Protocol summary and statistical analysis plan for Intensive Nutrition Therapy comparEd to usual care iN criTically ill adults (INTENT): a phase II randomised controlled trial.

INTRODUCTION: It is plausible that a longer duration of nutrition intervention may have a greater impact on clinical and patient-centred outcomes. The Intensive Nutrition care Therapy comparEd to usual care iN criTically ill adults (INTENT) trial will determine if a whole hospital nutrition intervention is feasible and will deliver more total energy compared with usual care in critically ill patients with at least one organ system failure. METHODS AND ANALYSIS: This study is a prospective, multicentre, unblinded, parallel-group, phase II randomised controlled trial (RCT) conducted in 23 hospitals in Australia and New Zealand. Mechanically ventilated critically ill adult patients with at least one organ failure who have been in intensive care unit (ICU) for 72-120 hours and meet all of the inclusion and none of the exclusion criteria will be randomised to receive either intensive or usual nutrition care. INTENT started recruitment in October 2018 and a sample size of 240 participants is anticipated to be recruited in 2022. The study period is from randomisation to hospital discharge or study day 28, whichever occurs first, and the primary outcome is daily energy delivery from nutrition therapy. Secondary outcomes include daily energy and protein delivery during ICU and in the post-ICU period, duration of ventilation, ventilator-free days, total bloodstream infection rate and length of hospital stay. All other outcomes are considered tertiary and results will be analysed on an intention-to-treat basis. ETHICS AND DISSEMINATION: Ethics approval has been received in Australia (Alfred Hospital Ethics Committee (HREC/18/Alfred/101) and Human Research Ethics Committee of the Northern Territory Department of Health (2019-3372)) and New Zealand (Northern A Health and Disability Ethics Committee (18/NTA/222). Results will be disseminated in an international peer-reviewed journal(s), at scientific meetings and via social media. TRIAL REGISTRATION NUMBER: NCT03292237.

The effect of a low-dose naloxone infusion on the incidence of respiratory depression after intrathecal morphine administration for major open hepatobiliary surgery: a randomised controlled trial.

Intrathecal morphine is an analgesic option for major hepatopancreaticobiliary procedures but is associated with a risk of respiratory depression. We hypothesised that a postoperative low-dose naloxone infusion would reduce the incidence of respiratory depression without an increase in pain scores. Patients scheduled for major open hepatopancreaticobiliary surgery and who were receiving 10 µg.kg-1 intrathecal morphine were eligible for inclusion. Patients were allocated randomly to receive a postoperative infusion of naloxone 5 µg.kg-1 .h-1 (naloxone group) or saline at an identical infusion rate (control group) until the morning after surgery. Clinicians, nursing staff and patients were blinded to group allocation. The primary outcome measure was the incidence of respiratory depression (respiratory rate < 10 breaths.min-1 and/or oxygen saturation < 90%). Secondary outcome measures included: arterial partial pressure of carbon dioxide; pain score; requirement for supplemental analgesic; and incidence of nausea and vomiting, pruritus and sedation. In total, data from 95 patients (48 in the naloxone group and 47 in the control group) were analysed. The incidence of respiratory depression was lower in the naloxone group compared with the control group (10/48 vs. 21/47 patients, respectively; p = 0.037, relative risk 0.47 (95%CI 0.25-0.87). Maximum pain scores were greater for patients allocated to the naloxone group compared with control (median 5 (95%CI 4-6) vs. 4 (95%CI 2-4), respectively; p < 0.001). A low-dose naloxone infusion decreases the incidence of respiratory depression following intrathecal morphine administration in patients having major hepatopancreaticobiliary surgery at the expense of a small increase in postoperative pain.

Higher risk breast screening: cancer detection rates, recall rates, and attendance rates in Northern Ireland.

AIM: To evaluate the outcomes of higher risk screening in Northern Ireland (NI) and compare with the UK National Health Service Breast Screening Programme (NHSBSP). MATERIALS AND METHODS: Higher risk breast screening commenced in NI in April 2013. Data on the programme were audited retrospectively through the Higher Risk screening centre. As there are no national standards for attendance rates and cancer detection rates, screening data and standards from the NHSBSP were used as a baseline for comparison. RESULTS: Attendance rates for the higher risk screening population have increased each of the last 3 years up to 77.7%. Recall rates have improved year on year from initial 14.2%-8.6%. Cancer detection rates have varied each year with a range from 21.5 per 1,000 women screened to 30.9 per 1,000 women screened. CONCLUSION: The Higher Risk Breast Screening Programme in NI represents a success story in risk stratified screening. Performance outcomes are excellent. The data outcomes may be used to inform standards of acceptable practice in the wider NHSBSP.

A randomised feasibility study to assess a novel strategy to rationalise fluid in patients after cardiac surgery.

BACKGROUND: After cardiac surgery, patients receive large amounts of fluid in the Intensive Care Unit (ICU). We plan to conduct a multi-centre randomised controlled trial, of a conservative fluid regime, in patients after cardiac surgery, and have reported results of a feasibility study that evaluated efficacy and safety of the proposed regime. METHODS: After ethical approval, a single-centre, prospectively randomised interventional study was undertaken. Participants were randomised to either usual care, or to a protocolised algorithm, utilising stroke volume variation, to guide fluid administration to patients who were deemed to have inadequate cardiac output and were likely to be volume responsive. The study protocol lasted from ICU admission to de-sedation or 24 h, whichever occurred first. RESULTS: We randomised 144 subjects over 9 months. Less bolus fluid and less total overall fluid volume was administered in the intervention group (median (IQR) 1620 ml (500-3410) and 2525 ml (1440-5250; P<0.001), compared with the usual care group (2050 ml (910-4280) and 2980 ml (2070-6580; P=0.001), from ICU admission to extubation. There was no significant difference in incidence of acute kidney injury or the average amount of fluid administered to the usual care group at the beginning compared with the end of the study. CONCLUSION: It is both possible and safe to achieve a significant reduction in the amount of fluid administered to patients, allocated to a conservative fluid protocol. These results suggest that a planned multi-centre study is both justified and feasible. CLINICAL TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry www.anzctr.org.au (ACTRN12612000754842).

Leprosy: diagnosis and management in a developed setting.

Leprosy remains an important global health concern, but little has been published about its diagnosis and management in developed settings. It has been postulated that delay in diagnosis is common in developed settings. We reviewed all the cases of leprosy seen at a major tertiary referral centre between 1999 and 2013 and demonstrated that delay in diagnosis is common, especially when patients present with symptoms of leprosy reactions rather than classical symptoms, such as hypo-pigmented hypo-aesthetic skin lesions and neuropathy.

Consensus guidelines for the treatment of invasive mould infections in haematological malignancy and haemopoietic stem cell transplantation, 2014.

Mould species represent the pathogens most commonly associated with invasive fungal disease in patients with haematological malignancies and patients of haemopoietic stem cell transplants. Invasive mould infections in these patient populations, particularly in the setting of neutropenia, are associated with high morbidity and mortality, and significantly increase the complexity of management. While Aspergillus species remain the most prevalent cause of invasive mould infections, Scedosporium and Fusarium species and the Mucormycetes continue to place a significant burden on the immunocompromised host. Evidence also suggests that infections caused by rare and emerging pathogens are increasing within the setting of broad-spectrum antifungal prophylaxis and improved survival times placing immunosuppressed patients at risk for longer. These guidelines present evidence-based recommendations for the antifungal management of common, rare and emerging mould infections in both adult and paediatric populations. Where relevant, the role of surgery, adjunctive therapy and immunotherapy is also discussed.

Open-label, phase II study of routine high-flow nasal oxygen therapy in cardiac surgical patients.

BACKGROUND: Respiratory complications after cardiac surgery increase morbidity, mortality, and length of stay. Studies suggest that routine delivery of positive airway pressure after extubation may be beneficial. We sought to determine whether the routine administration of nasal high-flow oxygen therapy (NHF) improves pulmonary function after cardiac surgery. METHODS: A pragmatic randomized controlled trial; participants received either NHF (45 litre min(-1)) or usual care from extubation to Day 2 after surgery. The primary outcome was number of patients with / ratio ≥445 on Day 3 after surgery. The secondary outcomes included atelectasis score on chest X-ray; spirometry; intensive care and hospital length of stay; mortality on Day 28; oxygenation indices; escalation of respiratory support; and patient comfort. RESULTS: We randomized 340 patients over 14 months. The number of patients with a / ratio of ≥445 on Day 3 was 78 (46.4%) in the NHF group vs 72 (42.4%) standard care [odds ratio (OR) 1.18, 95% confidence interval (CI) 0.77-1.81, P=0.45]. was reduced at both 4 h post-extubation and at 9 a.m. on Day 1 in the NHF group (5.3 vs 5.4 kPa, P=0.03 and 5.1 vs 5.3 kPa, P=0.03, respectively). Escalation in respiratory support at any time in the study occurred in 47 patients (27.8%) allocated to NHF compared with 77 (45%) standard care (OR 0.47, 95% CI 0.29-0.7, P=0.001). CONCLUSIONS: Routine use of NHF did not increase / ratio on Day 3 but did reduce the requirement for escalation of respiratory support. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry www.anzctr.org.au (ACTRN12610000973011).

Suicide in children over two decades: 1993-2008.

Suicide rates have increased in Ireland's youth over the past two decades. However, no research report has focussed on suicide rates in those aged under 18--the children of Ireland. We retrieved national disaggregated age and sex-specific suicide mortality data from 1993-1998 and compared it with similar suicide mortality data from 2003-2008. Significant age (older vs younger) and sex effects (boys greater risk than girls) are apparent in both decades Suicide rates in both males and females have increased (males: 9.3-13.5/100,000), (females: 2.4-5.1/100,000. Suicide rates in under 15 year olds boys and girls is extremely rare for both time periods studied (1.6/100,000). Results are discussed in light of the rights of children and the obligation of the nation in this regard, as well as more child-specific and transition to adulthood-specific suicide prevention policy implications.

Nasal high-flow therapy delivers low level positive airway pressure.

BACKGROUND: The aim of this prospective study was to determine whether a level of positive airway pressure was generated in participants receiving nasal high flow (NHF) delivered by the Optiflow system (Fisher and Paykel Healthcare Ltd, Auckland, New Zealand) in a cardiothoracic and vascular intensive care unit (ICU). METHODS: Nasopharyngeal airway pressure was measured in 15 postoperative cardiac surgery adult patients who received both NHF and standard facemask therapy at a flow rate of 35 litre min(-1). Measurements were repeated in the open mouth and closed mouth positions. Mean airway pressure was determined by averaging the pressures at the peak of inspiration of each breath within a 1 min period, allowing the entire pressure profile of each breath to be included within the calculation. RESULTS: Low level positive pressure was demonstrated with NHF at 35 litre min(-1) with mouth closed when compared with a facemask. NHF generated a mean nasopharyngeal airway pressure of mean (SD) 2.7 (1.04) cm H(2)O with the mouth closed. Airway pressure was significantly higher when breathing with mouth closed compared with mouth open (P

Research ethics committees: the role of ethics in a regulatory authority.

This paper is an examination of how research ethics committees have evolved from being advisory committees to more formal regulatory authorities. It is argued that the role of ethics committees should be broader than simple ethical review. Inconsistency in outcome should not be taken to signal failure. Procedural fairness is of the utmost importance. Nor should ethics committees be seen to diminish the ethical responsibilities of researchers themselves.

Caspase-dependent and -independent mechanisms in apoptosis induced by hydroquinone and catechol metabolites of remoxipride in HL-60 cells.

The hydroquinone and catechol like metabolites, NCQ344 and NCQ436 respectively, of the antipsychotic remoxipride have recently been demonstrated to induce apoptosis in myeloperoxidase (MPO)-rich human bone marrow progenitor and HL-60 cells [S.M. McGuinness, R. Johansson, J. Lundstrom, D. Ross, Induction of apoptosis by remoxipride metabolites in HL-60 and CD34+/CD19- human bone marrow progenitor cells: potential relevance to remoxipride-induced aplastic anemia, Chem. Biol. Interact. 121 (1999) 253-265]. In the present study, we determined the molecular mechanisms of apoptosis induced by these remoxipride metabolites in HL-60 cells. Our results show that apoptosis was accompanied by phosphatidylserine (PS) exposure, activation of caspases-9, -3, -7 and DNA cleavage. In HL-60 cells treated with the hydroquinone NCQ344 and catechol NCQ436, the general caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp. fluoromethyl ketone (Z-VAD.FMK) blocked DNA cleavage and activation of caspases-9, -3/-7. In addition, PS exposure was significantly but not completely inhibited by Z-VAD.FMK. These results demonstrate that although Z-VAD.FMK inhibitable caspases are necessary for maximal apoptosis induced by NCQ344 and NCQ436, additional caspase-independent processes may orchestrate changes leading to PS exposure during apoptosis induced by the remoxipride polyphenolic metabolites.

Resource use & patient outcomes in Medicare home care.

To what extent are patient outcomes associated with the amount of home care resources used by patients over episodes of Medicare home care? How can we use the Outcome and Assessment Information Set (OASIS) to improve planning and practical knowledge about the relationship between resource use and patient outcomes? This article addresses the questions and provides readers with some insightful answers.

Induction of apoptosis by remoxipride metabolites in HL60 and CD34+/CD19- human bone marrow progenitor cells: potential relevance to remoxipride-induced aplastic anemia.

The antipsychotic agent, remoxipride [(S)-(-)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenz amide] has been associated with acquired aplastic anemia. We have examined the ability of remoxipride, three pyrrolidine ring metabolites and five aromatic ring metabolites of the parent compound to induce apoptosis in HL60 cells and human bone marrow progenitor (HBMP) cells. Cells were treated for 0-24 h with each compound (0-200 microM). Apoptosis was assessed by fluorescence microscopy in Hoechst 33342- and propidium iodide stained cell samples. Results were confirmed by determination of internucleosomal DNA fragmentation using gel electrophoresis for HL60 cell samples and terminal deoxynucleotidyl transferase assay in HBMP cells. The catechol and hydroquinone metabolites, NCQ436 and NCQ344, induced apoptosis in HL60 and HBMP cells in a time- and concentration dependent manner, while the phenols, NCR181, FLA873, and FLA797, and the derivatives formed by oxidation of the pyrrolidine ring, FLA838, NCM001, and NCL118, had no effect. No necrosis was observed in cells treated with NCQ436 but NCQ344 had a biphasic effect in both cell types, inducing apoptosis at lower concentrations and necrosis at higher concentrations. These data show that the catechol and hydroquinone metabolites of remoxipride have direct toxic effects in HL60 and HBMP cells, leading to apoptosis, while the phenol metabolites were inactive. Similarly, benzene-derived catechol and hydroquinone, but not phenol, induce apoptosis in HBMP cells [Moran et al., Mol. Pharmacol., 50 (1996) 610-615]. We propose that remoxipride and benzene may induce aplastic anemia via production of similar reactive metabolites and that the ability of NCQ436 and NCQ344 to induce apoptosis in HBMP cells may contribute to the mechanism underlying acquired aplastic anemia that has been associated with remoxipride.

The diagnosis of multiple sclerosis: Peplau's Interpersonal Relations Model in practice.

Multiple sclerosis (MS) is a chronic, frequently progressive neurological disease of unknown etiology and uncertain trajectory. Physicians and nurses have historically been uncomfortable broaching the topic of a possible MS diagnosis with patients and have tended instead to talk about it in euphemistic terms. However, with the development of therapeutic agents that may be more effective early in the disease course, the early communication of diagnostic and treatment information has become increasingly important. In our MS clinic, individual with MS symptoms are rapidly referred and assessed by a team of experienced physicians and nurses. Our experience with this referral process has led to our adoption of Peplau's Interpersonal Relations Model as a guide to nursing practice. The central element of Peplau's model is the development of a therapeutic relationship between patient and nurse. This relationship develops through four overlapping stages: orientation, identification, exploitation, and resolution. The collaborative relationship that develops between nurse and patient enhances problem solving and creates a strong bond that is essential across the long trajectory of the illness.

Genotype-phenotype relationships in studies of a polymorphism in NAD(P)H:quinone oxidoreductase 1.

The NAD(P)H:quinone oxidoreductase 1 (NQO1) genotype-phenotype relationship was examined in individuals with a polymorphism in NQO1. The polymorphism comprises a C to T base change at position 609 of the human NQO1 cDNA (C609T) and codes for a proline to serine substitution in the amino acid structure of the NQO1 protein. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism analysis of genomic DNA. Phenotyping was performed using enzyme activity assays and/or immunoblotting of human tumor cell lines and of saliva and bone marrow samples from healthy donors. Phenotyping of uninvolved lung and lung tumors from archived biopsy material was performed by immunohistochemistry. NQO1 activity and protein could be detected in wild-type (C/C) human tumor cells (HT-29) under conditions where NQO1 protein could not be detected in cells (BE) homozygous for the C609T change (T/T). Trace levels of NQO1 protein could be detected in BE cells; however, when immunoblots were subjected to chemiluminescence detection for prolonged periods. In saliva samples from 11 individuals carrying the homozygous C609T change (T/T), no NQO1 protein could be detected even after prolonged chemiluminescence detection. The amount of NQO1 protein present in saliva was quantified and found to be significantly less in heterozygous individuals (C/T) than in wild-type individuals (C/C). In bone marrow stromal cultures, both NQO1 activity and protein could be detected in heterozygotes (C/T) and in wild-type (C/C) samples. In a bone marrow stromal culture from an individual genotyped as T/T at position 609, no NQO1 protein or activity could be detected. NQO1 is elevated in non-small cell lung cancers and could be readily observed as intense immunostaining throughout lung adenocarcinomas genotyped as C/C but no immunostaining could be detected in adenocarcinomas genotyped as T/T at position 609. NQO1 is expressed in normal human lung but is localized to respiratory epithelium and to vascular endothelium. In normal lung tissue from individuals genotyped as T/T, no or faint immunostaining for NQO1 could be detected in either respiratory epithelium or vascular endothelium. These results demonstrate that tissues from individuals homozygous for the C609T change have no detectable or, at best, only trace amounts of NQO1 protein and are devoid of NQO1 activity.

Urinary tract infections may trigger relapse in multiple sclerosis.

Multiple Sclerosis (MS), a demyelinating disease of the central nervous system, is the most common neurological disease affecting young adults in North America and, in the majority of cases, is associated with accumulating disability. Urinary tract dysfunction affects up to 90% of the MS population, and urinary tract infections are encountered in up to 74% of the tested population. Viral infections have previously been shown to trigger acute exacerbation and it is our experience that urinary tract infection also commonly precedes relapse, and, when recurrent, is associated with neurologic progression. We present three case studies from our MS Clinic where recurrent UTI was associated with acute exacerbation and neurologic progression refractory to intravenous steroid treatment. Interferons, protein signaling molecules, have recently been found to play a role in acute exacerbation and disease progression in individuals with MS. Viral infections induce interferon release which may activate T cells to produce gamma-interferon. Interferon-gamma precipitates relapse and stimulates production of tumour necrosis factor-alpha, a cytokine directly toxic to oligodendrocytes. Bacterial infections similarly induce interferon release and may activate immune pathways that result in MS exacerbation and neurologic progression.

Responding to reported clusters of common diseases: the case of multiple sclerosis.

Reports of disease clustering are becoming ever more common, and there is increasing pressure on public health agencies to respond rapidly and appropriately to these reports. We investigated a cluster of five cases of MS occurring in a small multidisciplinary hospital department. Data were collected by a variety of methods, including measurement and description of the workplace, completion of survey instruments by department staff, and construction of case histories of persons with MS. The results indicated that the department comprised a high-risk population and that only one case of MS could have any possible etiologic significance. Investigators should consider a number of factors when evaluating disease clusters, including the accuracy of diagnosis, the induction period and cause of the disease, and possible biases in the population at risk. Additionally, boundaries should not encircle the cases that led to identification of the cluster and should reflect environmental significance.