Divergent neural circuits for proprioceptive and exteroceptive sensing of the Drosophila leg.

Somatosensory neurons provide the nervous system with information about mechanical forces originating inside and outside the body. Here, we use connectomics to reconstruct and analyze neural circuits downstream of the largest somatosensory organ in the Drosophila leg, the femoral chordotonal organ (FeCO). The FeCO has been proposed to support both proprioceptive sensing of the fly's femur-tibia joint and exteroceptive sensing of substrate vibrations, but it remains unknown which sensory neurons and central circuits contribute to each of these functions. We found that different subtypes of FeCO sensory neurons feed into distinct proprioceptive and exteroceptive pathways. Position- and movement-encoding FeCO neurons connect to local leg motor control circuits in the ventral nerve cord (VNC), indicating a proprioceptive function. In contrast, signals from the vibration-encoding FeCO neurons are integrated across legs and transmitted to auditory regions in the brain, indicating an exteroceptive function. Overall, our analyses reveal the structure of specialized circuits for processing proprioceptive and exteroceptive signals from the fly leg. They also demonstrate how analyzing patterns of synaptic connectivity can distill organizing principles from complex sensorimotor circuits.

Development of Upper Extremity Deep Vein Thrombosis in a Patient With Seronegative Myasthenia Gravis: A Case Report and Review of Literature.

We present the case report of a patient with seronegative myasthenia gravis (MG) who was admitted for metabolic encephalopathy and acute on chronic hypoxic respiratory failure secondary to an MG crisis three days after an intravenous immunoglobulin treatment. In the intensive care unit, her MG was managed with intravenous immunoglobulin, plasmapheresis, prednisone, and pyridostigmine. During the course of her visit, she had urosepsis along with a left chest port that had cultured positive for Pseudomonas aeruginosa and developed a right upper extremity deep vein thrombosis (UEDVT) and superficial thrombosis in the left upper extremity despite being on heparin therapy. She had a transient drop in platelets to below 150,000 that resolved within a day. We analyzed the variables of this case report and reviewed the literature of similar cases to elucidate the factors that may have led to the development of the UEDVTs. The patient had many factors in her past medical history that could have contributed to her thrombosis including morbid obesity and prior history of pulmonary embolisms. It is hypothesized that MG disturbs the endothelial cell lining through an increased inflammatory state that could also be a causative factor. There is no definitive way we could link MG as a causative factor due to a lack of testing to assess alteration in the integrity or functionality of her endothelium. A case report we reviewed showed a presentation of UEDVT in an MG patient due to a thymoma compressing the subclavian vein. However, this is not the case in this example due to the patient having a history of thymectomy. She was also at risk due to her hospital stay which led to immobility and placement of a central venous catheter. We conclude the formation of the UEDVT was likely a combination of these factors.

A methodological review of randomised n-of-1 trials.

BACKGROUND: n-of-1 trials are a type of crossover trial designed to optimise the evaluation of health technologies in individual patients. This trial design may be considered for the evaluation of health technologies in rare conditions where fewer patients are available to take part in research. This review describes the characteristics of randomised n-of-1 trials conducted over the span of 12 years, including how the n-of-1 design has been employed to study both rare and non-rare conditions. METHODS: Databases and clinical trials registries were searched for articles including "n-of-1" in the title between 2011 and 2023. The reference lists of reviews identified by the searches were searched for any additional eligible articles. Randomised n-of-1 trials were selected for inclusion and data were extracted on a range of design, population, and analysis characteristics. Descriptive statistics were produced for all variables. RESULTS: We identified 74 studies meeting our eligibility criteria, 13 of which (17.6%) were conducted in rare conditions. They were conducted in a range of clinical areas with the most common being neurological conditions (n = 16, 21.6%). The median (Q1, Q3) number of participants randomised was 9 (4, 20) and 12 trials (16.2%) involved a single patient only. Forty-six (62.2%) trials evaluated pharmaceutical interventions and 49 (66.2%) trials were placebo controlled. Trials had a median (Q1, Q3) of six (4, 8) periods and 61 (82.4%) compared two health technologies. Fifty-seven (77.0%) trials incorporated blinding and 32 (43.2%) had a washout period. Forty-nine trials (66.2%) used patient-reported outcome measures (PROMs) to assess the primary outcome. Trials used a range of approaches to analysis and 48 (64.9%) combined data from multiple patients. The characteristics of the n-of-1 trials conducted in rare conditions were generally consistent with those in non-rare conditions. CONCLUSIONS: n-of-1 trials are still underused and the application of the n-of-1 design for the evaluation of health technologies for rare diseases has been particularly limited. We have summarised the characteristics of randomised n-of-1 trials in rare and non-rare conditions. We hope that it can inform researchers in the design of future n-of-1 studies. Further work is required to provide guidance on specific design considerations, implementation, and statistical analysis of these studies. TRIAL REGISTRATION: Not applicable.

Revisiting the anatomy of the left ventricle in the light of knowledge of its development.

Despite centuries of investigation, certain aspects of left ventricular anatomy remain either controversial or uncertain. We make no claims to have resolved these issues, but our review, based on our current knowledge of development, hopefully identifies the issues requiring further investigation. When first formed, the left ventricle had only inlet and apical components. With the expansion of the atrioventricular canal, the developing ventricle cedes part of its inlet to the right ventricle whilst retaining the larger parts of the cushions dividing the atrioventricular canal. Further remodelling of the interventricular communication provides the ventricle with its outlet, with the aortic root being transferred to the left ventricle along with the newly formed myocardium supporting its leaflets. The definitive ventricle possesses inlet, apical and outlet parts. The inlet component is guarded by the mitral valve, with its leaflets, in the normal heart, supported by papillary muscles located infero-septally and supero-laterally. There is but a solitary zone of apposition between the leaflets, which we suggest are best described as being aortic and mural. The trabeculated component extends beyond the inlet to the apex and is confluent with the outlet part, which supports the aortic root. The leaflets of the aortic valve are supported in semilunar fashion within the root, with the ventricular cavity extending to the sinutubular junction. The myocardial-arterial junction, however, stops well short of the sinutubular junction, with myocardium found only at the bases of the sinuses, giving rise to the coronary arteries. We argue that the relationships between the various components should now be described using attitudinally appropriate terms rather than describing them as if the heart is removed from the body and positioned on its apex.

Left atrial appendage inversion: First computational study to shed light on the phenomenon.

Inversion of the left atrial appendage is a rare phenomenon, which may occur during the de-airing maneuvers associated to routinely performed surgery procedures, such as cardiopulmonary bypass or left ventricular assist device implantation. In this case, the body of the inverted appendage can obstruct the mitral valve leading to severe complications. The mechanisms are still poorly known, and more specific studies are needed to better understand its causes and identify mitigating strategies. The current study attempts to gain a better comprehension of the conditions and the factors favourable to left atrial appendage inversion. Four patient specific appendage morphologies, obtained from computerised tomography and representative of the main typologies commonly used for the appendage classification (chicken wing, cactus, cauliflower, and windsock), were used for the study. The numerical models were subjected to the same loading pattern, made of subsequent different pressure curves. Results show that the morphologies invert and recover their original anatomical configuration at different pressure loads, indicating that their tendency to invert is associated to their specific morphological features. Moreover, the analysis highlights that, although restoring the physiological left atrium pressure is not sufficient to induce appendage recovery, pressures well below the ventricular ones can induce the return to the natural configuration. All models recovered the anatomical configuration at pressures well below the ventricular pressure (about 100 mmHg), suggesting that basic trans-catheter maneuvers, e.g. producing temporary mitral regurgitation, could be attempted to correct the appendage configuration, prior to opt for more invasive surgical approaches.

Facultatively ectoparasitic mites as vectors for entomopathogenic bacteria in Drosophila.

Opportunistic bacterial infections are common in insect populations but there is little information on how they are acquired or transmitted. We tested the hypothesis that Macrocheles mites can transmit systemic bacterial infections between Drosophila hosts. We found that 24% of mites acquired detectable levels of bacteria after feeding on infected flies and 87% of infected mites passed bacteria to naïve recipient flies. The probability that a mite could pass Serratia from an infected donor fly to a naïve recipient fly was 27.1%. These data demonstrate that Macrocheles mites are capable of serving as vectors of bacterial infection between insects.

Editor's Choice - Comparison of Open Surgery and Endovascular Techniques for Juxtarenal and Complex Neck Aortic Aneurysms: The UK COMPlex AneurySm Study (UK-COMPASS) - Peri-operative and Midterm Outcomes.

OBJECTIVE: Treatment of juxtarenal and complex neck abdominal aortic aneurysms (AAAs) is now commonly by endovascular rather than open surgical repair (OSR). Published comparisons show poor validity and scientific precision. UK-COMPASS is a comparative cohort study of endovascular treatments vs. OSR for patients with an AAA unsuitable for standard on label endovascular aneurysm repair (EVAR). METHODS: All procedures for AAA in England (November 2017 to October 2019) were identified, AAA anatomy assessed in a Corelab, peri-operative risk scores determined, and propensity scoring used to identify patients suitable for either endovascular treatment or OSR. Patients were stratified by aneurysm neck length (0 - 4 mm, 5 - 9 mm, or ≥ 10 mm) and operative risk; the highest quartile was considered high risk and the remainder standard risk. Death was the primary outcome measure. Endovascular treatments included fenestrated EVAR (FEVAR) and off label standard EVAR (± adjuncts). RESULTS: Among 8 994 patients, 2 757 had AAAs that were juxtarenal, short neck, or complex neck in morphology. Propensity score stratification and adjustment method comparisons included 1 916 patients. Widespread off label use of standard EVAR devices was noted (35.6% of patients). The adjusted peri-operative mortality rate was 2.9%, lower for EVAR (1.2%; p = .001) and FEVAR (2.2%; p = .001) than OSR (4.5%). In standard risk patients with a 0 - 4 mm neck, the mortality rate was 7.4% following OSR and 2.3% following FEVAR. Differences were smaller for patients with a neck length ≥ 5 mm: 2.1% OSR vs. 1.0% FEVAR. At 3.5 years of follow up, the overall mortality rate was 20.7% in the whole study population, higher following FEVAR (27.6%) and EVAR (25.2%) than after OSR (14.2%). However, in the 0 - 4 mm neck subgroup, overall survival remained equivalent. The aneurysm related mortality rate was equivalent between treatments, but re-intervention was more common after EVAR and FEVAR than OSR. CONCLUSION: FEVAR proves notably safer than OSR in the peri-operative period for juxtarenal aneurysms (0 - 4 mm neck length), with comparable midterm survival. For patients with short neck (5 - 9 mm) and complex neck (≥ 10 mm) AAAs, overall survival was worse in endovascularly treated patients compared with OSR despite relative peri-operative safety. This warrants further research and a re-appraisal of the current clinical application of endovascular strategies, particularly in patients with poor general survival outlook owing to comorbidity and age.

Effect of f-element complexation on the radiolysis of 2-ethylhexylphosphonic acid mono-2-ethylhexyl ester (HEH[EHP]).

A systematic study of the impact on the chemical reactivity of the oxidising n-dodecane radical cation (RH˙+) with f-element complexed 2-ethylhexylphosphonic acid mono-2-ethylhexyl ester (HEH[EHP]) has been undertaken utilizing time-resolved electron pulse radiolysis/transient absorption spectroscopy and high-level quantum mechanical calculations. Lanthanide ion complexed species, [Ln((HEH[EHP])2)3], exhibited vastly increased reactivity (over 10× faster) in comparison to the non-complexed ligand in n-dodecane solvent, whose rate coefficient was k = (4.66 ± 0.22) × 109 M-1 s-1. Similar reactivity enhancement was also observed for the corresponding americium ion complex, k = (5.58 ± 0.30) × 1010 M-1 s-1. The vastly increased reactivity of these f-element complexes was not due to simple increased diffusion-control of these reactions; rather, enhanced hole transfer mechanisms for the complexes were calculated to become energetically more favourable. Interestingly, the observed reactivity trend with lanthanide ion size was not linear; instead, the rate coefficients showed an initial increase (Lu to Yb) followed by a decrease (Tm to Ho), followed by another increase (Dy to La). This behaviour was excellently predicted by the calculated reaction volumes of these complexes. Complementary cobalt-60 gamma irradiations for select lanthanide complexes demonstrated that the measured kinetic differences translated to increased ligand degradation at steady-state timescales, affording ∼38% increase in ligand loss of a 1 : 1 [La((HEH[EHP])2)3] : HEH[EHP] ratio system.

Organization of an ascending circuit that conveys flight motor state in Drosophila.

Natural behaviors are a coordinated symphony of motor acts that drive reafferent (self-induced) sensory activation. Individual sensors cannot disambiguate exafferent (externally induced) from reafferent sources. Nevertheless, animals readily differentiate between these sources of sensory signals to carry out adaptive behaviors through corollary discharge circuits (CDCs), which provide predictive motor signals from motor pathways to sensory processing and other motor pathways. Yet, how CDCs comprehensively integrate into the nervous system remains unexplored. Here, we use connectomics, neuroanatomical, physiological, and behavioral approaches to resolve the network architecture of two pairs of ascending histaminergic neurons (AHNs) in Drosophila, which function as a predictive CDC in other insects. Both AHN pairs receive input primarily from a partially overlapping population of descending neurons, especially from DNg02, which controls wing motor output. Using Ca2+ imaging and behavioral recordings, we show that AHN activation is correlated to flight behavior and precedes wing motion. Optogenetic activation of DNg02 is sufficient to activate AHNs, indicating that AHNs are activated by descending commands in advance of behavior and not as a consequence of sensory input. Downstream, each AHN pair targets predominantly non-overlapping networks, including those that process visual, auditory, and mechanosensory information, as well as networks controlling wing, haltere, and leg sensorimotor control. These results support the conclusion that the AHNs provide a predictive motor signal about wing motor state to mostly non-overlapping sensory and motor networks. Future work will determine how AHN signaling is driven by other descending neurons and interpreted by AHN downstream targets to maintain adaptive sensorimotor performance.

Fluid-structure interaction analysis of the thromboembolic risk in the left atrial appendage under atrial fibrillation: Effect of hemodynamics and morphological features.

BACKGROUND: Complications of atrial fibrillation (AF) include ischemic events originating within the left atrial appendage (LAA), a protrusion of the left atrium with variable morphological characteristics. The role of the patient specific morphology and pathological haemodynamics on the risk of ischemia remains unclear. METHODS: This work performs a comparative assessment of the hemodynamic parameters among patient-specific LAA morphologies through fluid-structure interaction computational analyses. Three LAA models per each of the four commons patient-specific morphological families (chicken wing, cactus, windsock, and cauliflower) were analysed. Mechanical properties of the tissue were based on experimental uniaxial tests on a young pig's heart. Boundary conditions were imposed based on clinical assessments of filling and emptying volumes. Sinus rhythm and atrial fibrillation operative conditions were simulated and analysed. RESULTS: For each model, the effect of morphological and functional parameters, such as the number of trabeculae and LAA stroke volume, over the hemodynamics established into the appendage was analysed. Comparison between results obtained in healthy and diseased conditions suggested the introduction of a new parameter to quantify the risk of thrombosis, here called blood stasis factor (BSF). This is defined as the LAA surface area which permanently experiences levels of shear strain rate inferior to a threshold value, set to 5 s-1 (BSF5). CONCLUSIONS: This work suggests that the current morphological classification is unsuitable to evaluate the probability of thrombus formation. However, hemodynamic parameters easy to determine from clinical examinations, such as normalised stroke volume, LAA orifice flow rate and presence of extensive trabeculations can identify departures from healthy hemodynamics in AF and support a more systematic stratification of the thromboembolic risk.

Chemical Kinetics for the Oxidation of Californium(III) Ions with Select Radiation-Induced Inorganic Radicals (Cl2•- and SO4•-).

Despite the availability of transuranic elements increasing in recent years, our understanding of their most basic and inherent radiation chemistry is limited and yet essential for the accurate interpretation of their physical and chemical properties. Here, we explore the transient interactions between trivalent californium ions (Cf3+) and select inorganic radicals arising from the radiolytic decomposition of common anions and functional group constituents, specifically the dichlorine (Cl2•-) and sulfate (SO4•-) radical anions. Chemical kinetics, as measured using integrated electron pulse radiolysis and transient absorption spectroscopy techniques, are presented for the reactions of these two oxidizing radicals with Cf3+ ions. The derived and ionic strength-corrected second-order rate coefficients (k) for these radiation-induced processes are k(Cf3+ + Cl2•-) = (8.28 ± 0.61) × 105 M-1 s-1 and k(Cf3+ + SO4•-) = (9.50 ± 0.43) × 108 M-1 s-1 under ambient temperature conditions (22 ± 1 °C).

The IDEAL framework for surgical robotics: development, comparative evaluation and long-term monitoring.

The next generation of surgical robotics is poised to disrupt healthcare systems worldwide, requiring new frameworks for evaluation. However, evaluation during a surgical robot's development is challenging due to their complex evolving nature, potential for wider system disruption and integration with complementary technologies like artificial intelligence. Comparative clinical studies require attention to intervention context, learning curves and standardized outcomes. Long-term monitoring needs to transition toward collaborative, transparent and inclusive consortiums for real-world data collection. Here, the Idea, Development, Exploration, Assessment and Long-term monitoring (IDEAL) Robotics Colloquium proposes recommendations for evaluation during development, comparative study and clinical monitoring of surgical robots-providing practical recommendations for developers, clinicians, patients and healthcare systems. Multiple perspectives are considered, including economics, surgical training, human factors, ethics, patient perspectives and sustainability. Further work is needed on standardized metrics, health economic assessment models and global applicability of recommendations.

The Brescia Internationally Validated European Guidelines on Minimally Invasive Pancreatic Surgery (EGUMIPS).

OBJECTIVE: To develop and update evidence-based and consensus-based guidelines on laparoscopic and robotic pancreatic surgery. SUMMARY BACKGROUND DATA: Minimally invasive pancreatic surgery (MIPS), including laparoscopic and robotic surgery, is complex and technically demanding. Minimizing the risk for patients requires stringent, evidence-based guidelines. Since the International Miami Guidelines on MIPS in 2019, new developments and key publications have been reported, necessitating an update. METHODS: Evidence-based guidelines on 22 topics in 8 domains were proposed: terminology, indications, patients, procedures, surgical techniques and instrumentation, assessment tools, implementation and training, and artificial intelligence. The Brescia Internationally Validated European Guidelines on Minimally Invasive Pancreatic Surgery (EGUMIPS, September 2022) used the Scottish Intercollegiate Guidelines Network (SIGN) methodology to assess the evidence and develop guideline recommendations, the Delphi method to establish consensus on the recommendations among the Expert Committee, and the AGREE II-GRS tool for guideline quality assessment and external validation by a Validation Committee. RESULTS: Overall, 27 European experts, 6 international experts, 22 international Validation Committee members, 11 Jury Committee members, 18 Research Committee members, and 121 registered attendees of the 2-day meeting were involved in the development and validation of the guidelines. In total, 98 recommendations were developed, including 33 on laparoscopic, 34 on robotic, and 31 on general MIPS, covering 22 topics in 8 domains. Out of 98 recommendations, 97 reached at least 80% consensus among the experts and congress attendees, and all recommendations were externally validated by the Validation Committee. CONCLUSIONS: The EGUMIPS evidence-based guidelines on laparoscopic and robotic MIPS can be applied in current clinical practice to provide guidance to patients, surgeons, policy-makers, and medical societies.

Nowhere coexpanding functions.

We define a family of C1 functions, which we call "nowhere coexpanding functions," that is closed under composition and includes all C3 functions with non-positive Schwarzian derivatives. We establish results on the number and nature of the fixed points of these functions, including a generalization of a classic result of Singer.

Presynaptic inhibition selectively suppresses leg proprioception in behaving Drosophila.

The sense of proprioception is mediated by internal mechanosensory neurons that detect joint position and movement. To support a diverse range of functions, from stabilizing posture to coordinating movements, proprioceptive feedback to limb motor control circuits must be tuned in a context-dependent manner. How proprioceptive feedback signals are tuned to match behavioral demands remains poorly understood. Using calcium imaging in behaving Drosophila, we find that the axons of position-encoding leg proprioceptors are active across behaviors, whereas the axons of movement-encoding leg proprioceptors are suppressed during walking and grooming. Using connectomics, we identify a specific class of interneurons that provide GABAergic presynaptic inhibition to the axons of movement-encoding proprioceptors. These interneurons are active during self-generated but not passive leg movements and receive input from descending neurons, suggesting they are driven by predictions of leg movement originating in the brain. Predictively suppressing expected proprioceptive feedback provides a mechanism to attenuate reflexes that would otherwise interfere with voluntary movement.

The Atrioventricular Conduction Axis Revisited for the 21st Century.

Although first described in the final decade of the 19th century, the axis responsible for atrioventricular conduction has long been the source of multiple controversies. Some of these continue to reverberate. When first described by His, for example, many doubted the existence of the bundle we now name in his honour, while Kent suggested that multiple pathways crossed the atrioventricular junctions in the normal heart. It was Tawara who clarified the situation, although many of his key definitions have not universally been accepted. In key studies in the third decade of the 20th century, Mahaim then suggested the presence of ubiquitous connections that provided "paraspecific" pathways for atrioventricular conduction. In this review, we show the validity of these original investigations, based on our own experience with a large number of datasets from human hearts prepared by serial histological sectioning. Using our own reconstructions, we show how the atrioventricular conduction axis can be placed back within the heart. We emphasise that newly emerging techniques will be key in providing the resolution to map cellular detail to the gross evidence provided by the serial sections.

Appropriate design and reporting of superiority, equivalence and non-inferiority clinical trials incorporating a benefit-risk assessment: the BRAINS study including expert workshop.

Background: Randomised controlled trials are designed to assess the superiority, equivalence or non-inferiority of a new health technology, but which trial design should be used is not always obvious in practice. In particular, when using equivalence or non-inferiority designs, multiple outcomes of interest may be important for the success of a trial, despite the fact that usually only a single primary outcome is used to design the trial. Benefit-risk methods are used in the regulatory clinical trial setting to assess multiple outcomes and consider the trade-off of the benefits against the risks, but are not regularly implemented in publicly funded trials. Objectives: The aim of the project is to aid the design of clinical trials with multiple outcomes of interest by defining when each trial design is appropriate to use and identifying when to use benefit-risk methods to assess outcome trade-offs (qualitatively or quantitatively) in a publicly funded trial setting. Methods: A range of methods was used to elicit expert opinion to answer the project objectives, including a web-based survey of relevant researchers, a rapid review of current literature and a 2-day consensus workshop of experts (in 2019). Results: We created a list of 19 factors to aid researchers in selecting the most appropriate trial design, containing the following overarching sections: population, intervention, comparator, outcomes, feasibility and perspectives. Six key reasons that indicate a benefit-risk method should be considered within a trial were identified: (1) when the success of the trial depends on more than one outcome; (2) when important outcomes within the trial are in competing directions (i.e. a health technology is better for one outcome, but worse for another); (3) to allow patient preferences to be included and directly influence trial results; (4) to provide transparency on subjective recommendations from a trial; (5) to provide consistency in the approach to presenting results from a trial; and (6) to synthesise multiple outcomes into a single metric. Further information was provided to support the use of benefit-risk methods in appropriate circumstances, including the following: methods identified from the review were collated into different groupings and described to aid the selection of a method; potential implementation of methods throughout the trial process were provided and discussed (with examples); and general considerations were described for those using benefit-risk methods. Finally, a checklist of five pieces of information that should be present when reporting benefit-risk methods was defined, with two additional items specifically for reporting the results. Conclusions: These recommendations will assist research teams in selecting which trial design to use and deciding whether or not a benefit-risk method could be included to ensure research questions are answered appropriately. Additional information is provided to support consistent use and clear reporting of benefit-risk methods in the future. The recommendations can also be used by funding committees to confirm that appropriate considerations of the trial design have been made. Limitations: This research was limited in scope and should be considered in conjunction with other trial design methodologies to assess appropriateness. In addition, further research is needed to provide concrete information about which benefit-risk methods are best to use in publicly funded trials, along with recommendations that are specific to each method. Study registration: The rapid review is registered as PROSPERO CRD42019144882. Funding: Funded by the Medical Research Council UK and the National Institute for Health and Care Research as part of the Medical Research Council-National Institute for Health and Care Research Methodology Research programme.

Randomised controlled trials are considered the best way to gather evidence about potential NHS treatments. They can be designed from different perspectives depending whether the aim is to show that a new treatment is better than, equal to or no worse than the current best available treatment. The selection of this design relates to the single most important outcome; however, often multiple outcomes can be affected by a treatment. For example, a new treatment may improve disease management but increase side effects. Patients want a treatment to work but not at the price of poor quality of life; therefore, a trade-off must be made, and the recommended treatment depends on this trade-off. Benefit­risk methods can assess the trade-off between multiple outcomes and can include patient preference. These methods could improve the way that decisions are made about treatments in the NHS, but there is currently limited research about the use of these methods in publicly funded trials. The aim of this report is to improve the design of clinical trials by helping researchers to select the most appropriate trial design and to decide when to include a benefit­risk method. The recommendations were created using the opinions of experts within the field and consisted of a survey, review of the literature and a workshop. The project created a list of 19 factors that can assist researchers to select the most appropriate trial design. Furthermore, six key areas were identified in which researchers may consider including a benefit­risk method within a trial. Finally, if a benefit­risk assessment is being used, a checklist of items has been created that identifies the information important to include in reports. This report is, however, limited in its applicability and further research should extend this work, as well as provide more detail on individual methods that are available.