Patient-centered health technology assessment: a perspective on engagement in health technology assessment by three patient organizations and a health technology assessment body.

Patient engagement in health technology assessment (HTA) has become increasingly important over the past 20 years. Academic and practitioner literature has produced numerous case studies and best practice accounts of patient involvement practices around the world. This text analyzes the experience of being involved in an Institute for Clinical and Economic Review (ICER) HTA review in the United States. The analysis comes from the joint perspective of three patient organizations: Lupus and Allied Diseases Association, Inc.; Lupus Foundation of America; and Black Women's Health Imperative, as well as ICER. We suggest that meaningful, patient-centered engagement, where patient communities are systematically integrated throughout the review, can be a way of returning to the discipline's roots focusing on technologies' societal and ethical impact. It is a process that requires robust commitment from all involved but produces assessments relevant to those directly affected by them.

Timing precision in fly flight control: integrating mechanosensory input with muscle physiology.

Animals rapidly collect and act on incoming information to navigate complex environments, making the precise timing of sensory feedback critical in the context of neural circuit function. Moreover, the timing of sensory input determines the biomechanical properties of muscles that undergo cyclic length changes, as during locomotion. Both of these issues come to a head in the case of flying insects, as these animals execute steering manoeuvres at timescales approaching the upper limits of performance for neuromechanical systems. Among insects, flies stand out as especially adept given their ability to execute manoeuvres that require sub-millisecond control of steering muscles. Although vision is critical, here I review the role of rapid, wingbeat-synchronous mechanosensory feedback from the wings and structures unique to flies, the halteres. The visual system and descending interneurons of the brain employ a spike rate coding scheme to relay commands to the wing steering system. By contrast, mechanosensory feedback operates at faster timescales and in the language of motor neurons, i.e. spike timing, allowing wing and haltere input to dynamically structure the output of the wing steering system. Although the halteres have been long known to provide essential input to the wing steering system as gyroscopic sensors, recent evidence suggests that the feedback from these vestigial hindwings is under active control. Thus, flies may accomplish manoeuvres through a conserved hindwing circuit, regulating the firing phase-and thus, the mechanical power output-of the wing steering muscles.

Quality of life and caregiver burden in familial frontotemporal lobar degeneration: Analyses of symptomatic and asymptomatic individuals within the LEFFTDS cohort.

OBJECTIVE: The Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects evaluates familial frontotemporal lobar degeneration (FTLD) kindreds with MAPT, GRN, or C9orf72 mutations. Objectives were to examine whether health-related quality of life (HRQoL) correlates with clinical symptoms and caregiver burden, and whether self-rated and informant-rated HRQoL would correlate with each other. METHODS: Individuals were classified using the Clinical Dementia Rating (CDR® ) Scale plus National Alzheimer's Coordinating Center (NACC) FTLD. HRQoL was measured with DEMQOL and DEMQOL-proxy; caregiver burden with the Zarit Burden Interview (ZBI). For analysis, Pearson correlations and weighted kappa statistics were calculated. RESULTS: The cohort of 312 individuals included symptomatic and asymptomatic individuals. CDR® plus NACC FTLD was negatively correlated with DEMQOL (r = -0.20, P = .001), as were ZBI and DEMQOL (r = -0.22, P = .0009). There was fair agreement between subject and informant DEMQOL (κ = 0.36, P <.0001). CONCLUSION: Lower HRQoL was associated with higher cognitive/behavior impairment and higher caregiver burden. These findings demonstrate the negative impact of FTLD on individuals and caregivers.

Control of moth flight posture is mediated by wing mechanosensory feedback.

Flying insects rapidly stabilize after perturbations using both visual and mechanosensory inputs for active control. Insect halteres are mechanosensory organs that encode inertial forces to aid rapid course correction during flight but serve no aerodynamic role and are specific to two orders of insects (Diptera and Strepsiptera). Aside from the literature on halteres and recent work on the antennae of the hawkmoth Manduca sexta, it is unclear how other flying insects use mechanosensory information to control body dynamics. The mechanosensory structures found on the halteres, campaniform sensilla, are also present on wings, suggesting that the wings can encode information about flight dynamics. We show that the neurons innervating these sensilla on the forewings of M. sexta exhibit spike-timing precision comparable to that seen in previous reports of campaniform sensilla, including haltere neurons. In addition, by attaching magnets to the wings of moths and subjecting these animals to a simulated pitch stimulus via a rotating magnetic field during tethered flight, we elicited the same vertical abdominal flexion reflex these animals exhibit in response to visual or inertial pitch stimuli. Our results indicate that, in addition to their role as actuators during locomotion, insect wings serve as sensors that initiate reflexes that control body dynamics.

Flies tune the activity of their multifunctional gyroscope.

Members of the order Diptera, the true flies, are among the most maneuverable flying animals. These aerial capabilities are partially attributed to flies' possession of halteres, tiny club-shaped structures that evolved from the hindwings and play a crucial role in flight control. Halteres are renowned for acting as biological gyroscopes that rapidly detect rotational perturbations and help flies maintain a stable flight posture. Additionally, halteres provide rhythmic input to the wing steering system that can be indirectly modulated by the visual system. The multifunctional capacity of the haltere is thought to depend on arrays of embedded mechanosensors called campaniform sensilla that are arranged in distinct groups on the haltere's dorsal and ventral surfaces. Although longstanding hypotheses suggest that each array provides different information relevant to the flight control circuitry, we know little about how the haltere campaniforms are functionally organized. Here, we use in vivo calcium imaging during tethered flight to obtain population-level recordings of the haltere sensory afferents in specific fields of sensilla. We find that haltere feedback from both dorsal fields is continuously active, modulated under closed-loop flight conditions, and recruited during saccades to help flies actively maneuver. We also find that the haltere's multifaceted role may arise from the steering muscles of the haltere itself, regulating haltere stroke amplitude to modulate campaniform activity. Taken together, our results underscore the crucial role of efferent control in regulating sensor activity and provide insight into how the sensory and motor systems of flies coevolved.

Insect Flight: State of the Field and Future Directions.

The evolution of flight in an early winged insect ancestral lineage is recognized as a key adaptation explaining the unparalleled success and diversification of insects. Subsequent transitions and modifications to flight machinery, including secondary reductions and losses, also play a central role in shaping the impacts of insects on broadscale geographic and ecological processes and patterns in the present and future. Given the importance of insect flight, there has been a centuries-long history of research and debate on the evolutionary origins and biological mechanisms of flight. Here, we revisit this history from an interdisciplinary perspective, discussing recent discoveries regarding the developmental origins, physiology, biomechanics, and neurobiology and sensory control of flight in a diverse set of insect models. We also identify major outstanding questions yet to be addressed and provide recommendations for overcoming current methodological challenges faced when studying insect flight, which will allow the field to continue to move forward in new and exciting directions. By integrating mechanistic work into ecological and evolutionary contexts, we hope that this synthesis promotes and stimulates new interdisciplinary research efforts necessary to close the many existing gaps about the causes and consequences of insect flight evolution.

Mechanosensory Control of Locomotion in Animals and Robots: Moving Forward.

While animals swim, crawl, walk, and fly with apparent ease, building robots capable of robust locomotion remains a significant challenge. In this review, we draw attention to mechanosensation-the sensing of mechanical forces generated within and outside the body-as a key sense that enables robust locomotion in animals. We discuss differences between mechanosensation in animals and current robots with respect to (1) the encoding properties and distribution of mechanosensors and (2) the integration and regulation of mechanosensory feedback. We argue that robotics would benefit greatly from a detailed understanding of these aspects in animals. To that end, we highlight promising experimental and engineering approaches to study mechanosensation, emphasizing the mutual benefits for biologists and engineers that emerge from moving forward together.

Insect flight: Flies use a throttle to steer.

A new study of flight control in Drosophila using neurogenetic methods and a virtual reality flight arena has revealed a group of descending neurons that fully activate the flight motor and steer the fly by independent regulation of the left and right wings.

The ALPHA Project: Establishing consensus and prioritisation of global community recommendations to address major challenges in lupus diagnosis, care, treatment and research.

The Addressing Lupus Pillars for Health Advancement (ALPHA) Project is a global consensus effort to identify, prioritise and address top barriers in lupus impacting diagnosis, care, treatment and research. To conduct this process, the ALPHA Project convened a multistakeholder Global Advisory Committee (GAC) of lupus experts and collected input from global audiences, including patients. In phase I, the ALPHA Project used expert interviews and a global survey of lupus experts to identify and categorise barriers into three overarching pillars: drug development, clinical care and access to care. In phase II, reported here, the GAC developed recommended actionable solutions to address these previously identified barriers through an in-person stakeholder meeting, followed by a two-round scoring process. Recommendations were assessed for feasibility, impact and timeline for implementation (FIT), where potential FIT component values were between 1 and 3 and total scores were between 3 and 9. Higher scores represented higher achievability based on the composite of the three criteria. Simplifying and standardising outcomes measures, including steroid sparing as an outcome (drug development) and defining the lupus spectrum (clinical care) ranked as the highest two priority solutions during the GAC meeting and received high FIT scores (7.67 and 7.44, respectively). Leveraging social media (access to care) received the highest FIT score across all pillars (7.86). Cross-cutting themes of many solutions include leveraging digital technology and applying specific considerations for special populations, including paediatrics. Implementing the recommendations to address key barriers to drug development, clinical care and access to care is essential to improving the quality of life of adults and children with lupus. Multistakeholder collaboration and guidance across existing efforts globally is warranted.

Flies Regulate Wing Motion via Active Control of a Dual-Function Gyroscope.

Flies execute their remarkable aerial maneuvers using a set of wing steering muscles, which are activated at specific phases of the stroke cycle [1-3]. The activation phase of these muscles-which determines their biomechanical output [4-6]-arises via feedback from mechanoreceptors at the base of the wings and structures unique to flies called halteres [7-9]. Evolved from the hindwings, the tiny halteres oscillate at the same frequency as the wings, although they serve no aerodynamic function [10] and are thought to act as gyroscopes [10-15]. Like the wings, halteres possess minute control muscles whose activity is modified by descending visual input [16], raising the possibility that flies control wing motion by adjusting the motor output of their halteres, although this hypothesis has never been directly tested. Here, using genetic techniques possible in Drosophila melanogaster, we tested the hypothesis that visual input during flight modulates haltere muscle activity and that this, in turn, alters the mechanosensory feedback that regulates the wing steering muscles. Our results suggest that rather than acting solely as a gyroscope to detect body rotation, halteres also function as an adjustable clock to set the spike timing of wing motor neurons, a specialized capability that evolved from the generic flight circuitry of their four-winged ancestors. In addition to demonstrating how the efferent control loop of a sensory structure regulates wing motion, our results provide insight into the selective scenario that gave rise to the evolution of halteres.