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Background Varoglutamstat (formerly PQ912) is a small molecule that inhibits the activity of the glutaminyl cyclase to reduce the level of pyroglutamate-A-beta (pGluAB42). Recent studies confirm that pGluAB42 is a particular amyloid form that is highly synaptotoxic and plays a significant role in the development of AD. Methods This paper describes the design and methodology behind the phase 2b VIVIAD-trial in AD. The aim of this study is to evaluate varoglutamstat in a state-of-the-art designed, placebo-controlled, double-blind, randomized clinical trial for safety and tolerability, efficacy on cognition, and effects on brain activity and AD biomarkers. In addition to its main purpose, the trial will explore potential associations between novel and established biomarkers and their individual and composite relation to disease characteristics. Results To be expected early 2023 Conclusion This state of the art phase 2b study will yield important results for the field with respect to trial methodology and for the treatment of AD with a small molecule directed against pyroglutamate-A-beta. Trial registration ClinicalTrials.gov Identifier: NCT04498650

Key Points Question What is the evidence for nonpharmacological interventions to treat persistent postconcussion symptoms? Findings Following a systematic review and meta-analysis of 19 randomized clinical trials comprising 2007 participants, using the Grading of Recommendations, Assessment, Development, and Evaluations method, weak recommendations for the following were assigned: systematic provision of early information and advice, use of graded physical exercise, vestibular rehabilitation, manual treatment of neck and back, psychological treatment, and interdisciplinary rehabilitation. No studies were identified regarding oculomotor vision treatment, resulting in a consensus-based statement. Meaning Based on very low to low certainty of evidence or on consensus, individually tailored nonpharmacological treatment of persistent symptoms was recommended, both through specific disciplines and interdisciplinary rehabilitation., This systematic review and meta-analysis assesses the outcomes related to 7 nonpharmacological interventions for persistent postconcussion symptoms in adults and provides recommendations for clinical practice., Importance Persistent (>4 weeks) postconcussion symptoms (PPCS) are challenging for both patients and clinicians. There is uncertainty about the effect of commonly applied nonpharmacological treatments for the management of PPCS. Objective To systematically assess and summarize evidence for outcomes related to 7 nonpharmacological interventions for PPCS in adults (aged >18 years) and provide recommendations for clinical practice. Data Sources Systematic literature searches were performed via Embase, MEDLINE, PsycINFO, CINAHL, PEDro, OTseeker, and Cochrane Reviews (via MEDLINE and Embase) from earliest possible publication year to March 3, 2020. The literature was searched for prior systematic reviews and primary studies. To be included, studies had to be intervention studies with a control group and focus on PPCS. Study Selection A multidisciplinary guideline panel selected interventions based on frequency of use and need for decision support among clinicians, including early information and advice, graded physical exercise, vestibular rehabilitation, manual treatment of neck and back, oculomotor vision treatment, psychological treatment, and interdisciplinary coordinated rehabilitative treatment. To be included, studies had to be intervention studies within the areas of the predefined clinical questions, include a control group, and focus on symptoms after concussion or mild traumatic brain injury. Data Extraction and Synthesis Extraction was performed independently by multiple observers. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used for data abstraction and data quality assessment. Included studies were assessed using the Assessment of Multiple Systematic Reviews (AMSTAR) tool and the Cochrane Risk of Bias (randomized clinical trials) tool. Meta-analysis was performed for all interventions where possible. Random-effects models were used to calculate pooled estimates of effects. The level and certainty of evidence was rated and recommendations formulated according to the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. Main Outcomes and Measures All outcomes were planned before data collection began according to a specified protocol. The primary outcomes were the collective burden of PPCS and another outcome reflecting the focus of a particular intervention (eg, physical functioning after graded exercise intervention). Results Eleven systematic reviews were identified but did not contribute any primary studies; 19 randomized clinical trials comprising 2007 participants (1064 women [53.0%]) were separately identified and included. Evidence for the 7 interventions ranged from no evidence meeting the inclusion criteria to very low and low levels of evidence. Recommendations were weak for early information and advice, graded physical exercise, vestibular rehabilitation, manual treatment of the neck and back, psychological treatment, and interdisciplinary coordinated rehabilitative treatment. No relevant evidence was identified for oculomotor vision treatment, so the panel provided a good clinical practice recommendation based on consensus. Conclusions and Relevance Based on very low to low certainty of evidence or based on consensus, the guideline panel found weak scientific support for commonly applied nonpharmacological interventions to treat PPCS. Results align with recommendations in international guidelines. Intensified research into all types of intervention for PPCS is needed.

To compare the effectiveness of a specialized, interdisciplinary rehabilitation (S-REHAB) with standard care (STAND) for people with persistent post-concussive symptoms (PPCS6 month).Randomized controlled trial.Eighty-nine adults.22-week programme combining individual and group-based neuropsychological treatment with exercise therapy and physiotherapeutic coaching (S-REHAB), and the usual treatment offered by the public municipality services (STAND).The Rivermead Postconcussion Symptoms Questionnaire (RPSQ) (primary), The Headache Impact Test (HIT-6), Major Depression Inventory (MDI), Multidimensional Fatigue Inventory (MFI-20) and The Short Form (36) Health Survey (SF-36); all collected at baseline, post-treatment, and at 6-month follow-up.The S-REHAB group showed a significant reduction in symptoms measured by RPSQ compared to the STAND immediately post-treatment (effect size [ES] = 0.28) and at follow-up (ES = 0.26). The S-REHAB groups also showed significant improvements regarding HIT-6 post-treatment (ES = 0.38) and at follow-up (ES = 0.68), MFI-20 - dimension 'mental fatigue' post-treatment (ES = 0.42), MFI-20 - dimension 'reduced activities' at follow-up (ES = 0.74) and SF-36 - dimension 'social functioning' post-treatment (ES = 0.31).The S-REHAB is more effective than the STAND in reducing the PPCS affecting physical, cognitive and emotional domains. This symptom reduction was associated with experienced improvement in social functioning, increased levels of activity, a decrease in mental fatigue and increased life satisfaction.

Structural elements form the backbone of a spacecraft. They provide the overall mechanical integrity of the spacecraft under launch and in-orbit loads. Furthermore, the structure ensures that the spacecraft configuration is maintained during all mission phases, ensuring the relative alignment of components like antennas, reflectors, sensors and optical instruments. In the latter cases, the potential loss of dimensional stability of the spacecraft structure can severely degrade the mission performances.

Setting A passive case-finding strategy as present in the DOTS strategy presupposes a patient's willingness to seek care. This requires awareness of tuberculosis (TB) symptoms and the diagnostic process, and positive attitudes towards access and probability of cure. Objective To measure parameters of health-seeking intention in Southern Angola and to inform the design of context-specific interventions to improve case detection. Design A survey in four communities based on the cough-to-cure pathway represented by five domains with either one or two proxy measures. These were assessed for association with appropriate health-seeking behaviour (visiting a medical institution or service). Results In total, 805 individuals were included in the study. Appropriate health-seeking behaviour was positively associated with knowing the disease (OR 3.1, 95%CI 1.4-6.8), knowing key symptoms (OR 1.4, 95%CI 1.0-1.9), perceived curability (OR 1.3, 95%CI 1.0-1.6), and the perception that TB services were free of charge (OR 1.9, 95%CI 1.4-2.7). Respondents who perceived a personal risk for TB were less likely to have an appropriate intended health-seeking behaviour (OR 0.7, 95%CI 0.5-0.9). Conclusion Knowledge about TB should include key symptoms, perceived curability and information on access to services when designing interventions to improve case detection. The study highlights the importance of advocacy, social mobilisation and communication strategies.

It is an honour and a great pleasure for us to present this special issue of the CEAS Space Journal devoted to the development of large deployable antennas and related technologies. Large deployable antennas for space applications have been under development worldwide for several decades, driven by both mission performance enhancement goals as well as mission enabling goals. Developments in ESA started already in the 80s with a 5-m metal-mesh reflector built by MBB/ERNO in Germany, continued later with a 10-m inflatable reflector built by Contraves in Switzerland and more recently a 12-m antenna built by Thales Alenia Space in Italy. However, for various reasons all these developments did not result in a final available European antenna reflector product. As a matter of fact, today there is no European antenna reflector product larger than 4 m aperture available, forcing European spacecraft developers to procure large reflectors from non-European sources. Three years ago, an ESA Working Group on large reflector antennas was set up with the mandate to define recommendations on how to proceed with new large reflector developments in Europe. Several spacecraft missions in need of antenna reflectors were identified, including well-established telecommunication markets such as fixed and broadcasting satellite services, mobile interactive/broadcast services, broadband services, but also new applications such as air traffic management and emergency communications. These missions cover the frequency spectrum up to Ka-band. Synergies with Earth Observation, Navigation and Scientific deep space missions were also identified. One of the main conclusions of the Working Group was that near-term effort should be devoted to the development of technologies for reflectors with scalability and/or modularity features to cover sizes above 4 m and up to 25 m for frequency bands ranging from P to Ka. It was understood that many of the technologies were in fact available or within reach, and the missing task of coordination and industrial implementation was considered achievable. In October 2012, the first Large Deployable Antenna Workshop took place at ESA/ESTEC, The Netherlands, with a significant participation from European industry and research organisations. During this workshop, several recent technology developments for large antenna reflectors were presented and discussed together with a new reflector deployment demonstration. The workshop addressed as well developments for inflight reconfigurability of space antennas using reflector reshaping that is finally becoming technically feasible after many years of trials. Reflect-arrays and lenses were also addressed, as well as radio frequency testing, especially relevant due to the challenges ahead of us for the development of test facilities required for large apertures. This special issue of the CEAS Space Journal is intended to present the key technologies addressed in this workshop. A second edition of the workshop is under preparation for 2014 with the objective to report on the major developments performed over the last 2 years. T. K. Henriksen (&) Structures and Mechanisms Division, ESA/ESTEC, Keplerlaan 1, 2201 AZ Noordwijk, ZH, The Netherlands e-mail: Torben.Henriksen@esa.int

During the past fifteen years significant efforts have been made at national and European level to improve the technologies needed for future space transportation systems. Innovative concepts, advanced materials and manufacturing processes become of paramount importance to meet the challenging requirements of reusable launchers. The studies performed in the past years have highlighted promising capabilities in advanced composite materials and processes, which offer superior performance to that of conventional metals due to their high specific strength, high toughness, lightweight and high wear resistance obtained through appropriate fibres orientation. This paper addresses an ESA internal study on reusable launch vehicle primary structures, and specifically aspects related to advanced composite materials performance in such vehicle application.

The authors discuss software interface concerns in radiation oncology from a human factors perspective. An example of a series of disastrous consequences resulting from a poorly developed and tested interface design of a computer controlled treatment machine is described. Treatment planning computers are discussed in terms of their increasing requirement to provide complex data to the user resulting in the possibility of confusing the output or overloading the user. Finally, the priority given to software-based human interfaces in other industries is compared to that found in radiation oncology equipment manufacturers. The authors argue that radiation oncology equipment manufacturers lag behind other industries in terms of their emphasis on the human interface. >

Dr Lesley Colvin (Senior Lecturer in Anaesthesia, Western General Hospital, Edinburgh) discussed the challenges of pain management in patients with a history of addiction. Similar to other chronic conditions, substance misuse often follows a relapsing course. Pain is a frequently associated comorbidity. Mortality rates are high but can be reduced by successful methadone maintenance programmes, although pain, anxiety and depression have a negative effect on outcomes. Dr Colvin described experience of the Lothian Pain and Dependency Clinic. General guidance on patient management is available through the British Pain Society Guidelines.

A series of human factors evaluations were undertaken to better understand the contributing factors to human error in the teletherapy environment. Teletherapy is a multidisciplinary methodology for treating cancerous tissue through selective exposure to an external beam of ionizing radiation. A team of human factors specialists, assisted by a panel of radiation oncologists, medical physicists, and radiation therapists, conducted site visits to radiation oncology departments at community hospitals, university centers, and free-standing clinics. A function and task analysis was performed initially to guide subsequent evaluations in the areas of workplace environment, system-user interfaces, procedures, training, and organizational practices. To further acquire an in-depth and up-to-date understanding of the practice of teletherapy in support of these evaluations, a systematic literature review was conducted. Factors that have a potential impact on the accuracy of treatment delivery were of primary concern. The present volume is the literature review. The volume starts with an overview of the multiphased nature of teletherapy, and then examines the requirement for precision, the increasing role of quality assurance, current conceptualizations of human error, and the role of system factors such as the workplace environment, user-system interfaces, procedures, training, and organizational practices.

As a treatment methodology, teletherapy selectively destroys cancerous and other tissue by exposure to an external beam of ionizing radiation. Sources of radiation are either a radioactive isotope, typically Cobalt-60 (Co-60), or a linear accelerator. Records maintained by the NRC have identified instances of teletherapy misadministration where the delivered radiation dose has differed from the radiation prescription (e.g., instances where fractions were delivered to the wrong patient, to the wrong body part, or were too great or too little with respect to the defined treatment volume). Both human error and machine malfunction have led to misadministrations. Effective and safe treatment requires a concern for precision and consistency of human-human and human-machine interactions throughout the course of therapy. The present study is the first part of a series of human factors evaluations for identifying the root causes that lead to human error in the teletherapy environment. The human factors evaluations included: (1) a function and task analysis of teletherapy activities, (2) an evaluation of the human-system interfaces, (3) an evaluation of procedures used by teletherapy staff, (4) an evaluation of the training and qualifications of treatment staff (excluding the oncologists), (5) an evaluation of organizational practices and policies, and (6) anmore » identification of problems and alternative approaches for NRC and industry attention. The present report addresses the function and task analysis of teletherapy activities and provides the foundation for the conduct of the subsequent evaluations. The report includes sections on background, methodology, a description of the function and task analysis, and use of the task analysis findings for the subsequent tasks. The function and task analysis data base also is included.« less

A series of human factors evaluations was undertaken to better understand the contributing factors to human error in the teletherapy environment. Teletherapy is a multi-disciplinary methodology for treating cancerous tissue through selective exposure to an external beam of ionizing radiation. The principal sources of radiation are a radioactive isotope, typically cobalt60 (Co-60), or a linear accelerator device capable of producing very high energy x-ray and electron beams. A team of human factors specialists, assisted by a panel of radiation oncologists, medical physicists, and radiation technologists, conducted site visits to radiation oncology departments at community hospitals, university centers, and free-standing clinics. A function and task analysis was initially performed to guide subsequent evaluations in the areas of user-system interfaces, procedures, training and qualifications, and organizational policies and practices. The final phase of the project focused on identification of the most significant human factors problems with respect to safe and effective operation of the teletherapy system and an identification and assessment of alternative approaches for resolving the problems. This report presents the findings of this final phase.

A series of human factors evaluations were undertaken to better understand the contributing factors to human error in the teletherapy environment. Teletherapy is a multidisciplinary methodology for treating cancerous tissue through selective exposure to an external beam of ionizing radiation. A team of human factors specialists, assisted by a panel of radiation oncologists, medical physicists, and radiation therapists, conducted site visits to radiation oncology departments at community hospitals, university centers, and free-standing clinics. A function and task analysis was initially performed to guide subsequent evaluations in the areas of system-user interfaces, procedures, training and qualifications, and organizational policies and practices. The present work focuses solely on training and qualifications of personnel (e.g., training received before and during employment), and the potential impact of organizational factors on the performance of teletherapy. Organizational factors include such topics as adequacy of staffing, performance evaluations, commonly occurring errors, implementation of quality assurance programs, and organizational climate.

A series of human factors evaluations was undertaken to better understand the contributing factors to human error in the teletherapy environment. Teletherapy is a multidisciplinary methodology for treating cancerous tissue through selective exposure to an external beam of ionizing radiation. The principal sources of radiation are a radioactive isotope, typically cobalt60 (Co-60), or a linear accelerator device capable of producing very high energy x-ray and electron beams. A team of human factors specialists conducted site visits to radiation oncology departments at community hospitals, university centers, and free-standing clinics. In addition, a panel of radiation oncologists, medical physicists, and radiation technologists served as subject matter experts. A function and task analysis was initially performed to guide subsequent evaluations in the areas of user-system interfaces, procedures, training and qualifications, and organizational policies and practices. The present report focuses on an evaluation of the human-system interfaces in relation to the treatment machines and supporting equipment (e.g., simulators, treatment planning computers, control consoles, patient charts) found in the teletherapy environment. The report also evaluates operating, maintenance and emergency procedures and practices involved in teletherapy. The evaluations are based on the function and task analysis and established human engineering guidelines, where applicable.

Embracing simulation and team training—now is the time Ed Link had an early fascination with flying, yet the expensive costs of plane rentals and fuel to practice his piloting skills were beyond his modest salary as a tuner of pianos and organs. So in 1928, using organ parts, bellows, and compressed air, he finished construction of a mechanical device he called the “pilot maker” (see http://www.link.com/history.html). It had short wooden wings with a fuselage mounted on a universal joint, capable of pitching and rolling while the fledgling pilot worked the controls. Further improvements to the device in the 1930s enabled pilots to train to fly in adverse weather guided by instruments, ushering in the era of modern day training simulators. During wrld wr II, tens of thousands of pilots were trained in Link simulators, and a …

Data from scanning photometers equipped with fixed interference filters selecting the P and R branches of the N2+ first negative (0–1) band were used to derive the temperature height profile through an auroral arc. The height of the arc was determined by two-station triangulation techniques. The accuracy of the temperature determination is related to the relative intensity of the background aurora compared to the intensity of the arc. The need for a critical selection of the appropriate event to be analyzed and of the background to be subtracted is an important consideration in the analysis. In this particular example the most reliable part of the derived temperature profile lies between 105 and 140 km, and in this interval the temperatures agree well with the atmospheric temperature profile given by the U.S. Standard Atmosphere (1966) at 800°K exospheric temperature. No heating of the neutral atmosphere within the auroral arc was found.

A comprehensive review is presented concerning the role of zinc (Zn) nutrition in taste acuity, immunity and wound recovery in the elderly. Specific attention is given to Zn in foods, Zn bioavailability, evidence of Zn deficiency, and the need for Zn in immune function. It was concluded that the mean daily Zn intake in groups of US elderly ranges from 7-13 mg. Dietary Zn intake appears to be related to energy intake. An apparently adequate Zn intake can be achieved for $1.50-2.00/day with careful food selection; hence, people spending below $1.50/day for food have limited ability to satisfy dietary Zn requirements. Further Zn bioavailability should be considered in the food selection process. Evidence suggests that some elderly individuals have a deficient Zn nutriture, but available data are insufficient to ascertain the frequency of this deficiency. Most instances of hypogensia in the elderly, however, are unrelated to Zn nutriture. Deficient Zn nutriture seems to contribute to poor healing in the elderly, but, again, the data are too few to ascertain frequency. Self-treatment with Zn greater than the RDA may be unwise. (wz)

Starved Drosophila melanogaster were run individually in a T maze in which sucrose was provided as a reward. After three trials, flies were run similarly for a fourth trial in a clean maze lacking sucrose. The time in which the food area was located in the fourth trial compared with the first was significantly decreased. Control experiments rule out the possibility that smell. pheromones, or increased energy levels associated with the ingestion of sucrose are the basis of the highly significant differences. A likely alternative is that the flies to some degree learn the location of the food area.

Instrumentation has been developed for collection of three-dimensional X-ray and neutron diffraction data at temperatures below the boiling point of liquid nitrogen. A closed-cycle two-stage refrigerator has been mounted on the ϕ shaft of a four-circle goniometer. The sample crystal is attached to the nominal 10 K station. The refrigerator mount functions as a goniometer head without arcs. The x−y−z centering device has a range of ± 5 mm for the z direction along the ϕ axis and ± 2 mm along x and y. Dovetails and eccentrics with narrow tolerances allow a precise firmly lockable centering of the crystal. The whole refrigerator unit undergoes all the normal ϕ, χ and ω movements during data collection without any rotating vacuum seals. These are usually integral vulnerable parts of existing liquid-helium-temperature cryocoolers. When refrigeration is not required, the cryo-unit can be dismounted in a few minutes and replaced by a device for mounting an ordinary goniometer head for room-temperature data collection. Thus, the system is simple, robust and easy to operate, both at room temperature and at cryogenic temperatures. Furthermore, the use of a closed-cycle refrigerator makes the system more economical than comparable cryocooler systems based on flow cryostats.

The aim of the present study was to develop a simple disinfection method for reducing the content of bacteria in the water system of dental units to an acceptable level. The study was carried out at the Royal Dental College, Copenhagen, on 250 dental units. Samples of the cooling water supplying the ultrasonic scalers and of the water supplying the water glasses were obtained from eight different units representing different parts of the school. Disinfection of the water system was carried out by addition of chlorine to the pipe water near the institution's main water intake. The chlorination of the water was automatically regulated, and the installation was so flexible that the concentration of chlorine and the time and frequency of the chlorination could be varied. Different modes of chlorine dosage were examined. Before chlorination, the bacterial content in the water system of the units was about 104 - 105cfu/mL. It was found that an intermittent chlorination with 0.5-1 ppm chlorine for 10 minutes every day could reduce the normal bacterial counts in the water system to about a few hundred per mL.

Importance It is unknown whether coronary revascularization, when added to optimal medical therapy, improves prognosis in patients with stable ischemic heart disease (SIHD) at increased risk of cardiovascular events owing to moderate or severe ischemia. Objective To describe baseline characteristics of participants enrolled and randomized in the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial and to evaluate whether qualification by stress imaging or nonimaging exercise tolerance test (ETT) influenced risk profiles. Design, Setting, and Participants The ISCHEMIA trial recruited patients with SIHD with moderate or severe ischemia on stress testing. Blinded coronary computed tomography angiography was performed in most participants and reviewed by a core laboratory to exclude left main stenosis of at least 50% or no obstructive coronary artery disease (CAD) (