Anti-Amyloid Therapies for Alzheimer's Disease: An Alzheimer Europe Position Paper and Call to Action.

The growing prevalence and burden of Alzheimer's disease has catalysed huge investments in research on its causes, diagnosis, treatment and care. After many high-profile failures, recent clinical trials of anti-amyloid drugs have marked a turning point for the field, leading to the approval of the first disease-modifying therapies for Alzheimer's disease by the FDA. It is now up to European regulators to determine whether there is sufficient evidence to approve these drugs for patients with mild cognitive impairment or mild dementia due to Alzheimer's disease. Here, we outline Alzheimer Europe's position on anti-amyloid therapies for Alzheimer's disease, which was adopted by the Board of Alzheimer Europe following consultations with our member associations and with the European Working Group of People with Dementia. Beyond questions of drug efficacy, safety and cost, we highlight important issues that must be addressed by industry, regulators, payers, healthcare systems and governments, to ensure that patients have timely, appropriate and equitable access to innovative treatments, regardless of their socio-economic background, insurance status, or place of residence. We also call for continued investment in research on treatments that might benefit people with more advanced Alzheimer's disease - as well as support and care services that can help people live well with dementia at all stages of the disease.

Validation, Deployment, and Real-World Implementation of a Modular Toolbox for Alzheimer's Disease Detection and Dementia Risk Reduction: The AD-RIDDLE Project.

The Real-World Implementation, Deployment, and Validation of Early Detection Tools and Lifestyle Enhancement (AD-RIDDLE) project, recently launched with the support of the EU Innovative Health Initiative (IHI) public-private partnership and UK Research and Innovation (UKRI), aims to develop, test, and deploy a modular toolbox platform that can reduce existing barriers to the timely detection, and therapeutic approaches in Alzheimer's disease (AD), thus accelerating AD innovation. By focusing on health system and health worker practices, AD-RIDDLE seeks to improve and smooth AD management at and between each key step of the clinical pathway and across the disease continuum, from at-risk asymptomatic stages to early symptomatic ones. This includes innovation and improvement in AD awareness, risk reduction and prevention, detection, diagnosis, and intervention. The 24 partners in the AD-RIDDLE interdisciplinary consortium will develop and test the AD-RIDDLE toolbox platform and its components individually and in combination in six European countries. Expected results from this cross-sectoral research collaboration include tools for earlier detection and accurate diagnosis; validated, novel digital cognitive and blood-based biomarkers; and improved access to individualized preventative interventions (including multimodal interventions and symptomatic/disease-modifying therapies) across diverse populations, within the framework of precision medicine. Overall, AD-RIDDLE toolbox platform will advance management of AD, improving outcomes for patients and their families, and reducing costs.

Biologically derived epicardial patch induces macrophage mediated pathophysiologic repair in chronically infarcted swine hearts.

There are nearly 65 million people with chronic heart failure (CHF) globally, with no treatment directed at the pathologic cause of the disease, the loss of functioning cardiomyocytes. We have an allogeneic cardiac patch comprised of cardiomyocytes and human fibroblasts on a bioresorbable matrix. This patch increases blood flow to the damaged heart and improves left ventricular (LV) function in an immune competent rat model of ischemic CHF. After 6 months of treatment in an immune competent Yucatan mini swine ischemic CHF model, this patch restores LV contractility without constrictive physiology, partially reversing maladaptive LV and right ventricular remodeling, increases exercise tolerance, without inducing any cardiac arrhythmias or a change in myocardial oxygen consumption. Digital spatial profiling in mice with patch placement 3 weeks after a myocardial infarction shows that the patch induces a CD45pos immune cell response that results in an infiltration of dendritic cells and macrophages with high expression of macrophages polarization to the anti-inflammatory reparative M2 phenotype. Leveraging the host native immune system allows for the potential use of immunomodulatory therapies for treatment of chronic inflammatory diseases not limited to ischemic CHF.

Capturing nystagmus in the emergency room: posterior circulation stroke versus acute vestibular neuritis.

OBJECTIVES: To compare acute nystagmus characteristics of posterior circulation stroke (PCS) and acute vestibular neuritis (AVN) in the emergency room (ER) within 24 h of presentation. METHODS: ER-based video-nystagmography (VNG) was conducted, recording ictal nystagmus in 101 patients with PCS (on imaging) and 104 patients with AVN, diagnosed on accepted clinical and vestibular test criteria. RESULTS: Patients with stroke in the brainstem (38/101, affecting midbrain (n = 7), pons (n = 19), and medulla (n = 12)), cerebellum (31/101), both (15/101) or other locations (17/101) were recruited. Common PCS territories included posterior-inferior-cerebellar-artery (41/101), pontine perforators (18/101), multiple-territories (17/101) and anterior-inferior-cerebellar-artery (7/101). In PCS, 44/101 patients had no spontaneous nystagmus. Remaining PCS patients had primary position horizontal (44/101), vertical (8/101) and torsional (5/101) nystagmus. Horizontal nystagmus was 50% ipsiversive and 50% contraversive in lateralised PCS. Most PCS patients with horizontal nystagmus (28/44) had unidirectional "peripheral-appearing" nystagmus. 32/101 of PCS patients had gaze-evoked nystagmus. AVN affected the superior, inferior or both divisions of the vestibular nerve in 55/104, 4/104 and 45/104. Most (102/104) had primary position horizontal nystagmus; none had gaze-evoked nystagmus. Two inferior VN patients had contraversive torsional-downbeat nystagmus. Horizontal nystagmus with SPV ≥ 5.8 °/s separated AVN from PCS with sensitivity and specificity of 91.2% and 83.0%. Absent nystagmus, gaze-evoked nystagmus, and vertical-torsional nystagmus were highly specific for PCS (100%, 100% and 98.1%). CONCLUSION: Nystagmus is often absent in PCS and always present in AVN. Unidirectional 'peripheral-appearing' horizontal nystagmus can be seen in PCS. ER-based VNG nystagmus assessment could provide useful diagnostic information when separating PCS from AVN.

Design of the high-yield time-gated x-ray hot-spot imager for OMEGA.

Time-resolved x-ray self-emission imaging of hot spots in inertial confinement fusion experiments along several lines of sight provides critical information on the pressure and the transient morphology of the hot spot on the University of Rochester's OMEGA Laser System. At least three quasi-orthogonal lines of sight are required to infer the tomographic information of the hot spots of deuterium-tritium cryogenic layered implosions. OMEGA currently has two time-gated x-ray hot-spot imagers: the time-resolved Kirkpatrick-Baez x-ray microscope and the single-line-of-sight, time-resolved x-ray imager (SLOS-TRXI). The time-gated x-ray hot-spot imager (XRHSI) is being developed for use on OMEGA as the third line of sight for the high-yield operation of up to 4 × 1014 neutrons. XRHSI follows the SLOS-TRXI concept; however, it will have improved spatial and temporal resolutions of 5 µm and 20 ps, respectively. The simultaneous operation of the three instruments will provide 3-D reconstructions of the assembled hot-spot fuel at various times through peak thermonuclear output. The technical approach consists of a pinhole array imager and demagnifying time-dilation drift tube that are coupled to two side-by-side hybrid complementary metal-oxide semiconductor (hCMOS) image sensors. To minimize the background and to harden the diagnostics, an angled drift-tube assembly shifting the hCMOS sensors out of the direct line of sight and neutron shielding will be applied. The technical design space for the instrument will be discussed and the conceptual design will be presented.

LOW PREVALENCE OF HAEMOSPORIDIANS IN BLOOD AND TISSUE SAMPLES FROM HUMMINGBIRDS.

Hummingbirds are vital members of terrestrial ecosystems, and because of their high metabolic requirements, they serve as indicators of ecosystem health. Monitoring the parasitic infections of hummingbirds is thus especially important. Haemosporidians, a widespread group of avian blood parasites, are known to infect hummingbirds, but little is known about the prevalence and diversity of these parasites in hummingbirds. The prevalence of haemosporidians in several hummingbird species was examined and we compared 4 different tissue types in detecting parasites by polymerase chain reaction (PCR). Blood samples from 339 individuals of 3 different hummingbird species were tested, and 4 individuals were found positive for haemosporidian infection, a prevalence of 1.2%. Hummingbird carcasses (n = 70) from 5 different hummingbird species were also sampled to assess differences in detection success of haemosporidians in heart, kidney, liver, and pectoral muscle tissue samples. Detection success was similar among tissue types, with haemosporidian prevalence of 9.96% in heart tissue, 9.52% in kidney tissue, 10.76% in liver tissue, and 11.76% in pectoral muscle tissue. All tissue samples positive for haemosporidian infection were from the Black-chinned Hummingbird (Archilochus alexandri). Possible reasons for low prevalence of these blood parasites could include low susceptibility to insect vectors or parasite incompatibility in these hummingbirds.

Testing the interhemispheric deficit theory of dyslexia using the visual half-field technique.

A deficit in interhemispheric transfer has been proposed as a neuropsychological theory of dyslexia. Interactions between the hemispheres during word recognition can be studied using the visual half-field paradigm. The well-established recognition advantage for right visual field (RVF) words over left visual field (LVF) words is thought to reflect the additional processing costs associated with callosal transfer of LVF word representations to the language-specialised left hemisphere. In addition, a further gain in recognition for bilateral presentation of a word has been attributed to cooperative interactions between the hemispheres. These recognition advantages can therefore be seen as behavioural indices of the efficiency of callosal transfer. This study aimed to replicate the finding of an absence of the bilateral advantage in developmental dyslexia, previously reported by Henderson et al. In all, 47 dyslexic and 43 control adult participants were tested, and no significant difference was found in the size of the bilateral advantage between the two groups. Our data did however replicate the previous finding of an increased RVF-LVF difference in dyslexic participants caused by poorer accuracy for LVF words (i.e., a greater LVF cost). This evidence is compatible with the interhemispheric deficit theory of dyslexia, suggesting an impairment in the transfer of visual word information from the right to the left hemisphere during reading.

Benign positional vertigo, its diagnosis, treatment and mimics.

The diagnosis of benign positional vertigo (BPV) relies on a history of episodic positional vertigo and a distinctive pattern of nystagmus during provocative positional testing. The direction of the induced nystagmus is specific to the affected canal and the velocity profile reflects the underlying mechanism of canalithiasis (free-floating otoconia within the canal duct) or cupulolithiasis (otoconia adherent to the cupula). We review current theories on the pathophysiology of BPV, the clinical history and examination underlying its diagnosis, and recommended repositioning manoeuvres for each of the BPV subtypes. Disorders other than BPV which may present with a similar history and/or positional nystagmus are discussed.

Testing the unitary theory of language lateralization using functional transcranial Doppler sonography in adults.

Hemispheric dominance for language can vary from task to task, but it is unclear if this reflects error of measurement or independent lateralization of different language systems. We used functional transcranial Doppler sonography to assess language lateralization within the middle cerebral artery territory in 37 adults (seven left-handers) on six tasks, each given on two occasions. Tasks taxed different aspects of language function. A pre-registered structural equation analysis was used to compare models of means and covariances. For most people, a single lateralized factor explained most of the covariance between tasks. A minority, however, showed dissociation of asymmetry, giving a second factor. This was mostly derived from a receptive task, which was highly reliable but not lateralized. The results suggest that variation in the strength of language lateralization reflects true individual differences and not just error of measurement. The inclusion of several tasks in a laterality battery makes it easier to detect cases of atypical asymmetry.

Hypofractionated Concomitant Chemoradiation in Inoperable Locally Advanced Non-small Cell Lung Cancer: A Report on 100 Patients and a Systematic Review.

AIMS: Concomitant chemoradiation is the standard of care in patients with inoperable non-small cell lung cancer. The purpose of this study was to analyse the survival outcome and toxicity data of using hypofractionated chemoradiation. MATERIALS AND METHODS: One hundred patients were treated from June 2011 to November 2016. Treatment consisted of 55 Gy in 20 daily fractions concurrently with split-dose cisplatin vinorelbine chemotherapy over 4 weeks followed by two cycles of cisplatin vinorelbine only. Survival was estimated using Kaplan-Meier and Cox regression was carried out for known prognostic factors. A systematic search of literature was conducted using Medline, Embase and Cochrane databases and relevant references included. RESULTS: In total, 97% of patients completed radiotherapy and 73% of patients completed all four cycles of chemotherapy. One patient died of a cardiac event during consolidative chemotherapy. There were two cases of grade 4 toxicities (one sepsis, one renal impairment). Grade 3 toxicities included nausea/vomiting (17%), oesophagitis (15%), infection with neutropenia (12%) and pneumonitis (4%). Clinical benefit was seen in 86%. Two-year progression-free survival and overall survival rates were 49% and 58%, respectively. The median progression-free survival and overall survival were 23.4 and 43.4 months, respectively. The only significant prognostic factor was the number of chemotherapy cycles received (P = 0.02). The systematic review identified 13 relevant studies; a variety of regimens were assessed with variable reporting of outcomes and toxicity but with overall an improvement in survival over time. CONCLUSION: Our experience compared with the original phase II trial showed improved treatment completion rates and survival with acceptable morbidity. With appropriate patient selection this regimen is an effective treatment option for locally advanced non-small cell lung cancer. This study helps to benchmark efficacy and toxicity rates while considering the addition of new agents to hypofractionated concurrent chemoradiotherapy. The agreement of a standard regimen for assessment in future trials would be beneficial.

Development of an ultra-fast photomultiplier tube for gamma-ray Cherenkov detectors at the National Ignition Facility (PD-PMT).

A new ultra-fast photomultiplier tube and associated drivers have been developed for use in the next generation of gamma-ray high pressure gas Cherenkov detectors for inertial confinement fusion experiments at the National Ignition Facility. Pulse-dilation technology has been applied to a standard micro-channel-plate-based photomultiplier tube to improve the temporal response by about 10×. The tube has been packaged suitably for deployment on the National Ignition Facility, and remote electronics have been designed to deliver the required non-linear waveforms to the pulse dilation electrode. This is achieved with an avalanche pulse generator system capable of generating fast arbitrary waveforms over the useful parameter space. The pulse is delivered via fast impedance-matching transformers and isolators, allowing the cathode to be ramped on a sub-nanosecond time scale between two high voltages in a controlled non-linear manner. This results in near linear pulse dilation over several ns. The device has a built-in fiducial system that allows easy calibration and testing with fiber optic laser sources. Results are presented demonstrating the greatly improved response time and other parameters of the device.

Sub-nanosecond single line-of-sight (SLOS) x-ray imagers (invited).

A new generation of fast-gated x-ray framing cameras have been developed that are capable of capturing multiple frames along a single line-of-sight with 30 ps temporal resolution. The instruments are constructed by integrating pulse-dilation electron imaging with burst mode hybrid-complimentary metal-oxide-semiconductor sensors. Two such instruments have been developed, characterized, and fielded at the National Ignition Facility and the OMEGA laser. These instruments are particularly suited for advanced x-ray imaging applications in Inertial Confinement Fusion and High energy density experiments. Here, we discuss the system architecture and the techniques required for tuning the instruments to achieve optimal performance. Characterization results are also presented along with planned future improvements to the design.

The single-line-of-sight, time-resolved x-ray imager diagnostic on OMEGA.

The single-line-of-sight, time-resolved x-ray imager (SLOS-TRXI) on OMEGA is one of a new generation of fast-gated x-ray cameras comprising an electron pulse-dilation imager and a nanosecond-gated, burst-mode, hybrid complementary metal-oxide semiconductor sensor. SLOS-TRXI images the core of imploded cryogenic deuterium-tritium shells in inertial confinement fusion experiments in the ∼4- to 9-keV photon energy range with a pinhole imager onto a photocathode. The diagnostic is mounted on a fixed port almost perpendicular to a 16-channel, framing-camera-based, time-resolved Kirkpatrick-Baez microscope, providing a second time-gated line of sight for hot-spot imaging on OMEGA. SLOS-TRXI achieves ∼40-ps temporal resolution and better than 10-µm spatial resolution. Shots with neutron yields of up to 1 × 1014 were taken without observed neutron-induced background signal. The implosion images from SLOS-TRXI show the evolution of the stagnating core.

The dilation aided single-line-of-sight x-ray camera for the National Ignition Facility: Characterization and fielding.

Crystal x-ray imaging is frequently used in inertial confinement fusion and laser-plasma interaction applications as it has advantages compared to pinhole imaging, such as higher signal throughput, better achievable spatial resolution, and chromatic selection. However, currently used x-ray detectors are only able to obtain a single time resolved image per crystal. The dilation aided single-line-of-sight x-ray camera described here was designed for the National Ignition Facility (NIF) and combines two recent diagnostic developments, the pulse dilation principle used in the dilation x-ray imager and a ns-scale multi-frame camera that uses a hold and readout circuit for each pixel. This enables multiple images to be taken from a single-line-of-sight with high spatial and temporal resolution. At the moment, the instrument can record two single-line-of-sight images with spatial and temporal resolution of 35 µm and down to 35 ps, respectively, with a planned upgrade doubling the number of images to four. Here we present the dilation aided single-line-of-sight camera for the NIF, including the x-ray characterization measurements obtained at the COMET laser, as well as the results from the initial timing shot on the NIF.

Pulse dilation gas Cherenkov detector for ultra-fast gamma reaction history at the NIF (invited).

The Cherenkov mechanism used in Gas Cherenkov Detectors (GCDs) is exceptionally fast. However, the temporal resolution of GCDs, such as the Gamma Reaction History diagnostic at the National Ignition Facility (NIF), has been limited by the current state-of-the-art photomultiplier tube technology to ∼100 ps. The soon-to-be deployed Pulse Dilation Photomultiplier Tube (PD-PMT) at NIF will allow for temporal resolution comparable to that of the gas cell or ∼10 ps. Enhanced resolution will contribute to the quest for ignition in a crucial way through precision measurements of reaction history and ablator areal density (ρR) history, leading to better constrained models. Features such as onset of alpha heating, shock reverberations, and burn truncation due to dynamically evolving failure modes may become visible for the first time. Test measurements of the PD-PMT at Atomic Weapons Establishment confirmed that design goals have been met. The PD-PMT provides dilation factors of 2 to 40× in 6 increments. The GCD-3 recently deployed at the NIF has been modified for coupling to a PD-PMT and will soon be making ultrafast measurements.

Characterisation of a sub-20 ps temporal resolution pulse dilation photomultiplier tube.

A pulse-dilation photomultiplier tube (PD-PMT) with sub-20 ps temporal resolution has been developed for use with γ-ray-sensitive gas Cherenkov detectors at the National Ignition Facility to improve the diagnosis of nuclear fusion burn history and the areal density of the remaining capsule ablator. The pulse-dilation mechanism entails the application of a time-dependent, ramp waveform to a photocathode-mesh structure, introducing a time-dependent photoelectron accelerating potential. The electric field imparts axial velocity dispersion to outgoing photoelectrons. The photoelectron pulse is dilated as it transits a drift region prior to amplification in a microchannel plate and read out with a digital oscilloscope. We report the first measurements with the prototype PD-PMT demonstrating nominal <20 ps FWHM across a 400 ps measurement window and <30 ps FWHM for an extracted charge up to 300 pC. The output peak areas are linear to within 20% over 3 orders of magnitude of input intensity. 3D particle in cell simulations, which included space charge effects, have been carried out to investigate the device temporal magnification, resolution, and linearity.

Continuous Hyperfractionated Accelerated Radiotherapy (CHART) for Non-small Cell Lung Cancer (NSCLC): 7 Years' Experience From Nine UK Centres.

AIM: Continuous hyperfractionated accelerated radiotherapy (CHART) remains an option to treat non-small cell lung cancer (NSCLC; NICE, 2011). We have previously published treatment outcomes from 1998-2003 across five UK centres. Here we update the UK CHART experience, reporting outcomes and toxicities for patients treated between 2003 and 2009. MATERIALS AND METHODS: UK CHART centres were invited to participate in a retrospective data analysis of NSCLC patients treated with CHART from 2003 to 2009. Nine (of 14) centres were able to submit their data into a standard database. The Kaplan-Meier method estimated survival and the Log-rank test analysed the significance. RESULTS: In total, 849 patients had CHART treatment, with a median age of 71 years (range 31-91), 534 (63%) were men, 55% had undergone positron emission tomography-computed tomography (PET-CT) and 26% had prior chemotherapy; 839 (99%) patients received all the prescribed treatment. The median overall survival was 22 months with 2 and 3 year survival of 47% and 32%, respectively. Statistically significant differences in survival were noted for stage IA versus IB (33.2 months versus 25 months; P = 0.032) and IIIA versus IIIB (20 months versus 16 months; P = 0.018). Response at 3 months and outcomes were significantly linked; complete response showing survival of 34 months against 19 months, 15 months and 8 months for partial response, stable and progressive disease, respectively (P < 0.001). Age, gender, performance status, prior chemotherapy and PET-CT did not affect the survival outcomes. Treatment was well tolerated with <5% reporting ≥grade 3 toxicity. CONCLUSION: In routine practice, CHART results for NSCLC remain encouraging and we have been able to show an improvement in survival compared with the original trial cohort. We have confirmed that CHART remains deliverable with low toxicity rates and we are taking a dose-escalated CHART regimen forward in a randomised phase II study of sequential chemoradiotherapy against other accelerated dose-escalated schedules.

Analysis of hematopoietic recovery after autologous transplantation as method of quality control for long-term progenitor cell cryopreservation.

Hematopoietic precursor cells (HPC) are able to restore hematopoiesis after high-dose chemotherapy and their cryopreservation is routinely employed prior to the autologous hematopoietic cell transplantation (AHCT). Although previous studies showed feasibility of long-term HPC storage, concerns remain about possible negative effects on their potency. To study the effects of long-term cryopreservation, we compared time to neutrophil and platelet recovery in 50 patients receiving two AHCT for multiple myeloma at least 2 years apart between 2006 and 2016, using HPC obtained from one mobilization and collection attempt before the first transplant. This product was divided into equivalent fractions allowing a minimum of 2 × 106 CD34+ cells/kg recipient's weight. One fraction was used for the first transplant after median storage of 60 days (range, 17-165) and another fraction was used after median storage of 1448 days (range, 849-3510) at the second AHCT. Neutrophil recovery occurred at 14 days (median; range, 11-21) after the first and 13 days (10-20) after the second AHCT. Platelets recovered at a median of 16 days after both procedures. Considering other factors, such as disease status, conditioning and HPC dose, this single institution data demonstrated no reduction in the potency of HPC after long-term storage.

Detection and prevalence of Haemoproteus archilochus (Haemosporida, Haemoproteidae) in two species of California hummingbirds.

Haemosporidian blood parasites are transmitted to a wide range of avian hosts via blood-sucking dipteran vectors. Microscopy has revealed an impressive diversity of avian haemosporidia with more than 250 species described. Moreover, PCR and subsequent sequence analyses have suggested a much greater diversity of haemosporidia than morphological analyses alone. Given the importance of these parasites, very few studies have focused on the charismatic hummingbirds. To date, three Haemoproteus species (Haemoproteus archilochus, Haemoproteus trochili, and Haemoproteus witti) and one Leucocytozoon species (Leucocytozoon quynzae) have been described in blood samples taken from hummingbirds (Trochilidae). Unconfirmed Plasmodium lineages have also been detected in hummingbirds. Here, we report the detection of H. archilochus in two hummingbird species (Calypte anna and Archilochus alexandri) sampled in Northern California and perform a phylogenetic analysis of mitochondrial cytochrome b (cyt b) gene lineages. A total of 261 hummingbirds (157 C. anna, 104 A. alexandri) were sampled and screened for blood parasites using PCR and microscopy techniques. Combining both methods, 4 (2.55%) haemosporidian infections were detected in C. anna and 18 (17.31%) haemosporidian infections were detected in A. alexandri. Molecular analyses revealed four distinct H. archilocus cyt b lineages, which clustered as a monophyletic clade. No species of Plasmodium or Leucocytozoon were detected in this study, raising the possibility of specific vector associations with hummingbirds. These results provide resources for future studies of haemosporidian prevalence, diversity, and pathogenicity in California hummingbird populations.