Perceived benefits of patient support groups and their format for people with an implantable cardioverter defibrillator.

BACKGROUND: Support groups for people with Implantable Cardioverter Defibrillators (ICDs) are widely used, however, it is not clear what people with ICDs gain from a support group or what format they should take. OBJECTIVES: The aim of the present study is to define the perceived benefit of ICD support groups and develop practical recommendations for group format. METHODS: 14 individuals with ICDs were interviewed using a semi-structured interview guide. Reflexive thematic analysis methods were utilised to code and analyse the transcripts before generating themes. RESULTS: Four themes were defined: confronting mortality, coping through sharing, coping through learning, and providing space. Making connections with other people with ICDs, reassurance, access to information, and advice from health care professionals were important perceived benefits of the support group. CONCLUSION: People with ICDs may have to confront their own mortality and adapt to considerable life changes after implant. The findings from the present study have improved understanding of how support groups are perceived and how ICD indication and group format influence the experience. A blended format of in-person community meetings, online forums, HCP-led education and space for person-person interaction is recommended. Importantly, provision of support should not be time-limited to allow people to access it when it most likely to be of benefit to them.

Reducing first appointment delays for electron radiotherapy patients by improving the treatment planning pathway: a quality improvement project.

Clatterbridge Cancer Centre (CCC) is a specialist hospital trust in England with three sites.Delay to the start of an appointment for radiotherapy, especially the first appointment (a 'New Start') is poor, both for operational efficiency and patient experience, causing stress for both patients and staff. Our aim is for the New Start to begin within 30 min of the allotted appointment time. To this end, we established another aim: for 'Final Checks' to the radiotherapy plan to be completed at least 30 min prior to the New Start appointment time.Prior to this quality improvement (QI) project, only 33% of electron-treatment New Start appointments started within the target 30 min (the average delay was 52.4 min) and only 48% of the corresponding Final Checks had been completed by their 30 min prior target.The treatment pathway for these patients was redesigned, with the aim of 90% of New Start appointments starting within 30 min of the allotted appointment time.By the end of this QI project, 69.2% of New Start appointments started within 30 min of the appointment time (with average delay reduced to 27.2 min), and 92.3% of Final Checks were completed by their 30 min prior target. We also reduced the number of safety (Datix) incidents due to plan not ready from 10 to 0. A year after the project, we have held most of the time improvements and still have had 0 plan-not-ready Datix.The largest improvement was achieved by introducing a proxy (without the patient present) 'day 0' appointment. This takes place in advance of the New Start appointment to enable earlier planning. Subsequent improvements included: automating previously manual planning calculations, making the care path consistent with other external beam radiotherapy care paths at CCC to reduce staff cognitive load and sharing key performance data with staff.

Benefits of support groups for patients living with implantable cardioverter defibrillators: a mixed-methods systematic review and meta-analysis.

BACKGROUND: Patients with implantable cardioverter defibrillators (ICD) experience anxiety, depression and reduced quality of life (QoL). OBJECTIVES: This mixed-methods systematic review evaluates whether ICD support groups have a beneficial effect on mental well-being. METHODS: Literature searches were carried out in MEDLINE, Embase, CINAHL, PsycINFO and Web of Science. Eligible studies investigated patient-led support groups for ICD patients aged 18 years or older, using any quantitative or qualitative design. The Mixed-Methods Assessment Tool was used to assess quality. Meta-analysis of measures of mental well-being was conducted. Thematic synthesis was used to generate analytic themes from the qualitative data. The data were integrated and presented using the Pillar Integration Process. RESULTS: Ten studies were included in this review. All studies bar one were non-randomised or had a qualitative design and patients had self-selected to attend a support group. Five contributed to the quantitative data synthesis and seven to the qualitative synthesis. Meta-analysis of anxiety and QoL measures showed no significant impact of support groups on mental well-being, but qualitative data showed that patients perceived benefit from attendance through sharing experiences and acceptance of life with an ICD. DISCUSSION: ICD support group attendance improved the patients' perceived well-being. Attendees value the opportunity to share their experiences which helps to accept their new life with an ICD. Future research could consider outcomes such as patient acceptance and the role of healthcare professionals at support groups.

The low FODMAP diet for IBS; A multicentre UK study assessing long term follow up.

BACKGROUND: The low FODMAP diet (LFD) is effective in managing irritable bowel syndrome (IBS) in the short term. This study assessed the long-term effect of the LFD on symptoms, nutritional composition and socialising. METHODS: Patients with IBS who received dietetic-led LFD advice were approached at long term follow up (>6 months post LFD advice) from six centres across the United Kingdom. Participants completed questionnaires assessing gastrointestinal symptoms, adherence, nutritional intake, dietary acceptability and food related quality of life (QOL). RESULTS: 205 participants completed the study, with a mean follow up of 44 months (3.7 years). Adequate symptom relief was noted in 60% of individuals at long term follow up, with 76% being on the personalisation phase of the LFD (pLFD). Mean nutritional intake did not differ between individuals on the pLFD versus habitual diet, with no difference in fructan intake (2.9 g/d vs 2.9 g/d, p = 0.96). The majority (80%) of individuals on the pLFD consumed specific 'free-from' products at the long term, with the purchase of gluten or wheat free products being the commonest (68%). CONCLUSION: The majority of patients follow the pLFD in the long term, with a large proportion purchasing gluten or wheat free products to manage their symptoms.

miR-151a enhances Slug dependent angiogenesis.

MicroRNAs (miRs) are small non-coding RNAs, that modulate cognate gene expression either by inducing mRNA degradation or by blocking translation, and play crucial and complex roles in tissue homeostasis and during disease initiation and progression. The sprouting of new blood vessels by angiogenesis is critical in vascular development and homeostasis and aberrant angiogenesis is associated with pathological conditions such as ischemia and cancer. We have previously established that miR-151a functions as an onco-miR in non-small cell lung cancer (NSCLC) cells by inducing partial EMT and enhancing tumor growth. Here, we identify anti-miR-151a as a molecule that promotes endothelial cell contacts and barrier properties, suggesting that miR-151a regulates cell-cell junctions. We find that induced miR-151a expression enhances endothelial cell motility and angiogenesis and these functions depend on miR-151a-induced Slug levels. Moreover, we show that miR-151a overexpression enhances tumor-associated angiogenesis in 3D vascularized tumor spheroid assays. Finally, we verify that miR-151a is expressed in the vasculature of normal lung and NSCLC tissue. Our results suggest that miR-151a plays multi-faceted roles in the lung, by regulating multiple functions (cell growth, motility, partial EMT and angiogenesis) in distinct cell types.

Carboxylated branched poly(ß-amino ester) nanoparticles enable robust cytosolic protein delivery and CRISPR-Cas9 gene editing.

Efficient cytosolic protein delivery is necessary to fully realize the potential of protein therapeutics. Current methods of protein delivery often suffer from low serum tolerance and limited in vivo efficacy. Here, we report the synthesis and validation of a previously unreported class of carboxylated branched poly(ß-amino ester)s that can self-assemble into nanoparticles for efficient intracellular delivery of a variety of different proteins. In vitro, nanoparticles enabled rapid cellular uptake, efficient endosomal escape, and functional cytosolic protein release into cells in media containing 10% serum. Moreover, nanoparticles encapsulating CRISPR-Cas9 ribonucleoproteins (RNPs) induced robust levels of gene knock-in (4%) and gene knockout (>75%) in several cell types. A single intracranial administration of nanoparticles delivering a low RNP dose (3.5 pmol) induced robust gene editing in mice bearing engineered orthotopic murine glioma tumors. This self-assembled polymeric nanocarrier system enables a versatile protein delivery and gene editing platform for biological research and therapeutic applications.

Reducible Branched Ester-Amine Quadpolymers (rBEAQs) Codelivering Plasmid DNA and RNA Oligonucleotides Enable CRISPR/Cas9 Genome Editing.

Functional codelivery of plasmid DNA and RNA oligonucleotides in the same nanoparticle system is challenging due to differences in their physical properties as well as their intracellular locations of function. In this study, we synthesized a series of reducible branched ester-amine quadpolymers (rBEAQs) and investigated their ability to coencapsulate and deliver DNA plasmids and RNA oligos. The rBEAQs are designed to leverage polymer branching, reducibility, and hydrophobicity to successfully cocomplex DNA and RNA in nanoparticles at low polymer to nucleic acid w/w ratios and enable high delivery efficiency. We validate the synthesis of this new class of biodegradable polymers, characterize the self-assembled nanoparticles that these polymers form with diverse nucleic acids, and demonstrate that the nanoparticles enable safe, effective, and efficient DNA-siRNA codelivery as well as nonviral CRISPR-mediated gene editing utilizing Cas9 DNA and sgRNA codelivery.

Sudden-onset severe presyncope in a 67-year-old man.

A 67-year-old man presented to the emergency department with sudden onset of severe presyncope. He reported that he had a permanent pacemaker implanted in 2006 following atrioventricular node ablation for persistent atrial fibrillation (AF). After suffering increasing shortness of breath, he underwent upgrade to cardiac resynchronisation therapy (CRT) in 2016. He denied any recent falls, interventions or changes in medication. ECG monitoring showed AF with a broad ventricular escape rhythm at around 25 bpm with pauses of up to 3 s. Placement of a magnet over the device resulted in pacing (figure 1A). The implanted device (Medtronic Syncra C2TR01) was interrogated (figure 1B), and a chest radiograph was obtained (figure 2). heartjnl;105/8/657/F1F1F1Figure 1(A) Twelve-lead ECG demonstrating intrinsic rhythm and pacing after application of magnet. (B) Device interrogation with right ventricular threshold test. heartjnl;105/8/657/F2F2F2Figure 2(C) Anteroposterior chest radiograph demonstrating lead position on admission. QUESTION: What was the cause of this presentation?Noise oversensing on the right ventricular (RV) lead due to lead fracture.The RV septal lead has displaced into the right atrial (RA).RA and RV leads were switched in the can during the CRT upgrade.Increase in threshold of RV and left ventricular (LV) leads resulting in loss of capture.

miR-128 inhibits telomerase activity by targeting TERT mRNA.

Telomerase is a unique cellular reverse transcriptase (RT) essential for maintaining telomere stability and required for the unlimited proliferation of cancer cells. The limiting determinant of telomerase activity is the catalytic component TERT, and TERT expression is closely correlated with telomerase activity and cancer initiation and disease progression. For this reason the regulation of TERT levels in the cell is of great importance. microRNAs (miRs) function as an additional regulatory level in cells, crucial for defining expression boundaries, proper cell fate decisions, cell cycle control, genome integrity, cell death and metastasis. We performed an anti-miR library screen to identity novel miRs, which participate in the control of telomerase. We identified the tumor suppressor miR (miR-128) as a novel endogenous telomerase inhibitor and determined that miR-128 significantly reduces the mRNA and protein levels of Tert in a panel of cancer cell lines. We further evaluated the mechanism by which miR-128 regulates TERT and demonstrated that miR-128 interacts directly with the coding sequence of TERT mRNA in both HeLa cells and teratoma cells. Interestingly, the functional miR-128 binding site in TERT mRNA, is conserved between TERT and the other cellular reverse transcriptase encoded by Long Interspersed Elements-1 (LINE-1 or L1), which can also contribute to the oncogenic phenotype of cancer. This finding supports the novel idea that miRs may function in parallel pathways to inhibit tumorigenesis, by regulating a group of enzymes (such as RT) by targeting conserved binding sites in the coding region of both enzymes.

miR-128 represses L1 retrotransposition by binding directly to L1 RNA.

Long interspersed element 1 (LINE-1 or L1) retrotransposons compose 17% of the human genome. Active L1 elements are capable of replicative transposition (mobilization) and can act as drivers of genetic diversity. However, this mobilization is mutagenic and may be detrimental to the host, and therefore it is under strict control. Somatic cells usually silence L1 activity by DNA methylation of the L1 promoter. In hypomethylated cells, such as cancer cells and induced pluripotent stem cells (iPSCs), a window of opportunity for L1 reactivation emerges, and with it comes an increased risk of genomic instability and tumorigenesis. Here we show that miR-128 represses new retrotransposition events in human cancer cells and iPSCs by binding directly to L1 RNA. Thus, we have identified and characterized a new function of microRNAs: mediating genomic stability by suppressing the mobility of endogenous retrotransposons.

Fitting and verification of frequency modulation systems on children with normal hearing.

BACKGROUND: Several recent investigations support the use of frequency modulation (FM) systems in children with normal hearing and auditory processing or listening disorders such as those diagnosed with auditory processing disorders, autism spectrum disorders, attention-deficit hyperactivity disorder, Friedreich ataxia, and dyslexia. The American Academy of Audiology (AAA) published suggested procedures, but these guidelines do not cite research evidence to support the validity of the recommended procedures for fitting and verifying nonoccluding open-ear FM systems on children with normal hearing. Documenting the validity of these fitting procedures is critical to maximize the potential FM-system benefit in the above-mentioned populations of children with normal hearing and those with auditory-listening problems. PURPOSE: The primary goal of this investigation was to determine the validity of the AAA real-ear approach to fitting FM systems on children with normal hearing. The secondary goal of this study was to examine speech-recognition performance in noise and loudness ratings without and with FM systems in children with normal hearing sensitivity. RESEARCH DESIGN: A two-group, cross-sectional design was used in the present study. STUDY SAMPLE: Twenty-six typically functioning children, ages 5-12 yr, with normal hearing sensitivity participated in the study. INTERVENTION: Participants used a nonoccluding open-ear FM receiver during laboratory-based testing. DATA COLLECTION AND ANALYSIS: Participants completed three laboratory tests: (1) real-ear measures, (2) speech recognition performance in noise, and (3) loudness ratings. Four real-ear measures were conducted to (1) verify that measured output met prescribed-gain targets across the 1000-4000 Hz frequency range for speech stimuli, (2) confirm that the FM-receiver volume did not exceed predicted uncomfortable loudness levels, and (3 and 4) measure changes to the real-ear unaided response when placing the FM receiver in the child's ear. After completion of the fitting, speech recognition in noise at a -5 signal-to-noise ratio and loudness ratings at a +5 signal-to-noise ratio were measured in four conditions: (1) no FM system, (2) FM receiver on the right ear, (3) FM receiver on the left ear, and (4) bilateral FM system. RESULTS: The results of this study suggested that the slightly modified AAA real-ear measurement procedures resulted in a valid fitting of one FM system on children with normal hearing. On average, prescriptive targets were met for 1000, 2000, 3000, and 4000 Hz within 3 dB, and maximum output of the FM system never exceeded and was significantly lower than predicted uncomfortable loudness levels for the children. There was a minimal change in the real-ear unaided response when the open-ear FM receiver was placed into the ear. Use of the FM system on one or both ears resulted in significantly better speech recognition in noise relative to a no-FM condition, and the unilateral and bilateral FM receivers resulted in a comfortably loud signal when listening in background noise. CONCLUSIONS: Real-ear measures are critical for obtaining an appropriate fit of an FM system on children with normal hearing.

The rate of spontaneous mutations in human myeloid cells.

The mutation rate (µ) is likely to be a key parameter in leukemogenesis, but historically, it has been difficult to measure in humans. The PIG-A gene has some advantages for the detection of spontaneous mutations because it is X-linked, and therefore only one mutation is required to disrupt its function. Furthermore, the PIG-A-null phenotype is readily detected by flow cytometry. Using PIG-A, we have now provided the first in vitro measurement of µ in myeloid cells, using cultures of CD34+ cells that are transduced with either the AML-ETO or the MLL-AF9 fusion genes and expanded with cytokines. For the AML-ETO cultures, the median µ value was ∼9.4×10(-7) (range ∼3.6-23×10(-7)) per cell division. In contrast, few spontaneous mutations were observed in the MLL-AF9 cultures. Knockdown of p53 or introduction of mutant NRAS or FLT3 alleles did not have much of an effect on µ. Based on these data, we provide a model to predict whether hypermutability must occur in the process of leukemogenesis.

Leukemic blasts with the paroxysmal nocturnal hemoglobinuria phenotype in children with acute lymphoblastic leukemia.

It has been proposed that genomic instability is essential to account for the multiplicity of mutations often seen in malignancies. Using the X-linked PIG-A gene as a sentinel gene for spontaneous inactivating somatic mutations, we previously showed that healthy individuals harbor granulocytes with the PIG-A mutant (paroxysmal nocturnal hemoglobinuria) phenotype at a median frequency (f) of ∼12 × 10(-6). Herein, we used a similar approach to determine f in blast cells derived from 19 individuals with acute lymphoblastic leukemia (ALL) and in immortalized Epstein-Barr virus-transformed B-cell cultures (human B-lymphoblastoid cell lines) from 19 healthy donors. The B-lymphoblastoid cell lines exhibited a unimodal distribution, with a median f value of 11 × 10(-6). In contrast, analysis of the f values for the ALL samples revealed at least two distinct populations: one population, representing approximately half of the samples (n = 10), had a median f value of 13 × 10(-6), and the remaining samples (n = 9) had a median f value of 566 × 10(-6). We conclude that in ALL, there are two distinct phenotypes with respect to hypermutability, which we hypothesize will correlate with the number of pathogenic mutations required to produce the leukemia.

A quantitative analysis of genomic instability in lymphoid and plasma cell neoplasms based on the PIG-A gene.

It has been proposed that hypermutability is necessary to account for the high frequency of mutations in cancer. However, historically, the mutation rate (mu) has been difficult to measure directly, and increased cell turnover or selection could provide an alternative explanation. We recently developed an assay for mu using PIG-A as a sentinel gene and estimated that its average value is 10.6 x 10(-7) mutations per cell division in B-lymphoblastoid cell lines (BLCLs) from normal donors. Here we have measured mu in human malignancies and found that it was elevated in cell lines derived from T cell acute lymphoblastic leukemia, mantle cell lymphoma, follicular lymphoma in transformed phase, and 2 plasma cell neoplasms. In contrast, mu was much lower in a marginal zone lymphoma cell line and 5 other plasma cell neoplasms. The highest mu value that we measured, 3286 x 10(-7), is 2 orders of magnitude above the range we have observed in non-malignant human cells. We conclude that the type of genomic instability detected in this assay is a common but not universal feature of hematologic malignancies.

Spontaneously arising red cells with a McLeod-like phenotype in normal donors.

Very few human genes can be used to identify spontaneous inactivating somatic mutations. We hypothesized that because the XK gene is X-linked, it would be easy to identify spontaneously arising red cells with a phenotype resembling the McLeod syndrome, which results from inherited XK mutations. Here, by flow cytometry, we detect such phenotypic variants at a median frequency of 9 x 10(-6) in neonatal cord blood samples and 39 x 10(-6) in healthy adults (p=0.004). It may be possible to further investigate the relationship between aging, mutations, and cancer using this approach.

Harris Infant Neuromotor Test: comparison of US and Canadian normative data and examination of concurrent validity with the Ages and Stages Questionnaire.

BACKGROUND: The Harris Infant Neuromotor Test (HINT) was developed as a screening tool for potential motor and cognitive developmental disorders in infants. Scoring on the HINT has been shown to be reliable, and several studies have supported the validity of the HINT. Normative values for the tool have been developed using Canadian infants. OBJECTIVE: The aims of this study were (1) to further evaluate the validity of the HINT by comparing data obtained on US infants who were developing typically with data previously acquired on Canadian infants and (2) to determine the concurrent validity of the HINT with the Ages and Stages Questionnaire (ASQ). Secondary analyses of HINT scores for US white and nonwhite infants and for US infants who had parents with lower levels of education and US infants who had parents with higher levels of education (as a proxy for socioeconomic status [SES]) were conducted. DESIGN: Cross-sectional exploratory and quasi-experimental comparative research designs were used to evaluate the validity of the HINT. METHODS: Sixty-seven infants from the United States who were developing typically and who were aged 2.5 to 12.5 months were recruited via convenience sampling. Sixty-four of these infants were compared with Canadian infants matched for age, sex, ethnicity or race, and parental education. The HINT was administered by raters who had been trained to attain acceptable levels of interrater reliability, and parents completed the ASQ. The HINT scores for US white versus nonwhite infants (n=46) and infants who had parents with lower SES versus a higher SES (n=52) were compared. RESULTS: There were no significant differences between HINT total scores for US and Canadian infants or for US racial or ethnic groups and SES groups. There were high correlations (r=-.82 to -.84) between HINT and ASQ scores. LIMITATIONS: The study used a small US sample with limited geographical diversity. Small sample numbers also did not allow for comparisons of specific racial or ethnic groups. The SES groups were created primarily using parental education as a proxy for SES. CONCLUSIONS: The results suggest that HINT screening in the United States is supported on the basis of Canadian norms and the validity of the HINT in screening for motor and cognitive delays. Although there is preliminary support for the HINT as an appropriate screening tool for US infants who are nonwhite or who have parents with a lower SES, more research is warranted.

A high-fat meal enriched with eicosapentaenoic acid reduces postprandial arterial stiffness measured by digital volume pulse analysis in healthy men.

Diets rich in eicosapentaenoic acid [EPA; 20:5(n-3)] are associated with decreased arterial stiffness, but postprandial effects on vascular function are unknown. We investigated whether an EPA-enriched high-fat meal could improve postprandial vascular function. Seventeen healthy men ingested 2 test meals (51 g fat), 1 wk apart, in random order: 5 g EPA plus high-oleic sunflower oil (HOS) vs. HOS only. A second high-fat meal (44 g fat), the same on both study days, was provided 4 h later. Blood pressure and arterial function were measured using digital volume pulse (DVP) to derive a stiffness index (DVP-SI) and reflection index in fasting subjects at 3 and 6 h following the test meal. Blood samples were taken following the test meal for plasma 8-isoprostane F2alpha, nitric oxide (NO) metabolites (NOx), glucose, insulin, triacylglycerol, and fatty acid analysis. The plasma EPA concentration (mean +/- SD) reached a peak of 2.10 +/- 0.99 mmol/L following the EPA meal (5 h) and did not rise above 0.27 +/- 0.16 mmol/L 1 h following the placebo meal. DeltaDVP-SI did not differ between the 2 test meals at 3 h but was greater at 6 h following EPA (6 h -0.65 +/- 0.65 m/s) compared with placebo (6 h -0.33 +/- 1.26 m/s). Plasma 8-isoprostane F2alpha concentrations increased by 48% at 6 h compared with baseline following the EPA meal and plasma NOx decreased following both meals, with no differences between the meals in the changes. Changes in other variables measured also did not differ after subjects consumed the 2 meals. In conclusion, adding EPA to a high-fat meal results in acute changes in vascular tone, independent of changes in oxidative stress.