnetic resonance (CMR) has emerged as an integral non-invasive imaging tool to assist in the diagnosis. CMR remains critical, as it allows for assessment of ventricular function and tissue characterization, with newer techniques, such as myocardial strain, to help guide management both acutely and long term.

Rewarded Maze Training Increases Approach Behavior in Rats Through Neurogenesis-Dependent Growth of Ventral Hippocampus-Prelimbic Circuits.

Background: Learning complex navigation routes increases hippocampal volume in humans, but it is not clear whether this growth impacts behaviors outside the learning situation or what cellular mechanisms are involved. Methods: We trained rats with pharmacogenetic suppression of adult neurogenesis and littermate controls in 3 mazes over 3 weeks and tested novelty approach behavior several days after maze exposure. We then measured hippocampus and prelimbic cortex volumes using magnetic resonance imaging and assessed neuronal and astrocyte morphology. Finally, we investigated the activation and behavioral role of the ventral CA1 (vCA1)-to-prelimbic pathway using immediate-early genes and DREADDs (designer receptors exclusively activated by designer drugs). Results: Maze training led to volume increase of both the vCA1 region of the hippocampus and the prelimbic region of the neocortex compared with rats that followed fixed paths. Growth was also apparent in individual neurons and astrocytes in these 2 regions, and behavioral testing showed increased novelty approach in maze-trained rats in 2 different tests. Suppressing adult neurogenesis prevented the effects on structure and approach behavior after maze training without affecting maze learning itself. The vCA1 neurons projecting to the prelimbic area were more activated by novelty in maze-trained animals, and suppression of this pathway decreased approach behavior. Conclusions: Rewarded navigational learning experiences induce volumetric and morphologic growth in the vCA1 and prelimbic cortex and enhance activation of the circuit connecting these 2 regions. Both the structural and behavioral effects of maze training require ongoing adult neurogenesis, suggesting a role for new neurons in experience-driven increases in novelty exploration.

Distinguishing Distinct Neural Systems for Proximal vs Distal Upper Extremity Motor Control After Acute Stroke.

BACKGROUND AND OBJECTIVES: The classic and singular pattern of distal greater than proximal upper extremity motor deficits after acute stroke does not account for the distinct structural and functional organization of circuits for proximal and distal motor control in the healthy CNS. We hypothesized that separate proximal and distal upper extremity clinical syndromes after acute stroke could be distinguished and that patterns of neuroanatomical injury leading to these 2 syndromes would reflect their distinct organization in the intact CNS. METHODS: Proximal and distal components of motor impairment (upper extremity Fugl-Meyer score) and strength (Shoulder Abduction Finger Extension score) were assessed in consecutively recruited patients within 7 days of acute stroke. Partial correlation analysis was used to assess the relationship between proximal and distal motor scores. Functional outcomes including the Box and Blocks Test (BBT), Barthel Index (BI), and modified Rankin scale (mRS) were examined in relation to proximal vs distal motor patterns of deficit. Voxel-based lesion-symptom mapping was used to identify regions of injury associated with proximal vs distal upper extremity motor deficits. RESULTS: A total of 141 consecutive patients (49% female) were assessed 4.0 ± 1.6 (mean ± SD) days after stroke onset. Separate proximal and distal upper extremity motor components were distinguishable after acute stroke (p = 0.002). A pattern of proximal more than distal injury (i.e., relatively preserved distal motor control) was not rare, observed in 23% of acute stroke patients. Patients with relatively preserved distal motor control, even after controlling for total extent of deficit, had better outcomes in the first week and at 90 days poststroke (BBT, ρ = 0.51, p < 0.001; BI, ρ = 0.41, p < 0.001; mRS, ρ = 0.38, p < 0.001). Deficits in proximal motor control were associated with widespread injury to subcortical white and gray matter, while deficits in distal motor control were associated with injury restricted to the posterior aspect of the precentral gyrus, consistent with the organization of proximal vs distal neural circuits in the healthy CNS. DISCUSSION: These results highlight that proximal and distal upper extremity motor systems can be selectively injured by acute stroke, with dissociable deficits and functional consequences. Our findings emphasize how disruption of distinct motor systems can contribute to separable components of poststroke upper extremity hemiparesis.

Care at the end of life for people with dementia living in a care home: a qualitative study of staff experience and attitudes.

OBJECTIVE: The aim of this study is to examine barriers and facilitators to care home staff delivering improved end-of-life care for people with dementia. METHOD: Individual qualitative interviews of 58 staff in a 120-bed nursing home where the staff and the residents' religion differed were carried out. Interviews continued until a maximum variation sample was achieved and theoretical saturation was reached. RESULTS: The staff felt warmly towards the residents and felt they could recognise when they were near death. Care staff, nurses and doctors did not see themselves as a team and communicated poorly with relatives about approaching death. The staff used opaque euphemisms and worried about being blamed. They were often unaware of or had concerns about the validity of advance care plans. They knew of the religious rituals around death but frequently misunderstood religious tradition. CONCLUSION: The staff require education and support about discussing and implementing plans around care at the end of life in dementia and about cultural issues around death to improve practice. This would enable the staff to implement advance care plans, knowing that they will be supported. Education would encompass communicating the complicated, unpredictable path of dementia near the time of death explicitly but sensitively, including recognising that people often do not hear difficult messages and are unable to take on large quantities of information at once. The staff need to know about the resident's religious and cultural ideas as well as ritual practice.

Framing Concerns about Body Image during Pre- and Post-Surgical Consultations for Head and Neck Cancer: A Qualitative Study of Patient-Physician Interactions.

Patients with head and neck cancer report high unmet psychosocial needs as they undergo lifesaving treatments that can significantly alter their appearance and cause functional impairments. This qualitative analysis of recordings of 88 pre- and post-surgical consultations involving 20 patients respond to the need for empirical studies of patient-provider conversations about body image concerns. It indicates that the emphasis on concerns about survival, cure, and physical recovery during clinical consultations may leave concerns about the impacts of surgery on appearance and function unexplored and even silenced. The interviews with patients and medical team members that complement the analysis of the recordings suggest that an emphasis on survival, cure, and physical recovery can respond to the need for reassurance in the context of serious illness. However, it can also be problematic as it contributes to the silencing of patients' concerns and to a potential lack of preparedness for the consequences of surgery. The results of this study can contribute to raising surgeons' awareness of the interactional dynamics during clinical consultations. Moreover, the results highlight the unique role that surgeons can play in validating patients' psychosocial concerns to support patients' rehabilitation in both physical and psychosocial domains.

Molecular and cellular effects of multi-targeted cyclin-dependent kinase inhibition in myeloma: biological and clinical implications.

Cell cycle regulators, such as cyclin-dependent kinases (CDKs), are appealing targets for multiple myeloma (MM) therapy given the increased proliferative rates of tumour cells in advanced versus early stages of MM. We hypothesized that a multi-targeted CDK inhibitor with a different spectrum of activity compared to existing CDK inhibitors could trigger distinct molecular sequelae with therapeutic implications for MM. We therefore studied the small molecule heterocyclic compound NVP-LCQ195/AT9311 (LCQ195), which inhibits CDK1, CDK2 and CDK5, as well as CDK3 and CDK9. LCQ195 induced cell cycle arrest and eventual apoptotic cell death of MM cells, even at sub-µmol/l concentrations, spared non-malignant cells, and overcame the protection conferred to MM cells by stroma or cytokines of the bone marrow milieu. In MM cells, LCQ195 triggered decreased amplitude of transcriptional signatures associated with oncogenesis, drug resistance and stem cell renewal, including signatures of activation of key transcription factors for MM cells e.g. myc, HIF-1α, IRF4. Bortezomib-treated MM patients whose tumours had high baseline expression of genes suppressed by LCQ195 had significantly shorter progression-free and overall survival than those with low levels of these transcripts in their MM cells. These observations provide insight into the biological relevance of multi-targeted CDK inhibition in MM.

Multiple myeloma, race, insurance and treatment.

PURPOSE: Multiple Myeloma (MM), the second leading blood malignancy, has complex and costly disease management. We studied patterns of treatment disparities and unplanned interruptions among the MM patients after the Affordable Care Act to assess their prevalence and effect on survival. MATERIALS AND METHODS: This retrospective study of 1002 MM patients at a tertiary referral center used standard guidelines as a reference to identify underuse of effective treatments. We used multivariate logistic regression and Cox proportionate hazard to study the prognostic effect on survival. RESULTS: Median age in the cohort was 63.0 [IQR: 14] years. Non-Hispanic White (NHW) patients were older (p = 0.007) and more likely to present with stage I disease (p = 0.02). Underuse of maintenance therapy (aOR = 1.98; 95 % CI 1.12-3.48) and interruptions in treatment were associated with race/ethnicity and insurance (aOR = 4.14; 95 % CI: 1.78-9.74). Only underuse of induction therapy was associated with overall patient survival. CONCLUSION: Age, race, ethnicity and primary insurance contribute to the underuse of treatment and in unplanned interruptions in MM treatment. Addressing underuse causes in such patients is warranted.

Molecular and cellular effects of NEDD8-activating enzyme inhibition in myeloma.

The NEDD8-activating enzyme is upstream of the 20S proteasome in the ubiquitin/proteasome pathway and catalyzes the first step in the neddylation pathway. NEDD8 modification of cullins is required for ubiquitination of cullin-ring ligases that regulate degradation of a distinct subset of proteins. The more targeted impact of NEDD8-activating enzyme on protein degradation prompted us to study MLN4924, an investigational NEDD8-activating enzyme inhibitor, in preclinical multiple myeloma models. In vitro treatment with MLN4924 led to dose-dependent decrease of viability (EC(50) = 25-150 nmol/L) in a panel of human multiple myeloma cell lines. MLN4924 was similarly active against a bortezomib-resistant ANBL-6 subline and its bortezomib-sensitive parental cells. MLN4924 had submicromolar activity (EC(50) values <500 nmol/L) against primary CD138(+) multiple myeloma patient cells and exhibited at least additive effect when combined with dexamethasone, doxorubicin, and bortezomib against MM.1S cells. The bortezomib-induced compensatory upregulation of transcripts for ubiquitin/proteasome was not observed with MLN4924 treatment, suggesting distinct functional roles of NEDD8-activating enzyme versus 20S proteasome. MLN4924 was well tolerated at doses up to 60 mg/kg 2× daily and significantly reduced tumor burden in both a subcutaneous and an orthotopic mouse model of multiple myeloma. These studies provide the framework for the clinical investigation of MLN4924 in multiple myeloma.