An economic evaluation of eptinezumab for the preventive treatment of migraine in the UK, with consideration for natural history and work productivity.

BACKGROUND: Migraine is a highly prevalent neurological disease with a substantial societal burden due to lost productivity. From a societal perspective, we assessed the cost-effectiveness of eptinezumab for the preventive treatment of migraine. METHODS: An individual patient simulation of discrete competing events was developed to evaluate eptinezumab cost-effectiveness compared to best supportive care for adults in the United Kingdom with ≥ 4 migraine days per month and prior failure of ≥ 3 preventive migraine treatments. Individuals with sampled baseline characteristics were created to represent this population, which comprised dedicated episodic and chronic migraine subpopulations. Clinical efficacy, utility, and work productivity inputs were based on results from the DELIVER randomised controlled trial (NCT04418765). Timing of natural history events and treatment holidays-informed by the literature-were simulated to unmask any natural improvement of the disease unrelated to treatment. The primary outcomes were monthly migraine days, migraine-associated costs, quality-adjusted life years (QALYs), incremental cost-effectiveness ratio, and net monetary benefit, each evaluated over a 5-year time horizon from 2020. Secondary analyses explored a lifetime horizon and an alternative treatment stopping rule. RESULTS: Treatment with eptinezumab resulted in an average of 0.231 QALYs gained at a saving of £4,894 over 5 years, making eptinezumab dominant over best supportive care (i.e., better health outcomes and less costly). This result was confirmed by the probabilistic analysis and all alternative assumption scenarios under the same societal perspective. Univariate testing of inputs showed net monetary benefit was most sensitive to the number of days of productivity loss, and monthly salary. CONCLUSIONS: This economic evaluation shows that from a societal perspective, eptinezumab is a cost-effective treatment in patients with ≥ 4 migraine days per month and for whom ≥ 3 other preventive migraine treatments have failed. TRIAL REGISTRATION: N/A.

Variation in Model-Based Economic Evaluations of Low-Dose Computed Tomography Screening for Lung Cancer: A Methodological Review.

OBJECTIVES: There is significant heterogeneity in the results of published model-based economic evaluations of low-dose computed tomography (LDCT) screening for lung cancer. We sought to understand and demonstrate how these models differ. METHODS: An expansion and update of a previous systematic review (N = 19). Databases (including MEDLINE and Embase) were searched. Studies were included if strategies involving (single or multiple) LDCT screening were compared with no screening or other imaging modalities, in a population at risk of lung cancer. More detailed data extraction of studies from the previous review was conducted. Studies were critically appraised using the Consensus Health Economic Criteria list. RESULTS: A total of 16 new studies met the inclusion criteria, giving a total of 35 studies. There are geographic and temporal differences and differences in screening intervals and eligible populations. Studies varied in the types of models used, for example, decision tree, Markov, and microsimulation models. Most conducted a cost-effectiveness analysis (using life-years gained) or cost-utility analysis. The potential for overdiagnosis was considered in many models, unlike with other potential consequences of screening. Some studies report considering lead-time bias, but fewer mention length bias. Generally, the more recent studies, involving more complex modeling, tended to meet more of the critical appraisal criteria, with notable exceptions. CONCLUSIONS: There are many differences across the economic evaluations contributing to variation in estimates of the cost-effectiveness of LDCT screening for lung cancer. Several methodological factors and evidence needs have been highlighted that will require consideration in future economic evaluations to achieve better agreement.

Distinct functional roles of Vps41-mediated neuroprotection in Alzheimer's and Parkinson's disease models of neurodegeneration.

Commonalities and, in some cases, pathological overlap between neurodegenerative diseases have led to speculation that targeting of underlying mechanisms might be of potentially shared therapeutic benefit. Alzheimer's disease is characterized by the formation of plaques, composed primarily of the amyloid-ß 1-42 (Aß) peptide in the brain, resulting in neurodegeneration. Previously, we have shown that overexpression of the lysosomal-trafficking protein, human Vps41 (hVps41), is neuroprotective in a transgenic worm model of Parkinson's disease, wherein progressive dopaminergic neurodegeneration is induced by α-synuclein overexpression. Here, we report the results of a systematic comparison of hVps41-mediated neuroprotection between α-synuclein and Aß in transgenic nematode models of Caenorhabditis elegans. Our results indicate that an ARF-like GTPase gene product, ARL-8, mitigates endocytic Aß neurodegeneration in a VPS-41-dependent manner, rather than through RAB-7 and AP3 as with α-synuclein. Furthermore, the neuroprotective effect of ARL-8 or hVps41 appears to be dependent on their colocalization and the activity of ARL-8. Additionally, we demonstrate that the LC3 orthologue, LGG-2, plays a critical role in Aß toxicity with ARL-8. Further analysis of functional effectors of Aß protein processing via the lysosomal pathway will assist in the elucidation of the underlying mechanism involving VPS-41-mediated neuroprotection. These results reveal functional distinctions in the intracellular management of neurotoxic proteins that serve to better inform the path for development of therapeutic interventions to halt neurodegeneration.

Cost-Effectiveness Analysis of Natriuretic Peptide Testing and Specialist Management in Patients with Suspected Acute Heart Failure.

OBJECTIVES: To determine the cost-effectiveness of natriuretic peptide (NP) testing and specialist outreach in patients with acute heart failure (AHF) residing off the cardiology ward. METHODS: We used a Markov model to estimate costs and quality-adjusted life-years (QALYs) for patients presenting to hospital with suspected AHF. We examined diagnostic workup with and without the NP test in suspected new cases, and we examined the impact of specialist heart failure outreach in all suspected cases. Inputs for the model were derived from systematic reviews, the UK national heart failure audit, randomized controlled trials, expert consensus from a National Institute for Health and Care Excellence guideline development group, and a national online survey. The main benefit from specialist care (cardiology ward and specialist outreach) was the increased likelihood of discharge on disease-modifying drugs for people with left ventricular systolic dysfunction, which improve mortality and reduce re-admissions due to worsened heart failure (associated with lower utility). Costs included diagnostic investigations, admissions, pharmacological therapy, and follow-up heart failure care. RESULTS: NP testing and specialist outreach are both higher cost, higher QALY, cost-effective strategies (incremental cost-effectiveness ratios of £11,656 and £2,883 per QALY gained, respectively). Combining NP and specialist outreach is the most cost-effective strategy. This result was robust to both univariate deterministic and probabilistic sensitivity analyses. CONCLUSIONS: NP testing for the diagnostic workup of new suspected AHF is cost-effective. The use of specialist heart failure outreach for inpatients with AHF residing off the cardiology ward is cost-effective. Both interventions will help improve outcomes for this high-risk group.

Tobramycin-Treated Pseudomonas aeruginosa PA14 Enhances Streptococcus constellatus 7155 Biofilm Formation in a Cystic Fibrosis Model System.

UNLABELLED: Cystic fibrosis (CF) is a human genetic disorder which results in a lung environment that is highly conducive to chronic microbial infection. Over the past decade, deep-sequencing studies have demonstrated that the CF lung can harbor a highly diverse polymicrobial community. We expanded our existing in vitro model of Pseudomonas aeruginosa biofilm formation on CF-derived airway cells to include this broader set of CF airway colonizers to investigate their contributions to CF lung disease, particularly as they relate to the antibiotic response of the population. Using this system, we identified an interspecies interaction between P. aeruginosa, a bacterium associated with declining lung function and worsening disease, and Streptococcus constellatus, a bacterium correlated with the onset of pulmonary exacerbations in CF patients. The growth rate and cytotoxicity of S. constellatus 7155 and P. aeruginosa PA14 were unchanged when grown together as mixed biofilms in the absence of antibiotics. However, the addition of tobramycin, the frontline maintenance therapy antibiotic for individuals with CF, to a mixed biofilm of S. constellatus 7155 and P. aeruginosa PA14 resulted in enhanced S. constellatus biofilm formation. Through a candidate genetic approach, we showed that P. aeruginosa rhamnolipids were reduced upon tobramycin exposure, allowing for S. constellatus 7155 biofilm enhancement, and monorhamnolipids were sufficient to reduce S. constellatus 7155 biofilm viability in the absence of tobramycin. While the findings presented here are specific to a biofilm of S. constellatus 7155 and P. aeruginosa PA14, they highlight the potential of polymicrobial interactions to impact antibiotic tolerance in unanticipated ways. IMPORTANCE: Deep-sequencing studies have demonstrated that the CF lung can harbor a diverse polymicrobial community. By recapitulating the polymicrobial communities observed in the CF lung and identifying mechanisms of interspecies interactions, we have the potential to select the best therapy for a given bacterial community and reveal potential opportunities for novel therapeutic interventions. Using an in vitro model of bacterial infection on CF airway cells, we tested how a particular polymicrobial community grows, damages human cells, and responds to antibiotics in single and mixed infections. We describe here the mechanism of an interspecies interaction between two pathogens in the CF lung, P. aeruginosa and S. constellatus, which is potentiated by a commonly prescribed antibiotic, tobramycin.

Borrelia burgdorferi-A Bacterium Worthy of Consideration in Culture-Negative Prosthetic Joint Infection.

A 68-year-old woman presented to the orthopaedic office with 2 weeks of atraumatic right prosthetic knee pain and swelling. She previously lived pain free and fully functional after a total knee arthroplasty 8 years ago. Initial radiographs showed a small joint effusion, and serum inflammatory markers were elevated. Arthrocentesis yielded 12ccs of culture-negative cloudy serous fluid containing 3,270 white blood cells, 92% polymorphonuclear neutrophils. The patient underwent prosthesis explant, antibiotic spacer placement, and began empiric IV antibiotic therapy as stage one of a planned two-stage revision. Intraoperative tissue cultures were negative, and the postoperative plan was to continue IV vancomycin for a total of 6 weeks. Two weeks post-op, serum Lyme antibody testing returned positive. The patient was switched to doxycycline and ceftriaxone for a total duration of 4 weeks, followed by a successful second-stage revision and remains asymptomatic after 1 year. Five cases of culture-negative prosthetic joint infections caused by the spirochete, Borrelia burgdorferi, have been reported in the orthopaedic literature.1-4 We present a sixth case, occurring in a 68-year-old woman in Northwestern Pennsylvania, 8 years after a primary right total knee arthroplasty.

Pseudomonas aeruginosa exopolysaccharide Psl promotes resistance to the biofilm inhibitor polysorbate 80.

Polysorbate 80 (PS80) is a nonionic surfactant and detergent that inhibits biofilm formation by Pseudomonas aeruginosa at concentrations as low as 0.001% and is well tolerated in human tissues. However, certain clinical and laboratory strains (PAO1) of P. aeruginosa are able to form biofilms in the presence of PS80. To better understand this resistance, we performed transposon mutagenesis with a PS80-resistant clinical isolate, PA738. This revealed that mutation of algC rendered PA738 sensitive to PS80 biofilm inhibition. AlgC contributes to the biosynthesis of the exopolysaccharides Psl and alginate, as well as lipopolysaccharide and rhamnolipid. Analysis of mutations downstream of AlgC in these biosynthetic pathways established that disruption of the psl operon was sufficient to render the PA738 and PAO1 strains sensitive to PS80-mediated biofilm inhibition. Increased levels of Psl production in the presence of arabinose in a strain with an arabinose-inducible psl promoter were correlated with increased biofilm formation in PS80. In P. aeruginosa strains MJK8 and ZK2870, known to produce both Pel and Psl, disruption of genes in the psl but not the pel operon conferred susceptibility to PS80-mediated biofilm inhibition. The laboratory strain PA14 does not produce Psl and does not form biofilms in PS80. However, when PA14 was transformed with a cosmid containing the psl operon, it formed biofilms in the presence of PS80. Taken together, these data suggest that production of the exopolysaccharide Psl by P. aeruginosa promotes resistance to the biofilm inhibitor PS80.

In vitro evaluation of tobramycin and aztreonam versus Pseudomonas aeruginosa biofilms on cystic fibrosis-derived human airway epithelial cells.

OBJECTIVES: Aztreonam for inhalation solution (AZLI) was recently approved by the FDA for treating cystic fibrosis (CF) patients infected with Pseudomonas aeruginosa. Here we investigated the effect of aztreonam alone or in combination with tobramycin on P. aeruginosa biofilms grown on CF airway epithelial cells. METHODS: P. aeruginosa biofilms, produced by laboratory strains or clinical isolates, were formed on confluent CF airway cells before treatment overnight with aztreonam or tobramycin alone or in combination. Alternatively, antibiotics were added 1 h after bacterial inoculation to assess their ability to impair biofilm formation at 5 h. Bacterial cfu remaining after treatment were then determined by plate counting. RESULTS: In the absence of antibiotics, all strains developed biofilms that disrupted CF airway epithelial monolayers overnight. Tobramycin reduced the cfu of all strains grown as biofilms. Aztreonam reduced the cfu of some strains by ∼1 log unit without preserving the integrity of cystic fibrosis airway cell monolayers, while decreasing the biofilms of other clinical isolates by ∼4 log units and protecting the monolayers from being compromised. The combination of aztreonam and tobramycin reduced the cfu of two strains by an additional 0.5 and 2 log units, respectively. Of all the mechanisms explored, Psl exopolysaccharide production might explain the variations in biofilm tolerance to aztreonam in some of the strains. CONCLUSIONS: Effects of aztreonam on P. aeruginosa biofilms in the in vitro co-culture model are strain-dependent. The simultaneous application of aztreonam and tobramycin may be beneficial for a subset of CF patients by eliminating susceptible P. aeruginosa strains.

An Economic Analysis of Critical Care Nurse Resourcing Following the Uptake of Ready-to-Administer Noradrenaline for Hypotensive Shock in Adults in England.

INTRODUCTION: Ready-to-administer formulations for intravenous administration of noradrenaline are now broadly recommended and predicted to reduce pressure on critical care nursing. This analysis sought to quantify the nurse resource released from national level transition. METHODS: The annual number of noradrenaline support days for hypotensive shock was determined and the administration of noradrenaline was simulated over 24 h using a decision tree. A 'best-practice' ready-to-administer strategy (RtA) of volumetrically pumped noradrenaline was compared to a 'nil uptake' strategy (AfC) of bedside prepared solution delivered either volumetrically or using a double syringe pump. A mix of noradrenaline concentrations, flow rates, product sizes, and preferences for ampoule pooling, preparation volume, and sterility were included. The consumption of nurse days and product units was then projected over 1 year for a population of adults in critical care in England. RESULTS: Noradrenaline was administered over 231,011 days per year across 4123 critical care beds in England. Implementing a transition from AfC to RtA strategies on this scale released 35,791 nurse days or 176 whole-time nurse equivalents at 50/50 NHS band 5 and 6, a monetised release of £11.6 million. There was an increase in drug acquisition cost of £2.1 million using the licensed commercial product Sinora®. Annual net monetary benefit was + £9.5 million, or + £65,961 per critical care unit (CCU) of 29 beds, equivalent to one nurse released per unit for patient care. CONCLUSIONS: This modelling of ready-to-administer noradrenaline with volumetric delivery quantifies and bears out the recommendations of the Lord Carter review, the Royal Pharmaceutical Society, and the NHS Specialist Pharmacy Service in their encouragement of ready-to-administer formulations for safe and resource-effective critical care.

An Introduction to Reviewing Research Articles for Academic Journals.

Description Among the pillars of science is the galvanizing process of peer review. Editors of medical and scientific publications recruit specialty leaders to evaluate the quality of manuscripts. These peer reviewers help to ensure that data are collected, analyzed, and interpreted as accurately as possible, thereby moving the field forward and ultimately improving patient care. As physician-scientists, we are given the opportunity and responsibility to participate in the peer review process. There are many benefits to engaging in the peer review process including exposure to cutting-edge research, growing your connection with the academic community, and fulfilling the scholarly activity requirements of your accrediting organization. In the present manuscript, we discuss the key components of the peer review process and hope that it will serve as a primer for the novice reviewer and as a useful guide for the experienced reviewer.

Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation.

Vacuolar protein sorting 41 (VPS41) is as part of the Homotypic fusion and Protein Sorting (HOPS) complex required for lysosomal fusion events and, independent of HOPS, for regulated secretion. Here, we report three patients with compound heterozygous mutations in VPS41 (VPS41S285P and VPS41R662* ; VPS41c.1423-2A>G and VPS41R662* ) displaying neurodegeneration with ataxia and dystonia. Cellular consequences were investigated in patient fibroblasts and VPS41-depleted HeLa cells. All mutants prevented formation of a functional HOPS complex, causing delayed lysosomal delivery of endocytic and autophagic cargo. By contrast, VPS41S285P enabled regulated secretion. Strikingly, loss of VPS41 function caused a cytosolic redistribution of mTORC1, continuous nuclear localization of Transcription Factor E3 (TFE3), enhanced levels of LC3II, and a reduced autophagic response to nutrient starvation. Phosphorylation of mTORC1 substrates S6K1 and 4EBP1 was not affected. In a C. elegans model of Parkinson's disease, co-expression of VPS41S285P /VPS41R662* abolished the neuroprotective function of VPS41 against α-synuclein aggregates. We conclude that the VPS41 variants specifically abrogate HOPS function, which interferes with the TFEB/TFE3 axis of mTORC1 signaling, and cause a neurodegenerative disease.

The effectiveness of an interactive audio-tactile map for the process of cognitive mapping and recall among people with visual impairments.

BACKGROUND: People with visual impairments can experience numerous challenges navigating unfamiliar environments. Systems that operate as prenavigation tools can assist such individuals. This mixed-methods study examined the effectiveness of an interactive audio-tactile map tool on the process of cognitive mapping and recall, among people who were blind or had visual impairments. The tool was developed with the involvement of visually impaired individuals who additionally provided further feedback throughout this research. METHODS: A mixed-methods experimental design was employed. Fourteen participants were allocated to either an experimental group who were exposed to an audio-tactile map, or a control group exposed to a verbally annotated tactile map. After five minutes' exposure, multiple-choice questions examined participants' recall of the spatial and navigational content. Subsequent semi-structured interviews were conducted to examine their views surrounding the study and the product. RESULTS: The experimental condition had significantly better overall recall than the control group and higher average scores in all four areas examined by the questions. The interviews suggested that the interactive component offered individuals the freedom to learn the map in several ways and did not restrict them to a sequential and linear approach to learning. CONCLUSION: Assistive technology can reduce challenges faced by people with visual impairments, and the flexible learning approach offered by the audio-tactile map may be of particular value. Future researchers and assistive technology developers may wish to explore this further.

Metastatic Lung Cancer to the Distal Finger Presenting as Osteomyelitis.

Metastasis to distal phalanx is a rare site for metastasis. It is often misdiagnosed as osteomyelitis because of similar clinical features, symptoms, and radiologic findings. If preceded by trauma, the diagnosis could be difficult. We are presenting a case of a 69-year-old male cigarette smoker, who presented with progressive painful swelling of the right second digit for two months duration after he lacerated his finger by a fingernail clipper. After receiving several unsuccessful courses of antibiotics, he was admitted for further treatment. Based on the CT scan of the right hand, he was treated for osteomyelitis and scheduled for elective surgery. As a part of the preoperative workup, his chest X-ray (CXR) revealed a left lower lobe infiltrate, and a subsequent CT of the chest demonstrated a 6 cm mass in the left lower lobe. The pathologic findings of lung mass and finger biopsy revealed a poorly differentiated carcinoma. The patient was treated with several cycles of chemotherapy before he decided to seek hospice care.  Certain malignancies have increased receptors for wound-healing factors. For those malignancies, trauma will promote local metastasis by releasing wound-healing factors that create a favorable environment for micrometastasis cell growth. Some of these components currently are targets for therapy, while other components may be targets for therapy in the future.

Lung cancer screening by low-dose computed tomography: a cost-effectiveness analysis of alternative programmes in the UK using a newly developed natural history-based economic model.

BACKGROUND: A systematic review of economic evaluations for lung cancer identified no economic models of the UK setting based on disease natural history. We first sought to develop a new model of natural history for population screening, then sought to explore the cost-effectiveness of multiple alternative potential programmes. METHODS: An individual patient model (ENaBL) was constructed in MS Excel® and calibrated against data from the US National Lung Screening Trial. Costs were taken from the UK Lung Cancer Screening Trial and took the perspective of the NHS and PSS. Simulants were current or former smokers aged between 55 and 80 years and so at a higher risk of lung cancer relative to the general population. Subgroups were defined by further restricting age and risk of lung cancer as predicted by patient self-questionnaire. Programme designs were single, triple, annual and biennial arrangements of LDCT screens, thereby examining number and interval length. Forty-eight distinct screening strategies were compared to the current practice of no screening. The primary outcome was incremental cost-effectiveness of strategies (additional cost per QALY gained). RESULTS: LDCT screening is predicted to bring forward the stage distribution at diagnosis and reduce lung cancer mortality, with decreases versus no screening ranging from 4.2 to 7.7% depending on screen frequency. Overall healthcare costs are predicted to increase; treatment cost savings from earlier detection are outweighed by the costs of over-diagnosis. Single-screen programmes for people 55-75 or 60-75 years with ≥ 3% predicted lung cancer risk may be cost-effective at the £30,000 per QALY threshold (respective ICERs of £28,784 and £28,169 per QALY gained). Annual and biennial screening programmes were not predicted to be cost-effective at any cost-effectiveness threshold. LIMITATIONS: LDCT performance was unaffected by lung cancer type, stage or location and the impact of a national screening programme of smoking behaviour was not included. CONCLUSION: Lung cancer screening may not be cost-effective at the threshold of £20,000 per QALY commonly used in the UK but may be cost-effective at the higher threshold of £30,000 per QALY.

Student experiences of neurodiversity in higher education: insights from the BRAINHE project.

The number of students with identified learning differences (LDs) of all kinds is increasing in higher education. This qualitative study explored the experiences of 27 current and previous students with a range of specific LDs by means of semi-structured interviews, using a thematic approach. The findings revealed that participants shared many life experiences and preferences for learning irrespective of their type of LD. Participants generally held one of two views about their identity as 'neurodiverse': a 'difference' view--where neurodiversity was seen as a difference incorporating a set of strengths and weaknesses, or a 'medical/deficit' view--where neurodiversity was seen as a disadvantageous medical condition. The former view was associated with expressions of greater career ambition and academic self-esteem, while the latter view was associated more with processes for obtaining the Disabled Students' Allowance. Many of the participants reported similar experiences in education and with university support; many did not feel adequately supported by their institutions. Recommendations are made for increased awareness training among lecturers and better liaison between university departments.

ApoE-associated modulation of neuroprotection from Aß-mediated neurodegeneration in transgenic Caenorhabditis elegans.

Allele-specific distinctions in the human apolipoprotein E (APOE) locus represent the best-characterized genetic predictor of Alzheimer's disease (AD) risk. Expression of isoform APOEε2 is associated with reduced risk, while APOEε3 is neutral and APOEε4 carriers exhibit increased susceptibility. Using Caenorhabditis elegans, we generated a novel suite of humanized transgenic nematodes to facilitate neuronal modeling of amyloid-beta peptide (Aß) co-expression in the context of distinct human APOE alleles. We found that co-expression of human APOEε2 with Aß attenuated Aß-induced neurodegeneration, whereas expression of the APOEε4 allele had no effect on neurodegeneration, indicating a loss of neuroprotective capacity. Notably, the APOEε3 allele displayed an intermediate phenotype; it was not neuroprotective in young adults but attenuated neurodegeneration in older animals. There was no functional impact from the three APOE isoforms in the absence of Aß co-expression. Pharmacological treatment that examined neuroprotective effects of APOE alleles on calcium homeostasis showed allele-specific responses to changes in ER-associated calcium dynamics in the Aß background. Additionally, Aß suppressed survival, an effect that was rescued by APOEε2 and APOEε3, but not APOEε4. Expression of the APOE alleles in neurons, independent of Aß, exerted no impact on survival. Taken together, these results illustrate that C. elegans provides a powerful in vivo platform with which to explore how AD-associated neuronal pathways are modulated by distinct APOE gene products in the context of Aß-associated neurotoxicity. The significance of both ApoE and Aß to AD highlights the utility of this new pre-clinical model as a means to dissect their functional inter-relationship.This article has an associated First Person interview with the first author of the paper.

Damage Control Resuscitation.

Damage control resuscitation (DCR) is a strategy for resuscitating patients from hemorrhagic shock to rapidly restore homeostasis. Efforts are focused on blood product transfusion with whole blood or component therapy closely approximating whole blood, limited use of crystalloid to avoid dilutional coagulopathy, hypotensive resuscitation until bleeding control is achieved, empiric use of tranexamic acid, prevention of acidosis and hypothermia, and rapid definitive surgical control of bleeding. Patients receiving uncrossmatched Type O blood in the emergency department and later receiving cumulative transfusions of 10 or more red blood cell units in the initial 24-hour post-injury (massive transfusion) are widely recognized as being at increased risk of morbidity and mortality due to exsanguination. Ideally, these patients should be rapidly identified, however anticipating transfusion needs is challenging. Useful indicators of massive transfusion reviewed in this guideline include: systolic blood pressure <110 mmHg, heart rate > 105 bpm, hematocrit <32%, pH < 7.25, injury pattern (above-the-knee traumatic amputation especially if pelvic injury is present, multi-amputation, clinically obvious penetrating injury to chest or abdomen), >2 regions positive on Focused Assessment with Sonography for Trauma (FAST) scan, lactate concentration on admission >2.5, admission international normalized ratio ≥1.2-1.4, near infrared spectroscopy-derived StO2 < 75% (in practice, rarely available), BD > 6 meq/L. Unique aspects of out-of-hospital DCR (point of injury, en-route, and remote DCR) and in-hospital (Medical Treatment Facilities: Role 2b/Forward surgical teams - role 3/ combat support hospitals) are reviewed in this guideline, along with pediatric considerations.

New Zealand Healthline call data used to measure the effect of travel time on the use of the emergency department.

Telephone triage is a health tool increasingly used to connect geographically distant populations. Such services are also utilised to address issues of Emergency Department (ED) overuse. New Zealand's tele-triage service, Healthline, has existed since 2001 but is yet to be the focus of analysis. This research sought to understand the role that travel time to ED had upon Healthline users' compliance with telephone advice. Additionally, the role of deprivation in Healthline (as a determinant of caller behaviour) was examined. Travel time to ED was found to influence the impact of Healthline advice upon callers but this was not confounded by deprivation. Those living closest to the ED were more likely to attend when advised to, and less likely to stay away if told to avoid the ED. Different time brackets showed stronger trends, suggesting that callers at varying distances from EDs may be more or less influenced by both travel time and Healthline advice.

Genetic and Pharmacological Discovery for Alzheimer's Disease Using Caenorhabditis elegans.

The societal burden presented by Alzheimer's disease warrants both innovative and expedient means by which its underlying molecular causes can be both identified and mechanistically exploited to discern novel therapeutic targets and strategies. The conserved characteristics, defined neuroanatomy, and advanced technological application of Caenorhabditis elegans render this metazoan an unmatched tool for probing neurotoxic factors. In addition, its short lifespan and importance in the field of aging make it an ideal organism for modeling age-related neurodegenerative disease. As such, this nematode system has demonstrated its value in predicting functional modifiers of human neurodegenerative disorders. Here, we review how C. elegans has been utilized to model Alzheimer's disease. Specifically, we present how the causative neurotoxic peptides, amyloid-ß and tau, contribute to disease-like neurodegeneration in C. elegans and how they translate to human disease. Furthermore, we describe how a variety of transgenic animal strains, each with distinct utility, have been used to identify both genetic and pharmacological modifiers of toxicity in C. elegans. As technological advances improve the prospects for intervention, the rapidity, unparalleled accuracy, and scale that C. elegans offers researchers for defining functional modifiers of neurodegeneration should speed the discovery of improved therapies for Alzheimer's disease.

Examining the significance of urban-rural context in tobacco quitline use: does rurality matter?

OBJECTIVES: The purpose of this study was to examine the importance of urban-rural context as a determinant of call rates to smoking cessation lines. METHODS: This study used individual level New Zealand Quitline call data from 2005 to 2009, and 2006 New Zealand Census data on smoking to calculate Quitline call rates for smokers. Negative binomial regression examined the relationship between call rates and a sevenfold urban-rural classification, controlling for age, sex, ethnicity and deprivation. RESULTS: We found a significant urban-rural gradient in the rate of smokers calling Quitline. Rates were highest among smokers in main-urban areas [0.09 (95 % confidence interval (CI) = 0.089, 0.091)] decreasing with successive urban-rural classifications to the lowest rate in rural/remote areas [0.036 (95 % CI = 0.03, 0.04)]. This association was not confounded by age, sex, ethnicity or deprivation. CONCLUSIONS: Smokers in rural areas are less likely to use the New Zealand Quitline, even after controlling for confounding factors. This suggests that the national quitline is less effective in reaching rural smokers and more attention to the promotion of smoking cessation in rural communities is needed.