Designing and implementing an Advanced Nurse Practice in Critical Care programme from a university perspective within Northern Ireland.

The number of advanced practice roles in healthcare is increasing in response to several factors such as changes in medical education, economic pressures, workforce shortages and the increasing complexity of health needs of the population. The Advanced Critical Care Practitioner Curriculum, developed by the Faculty of Intensive Care Medicine in the UK (United Kingdom), enables the development and delivery of a structured education programme which can contribute to addressing these challenges. This article outlines how one university designed and implemented this programme, the first of its kind in Northern Ireland.

A prospective, multi-center, randomised controlled trial for evaluation of the effectiveness of the Blimp scoring balloon in lesions not crossable with a conventional balloon or microcatheter: the BLIMP study.

BACKGROUND: Balloon uncrossable coronary lesions are lesions that cannot be crossed with a conventional balloon. Multiple balloons have been designed to overcome this problem. The Blimp balloon has a very low scoring profile (0.6 mm) with a very high rated burst pressure (30 atmospheres). We aimed to evaluate the efficacy of this balloon compared to customary low-profile balloons. METHODS: We conducted a multicenter, prospective, randomised, controlled trial in which 126 patients with an uncrossable lesion were randomly (1:1 randomization) assigned to treatment first with the Blimp balloon or low-profile balloon. The primary endpoint was the success of crossing the lesion after initial failure with a microcatheter (group A) or with a conventional balloon (group B). RESULTS: Overall, the first attempt of Blimp was successful in 29 out of 61 cases (48%) while the LP balloon immediately crossed in 30 out 67 cases (45%; p = 0.761). Using a low-profile balloon in the BLIMP group after failure of the Blimp balloon increased the success to 64% (39 out of 61 cases). Using the Blimp balloon in the low-profile first group after failure of the low-profile balloon increased the success to 60% (40 out of 67 cases). After the placement of a guide catheter extension, the overall successful lesion crossing in the BLIMP group was 80% (49 out of 61 cases) compared to 76% (51 out of 67 cases) in the LP Balloon group (p = 0.327). CONCLUSIONS: The Blimp balloon catheter showed no superiority to customary low-profile balloons in uncrossable lesions. It can however be complementary in treating uncrossable lesions.

Beta-blocker target dosing and tolerability in a dedicated heart failure clinic in Johannesburg.

BACKGROUND: Despite the significant clinical benefits of beta-blockers in heart failure with reduced ejection fraction (HFrEF), prescription for and adherence to these agents is reported to be poor. There are few data on the use and tolerance of beta-blocker therapy in patients with HFrEF in South Africa and it is unknown whether these patients would benefit from further heart rate-lowering therapy. METHODS: Data from all patients with HFrEF attending the heart failure clinic of Charlotte Maxeke Johannesburg Academic Hospital from January 2000 to December 2014 were retrospectively collected. We first determined the rates of beta-blocker intolerance in this population and then categorised the patients according to their most recent dose of beta-blocker (low, moderate or target dose) in order to identify factors associated with beta-blocker intolerance. Lastly, we used the data to identify patients who would be suitable for further treatment with heart rate-lowering therapy. RESULTS: Five hundred patients, with a median follow up of 58.7 months, were identified during the study period. Black South Africans constituted the majority (66.4%) and most patients had HFrEF due to hypertension (32.8%). At the last recorded clinic visit at the end of the study period, 489 patients (97.8%) were taking a beta-blocker with 59.8% prescribed a beta-blocker at target dose. Consistent with previous data, bradycardia was the commonest cause for failing to reach target beta-blocker dose. Only 61 (12%) patients were on no (n = 11) or low (n = 50) dose of beta-blocker at final clinic visit. As per current guidelines, only 10.6% (n = 53) of this cohort of patients would qualify for further treatment with heart rate-lowering therapy. CONCLUSIONS: In a dedicated heart failure clinic in South Africa, beta-blockers were well-tolerated in the treatment of HFrEF. The potential role of specific heart rate-lowering therapy in patients treated adequately with heart failure medication and proper up-titration of beta-blockers is relatively small.

5-Year clinical follow-up of the COBRA (complex coronary bifurcation lesions: Randomized comparison of a strategy using a dedicated self-expanding biolimus A9-eluting stent vs. a culotte strategy using everolimus-eluting stents) study.

OBJECTIVES: We evaluated healing responses with optical coherence tomography, and long-term clinical outcomes after treatment with a dedicated stent versus a conventional culotte technique. BACKGROUND: Dedicated bifurcation stents have been proposed as an alternative treatment for coronary bifurcation lesions. The long-term performance of dedicated stents versus conventional dual-stent techniques for the treatment of complex coronary bifurcation lesions is unknown. METHODS: Forty patients with true coronary bifurcation lesions were randomized to treatment with a dedicated Axxess bifurcation stent in the proximal main vessel and additional Biomatrix stents in branches versus culotte stenting using Xience stents. RESULTS: The percentage of uncovered struts in each bifurcation segment at 9 months (primary endpoint) was similar between groups. Five-year clinical follow-up was available for all patients and included major adverse cardiac events [MACE; a composite of cardiac death, myocardial infarction (MI) and ischemia-driven target lesion revascularization (TLR)], target-vessel (TVR) and non-target-vessel revascularization (non-TVR), non-TLR and stent thrombosis. At 5 years, in the culotte group, one patient had undergone TLR and another suffered a clinical MI, resulting in 10% MACE versus none in the Axxess group. TVR (5% vs. 10%, P = 0.54) and non-TVR (5% vs. 20%, P = 0.39) rates were similar between the Axxess and culotte groups, respectively. There was no stent thrombosis. CONCLUSION: Compared with culotte stenting with Xience, complex coronary bifurcation stenting using a dedicated strategy combining the Axxess and Biomatrix stents results in similar stent strut coverage at 9 months, and excellent clinical outcomes at 5 years.

Nursing and midwifery revalidation.

This article details the Nursing and Midwifery Council revalidation requirements essential for all registered nurses and midwives in the United Kingdom. Nursing revalidation is effective from April 2016 and is built on the pre-existing post-registration education and practice. Unlike the previous process, revalidation provides a more robust system which is clearly linked to the code and should assist towards the delivery of quality and safe effective care.

The Interferon Type I/III Response to Respiratory Syncytial Virus Infection in Airway Epithelial Cells Can Be Attenuated or Amplified by Antiviral Treatment.

UNLABELLED: Human respiratory syncytial virus (RSV) is a single-stranded RNA virus that causes acute, and occasionally fatal, lower respiratory illness in young infants, the elderly, and immunocompromised patients. Therapeutic interventions able to cut short viral replication and quickly return the airways to normal function are needed. An understanding of antiviral activities and their effects on host defense mechanisms is important for the design of safe and effective therapy. We targeted functionally and temporally distinct steps within the viral life cycle using small-molecule RSV inhibitors and studied their antiviral activities and their effects on innate interferon responses of airway epithelial cells in vitro. Antivirals acting upstream of RSV polymerase activity (i.e., compounds targeting the fusion protein or the nucleoprotein) reduced viral load immediately postinfection and partially attenuated interferon responses. In contrast, antivirals directed to the RSV polymerase demonstrated activity throughout the viral replication cycle and specifically modulated the RIG-I/mitochondrial antiviral signaling protein (MAVS)/TBK1/IRF3/interferon-stimulated gene (ISG) axis, causing either an upregulation or a downregulation of interferon responses, depending on the mechanism of polymerase inhibition. Notably, polymerase inhibition leading to the accumulation of abortive RNA products correlated with the amplification of interferon-stimulated genes to up to 10 times above normal infection levels. Understanding how antiviral activities and their modulation of innate immunity may affect recovery from RSV infection will help guide the development of safe and effective therapies. IMPORTANCE: RSV circulates seasonally, causing acute lower respiratory disease. Therapeutic interventions with efficacy throughout the viral replication cycle, rapid viral clearance, and prevention of potentially harmful inflammatory responses are desirable. Compounds targeting the RSV polymerase inhibited virus replication late in the viral life cycle and, depending on the functional domain targeted, either attenuated or amplified RIG-I and downstream interferon pathways in infected cells. These data will help guide the development of safe and effective therapies by providing new molecular evidence that the mechanism of inhibition by an antiviral compound can directly impact innate antiviral immune responses in the airway epithelium.

Four steps to interpreting arterial blood gases.

This article examines acid-base balance and the interpretation of arterial blood gases (ABG). The article begins with a brief revision of related physiology, followed by a description of the primary disorders associated with acid-base imbalance. The normal ranges and the significance of abnormal ABG results are explored. The article concludes by providing an easy to follow four-step guide to ABG interpretation with practice examples presented in the CPD task section.

The principles and practice of interpreting cardiac rhythm strips: a seven-step model.

This open learning zone article examines the cardiac cycle and the interpretation of cardiac rhythm strips. The article begins with a brief revision of related physiology followed by a description of normal sinus rhythm and the main cardiac rhythm abnormalities. The article concludes by providing easy to follow steps for use in the interpretation of cardiac rhythm strips with practice examples presented in the continuing professional development (CPD) task section.

Effects of elevating the head of bed on interface pressure in volunteers.

OBJECTIVE: Intensive care unit patients are at particular risk for pressure ulcers and ventilator-associated pneumonia. Current guidelines recommend that mechanically ventilated patients be kept in a semirecumbent position with the head of bed elevated 30 degrees -45 degrees to prevent aspiration and ventilator-associated pneumonia. We tested the effects of elevating the head of bed on the interface pressure between the skin of the sacral area and the bed with healthy volunteers. INTERVENTIONS: Interface pressure profiles of the sacral area were obtained for the 0 degrees , 10 degrees , 20 degrees , 30 degrees , 45 degrees , 60 degrees , and 75 degrees head of bed elevated positions from 15 subjects (14 men, one woman). MEASUREMENTS AND MAIN RESULTS: Peak sacral interface pressures increased with large increases in head of bed elevation. The 30 degrees , 45 degrees , 60 degrees , and 75 degrees head of bed positions all had peak interface pressures that were significantly (p < 0.02) greater than the supine measurement and also were different from all other head of bed positions. Affected areas, defined as areas over which an interface pressure >or=32 mm Hg was obtained, increased with large elevation of the head of bed. The affected areas of the 45 degrees , 60 degrees , and 75 degrees head of bed positions were significantly greater than the supine position and were also significantly different from all other head of bed positions. CONCLUSIONS: Raising the head of bed to 30 degrees or higher on a intensive care unit bed increases the peak interface pressure between the skin at the sacral area and support surface in healthy volunteers. At 45 degrees head of bed elevation or higher, the affected area attributed to a skin-intensive care unit bed interface pressure >or=32 mm Hg increased as well. Further study is needed to determine whether the increased peak interface pressures and affected areas that result from raising the head of bed actually increase the incidence of pressure ulcer formation.

HIP12 is a non-proapoptotic member of a gene family including HIP1, an interacting protein with huntingtin.

Huntingtin-interacting protein I (HIP1) is a membrane-associated protein that interacts with huntingtin, the protein altered in Huntington disease. HIP1 shows homology to Sla2p, a protein essential for the assembly and function of the cytoskeleton and endocytosis in Saccharomyces cerevisiae. We have determined that the HIP1 gene comprises 32 exons spanning approximately 215 kb of genomic DNA and gives rise to two alternate splice forms termed HIP1-1 and HIP1-2. Additionally, we have identified a novel protein termed HIP12 with significant sequence and biochemical similarities to HIP1 and high sequence similarity to Sla2p. HIP12 differs from HIP1 in its pattern of expression both at the mRNA and protein level. However, HIP1 and HIP12 are both found within the brain and show a similar subcellular distribution pattern. In contrast to HIP1, which is toxic in cell culture, HIP12 does not confer toxicity in the same assay systems. Interestingly, HIP12 does not interact with huntingtin but can interact with HIP1. suggesting a potential interaction in vivo that may influence the function of each respective protein.

Higher brain blood flow at amygdala and lower frontal cortex blood flow in PTSD patients with comorbid cocaine and alcohol abuse compared with normals.

Posttraumatic stress disorder (PTSD) patients with histories of cocaine and alcohol abuse (CA-PTSD) were compared with normal volunteers. Positron emission tomography (PET) scans with 15O-butanol were used to compare regional cerebral blood flow (rCBF) between the groups during rest and during an auditory continuous performance task (ACPT). CA-PTSD patients had significantly higher rCBF in right amygdala and left parahippocampal gyrus than normals during the ACPT. Normals had higher rCBF at frontal cortex during the resting scan and during the ACPT. The role of the amygdala in attention and fear conditioning suggests that increased amygdala rCBF may be related to clinical features of PTSD. Cocaine use may be associated with increased amygdala rCBF in PTSD patients. Amygdala and frontal cortex attention system components may be reciprocally related and their relative contributions to processing of neutral stimuli perturbed in CA-PTSD.

Chloroquine-resistant isolates of Plasmodium falciparum with alternative CG2 omega repeat length polymorphisms.

A particular polymorphism in the cg2 gene has previously been linked to chloroquine resistance in reference isolates of Plasmodium falciparum. To assess the association of this polymorphism with chloroquine resistance in field specimens of P. falciparum, we analyzed the omega repeat region of the cg2 gene in 47 isolates of P. falciparum collected in the Ingwavuma District of northern KwaZulu-Natal, South Africa. Polymerase chain reaction (PCR) primers, which were designed to amplify the region of DNA surrounding the omega repeat, were used to obtain omega repeat PCR products from the field isolates. The PCR product for each isolate varied in length, depending on the number of cg2 omega repeats for that isolate. We found that several in vivo and in vitro chloroquine-resistant isolates of P. falciparum did not have the expected 16 omega repeats. These results suggest that the link between the cg2 polymorphism and chloroquine resistance identified previously may not apply in all malarious areas.

A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration.

We have produced yeast artificial chromosome (YAC) transgenic mice expressing normal (YAC18) and mutant (YAC46 and YAC72) huntingtin (htt) in a developmental and tissue-specific manner identical to that observed in Huntington's disease (HD). YAC46 and YAC72 mice show early electrophysiological abnormalities, indicating cytoplasmic dysfunction prior to observed nuclear inclusions or neurodegeneration. By 12 months of age, YAC72 mice have a selective degeneration of medium spiny neurons in the lateral striatum associated with the translocation of N-terminal htt fragments to the nucleus. Neurodegeneration can be present in the absence of macro- or microaggregates, clearly showing that aggregates are not essential to initiation of neuronal death. These mice demonstrate that initial neuronal cytoplasmic toxicity is followed by cleavage of htt, nuclear translocation of htt N-terminal fragments, and selective neurodegeneration.

Subtype-specific enhancement of NMDA receptor currents by mutant huntingtin.

Evidence suggests that NMDA receptor-mediated neurotoxicity plays a role in the selective neurodegeneration underlying Huntington's disease (HD). The gene mutation that causes HD encodes an expanded polyglutamine tract of >35 in huntingtin, a protein of unknown function. Both huntingtin and NMDA receptors interact with cytoskeletal proteins, and, for NMDA receptors, such interactions regulate surface expression and channel activity. To determine whether mutant huntingtin alters NMDA receptor expression or function, we coexpressed mutant or normal huntingtin, containing 138 or 15 glutamine repeats, respectively, with NMDA receptors in a cell line and then assessed receptor channel function by patch-clamp recording and surface expression by western blot analysis. It is interesting that receptors composed of NR1 and NR2B subunits exhibited significantly larger currents when coexpressed with mutant compared with normal huntingtin. Moreover, this effect was selective for NR1/NR2B, as NR1/NR2A showed similar currents when coexpressed with mutant versus normal huntingtin. However, ion channel properties and total surface expression of the NR1 subunit were unchanged in cells cotransfected with NR1/NR2B and mutant huntingtin. Our results suggest that mutant huntingtin may increase numbers of functional NR1/NR2B-type receptors at the cell surface. Because NR1/NR2B is the predominant NMDA receptor subtype expressed in medium spiny neostriatal neurons, our findings may help explain the selective vulnerability of these neurons in HD.

Life without huntingtin: normal differentiation into functional neurons.

Huntington disease (HD) is a neurodegenerative disorder associated with polyglutamine expansion in a recently identified protein, huntingtin. Huntingtin is widely expressed and plays a crucial role in development, because gene-targeted HD-/- mouse embryos die early in embryogenesis. To analyze the function of normal huntingtin, we have generated HD-/- embryonic stem (ES) cells and used an in vitro model of ES cell differentiation to analyze their ability to develop into neuronal cells. Expression analysis of wild-type ES cells revealed that huntingtin is expressed at all stages during ES cell differentiation with high expression in neurons. Expression levels increased with the maturation of differentiating neurons, demonstrating that expression of huntingtin is developmentally regulated in cell culture and resembles the pattern of expression observed in differentiating neurons in the mouse brain. It is interesting that HD-/- ES cells could differentiate into mature postmitotic neurons that expressed functional voltage- and neurotransmitter-gated ion channels. Moreover, both excitatory and inhibitory spontaneous postsynaptic currents were observed, indicating the establishment of functional synapses in the absence of huntingtin. These results demonstrate that huntingtin is not required for the generation of functional neurons with features characteristic of postmitotic neurons in the developing mouse brain.

The influence of huntingtin protein size on nuclear localization and cellular toxicity.

Huntington disease is an autosomal dominant neurodegenerative disorder caused by the pathological expansion of a polyglutamine tract. In this study we directly assess the influence of protein size on the formation and subcellular localization of huntingtin aggregates. We have created numerous deletion constructs expressing successively smaller fragments of huntingtin and show that these smaller proteins containing 128 glutamines form both intranuclear and perinuclear aggregates. In contrast, larger NH2-terminal fragments of huntingtin proteins with 128 glutamines form exclusively perinuclear aggregates. These aggregates can form in the absence of endogenous huntingtin. Furthermore, expression of mutant huntingtin results in increased susceptibility to apoptotic stress that is greater with decreasing protein length and increasing polyglutamine size. As both intranuclear and perinuclear aggregates are clearly associated with increased cellular toxicity, this supports an important role for toxic polyglutamine-containing fragments forming aggregates and playing a key role in the pathogenesis of Huntington disease.

Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract.

The neurodegenerative diseases Huntington disease, dentatorubropallidoluysian atrophy, spinocerebellar atrophy type 3, and spinal bulbar muscular atrophy are caused by expansion of a polyglutamine tract within their respective gene products. There is increasing evidence that generation of truncated proteins containing an expanded polyglutamine tract may be a key step in the pathogenesis of these disorders. We now report that, similar to huntingtin, atrophin-1, ataxin-3, and the androgen receptor are cleaved in apoptotic extracts. Furthermore, each of these proteins is cleaved by one or more purified caspases, cysteine proteases involved in apoptotic death. The CAG length does not modulate susceptibility to cleavage of any of the full-length proteins. Our results suggest that by generation of truncated polyglutamine-containing proteins, caspase cleavage may represent a common step in the pathogenesis of each of these neurodegenerative diseases.

Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates.

It is unclear how polyglutamine expansion is associated with the pathogenesis of Huntington disease (HD). Here, we provide evidence that polyglutamine expansion leads to the formation of large intracellular aggregates in vitro and in vivo. In vitro these huntingtin-containing aggregates disrupt normal cellular architecture and increase in frequency with polyglutamine length. Huntingtin truncated at nucleotide 1955, close to the caspase-3 cleavage site, forms perinuclear aggregates more readily than full-length huntingtin and increases the susceptibility of cells to death following apoptotic stimuli. Further truncation of huntingtin to nucleotide 436 results in both intranuclear and perinuclear aggregates. For a given protein size, increasing polyglutamine length is associated with increased cellular toxicity. Asymptomatic transgenic mice expressing full-length huntingtin with 138 polyglutamines form exclusively perinuclear aggregates in neurons. These data support the hypothesis that proteolytic cleavage of mutant huntingtin leads to the development of aggregates which compromise cell viability, and that their localization is influenced by protein length.