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Neural precursor cells (NPCs) are generated in the subventricular zone (SVZ) and travel through the rostral migratory stream (RMS) to replace olfactory bulb interneurons in the brains of most adult mammals. Following brain injury, SVZ-derived NPCs can divert from the RMS and migrate toward injured brain regions but arrive in numbers too low to promote functional recovery without experimental intervention. Our lab has biofabricated a “living scaffold” that replicates the structural and functional features of the endogenous RMS. This tissue-engineered rostral migratory stream (TE-RMS) is a new regenerative medicine strategy designed to facilitate stable and sustained NPC delivery into neuron-deficient brain regions following brain injury or neurodegenerative disease and an in vitro tool to investigate the mechanisms of neuronal migration and cell–cell communication. We have previously shown that the TE-RMS replicates the basic structure and protein expression of the endogenous RMS and can direct immature neuronal migration in vitro and in vivo. Here, we further describe profound morphological changes that occur following precise physical manipulation and subsequent self-assembly of astrocytes into the TE-RMS, including significant cytoskeletal rearrangement and nuclear elongation. The unique cytoskeletal and nuclear architecture of TE-RMS astrocytes mimics astrocytes in the endogenous rat RMS. Advanced imaging techniques reveal the unique morphology of TE-RMS cells that has yet to be described of astrocytes in vitro. The TE-RMS offers a novel platform to elucidate astrocyte cytoskeletal and nuclear dynamics and their relationship to cell behavior and function.

Aim: To describe initial treatment patterns and survival of patients diagnosed with non-small-cell lung cancer (NSCLC) in Denmark, before immune checkpoint inhibitor and later-generation tyrosine kinase inhibitor use. Patients & methods: Adults diagnosed with incident NSCLC (2005–2015; follow-up: 2016). Initial treatments and overall survival (OS) are reported. Results: 31,939 NSCLC patients (51.6% stage IV) were included. Increasing use of curative radiotherapy/chemoradiation for stage I, II/IIIA and IIIB NSCLC coincided with improved 2-year OS. Systemic anticancer therapy use increased for patients with stage IV non-squamous NSCLC (53.0–60.6%) but not squamous NSCLC (44.9–47.3%). 1-year OS improved in patients with stage IV non-squamous NSCLC (23–31%) but not squamous NSCLC (22–25%). Conclusion: Trends indicated improved OS as treatments evolved between 2005 and 2015, but the effect was limited to 1-year OS in stage IV disease.

Neurocritical care significantly impacts outcomes after moderate-to-severe acquired brain injury, but it is rarely applied in preclinical studies. We created a comprehensive neurointensive care unit (neuroICU) for use in swine to account for the influence of neurocritical care, collect clinically relevant monitoring data, and create a paradigm that is capable of validating therapeutics/diagnostics in the unique neurocritical care space. Our multidisciplinary team of neuroscientists, neurointensivists, and veterinarians adapted/optimized the clinical neuroICU (e.g., multimodal neuromonitoring) and critical care pathways (e.g., managing cerebral perfusion pressure with sedation, ventilation, and hypertonic saline) for use in swine. Moreover, this neurocritical care paradigm enabled the first demonstration of an extended preclinical study period for moderate-to-severe traumatic brain injury with coma beyond 8 h. There are many similarities with humans that make swine an ideal model species for brain injury studies, including a large brain mass, gyrencephalic cortex, high white matter volume, and topography of basal cisterns, amongst other critical factors. Here we describe the neurocritical care techniques we developed and the medical management of swine following subarachnoid hemorrhage and traumatic brain injury with coma. Incorporating neurocritical care in swine studies will reduce the translational gap for therapeutics and diagnostics specifically tailored for moderate-to-severe acquired brain injury.

Although traditional small animal and cell culture models of neurodegenerative disease have been valuable in foundational discoveries, their inherent imprecision may have biased our understanding of etiology in humans and hindered translation of therapeutics. Recent breakthroughs to generate human stem cell–derived brain organoids — including from patient-specific cell sources — provide powerful platforms to improve disease modeling accuracy. However, brain organoids do not recapitulate crucial anatomical structures such as long bundled axon tracts — a central systems-level feature of human brains — critical to neurodegenerative disease pathogenesis, including Parkinson's disease. To address this challenge, advances in tissue engineering recapitulate brain pathways with three-dimensional anatomical fidelity to discrete systems-level brain structures, such as the first tissue engineered nigrostriatal pathway. Promulgating anatomically inspired human-derived engineered microtissue may improve translational relevance, empower personalized medicine, and ultimately reduce costs compared to conventional model systems, thus proving useful for targeted development and screening of new therapeutic strategies.

Mild traumatic brain injury affects millions of individuals annually primarily through falls, traffic collisions, or blunt trauma and can generate symptoms that persist for years. Closed-head rotational loading is the most common cause of mild traumatic brain injury and is defined by a rapid rotational acceleration of brain tissue within an intact skull. Injury kinematics—the mechanical descriptors of injury-inducing motion—explain movement of the head, which govern energy transfer, and, therefore, determine injury severity. However, the relationship between closed-head rotational injury kinematics—such as angular velocity, angular acceleration, and injury duration—and outcome after mild traumatic brain injury is not completely understood. To address this gap in knowledge, we analysed archived surgical records of 24 swine experiencing a diffuse closed-head rotational acceleration mild traumatic brain injury against 12 sham animals. Kinematics were contrasted against acute recovery outcomes, specifically apnea time, extubation time, standing time, and recovery duration. Compared to controls, animals experiencing a mild traumatic brain injury were far more likely to have apnea (P < 0.001), shorter time to extubation (P = 0.023), and longer time from extubation to standing (P = 0.006). Using least absolute shrinkage and selection operator-based regressions, kinematic parameters, including maximum negative angular velocity and time from peak angular velocity to maximum angular deceleration, were selected to explain variation in apnea time, standing time, and recovery duration. Simplified linear models employing the least absolute shrinkage and selection operator-selected variables explained a modest degree of variation in apnea time (adjusted R2 = 0.18), standing time (adjusted R2 = 0.19), and recovery duration (adjusted R2 = 0.27). Neuropathology was correlated with multiple injury kinematics, with maximum angular acceleration exhibiting the strongest correlation (R2 = 0.66). Together, these data suggest the interplay between multiple injury kinematics, including maximum negative angular velocity (immediately preceding cessation of head motion) and time from peak angular velocity to maximum angular deceleration, best explain acute recovery metrics and neuropathology after mild traumatic brain injury in swine. Future experiments that independently manipulate individual kinematic parameters could be instrumental in developing translational diagnostics for clinical mild traumatic brain injury.

ObjectivesTo assess how a decade of developments in systematic anticancer therapy (SACT) for advanced non-small cell lung cancer (NSCLC) affected overall survival (OS) in a large UK University Hospital.DesignReal-world retrospective observational cohort study using existing data recorded in electronic medical records.SettingA large National Health Service (NHS) university teaching hospital serving 800 000 people living in a diverse metropolitan area of the UK.Participants2119 adults diagnosed with advanced NSCLC (tumour, node, metastasis stage IIIB or IV) between 2007 and 2017 at Leeds Teaching Hospitals NHS Trust.Main outcomes and measuresOS following diagnosis and the analysis of factors associated with receiving SACT.ResultsMedian OS for all participants was 2.9 months, increasing for the SACT-treated subcohort from 8.4 months (2007–2012) to 9.1 months (2013–2017) (p=0.02); 1-year OS increased from 33% to 39% over the same period for the SACT-treated group. Median OS for the untreated subcohort was 1.6 months in both time periods. Overall, 30.6% (648/2119) patients received SACT; treatment rates increased from 28.6% (338/1181) in 2007–2012 to 33.0% (310/938) in 2013–2017 (p=0.03). Age and performance status were independent predictors for SACT treatment; advanced age and higher performance status were associated with lower SACT treatment rates.ConclusionAlthough developments in SACT during 2007–2017 correspond to some changes in survival for treated patients with advanced NSCLC, treatment rates remain low and the prognosis for all patients remains poor.

Mild traumatic brain injury (mTBI) affects millions of individuals annually primarily through falls, traffic collisions, or blunt trauma and can generate symptoms that persist for years. Closed-head rotational injury is the most common form of mTBI and is defined by a rapid change in acceleration within an intact skull. Injury kinematics – the mechanical descriptors of injury-inducing motion – explain movement of the head, energy transfer to the brain, and, therefore, determine injury severity. However, the relationship between closed-head rotational injury kinematics – such as angular velocity, angular acceleration, and injury duration – and outcome after mTBI is currently unknown. To address this gap in knowledge, we analyzed archived surgical records of 24 swine experiencing a diffuse closed-head rotational acceleration mTBI against 12 sham animals. Kinematics were contrasted against acute recovery outcomes, specifically apnea, extubation time, standing time, and recovery duration. Compared to controls, animals with mTBI were far more likely to have apnea (p2=0.27), standing time (R2=0.39) and recovery duration (R2=0.42). Neuropathology was correlated with multiple kinematics, with maximum acceleration exhibiting the strongest correlation (R2=0.66). Together, these data suggest the interplay between multiple injury kinematics, including minimum velocity and middle to minimum acceleration time, best explain acute recovery parameters and neuropathology after mTBI in swine. Future experiments that independently manipulate individual kinematics could be instrumental in developing translational diagnostics for clinical mTBI.HIGHLIGHTSAcute recovery parameters including apnea, extubation time, and recovery duration were altered after a single closed-head mTBI in swine.Lasso-based regressions utilized kinematic parameters, including minimum velocity and middle to minimum acceleration time, to relate kinematics to apnea time, standing time, and recovery duration.Lasso regression equations were able to modestly predict apnea time (R2=0.27) and moderately predict standing time (R2=0.39) and recovery duration (R2=0.42).Injury kinematic parameters, primarily maximum acceleration, were correlated with white matter pathology after mTBI.

In recent years, regulatory bodies have increasingly recognized the utility of real-world evidence (RWE) for supplementing and supporting clinical trial data in new drug applications. Nevertheless, the integration of RWE into established regulatory processes is complex and the generation of ‘regulatory-grade’ real-world data faces operational, methodological, data-related and policy-related challenges. In parallel with this evolving role for RWE, immuno-oncology therapies have emerged as leading cancer treatments and are expected to continue to play a central role in the future. In this article, we review the current literature on the use of RWE for regulatory submissions, with a focus on novel anticancer immunotherapies, and discuss the utility and current limitations of RWE in the context of drug development and regulatory approvals.

The rostral migratory stream (RMS) facilitates neuroblast migration from the subventricular zone to the olfactory bulb throughout adulthood. Brain lesions attract neuroblast migration out of the RMS, but resultant regeneration is insufficient. Increasing neuroblast migration into lesions has improved recovery in rodent studies. We previously developed techniques for fabricating an astrocyte-based Tissue-Engineered RMS (TE-RMS) intended to redirect endogenous neuroblasts into distal brain lesions for sustained neuronal replacement. Here, we demonstrate that astrocyte-like-cells can be derived from adult human gingiva mesenchymal stem cells and used for TE-RMS fabrication. We report that key proteins enriched in the RMS are enriched in TE-RMSs. Furthermore, the human TE-RMS facilitates directed migration of immature neurons in vitro. Finally, human TE-RMSs implanted in athymic rat brains redirect migration of neuroblasts out of the endogenous RMS. By emulating the brain’s most efficient means for directing neuroblast migration, the TE-RMS offers a promising new approach to neuroregenerative medicine., O’Donnell et al. describe their Tissue-Engineered Rostral Migratory Stream (TE-RMS) comprised of human astrocyte-like cells that can be derived from adult gingival stem cells within one week, which reorganizes into bundles of bidirectional, longitudinally-aligned astrocytes to emulate the endogenous RMS. Establishing immature neuronal migration in vitro and in vivo, their study demonstrates surgical feasibility and proof-of-concept evidence for this nascent technology.

Neurogenesis in the postnatal mammalian brain is known to occur in the dentate gyrus of the hippocampus and the subventricular zone. These neurogenic niches serve as endogenous sources of neural precursor cells that could potentially replace neurons that have been lost or damaged throughout the brain. As an example, manipulation of the subventricular zone to augment neurogenesis has become a popular strategy for attempting to replace neurons that have been lost due to acute brain injury or neurodegenerative disease. In this review article, we describe current experimental strategies to enhance the regenerative potential of endogenous neural precursor cell sources by enhancing cell proliferation in neurogenic regions and/or redirecting migration, including pharmacological, biomaterial, and tissue engineering strategies. In particular, we discuss a novel replacement strategy based on exogenously biofabricated "living scaffolds" that could enhance and redirect endogenous neuroblast migration from the subventricular zone to specified regions throughout the brain. This approach utilizes the first implantable, biomimetic tissue-engineered rostral migratory stream, thereby leveraging the brain's natural mechanism for sustained neuronal replacement by replicating the structure and function of the native rostral migratory stream. Across all these strategies, we discuss several challenges that need to be overcome to successfully harness endogenous neural precursor cells to promote nervous system repair and functional restoration. With further development, the diverse and innovative tissue engineering and biomaterial strategies explored in this review have the potential to facilitate functional neuronal replacement to mitigate neurological and psychiatric symptoms caused by injury, developmental disorders, or neurodegenerative disease.

Aim: To describe I-O Optimise, a multinational program providing real-world insights into lung cancer management. Materials & methods: Real-world data source selection for I-O Optimise followed a structured approach focused on population coverage, key variable capture, continuous/consistent data availability, record duration and data latency, and database expertise. Results: As of 31 October 2018, seven real-world data sources were included in I-O Optimise, providing data on characteristics, treatment patterns and clinical outcomes from more than 45,000 patients/year with non-small-cell lung cancer, small-cell lung cancer and mesothelioma across Denmark, Norway, Portugal, Spain, Sweden and the UK. Conclusion: The ongoing I-O Optimise initiative has the potential to provide a broad, robust and dynamic research platform to continually address numerous research objectives in the lung cancer arena. This article describes the design and creation of I-O Optimise, a project that will collect real-world evidence about patients with lung cancer across many different countries. A specific structured approach was followed to select real-world data sources for inclusion in I-O Optimise and, as of 31 October 2018, seven real-world data sources were included, providing information on more than 45,000 patients per year with lung cancer in Denmark, Norway, Portugal, Spain, Sweden and the UK. I-O Optimise is an ongoing project that has the potential to provide information that will be important in improving the care of patients with lung cancer.

Background I-O Optimise is a new multinational data platform developed to enable real-world insights into the management of thoracic malignancies. As part of this initiative, the current analysis reports the characteristics and treatment patterns for adult patients diagnosed with stage IIIB or IV NSCLC at one of the largest integrated cancer centres in the UK. Methods Retrospective cohort study using longitudinal data already collected from electronic medical records, including all adult patients diagnosed with stage IIIB-IV NSCLC between January 2007 and August 2017. Minimum follow-up was 6 months. Distinct lines of therapy (LoT) were identified using a clinically-verified algorithm based on the name and date of systemic anti-cancer therapy (SACT) administered and the gap between two treatments. Results Overall, 2119 patients were included. Mean age at diagnosis was 71.4±11.2 years. Nearly one-third (32.7%) were clinically diagnosed without pathological confirmation (table 1) and very few of these patients have SACT administration recorded. Following diagnosis, 648 patients (30.6%) received ≥1 LoT, 223 (10.5%)≥2 LoT and 60 (2.8%)≥3 LoT. Proportions of patients treated decreased with age (73.5% [25/34] aged 18–44 years; 52.7% [267/507] aged 45–64 years; 29.8% [310/1040] aged 65–79 years; 8.6% [46/538] aged 80+years) and performance score (58.5% [387/662] PS0–1; 38.2% [158/414] PS2; 6.1% [52/848] PS3–4). Between the periods 2007–2011 and 2012–2017, increased proportions were treated (28.2% [263/933] and 32.5% [385/1186] respectively). Patient characteristics of the treated cohort and regimens administered for 1st and 2nd LoT are shown (table 1). Conclusions Around 70% of this real-world cohort did not receive any SACT, and the administration of treatment was strongly associated with age and performance status. The changing availability of treatment options over time (including the emergence of immunotherapy) and survival outcomes by LoT will be presented in more detail for the cohort described.

Recently, mitochondria have been localized to astrocytic processes where they shape Ca2+ signaling; this relationship has not been examined in models of ischemia/reperfusion. We biolistically transfected astrocytes in rat hippocampal slice cultures to facilitate fluorescent confocal microscopy, and subjected these slices to transient oxygen/glucose deprivation (OGD) that causes delayed excitotoxic death of CA1 pyramidal neurons. This insult caused a delayed loss of mitochondria from astrocytic processes and increased colocalization of mitochondria with the autophagosome marker LC3B. The losses of neurons in area CA1 and mitochondria in astrocytic processes were blocked by ionotropic glutamate receptor (iGluR) antagonists, tetrodotoxin, ziconotide (Ca2+ channel blocker), two inhibitors of reversed Na+/Ca2+ exchange (KB-R7943, YM-244769), or two inhibitors of calcineurin (cyclosporin-A, FK506). The effects of OGD were mimicked by NMDA. The glutamate uptake inhibitor (3S)-3-[[3-[[4-(trifluoromethyl)benzoyl]amino]phenyl]methoxy]-l-aspartate increased neuronal loss after OGD or NMDA, and blocked the loss of astrocytic mitochondria. Exogenous glutamate in the presence of iGluR antagonists caused a loss of mitochondria without a decrease in neurons in area CA1. Using the genetic Ca2+ indicator Lck-GCaMP-6S, we observed two types of Ca2+ signals: (1) in the cytoplasm surrounding mitochondria (mitochondrially centered) and (2) traversing the space between mitochondria (extramitochondrial). The spatial spread, kinetics, and frequency of these events were different. The amplitude of both types was doubled and the spread of both types changed by ∼2-fold 24 h after OGD. Together, these data suggest that pathologic activation of glutamate transport and increased astrocytic Ca2+ through reversed Na+/Ca2+ exchange triggers mitochondrial loss and dramatic increases in Ca2+ signaling in astrocytic processes. SIGNIFICANCE STATEMENT Astrocytes, the most abundant cell type in the brain, are vital integrators of signaling and metabolism. Each astrocyte consists of many long, thin branches, called processes, which ensheathe vasculature and thousands of synapses. Mitochondria occupy the majority of each process. This occupancy is decreased by ∼50% 24 h after an in vitro model of ischemia/reperfusion injury, due to delayed fragmentation and mitophagy. The mechanism appears to be independent of neuropathology, instead involving an extended period of high glutamate uptake into astrocytes. Our data suggest that mitochondria serve as spatial buffers, and possibly even as a source of calcium signals in astrocytic processes. Loss of mitochondria resulted in drastically altered calcium signaling that could disrupt neurovascular coupling and gliotransmission.

Following severe traumatic brain injury (TBI), many patients experience coma - an unresponsive state lacking wakefulness or awareness. Coma rarely lasts more than two weeks, and emergence involves passing through a state of wakefulness without awareness of self or environment. Patients that linger in these Disorders of Consciousness (DoC) undergo clinical assessments of awareness for diagnosis into Unresponsive Wakefulness Syndrome (no awareness, also called vegetative state) or Minimally Conscious State (periodic increases in awareness). These diagnoses are notoriously inaccurate, offering little prognostic value. Recovery of awareness is unpredictable, returning within weeks, years, or never. This leaves patients' families with difficult decisions and little information on which to base them. Clinical studies have made significant advancements, but remain encumbered by high variability, limited data output, and a lack of necessary controls. Herein we discuss the clear and present need to establish a preclinical model of TBI-induced DoC, the significant challenges involved, and how such a model can be applied to support DoC research.

Neurotrauma and neurodegenerative disease often result in lasting neurological deficits due to the limited capacity of the central nervous system (CNS) to replace lost neurons and regenerate axonal pathways. However, during nervous system development, neuronal migration and axonal extension often occur along pathways formed by other cells, referred to as "living scaffolds". Seeking to emulate these mechanisms and to design a strategy that circumvents the inhibitory environment of the CNS, this manuscript presents a protocol to fabricate tissue engineered astrocyte-based "living scaffolds". To create these constructs, we employed a novel biomaterial encasement scheme to induce astrocytes to self-assemble into dense three-dimensional bundles of bipolar longitudinally-aligned somata and processes. First, hollow hydrogel micro-columns were assembled, and the inner lumen was coated with collagen extracellular-matrix. Dissociated cerebral cortical astrocytes were then delivered into the lumen of the cylindrical micro-column and, at a critical inner diameter of 97% cell viability and were virtually exclusively comprised of astrocytes expressing a combination of the intermediate filament proteins glial-fibrillary acidic protein (GFAP), vimentin, and nestin. These aligned astrocyte networks were found to provide a permissive substrate for neuronal attachment and aligned neurite extension. Moreover, these constructs maintain integrity and alignment when extracted from the hydrogel encasement, making them suitable for CNS implantation. These preformed constructs structurally emulate key cytoarchitectural elements of naturally occurring glial-based "living scaffolds" in vivo. As such, these engineered living scaffolds may serve as test-beds to study neurodevelopmental mechanisms in vitro or facilitate neuroregeneration by directing neuronal migration and/or axonal pathfinding following CNS degeneration in vivo.

Background: As part of I-O Optimise, a multinational research platform providing real-world insights into the management of lung cancers, the SCAN-LEAF study aims to describe the epidemiology, clinical care, and outcomes for pts with NSCLC in Scandinavia. Here, we report temporal OS trends among pts diagnosed with incident NSCLC from 2005 to 2015 in Denmark and Sweden. Methods: The SCAN-LEAF Danish and Swedish cohorts were established by linking respective national registries and include all adult pts diagnosed with incident NSCLC from Jan 2005 to Dec 2015 (follow-up to Dec 2016). The Kaplan–Meier method was used to estimate OS at 1, 3, and 5 yrs by histology (non-squamous cell [NSQ] or squamous cell [SQ]), TNM stage, and yr of diagnosis; changes in OS over time were assessed using the Cochrane–Armitage test. Results: 31,939 pts in Denmark and 30,067 pts in Sweden were diagnosed with NSCLC from 2005 to 2015. Most were diagnosed at stage IV (51.6% and 48.4%, respectively) and had NSQ histology (54.4% and 60.4%). Statistically significant trends (P 5% over the analysis period were seen for NSQ pts at 1 yr for all stages in both countries (Table); at 3 yrs for stages I–IIIB in Denmark (P ≤ 0.027), and stages I–II (P ≤ 0.0013) in Sweden; and at 5 yrs for stages I–II (P ≤ 0.026) in both countries. For SQ pts, this was seen only at 1 yr for stage IIIA in Denmark and stage I in Sweden (Table), and at 5 yrs for stage IIIA in Denmark (p = 0.02). Conclusions: Despite some improvements between 2005 and 2015, mainly in the short-term survival of pts with early-stage NSCLC, long-term OS rates for pts with late-stage disease did not change significantly and remained low. Even in pts with early-stage disease, OS outcomes were suboptimal, with a particular unmet need in the SQ population. Future analyses including data after 2015 will evaluate the potential impact on OS of increased use of new TKIs and immune checkpoint inhibitors.

Within neurons, mitochondria are nonuniformly distributed and are retained at sites of high activity and metabolic demand. Glutamate transport and the concomitant activation of the Na+/K+-ATPase represent a substantial energetic demand on astrocytes. We hypothesized that mitochondrial mobility within astrocytic processes might be regulated by neuronal activity and glutamate transport. We imaged organotypic hippocampal slice cultures of rat, in which astrocytes maintain their highly branched morphologies and express glutamate transporters. Using time-lapse confocal microscopy, the mobility of mitochondria within individual astrocytic processes and neuronal dendrites was tracked. Within neurons, a greater percentage of mitochondria were mobile than in astrocytes. Furthermore, they moved faster and farther than in astrocytes. Inhibiting neuronal activity with tetrodotoxin (TTX) increased the percentage of mobile mitochondria in astrocytes. Mitochondrial movement in astrocytes was inhibited by vinblastine and cytochalasin D, demonstrating that this mobility depends on both the microtubule and actin cytoskeletons. Inhibition of glutamate transport tripled the percentage of mobile mitochondria in astrocytes. Conversely, application of the transporter substrated-aspartate reversed the TTX-induced increase in the percentage of mobile mitochondria. Inhibition of reversed Na+/Ca2+exchange also increased the percentage of mitochondria that were mobile. Last, we demonstrated that neuronal activity increases the probability that mitochondria appose GLT-1 particles within astrocyte processes, without changing the proximity of GLT-1 particles to VGLUT1. These results imply that neuronal activity and the resulting clearance of glutamate by astrocytes regulate the movement of astrocytic mitochondria and suggest a mechanism by which glutamate transporters might retain mitochondria at sites of glutamate uptake.

Background The benefits of ICIs for patients (pts) with NSCLC have been shown in several clinical trials, but real-world data are limited. We describe the early impact of 2L ICI Tx on clinical practice at the Leeds Cancer Centre (LCC), a UK site of I-O Optimise, a multinational research platform providing insights into real-world lung cancer management. Methods This retrospective cohort study used longitudinal data from electronic medical records of adults diagnosed with advanced NSCLC (stage IIIB/IV) between Jan 2013 and Oct 2018 (2-month minimum follow-up). Pts with EGFR or ALK mutations were excluded from the analysis due to different Tx patterns expected in this population eligible for targeted Tx. Pre- and post-ICI sub-cohorts were defined by date of first 2L ICI use at LCC (Mar 2016). Distinct lines of Tx were identified using a clinically verified algorithm based on date of prescribed systemic anti-cancer therapy (SACT) and time between prescriptions. Age and ECOG performance score (PS) at time of initial diagnosis were recorded. Results Of 1196 pts with advanced NSCLC during the study period, 409 (34.2%) received SACT; (annual rates were 33.5–38.1%). In all, 103 pts (8.6%) received 2L Tx, of which 26 (25.2%) had EGFR/ALK mutations; of the remaining 77 pts without EGFR/ALK mutations, 29 were treated pre-ICI and 48 post-ICI. In the pre-ICI sub-cohort, median age was 65.0 yrs and 82.8% had an ECOG PS Conclusions Two years on from the introduction of ICIs as a 2L option in UK clinical practice, their use is well established among eligible pts, but overall 2L SACT Tx remains very low. The impact on survival will be presented. Editorial acknowledgement Richard Daniel, PhD and Kate Bradford, PhD of PAREXEL, funded by Bristol-Myers Squibb. Legal entity responsible for the study Bristol-Myers Squibb. Funding Bristol-Myers Squibb. Disclosure M. Snee: Research grant / Funding (institution), I am a paid consultant to IQVIA. My employer Leeds teaching hospitals NHS trust has received a grant from IQVIA: IQVIA. L. Lacoin: Advisory / Consultancy, Consultant for BMS: Bristol-Myers Squibb. W. Sopwith: Full / Part-time employment, I am employed by IQVIA to work on this project: IQVIA. C. Chaib: Full / Part-time employment, Employee: Bristol-Myers Squibb. J.R. Penrod: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. J.C. O’Donnell: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

Background: As part of I-O Optimise, a multinational research platform providing real-world insights into the management of lung cancers, the SCAN-LEAF study aims to describe the epidemiology, clinical care and outcomes for pts with NSCLC in Scandinavia. We report initial Tx and OS for pts with NSCLC prior to the availability of immunotherapies in Sweden. Methods: The analysis includes all adult pts diagnosed with NSCLC at Uppsala and Karolinska (Stockholm) University Hospitals from 2012 to 2015 (follow-up to Dec 2016). Electronic medical record data were extracted using Pygargus CXP software and linked with national registries. Bespoke rule-based algorithms were applied to describe Tx patterns; Kaplan–Meier methods were used to estimate OS. Results: 2779 pts were diagnosed with incident NSCLC (median age, 70 yrs [range: 22–96; 14.2% ≥80]; male, 48.5%; histology: non-squamous (NSQ), 70.9%, squamous (SQ), 17.7%, other, 11.4%; stage distribution: I, 19.3%; II, 7.7%; IIIA, 12.3%; IIIB, 7.2%; IV, 51.2%). Initial Tx (≤6 months from diagnosis) by stage and yr of diagnosis is shown in the table. Median OS (months) for NSQ and SQ pts: not reached and 52.8 in stage I, 43.2 and 23.6 in stage II, 26.7 and 20.4 in stage IIIA, 12.5 and 12.9 in stage IIIB, and 7.6 and 6.1 in stage IV, respectively. Among stage IIIB–IV pts, 60.7% (NSQ) and 53.5% (SQ) had ≥1 line of systemic anti-cancer therapy (SACT); median OS was 12.2 (NSQ) and 10.4 (SQ) months in pts on SACT, and 3.1 (NSQ) and 3.7 (SQ) months in pts not on SACT. Ongoing analyses will assess factors associated with SACT receipt in stage IIIB–IV pts. Conclusions: Swedish pts with NSCLC had a high burden of disease, with most diagnosed at stage IV and a median OS of 1 yr in late-stage pts receiving SACT. There is also scope for improved prognosis in pts diagnosed at early stages, particularly in SQ pts. Future analyses will assess the potential impact of recent improvements in diagnostics and therapeutics on Tx patterns and OS in Swedish NSCLC pts. (Less)

This study compared the ability of nine oximes (HI-6, HLo7, MMB-4, TMB-4, carboxime, ICD585, ICD692, ICD3805, and 2-PAM) to reactivate in vivo cholinesterase (ChE) in blood, brain, and peripheral tissues in guinea pigs intoxicated by one of four organophosphorus nerve agents. Two bis-pyridinium compounds without an oxime group, SAD128 and ICD4157, served as non-oxime controls. Animals were injected subcutaneously with 1.0× LD50 of the nerve agents sarin, cyclosarin, VR or VX and treated intramuscularly 5 min later with one of these oximes. Toxic signs and lethality were monitored; tissue ChE activities were determined at 60 min after nerve agent. Some animals exposed to sarin or cyclosarin, with or without non-oxime treatment, died within 60 min; however, no animal treated with an oxime died. For VR or VX, all animals survived the 60 min after exposure, with or without non-oxime or oxime therapy. The four nerve agents caused differential degrees of inhibition in blood, brain regions and peripheral tissues. The tested oximes exhibited differential potency in reactivating nerve agent-inhibited ChE in various peripheral tissues, but did not affect ChE activity in the brain regions. There was no direct relation between blood and peripheral tissues in the reactivating efficacy of oxime treatments. ChE inhibited by sarin was the most susceptible to oxime reactivation while cyclosarin the least susceptible. There was no difference in the ChE reactivating potency between the dimethanesulfonate and dichloride salts of HI-6. MMB-4 significantly reactivated the ChE inhibited by these four nerve agents in blood and all three peripheral tissues of the guinea pig, and among all the oximes tested it was the most effective in vivo ChE reactivator against all four nerve agents.

Organophosphorus compounds (OPs) are potent inhibitors of acetylcholinesterase (AChE). Treatment for OP poisoning is by administration of atropine sulfate, an oxime, and diazepam. Oximes such as 2-PAM are used to reactivate OP-inhibited AChE so as to restore normal enzymatic function and serve as a true antidote. There are reports of non-enzymatic hydrolysis by oximes of acetylthiocholine in in vitro preparations in the widely used Ellman assay for AChE activity, which may confound the interpretation of AChE activity by producing elevated results. The purpose of this experiment was to determine if there is appreciable interference by therapeutic levels of oximes on the results of the Ellman assay in assessing AChE reactivation by oxime compounds in vivo. When therapeutic doses of oximes (2-PAM, HI-6, MMB-4, or MINA) were administered intramuscularly to guinea pigs and samples collected 60 min later, there was no statistical difference between oxime and saline control groups in measured AChE activity in various tissue samples, including blood. With appropriate dilution of samples prior to spectrophotometric assay, the Ellman assay is an acceptable method to measure in vivo oxime reactivation of inhibited AChE. Inclusion of an oxime control group to insure that this particular type of interference is not causing false readings in the assay is a prudent step.

Diurnal oscillations in the expression of antioxidant genes imply that protection against oxidative stress is circadian-gated. We hypothesized that stabilization of the core circadian gene Rev-erbα (Nr1d1) improves cellular bioenergetics and protects against nutrient deprivation and oxidative stress. Compared to WT, mouse lung fibroblasts (MLG) stably transfected with a degradation resistant Rev-erbα (Ser(55/59) to Asp; hence referred to as SD) had 40% higher protein content, 1.5-fold higher mitochondrial area (confocal microscopy), doubled oxidative phosphorylation by high-resolution respirometry (Oroboros) and were resistant to glucose deprivation for 24h. This resulted from a 4-fold reduction in mitophagy (L3CB co-localized with MitoTracker Red) versus WT. Although PGC1α protein expression was comparable between SD and WT MLG cells, the role of mitochondrial biogenesis in explaining increased mitochondrial mass in SD cells was less clear. Embryonic fibroblasts (MEF) from C57Bl/6-SD transgenic mice, had a 9-fold induction of FoxO1 mRNA and increased mRNA of downstream antioxidant targets heme oxygenase-1 (HO-1), Mn superoxide dismutase and catalase (1.5, 2 fold and 2 fold respectively) versus WT. This allowed the SD cells to survive 1h incubation with 500 µM H2O2 as well as 24h of exposure to 95% O2 and remain attached whereas most WT cells did not. These observations establish a mechanistic link between the metabolic functions of Rev-erbα with mitochondrial homeostasis and protection against oxidative stress.

The glutamate transporter GLT-1 is the major route for the clearance of extracellular glutamate in the forebrain, and most GLT-1 protein is found in astrocytes. This protein is coupled to the Na+-electrochemical gradient, supporting the active intracellular accumulation of glutamate. We recently used a proteomic approach to identify proteins that may interact with GLT-1 in rat cortex, including the Na+/K+-ATPase, most glycolytic enzymes, and several mitochondrial proteins. We also showed that most GLT-1 puncta (~70%) are overlapped by mitochondria in astroglial processes in organotypic slices. Based on this analysis, we proposed that the glycolytic enzyme hexokinase 1 (HK1) might physically form a scaffold to link GLT-1 and mitochondria because HK1 is known to interact with the outer mitochondrial membrane protein, voltage-dependent anion channel (VDAC). In the present study, we first validated the interactions between HK-1, VDAC and GLT-1 using forward and reverse immunoprecipitations. We also provided evidence that a subfraction of HK1 co-localizes with GLT-1 in vivo. We found that a peptide, known to disrupt the interaction between HK and VDAC, did not disrupt interactions between GLT-1 and several mitochondrial proteins. In parallel experiments, we found that displacement of HK from VDAC reduced GLT-1-mediated glutamate uptake. These results suggest that although HK1 forms co-immunoprecipitatable complexes with both VDAC and GLT-1, it does not physically link GLT-1 to mitochondrial proteins. However, the interaction of HK1 with VDAC supports GLT-1-mediated transport activity.

This study sought to determine if the self-assessed mental health of older, community-dwelling veterans differs from that of older nonveterans controlling for known demographic, socioeconomic, and clinical covariates of health and well-being. Participants are the older male respondents (65+ years) to the Medical Expenditure Panel Survey (Round 1), conducted in 1996 (N = 1,068). In bivariable analyses using population weights, veterans were significantly less likely than nonveterans to report their mental health as fair to poor. However, when demographic, socioeconomic, and health-related characteristics were controlled, no statistically significant difference in self-assessed mental health was detected between veterans and nonveterans. Military service per se is not a risk factor for poorer self-appraised mental health in old age. Nor does military service confer protection from late-life deficits in mental health. Rather, mental health in later life is largely a function of an individual's health and socioeconomic status.

Pion-nucleus elastic scattering at energies above the {Delta}(1232) resonance is studied using both {pi}{sup +} and {pi}{sup {minus}} beams on {sup 12}C, {sup 40}Ca, {sup 90}Zr, and {sup 208}Pb. The present data provide an opportunity to study the interaction of pions with nuclei at energies where second-order corrections to impulse approximation calculations should be small. The results are compared with other data sets at similar energies and with four different first-order impulse approximation calculations. Significant disagreement exists between the calculations and the data from this experiment. {copyright} {ital 1997} {ital The American Physical Society}

OBJECTIVES: To compare the effectiveness of geriatric evaluation and management (GEM) with usual primary care (UPC). DESIGN: A 2 × 3 randomized controlled group design. SETTING: A 450-bed Department of Veterans Affairs Medical Center (VAMC) that provides general medical and surgical care to eligible veterans. PARTICIPANTS: One-hundred sixty male subjects (mean age = 72 years), who were above average users of VAMC outpatient clinics and who had at least two Activity of Daily Living (ADL) or Instrumental Activity of Daily Living (IADL) impairments, were assigned to GEM (n = 80) or UPC (n = 80). MEASUREMENTS: Data were collected about patients' (1) health and functional status, (2) psychosocial well-being, (3) quality of health and social care, (4) health care utilization, and (5) health care costs. Data were obtained before randomization, and again at 8 and 16 months. RESULTS: The results indicated that GEM was more effective than UPC in improving some aspects of the quality of health and social care and in increasing patient satisfaction with care. GEM also reduced emergency room use, and showed a trend toward decreasing acute admissions. It was not effective, however, in improving patients' psychosocial well-being. Except for a short-term survival advantage, it was also not effective in preventing deterioration in their health and functional status. Further, GEM did not reduce overall utilization of outpatient or inpatient services, and it significantly increased total outpatient health care costs. CONCLUSIONS: Outpatient GEM improves patient satisfaction and some aspects of the quality of care patients' receive but does not reduce the cost of outpatient or inpatient care. Longer-term follow-up studies are needed to determine whether reductions in emergency room use and inpatient admissions persist over time and result in reductions in the overall cost of care.

Efficient excitatory transmission depends on a family of transporters that use the Na+-electrochemical gradient to maintain low synaptic concentrations of glutamate. These transporters consume substantial energy in the spatially restricted space of fine astrocytic processes. GLT-1 (EAAT2) mediates the bulk of this activity in forebrain. To date, relatively few proteins have been identified that associate with GLT-1. In the present study, GLT-1 immunoaffinity isolates were prepared from rat cortex using three strategies and analyzed by liquid chromatography-coupled tandem mass spectrometry. In addition to known interacting proteins, the analysis identified glycolytic enzymes and outer mitochondrial proteins. Using double-label immunofluorescence, GLT-1 was shown to colocalize with the mitochondrial matrix protein, ubiquinol-cytochromecreductase core protein 2 or the inner mitochondrial membrane protein, ADP/ATP translocase, in rat cortex. In biolistically transduced hippocampal slices, fluorescently tagged GLT-1 puncta overlapped with fluorescently tagged mitochondria along fine astrocytic processes. In a Monte Carlo-type computer simulation, this overlap was significantly more frequent than would occur by chance. Furthermore, fluorescently tagged hexokinase-1 overlapped with mitochondria or GLT-1, strongly suggesting that GLT-1, mitochondria, and the first step in glycolysis are cocompartmentalized in astrocytic processes. Acute inhibition of glycolysis or oxidative phosphorylation had no effect on glutamate uptake in hippocampal slices, but simultaneous inhibition of both processes significantly reduced transport. Together with previous results, these studies show that GLT-1 cocompartmentalizes with Na+/K+ATPase, glycolytic enzymes, and mitochondria, providing a mechanism to spatially match energy and buffering capacity to the demands imposed by transport.

Organophosphorus nerve agents such as sarin (GB) and VX irreversibly inhibit acetylcholinesterase, causing a buildup of acetylcholine (ACh) in synapses and neuromuscular junctions, which leads to excess bronchial secretions, convulsions, seizures, coma, and death. Understanding the unique toxic characteristics of different nerve agents is vital in the effort to develop broad spectrum medical countermeasures. To this end, we employed a repeated measure multivariate design with striatal microdialysis collection and high-performance liquid chromatography analysis to measure changes in concentrations of several neurotransmitters (ACh, glutamate, aspartate, GABA) in the same samples during acute exposure to GB or VX in freely moving guinea pigs. Concurrent with microdialysis collection, we used cortical electrodes to monitor brain seizure activity. This robust double multivariate design provides greater fidelity when comparing data while also reducing the required number of subjects. No correlation between nerve agents' propensity for causing seizure and seizure-related lethality was observed. The GB seizure group experienced more rapid and severe cholinergic toxicity and lethality than that of the VX seizure group. Seizures generated from GB and VX exposure resulted in further elevation of ACh level and then a gradual return to baseline. Glutamate levels increased in the GB, but not in the VX, seizure group. There were no consistent changes in either aspartate or GABA as a result of either nerve agent. These observations reinforce findings with other nerve agents that seizure activity per se contributes to the elevated levels of brain ACh observed after nerve agent exposure.

Organophosphorus nerve agents like cyclosarin and tabun are potent cholinesterase inhibitors. The inhibition of acetylcholinesterase, which is responsible for breaking down acetylcholine (ACh) at the synapse and neuromuscular junction, leads to a build-up of extracellular ACh and a series of toxic consequences including hypersecretion, tremor, convulsion/seizure, respiratory distress, coma, and death. This study employed simultaneous and continuous electroencephalographic recording and striatal microdialysis collection for quantification of ACh changes (via subsequent HPLC analysis) during acute exposure to a 1.0 × LD(50) subcutaneous dose of either cyclosarin or tabun to investigate differences in cholinergic and behavioral effects. Information about the unique mechanisms and consequences of different nerve agents is intended to aid in the development of broad-spectrum medical countermeasures for nerve agents. At the dose administered, non-seizure and sustained seizure responses were observed in both agent groups and in the tabun-exposed group some subjects experienced an unsustained seizure response. Significant extracellular ACh increases were only observed in seizure groups. Cyclosarin and tabun were found to exhibit some unique cholinergic and ictogenic characteristics. Lethality only occurred in subjects experiencing sustained seizure, and there was no difference in lethality between agent groups that progressed to sustained seizure.

Organophosphorus nerve agents irreversibly inhibit acetylcholinesterase (AChE) in the peripheral and central nervous systems, causing an increase in the concentration of acetylcholine (ACh) in the synapse or neuromuscular junction and subsequent adverse effects. In this study, in vivo microdialysis was utilized to collect samples from the striatum for monitoring changes in extracellular ACh levels along with cortical electroencephalographic (EEG) recordings for identifying seizure activity after acute subcutaneous (s.c.) exposure to 1.0 x LD(50) of the nerve agents sarin, soman, or one of two V-type agents (VX, or a Russian V-agent, designated VR) in unanesthetized freely moving guinea pigs. Based on EEG recordings, these animals were subsequently divided into groups that developed seizures (S) and those that did not develop seizures (NS). Maximum ACh levels in the striatum were observed at 60-70 min for sarin and soman S groups and 105 min for VX and VR S groups. In all NS groups the greatest increase in extracellular ACh occurred within 30 min after exposure, although in the sarin NS group a few sporadic increases of ACh from control occurred. Animals that developed seizures, regardless of the nerve agent, had significantly higher extracellular striatal ACh levels compared to the controls or those animals that did not develop seizures, yet both S and NS groups displayed similar levels of blood AChE inhibition. Regardless of the agent, all animals in the non-seizure groups survived 24 h, while lethality (25-42%) was observed only in animals that experienced seizure activity.

The capability of several oximes (HI-6, HLo7, MMB-4, TMB-4, carboxime, ICD 585, ICD 692, ICD 3805, and 2-PAM) to reactivate in vivo AChE inhibited by the nerve agents sarin, cyclosarin, VX, or VR in blood, brain regions, and peripheral tissues in guinea pigs was examined and compared. Animals were injected subcutaneously with 1.0 LD(50) of sarin, cyclosarin, VR, or VX, and treated intramuscularly 5 min later with one of these compounds. Toxic signs and lethality were monitored, and tissue AChE activities were determined at 60 min after nerve agent. The animals exposed to sarin or cyclosarin, alone or with non-oxime treatment, some died within 60 min; however, when treated with an oxime, no animal died. For VR or VX, all animals survived for 60 min after exposure, with or without non-oxime or oxime therapy. These nerve agents caused differential degrees of inhibition: in whole blood sarin = cyclosarin > VR = VX; in brain regions sarin > cyclosarin > VX > VR; and in peripheral tissues sarin > VX > cyclosarin > VR. These oximes exhibited differential potency in reactivating nerve agent-inhibited AChE in various peripheral tissues, but not AChE activity in the brain regions. There was no difference in the AChE reactivating potency between the dichloride and dimethanesulfonate salts of HI-6. AChE inhibited by sarin was the most and cyclosarin the least susceptible to oxime reactivation. Overall, MMB-4 appeared to be, among all oximes tested, the most effective in vivo AChE reactivator against the broadest spectrum of nerve agents.

Current oxime therapies do not readily cross the blood-brain barrier to reactivate organophosphorus nerve agent-inhibited cholinesterase (ChE) within the CNS. We investigated the ability of monoisonitrosoacetone (MINA), a tertiary oxime, to reactivate ChE inhibited by the nerve agent sarin (GB), cyclosarin (GF), or VX, in peripheral tissues and brain of guinea pigs and determined whether reactivation in the CNS will enhance protection against the lethal effects of these three agents. In the reactivation experiment, animals were pretreated with atropine methylnitrate (1.0mg/kg, i.m.) 15 min prior to subcutaneous (s.c.) challenge with 1.0 x LD(50) of GB, GF, or VX. Fifteen minutes later animals were treated intramuscularly (i.m.) with MINA (ranging from 22.1 to 139.3mg/kg) or 2-PAM (25.0mg/kg). At 60 min after nerve agent, CNS (brainstem, cerebellum, cortex, hippocampus, midbrain, spinal cord, and striatum) and peripheral (blood, diaphragm, heart, and skeletal muscle) tissues were collected for ChE analysis. MINA reactivated nerve agent-inhibited ChE in the CNS and peripheral tissues in a dose-dependent manner in the following order of potency: GB>GF>VX. In a survival experiment, animals were injected i.m. with atropine sulfate (0.5mg/kg), 2-PAM (25.0mg/kg), or MINA (35.0, 60.0, or 100.0mg/kg) alone or in combination 1 min after challenge with varying s.c. doses of GB, GF, or VX to determine the level of protection. The rank order of MINA's efficacy in guinea pigs against nerve agent lethality was the same as for reactivation of inhibited ChE in the CNS. These data show that MINA is capable of reactivating nerve agent-inhibited ChE and that the extent of ChE reactivation within the CNS strongly relates to its therapeutic efficacy.

The capability of the tertiary oximes, monoisonitrosoacetone (MINA) and diacetylmonoxime (DAM), to reactivate acetylcholinesterase (AChE) inhibited by sarin (GB) in the blood, brain, and peripheral tissues of guinea pigs was compared with that of the quaternary oximes 2-PAM, HLö7, and MMB-4. Animals were injected subcutaneously (s.c.) with 1.0 x LD(50) of GB and treated intramuscularly (i.m.) 5 min later with one of these oximes. Sixty minutes after GB exposure, tissues were collected for AChE analysis. At low doses, MINA and DAM produced significant increases in AChE activity in all brain areas examined, but no significant AChE reactivation in peripheral tissues or blood. At higher doses, MINA and DAM increased AChE activity in the brain, peripheral tissues, and blood. In contrast, the quaternary oximes produced significant reactivation in peripheral tissues and blood AChE, but no significant reactivation of brain AChE. In another study, animals were pretreated i.m. with pyridostigmine 30 min prior to s.c. challenge with 2.0 x LD(50) of GB and treated i.m. 1 min later with atropine sulfate (2.0 mg/kg), plus a varied dose of oximes. MINA and DAM prevented or terminated GB-induced seizure activity and protected against GB lethality in a dose-dependent fashion. In contrast, none of the quaternary oximes prevented or stopped GB-induced seizures. Thus, tertiary oximes reactivated AChE in the brain, improved survival, and terminated seizures following GB intoxication.

Few recent issues in drug development and health systems management have generated more commentary, and more controversy, than health technology assessment (HTA). The keen interest in HTA stems from the high stakes involved. For regardless of differences in definition and application, it is clear that HTA brings together public and private interests in a process in which there are potentially winners and losers, and the perception of outcome is highly contingent on each party’s point of view. Critics charge that HTA has been used simply to restrict access to new health-care technology, whereas advocates underscore use of HTA to promote efficient resource allocation and to advance population-based health. Any contemporary body of work on HTA needs to reconcile, by definition, the relationship between HTA [a form of policy research that examines shortand long-term consequences of the application of a health-care technology] and evidence-based medicine (EBM) [clinical evidence analysis for individual decision-making practice guideline, and policy decisionmaking]. Underlying these concepts is the demand for information on the comparative effectiveness (CE) of health-care interventions when used in actual practice. With this Value in Health Special Issue, we seek to inform this ongoing debate on the nature and role of HTA by bringing together leading academicians and practitioners from around the world to offer their perspectives on HTA in their country and to identify lessons learned. In Article 2, “Health Technology Assessment and Evidence Based Medicine: What Are We Talking About?” the relationship between HTA and EBM are presented as well as an overview of HTA as a process. In Articles 3 to 7 (“Nasty or Nice? A Perspective on the Use of Health Technology Assessment in the United Kingdom”; “Health Technology Assessment in Canada: 20 Years Strong?”; Health Technology Assessment: A Perspective from Germany”; “Health Technology Assessment: Reflections from the Antipodes”; and “Health Technology Assessment in Health-Care Decisions in the United States”), we asked contributors from the United Kingdom, Canada, Germany, Australia, and the United States to describe the health-care organizations involved in HTA, their processes, and the use of HTA in healthcare decisions of their respective countries, and to assess their HTA processes across a range of important attributes: transparency of information and process, independence of, and participation in the assessment and appraisal, use of QALY thresholds, methods to deal with uncertainty, and the role of “real-world” data. We further asked contributors to elicit how HTA function in practice care across a range of equity, efficiency and access dimensions, effects on patient and provider choice and access, effects on health-care budgets and health outcomes, and the role of politics in the process. Some contributors addressed all of these attributes and practical considerations, whereas others only addressed attributes and practical considerations deemed relevant in their country. Article 8—“Lessons for Health Technology Assessment: It Is Not Only about the Evidence”—emphasizes the similarity of country-specific HTA systems and processes and presents future direction. Although the country-specific HTA health organizations and processes presented in this Special Issue may vary, we see emerging from these articles a set of common issues about the role of HTA in society, its effects on public health and access to care, its effects on innovation, and on the integrity and viability of publicly financed health care in general. We see HTA at the focal point of an ongoing struggle across a range of countries attempting to come to terms with expanding expenditures for health care, the availability of remarkable new innovations in healthcare technology, and constrained budgets. Although this Special Issue will not resolve these concerns, it is hoped that by articulating, comparing, and contrasting HTA systems and processes, it enriches the discourse and helps build the common ground needed to seek meaningful solutions; and that the lessons learned can inform the development of HTA in societies confronting the challenges of supporting economic growth and providing basic health care. The last article in this Special Issue, “Editorial: Pursing Efficiency: A Dead End for HTA?” is provided by a guest editor. Guest editors are selected by the Value in Health editor-in-chief to critique this Special Issue to ensure that a broad range of views are expressed. We hope that you will find this Value in Health Special Issue on HTA both informative and engaging as we grapple with the HTA challenges ahead.

Item does not contain fulltext OBJECTIVE: The effectiveness of statin therapy in a real life setting may differ from that in clinical trials, as physicians make non-randomised treatment decisions for patients with less uniform and possibly different characteristics. We therefore performed a study to compare the effectiveness of different statins and doses in routine clinical practice with respect to total serum cholesterol and LDL-cholesterol (LDL-C) reduction and goal attainment according to European guidelines on the prevention of cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS: Naive statin users starting treatment in 2003 and 2004 with LDL-C measurements at baseline and between 30 and 365 days after start of treatment were extracted from the PHARMO database. During treatment with their initial statin dose LDL-C reduction and attainment of cholesterol goals were compared between different statins and doses. RESULTS: Of 2303 identified naive patients, approximately 30% were allocated to the high CVD-risk group. Average LDL-C reductions were 48%, 42%, 39%, and 32% at mean doses of 11 mg rosuvastatin, 17 mg atorvastatin, 22 mg simvastatin and 35 mg pravastatin, respectively. The proportion of patients attaining cholesterol goals was 75% for rosuvastatin, 68% for atorvastatin, 56% for simvastatin, and 42% for pravastatin. Dose comparisons showed greater LDL-C reduction and increased goal attainment for rosuvastatin 10 mg compared to other statins at most doses (adjusted p < 0.05). CONCLUSIONS: In a real life setting, both LDL-C reduction and the proportion of patients attaining cholesterol goals appear to be significantly increased among users of rosuvastatin compared to other statins. These results confirm and extend reported clinical trial results to a real world setting.

To identify determinants of medication compliance and low-density lipoprotein cholesterol goal attainment.This retrospective analysis used claims data from a large, national, employment-based independent practice association database. Subjects were identified based on the existence of a filled prescription for statin therapy between April 1, 1999, and June 30, 2001. Subjects had to be 18 years or older, continuously enrolled in the health plan for 2 years, and new users of statin therapy.Multivariate logistic regression models were used to identify predictors of compliance and goal attainment in high-risk subjects.As the mean copayment for statins increased, there was a decrease in the likelihood of compliance. Of the subjects with laboratory results, 50.7% attained their low-density lipoprotein cholesterol goal level established by National Cholesterol Education Program Adult Treatment Panel III guidelines. Older individuals and men were more likely to reach their low-density lipoprotein cholesterol target goal, as were individuals who were compliant with their statin therapy.Compliance with statin therapy in the managed care setting remains poor. Of particular concern is the lower level of compliance among women and younger high-risk patients, along with patients who have fewer outpatient visits associated with hyperlipidemia and lower incidences of cholesterol testing.

Background Rosuvastatin calcium (CRESTOR®) has demonstrated superior efficacy in reducing low-density lipoprotein cholesterol (LDL-C). However, healthcare providers and authorities require information on its cost-effectiveness in the treatment of dyslipidaemia. Design A retrospective pharmacoeconomic analysis was performed using data from the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial. The cost-effectiveness of rosuvastatin 10-40 mg was compared with atorvastatin 10-80 mg, pravastatin 10-40 mg and both branded and generic simvastatin 10-80 mg in achieving Third Joint European Task Force LDL-C goals in patients with hypercholesterolaemia. Methods The analysis was conducted from the perspective of the UK National Health Service, using clinical data from the STELLAR trial and drug acquisition costs. Cost-effectiveness was compared using incremental cost-effectiveness ratios (ICERs), with sensitivity analyses applied to both efficacy and cost parameters. Results In terms of patients achieving goal, rosuvastatin 10 mg dominated (was more effective at equal or lower cost) atorvastatin 10 and 20 mg, pravastatin 20 and 40 mg, branded simvastatin 10-80 mg and generic simvastatin 40 and 80 mg. Where rosuvastatin 10 mg did not dominate, ICERs ranged from £36 to £162 per extra patient to goal. Rosuvastatin 20 and 40 mg were cost-effective compared with milligram-equivalent and higher doses of other branded statins. Sensitivity analyses showed that the results were robust to variations in both statin efficacy and price. Conclusion In patients with hypercholesterolaemia, rosuvastatin is a cost-effective statin option in treating to LDL-C goals. Eur J Cardiovasc Prev Rehabil 12:18-28 © 2005 The European Society of Cardiology

Objective To compare asthma-related health-care utilization and expenditures for patients prescribed one of three dual-controller therapies: fluticasone plus salmeterol, inhaled corticosteroids (ICS) [excluding fluticasone] plus salmeterol, and ICS plus a leukotriene modifier (LTM). Materials and methods: Asthma-related medical claims from two major health plans were obtained for the 12 months before and after the initiation of dual therapy. A total of 1,325 patients ≥ 12 years old with no claims for COPD or respiratory tract cancer were selected from the approximately 3.5 million lives covered. Multivariable regression was used to assess differences in asthma-related expenditures. To compensate for positive skew, all cost variables were log-transformed. Results: Risk-adjusted total asthma-related costs for the fluticasone-plus-salmeterol cohort (n = 121), the ICS-plus-salmeterol cohort (n = 844), and the ICS-plus-LTM cohort (n = 30) were $975, $1,089, and $1,268, respectively. Risk-adjusted pharmacy costs were $813, $841, and $996, respectively. Generalized linear modeling, controlling for baseline covariates, indicated that compared to ICS-plus-LTM therapy, fluticasone-plus-salmeterol therapy was associated with a significant reduction in asthma-related total (p = 0.0014) and pharmacy (p = 0.001) costs. Similar results were found when the ICS-plus-salmeterol group and the ICS-plus-LTM group were compared (p = 0.0001). The number of inpatient, outpatient, and emergency department visits and their corresponding costs were lower for the fluticasone-plus-salmeterol cohort, but were not statistically significant (p > 0.05). Conclusion Results from managed-care practice suggest that treatment with fluticasone plus salmeterol, and more broadly ICS plus salmeterol, yield important cost savings when compared to treatment with ICS plus LTM.

Background: Experimental clinical studies have demonstrated that the addition of salmeterol to inhaled corticosteroids (ICSs) is superior to the addition of montelukast to ICSs. Observational research from real-world clinical practice is needed to confirm these results. Objective: The present study was designed to assess, in clinical practice, the comparative impact on health care utilization and cost of 2 dual-controller therapies, ICS + salmeterol and ICS + montelukast. Methods: This study involved the use of a 24-month pre/post retrospective design in patients continuously enrolled in any of 14 United HealthCare plans. Outcomes assessed were post-index pharmacy costs, rates of emergency department visits and hospitalizations, numbers of filled prescriptions for short-acting β-agonists (SABAs), total asthma costs, and total health care costs. Results: Subjects in the ICS + salmeterol group had 35% fewer post-index SABA claims than subjects in the montelukast add-on group ( P ≤ .05). Subjects using ICS + montelukast were 2.5 times more likely to have an asthma-related hospitalization than subjects using ICS + salmeterol ( P ≤ .065). Total adjusted asthma costs were 63% higher for the patients receiving ICS + montelukast than for the patients receiving ICS + salmeterol ( P ≤ .0001). In addition, total health care costs were 25% lower in the ICS + salmeterol group. ( P ≤ .0004). Additional reductions in hospitalization and emergency department visits were observed when the patients on FP + salmeterol were studied separately. Conclusion: In comparison with the use of montelukast and ICS, the use of salmeterol and ICS was associated with a significant reduction in SABA use, decreased hospital event rates, and significantly lower total asthma care costs. (J Allergy Clin Immunol 2002;109:433-9.)

Objective: To assess variation in stroke outcomes and create a case-mix adjustment model for stroke rehabilitation in Veterans Affairs Medical Centers. Design: Observational Setting and Patients: Within Veteran's Health Administration hospitals, there are 63 acute rehabilitation bedservice units that care for approximately 2,000 stroke patients annually. Main Outcome Measures: Functional gain in FIM points, length of stay (LOS), LOS efficiency (FIM gain/LOS). Results: Significant variation in average patient functional gain, LOS, and LOS efficiency was observed among the 37 highest-volume rehabilitation units. Using analysis of covariance, a model was developed that adjusted functional gain and LOS (logged LOS) unit means using 10 potential covariates identified in a literature review and in pilot studies. Four and six covariates, respectively, were retained in the final models for FIM gain and LOS. The R 2 for FIM gain and LOS accounted for by rehabilitation unit alone increased from .07 to .31 (FIM gain) and from .13 to .34 (logLOS) with the addition of the significant covariates to each model. Conclusions: As much as 24% of the variation in two important stroke rehabilitation outcomes is attributable to largely immutable patient and system characteristics (eg, patient function on admission, age, days since stroke onset, year of discharge, marital status, and referral source). Hence, controlling for case-mix is critical for accurate comparison of unit outcomes. Further, the variation in LOS efficiency between VA rehabilitation units suggests a large potential for cost and resource utilization savings system-wide.

A randomized, controlled trial compared prospective 16-month health service use among 160 frail, elderly veterans receiving outpatient geriatric evaluation and management (GEM) or usual primary care (UPC). In this secondary analysis, multivariable regression was used to determine if the psychosocial assessment and support provided by the GEM team moderated the use of medical services by patients in psychological distress. The results indicate that GEM reduced outpatient use among patients who scored higher on a measure of somatization (p less than or equal to .05), but GEM increased outpatient use among patients with higher manifest anxiety (p less than or equal to .05) Psychological distress was not a factor in the use of inpatient services. GEM had a modest beneficial effect on the health behavior of frail older persons manifesting some symptoms of psychological distress.

Objective: To assess the relation between the source of stroke patients' referral to the rehabilitation unit and rehabilitation outcome. Design: Multivariate analysis of rehabilitation outcomes prospectively collected and supplemented by data from Department of Veterans Affairs (VA) administrative records. Setting: Fifty-three hospital-based VA rehabilitation units located nationwide. Patients: A total of 2,031 first-admission stroke patients discharged from VA rehabilitation units in fiscal years 1993–1994. Interventions: Observational study. Outcome Measures: Functional Independence Measure (FIM) at admission, gains in motor and cognitive function, rehabilitation length of stay (LOS), and the probability of discharge to home. Results: Controlling for clinical, demographic, and unit characteristics, referral source predicted admission function, LOS, and home discharge ( p ≤ .0001), but did not predict motor or cognitive gain ( p > .05). Patients referred from long-term care and other acute hospitals (Acute Other) had significantly lower adjusted admission FIM scores than patients referred directly from home (respectively, 12.9 and 17.0 FIM units lower), and from the acute care services of the VA hospital providing rehabilitation (4.8 and 8.9 units lower). Acute Other referrals had longer risk-adjusted LOS than referrals from any other source (4.6 to 6.4 days longer), and patients from both Acute Other and long-term care had a lower probability of home discharge than the remaining two referral groups (reduction in probability range: .06 to .27). Conclusion: VA administrators and clinicians need to consider referral source when evaluating and comparing unit performance in stroke rehabilitation. Patients referred from Acute Other and long-term care settings may require more intensive management to offset their functional and social deficits, and to reduce LOS and increase home discharge rates. Referral source also identified highly functional patients who possibly could be cared for appropriately in less costly rehabilitation settings. These issues warrant further research especially as the VA seeks to achieve cost savings in this era of reduced funding.