A tailored psychological intervention for anxiety and depression management in people with chronic obstructive pulmonary disease: TANDEM RCT and process evaluation.

Background: People with chronic obstructive pulmonary disease have high levels of anxiety and depression, which is associated with increased morbidity and poor uptake of effective treatments, such as pulmonary rehabilitation. Cognitive-behavioural therapy improves mental health of people with long-term conditions and could potentially increase uptake of pulmonary rehabilitation, enabling synergies that could enhance the mental health of people with chronic obstructive pulmonary disease. Aim: Our aim was to develop and evaluate the clinical effectiveness and cost effectiveness of a tailored cognitive-behavioural approach intervention, which links into, and optimises the benefits of, routine pulmonary rehabilitation. Design: We carried out a pragmatic multicentre randomised controlled trial using a 1.25 : 1 ratio (intervention : control) with a parallel process evaluation, including assessment of fidelity. Setting: Twelve NHS trusts and five Clinical Commissioning Groups in England were recruited into the study. The intervention was delivered in participant's own home or at a local NHS facility, and by telephone. Participants: Between July 2017 and March 2020 we recruited adults with moderate/very severe chronic obstructive pulmonary disease and mild/moderate anxiety and/or depression, meeting eligibility criteria for assessment for pulmonary rehabilitation. Carers of participants were invited to participate. Intervention: The cognitive-behavioural approach intervention (i.e. six to eight 40- to 60-minute sessions plus telephone support throughout pulmonary rehabilitation) was delivered by 31 trained respiratory healthcare professionals to participants prior to commencing pulmonary rehabilitation. Usual care included routine pulmonary rehabilitation referral. Main outcome measures: Co-primary outcomes were Hospital Anxiety and Depression Scale - anxiety and Hospital Anxiety and Depression Scale - depression at 6 months post randomisation. Secondary outcomes at 6 and 12 months included health-related quality of life, smoking status, uptake of pulmonary rehabilitation and healthcare use. Results: We analysed results from 423 randomised participants (intervention, n = 242; control, n = 181). Forty-three carers participated. Follow-up at 6 and 12 months was 93% and 82%, respectively. Despite good fidelity for intervention delivery, mean between-group differences in Hospital Anxiety and Depression Scale at 6 months ruled out clinically important effects (Hospital Anxiety and Depression Scale - anxiety mean difference -0.60, 95% confidence interval -1.40 to 0.21; Hospital Anxiety and Depression Scale - depression mean difference -0.66, 95% confidence interval -1.39 to 0.07), with similar results at 12 months. There were no between-group differences in any of the secondary outcomes. Sensitivity analyses did not alter these conclusions. More adverse events were reported for intervention participants than for control participants, but none related to the trial. The intervention did not generate quality-of-life improvements to justify the additional cost (adjusted mean difference £770.24, 95% confidence interval -£27.91 to £1568.39) to the NHS. The intervention was well received and many participants described positive affects on their quality of life. Facilitators highlighted the complexity of participants' lives and considered the intervention to be of potential valuable; however, the intervention would be difficult to integrate within routine clinical services. Our well-powered trial delivered a theoretically designed intervention with good fidelity. The respiratory-experienced facilitators were trained to deliver a low-intensity cognitive-behavioural approach intervention, but high-intensity cognitive-behavioural therapy might have been more effective. Our broad inclusion criteria specified objectively assessed anxiety and/or depression, but participants were likely to favour talking therapies. Randomisation was concealed and blinding of outcome assessment was breached in only 15 participants. Conclusions: The tailored cognitive-behavioural approach intervention delivered with fidelity by trained respiratory healthcare professionals to people with chronic obstructive pulmonary disease was neither clinically effective nor cost-effective. Alternative approaches that are integrated with routine long-term condition care are needed to address the unmet, complex clinical and psychosocial needs of this group of patients. Trial registration: This trial is registered as ISRCTN59537391. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/146/02) and is published in full in Health Technology Assessment; Vol. 28, No. 1. See the NIHR Funding and Awards website for further award information.

People with long-standing lung problems, such as chronic obstructive pulmonary disease, often also have anxiety and depression, which further reduces their quality of life. Two existing treatments could help. Pulmonary rehabilitation (a programme of exercise and education) improves both the physical and mental health of people with chronic obstructive pulmonary disease. Cognitive­behavioural therapy (a talking therapy) may reduce anxiety and depression. The TANDEM [Tailored intervention for Anxiety and Depression Management in chronic obstructive pulmonary disease (COPD)] intervention linked these two treatments by providing talking therapy based on cognitive­behavioural therapy during the waiting time following referral for pulmonary rehabilitation. The TANDEM treatment was delivered by respiratory healthcare professionals (e.g. nurses or physiotherapists) trained to deliver the talking therapy in six to eight weekly sessions. The sessions were conducted in the participant's home (or another convenient location), with brief telephone support during the pulmonary rehabilitation. Of 423 participants recruited to the study, 242 participants received TANDEM talking therapy and 181 participants received usual care (including a referral to pulmonary rehabilitation). We measured mental health, quality of life, social life, attendance at pulmonary rehabilitation and healthcare use in both groups at 6 and 12 months. Forty-three carers joined the study and we assessed their mental well-being. We interviewed patients, carers and health professionals to find out their views and experience of the TANDEM treatment. We also examined whether or not the TANDEM treatment was good value for money. The TANDEM treatment did not improve the mental or the physical health of people with chronic obstructive pulmonary disease. In addition, the TANDEM treatment cost the NHS an extra £770 per patient, which was not good value for money. The TANDEM treatment was well received, and many participants told us how it had helped them. Heath-care professionals noted how participants did not just have chronic obstructive pulmonary disease, but were coping with many physical, mental and social problems. The TANDEM intervention was not effective and, therefore, other strategies will be needed to help people with chronic obstructive pulmonary disease and mental health problems live with their condition.

A new species of Austrocypraea (Mollusca, Gastropoda, Cypraeidae) from the Pliocene of Flinders Island, Tasmania.

A new morphologically distinct species of cowry (family Cypraeidae Rafinesque, 1815) is described from the Pliocene of Flinders Island, Tasmania. Austrocypraeajimgracei sp. nov. differs morphologically from other members of the genus and is particularly characterised by the development of a heavily callused labral margin, with a distinct marginal edge that bends up towards the dorsum centrally. This feature is unique within the genus. The new taxon is only the second known Austrocypraea from the Pliocene. A revised key to the known Austrocypraea fossil species is presented.

COVID-19: UK frontline intensivists' emerging learning.

The Intensive Care Society held a webinar on 3 April 2020 at which representatives from 11 of the most COVID-19 experienced hospital trusts in England and Wales shared learning around five specific topic areas in an open forum. This paper summarises the emerging learning and practice shared by those frontline clinicians.

Blinded Comparative Review of Lubricants Commonly Used for Split-Thickness Skin Graft Harvest.

Lubricating agents facilitate effective harvesting of split-thickness skin grafts. Multiple agents, including water-based gel, mineral oil, glycerin, and poloxamer 188, have been utilized in this capacity. The agent selected is typically at the discretion of the provider and institution, as a single "ideal" lubricant remains to be objectively established. Furthermore, a recent discontinuation of Shur-Clens® Skin Wound Cleanser1 (a wound cleansing solution consisting of the surfactant poloxamer 188) has prompted the search for a suitable substitute for many providers. The purpose of this study is to directly compare five lubricants (including a novel surgical lubricant-based solution) to select a preferred agent. Four practitioners blindly tested five lubricants while harvesting a split-thickness skin graft on a porcine skin model (glycerin, mineral oil, saline, poloxamer 188, and a novel lubricant solution created with surgical lube and sterile water). The results were recorded on a Likert scale where 1 indicated poor performance and 5 indicated excellent performance. Data were pooled, and means were compared with analysis of variance and post hoc Tukey test. The cost of each lubricating solution was also reported. Mean scores for each of the solutions were as follows: dry control = 1.1 ± 0.1; glycerin = 2.62 ± 1.02, saline = 3.88 ± 0.81, mineral oil = 3.75 ± 1.00, novel water-based lubricant solution = 4.63 ± 0.71, and poloxamer 188 = 3.88 ± 0.81. All solutions were superior to dry control (P < .01). Glycerin was noted to have statistically lower scores than all of the other solutions (P < .01). The novel water-based surgical lubricant solution had significantly higher mean scores than both glycerin (P < .01) and mineral oil (P < .05). Each solution was compared according to dollars per 100cc with glycerin and Shur-Clens® representing the most expensive options at almost $3/100cc and saline the least expensive at less than $0.15/100cc. In a porcine skin model, the novel water-based surgical lubricant solution had the best performance. It was statistically superior to glycerin and mineral oil and was also found to be the most cost-effective option in terms of overall performance compared with relative cost. Glycerin had the worst performance with statistically lower scores than all other solutions. Glycerin was also found to be the least cost-effective due to a large discrepancy between high cost and low overall performance. Saline performed better than expected. These results may be skewed due to the inherently greasy nature of the butcher shop porcine skin, creating limitations and decreasing the fidelity of the model. In a search for the "ideal" lubricant, other models should be further studied.

Recommended approaches to the scientific evaluation of ecotoxicological hazards and risks of endocrine-active substances.

A SETAC Pellston Workshop® "Environmental Hazard and Risk Assessment Approaches for Endocrine-Active Substances (EHRA)" was held in February 2016 in Pensacola, Florida, USA. The primary objective of the workshop was to provide advice, based on current scientific understanding, to regulators and policy makers; the aim being to make considered, informed decisions on whether to select an ecotoxicological hazard- or a risk-based approach for regulating a given endocrine-disrupting substance (EDS) under review. The workshop additionally considered recent developments in the identification of EDS. Case studies were undertaken on 6 endocrine-active substances (EAS-not necessarily proven EDS, but substances known to interact directly with the endocrine system) that are representative of a range of perturbations of the endocrine system and considered to be data rich in relevant information at multiple biological levels of organization for 1 or more ecologically relevant taxa. The substances selected were 17α-ethinylestradiol, perchlorate, propiconazole, 17ß-trenbolone, tributyltin, and vinclozolin. The 6 case studies were not comprehensive safety evaluations but provided foundations for clarifying key issues and procedures that should be considered when assessing the ecotoxicological hazards and risks of EAS and EDS. The workshop also highlighted areas of scientific uncertainty, and made specific recommendations for research and methods-development to resolve some of the identified issues. The present paper provides broad guidance for scientists in regulatory authorities, industry, and academia on issues likely to arise during the ecotoxicological hazard and risk assessment of EAS and EDS. The primary conclusion of this paper, and of the SETAC Pellston Workshop on which it is based, is that if data on environmental exposure, effects on sensitive species and life-stages, delayed effects, and effects at low concentrations are robust, initiating environmental risk assessment of EDS is scientifically sound and sufficiently reliable and protective of the environment. In the absence of such data, assessment on the basis of hazard is scientifically justified until such time as relevant new information is available. Integr Environ Assess Manag 2017;13:267-279. © 2017 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Ecotoxicological hazard and risk assessment of endocrine active substances.

This collection of papers provides state-of-the-art science on a complex topic that has been challenging for scientists and regulators for a long time. The papers emanated from the Society of Environmental Toxicology and Chemistry (SETAC) Pellston Workshop® Environmental Hazard and Risk Assessment Approaches for Endocrine-Active Substances (EHRA). Forty-eight international experts met in early February 2016 to discuss whether the environmental risks posed by endocrine-disrupting substances (EDS) can be reliably assessed. The primary conclusion of the workshop was that if data on environmental exposure, effects on sensitive species and life-stages, delayed effects, and effects at low concentrations are robust, initiating environmental risk assessment of EDS is scientifically sound and reliable. Integr Environ Assess Manag 2017;13:264-266. © 2016 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Safety of TeaCrine®, a non-habituating, naturally-occurring purine alkaloid over eight weeks of continuous use.

BACKGROUND: Theacrine (1,3,7,9-tetramethyluric acid) is a purine alkaloid found in certain coffee (Coffea) species, fruits (Cupuacu [Theobroma grandiflorum]), and tea (Camellia assamica, var. kucha) that has anti-inflammatory, analgesic, and neuro-locomotor properties. Recent preliminary research has also reported increased feelings of energy, reduced fatigue, and strong effects on improving focus, concentration, and motivation to exercise. The purpose of this study was to examine the safety and non-habituating effects of TeaCrine®, a nature-identical, chemically equivalent bioactive version of theacrine. METHODS: Sixty healthy men (mean ± SD age, height, weight: 22.9 ± 4.7 years, 183.5 ± 9.2 cm, 86.5 ± 13.7 kg) and women (22.3 ± 4.5 years, 165.2 ± 12.3 cm, 69.0 ± 17.4 kg) were placed into one of three groups: placebo (PLA, n = 20), 200 mg TeaCrine® (LD, n = 19) or 300 mg Teacrine® (HD, n = 21) and ingested their respective supplement once daily for 8 weeks. Primary outcomes were fasting clinical safety markers (heart rate, blood pressure, lipid profiles, hematologic blood counts, biomarkers of liver/kidney/immune function) and energy, focus, concentration, anxiety, motivation to exercise, and POMS measured prior to daily dosing to ascertain potential tachyphylactic responses and habituation effects. Data were analyzed via two-way (group × time) ANOVAs and statistical significance was accepted at p < 0.05. RESULTS: All values for clinical safety markers fell within normal limits and no group × time interactions were noted. No evidence of habituation was noted as baseline values for energy, focus, concentration, anxiety, motivation to exercise, and POMS remained stable in all groups across the 8-week study protocol. CONCLUSIONS: These findings support the clinical safety and non-habituating neuro-energetic effects of TeaCrine® supplementation over 8 weeks of daily use (up to 300 mg/day). Moreover, there was no evidence of a tachyphylactic response that is typical of neuroactive agents such as caffeine and other stimulants.

Saturated Reconstruction of a Volume of Neocortex.

We describe automated technologies to probe the structure of neural tissue at nanometer resolution and use them to generate a saturated reconstruction of a sub-volume of mouse neocortex in which all cellular objects (axons, dendrites, and glia) and many sub-cellular components (synapses, synaptic vesicles, spines, spine apparati, postsynaptic densities, and mitochondria) are rendered and itemized in a database. We explore these data to study physical properties of brain tissue. For example, by tracing the trajectories of all excitatory axons and noting their juxtapositions, both synaptic and non-synaptic, with every dendritic spine we refute the idea that physical proximity is sufficient to predict synaptic connectivity (the so-called Peters' rule). This online minable database provides general access to the intrinsic complexity of the neocortex and enables further data-driven inquiries.

Large-scale automatic reconstruction of neuronal processes from electron microscopy images.

Automated sample preparation and electron microscopy enables acquisition of very large image data sets. These technical advances are of special importance to the field of neuroanatomy, as 3D reconstructions of neuronal processes at the nm scale can provide new insight into the fine grained structure of the brain. Segmentation of large-scale electron microscopy data is the main bottleneck in the analysis of these data sets. In this paper we present a pipeline that provides state-of-the art reconstruction performance while scaling to data sets in the GB-TB range. First, we train a random forest classifier on interactive sparse user annotations. The classifier output is combined with an anisotropic smoothing prior in a Conditional Random Field framework to generate multiple segmentation hypotheses per image. These segmentations are then combined into geometrically consistent 3D objects by segmentation fusion. We provide qualitative and quantitative evaluation of the automatic segmentation and demonstrate large-scale 3D reconstructions of neuronal processes from a 27,000 µm(3) volume of brain tissue over a cube of 30 µm in each dimension corresponding to 1000 consecutive image sections. We also introduce Mojo, a proofreading tool including semi-automated correction of merge errors based on sparse user scribbles.

Principles of sound ecotoxicology.

We have become progressively more concerned about the quality of some published ecotoxicology research. Others have also expressed concern. It is not uncommon for basic, but extremely important, factors to apparently be ignored. For example, exposure concentrations in laboratory experiments are sometimes not measured, and hence there is no evidence that the test organisms were actually exposed to the test substance, let alone at the stated concentrations. To try to improve the quality of ecotoxicology research, we suggest 12 basic principles that should be considered, not at the point of publication of the results, but during the experimental design. These principles range from carefully considering essential aspects of experimental design through to accurately defining the exposure, as well as unbiased analysis and reporting of the results. Although not all principles will apply to all studies, we offer these principles in the hope that they will improve the quality of the science that is available to regulators. Science is an evidence-based discipline and it is important that we and the regulators can trust the evidence presented to us. Significant resources often have to be devoted to refuting the results of poor research when those resources could be utilized more effectively.

Design and Evaluation of Interactive Proofreading Tools for Connectomics.

Proofreading refers to the manual correction of automatic segmentations of image data. In connectomics, electron microscopy data is acquired at nanometer-scale resolution and results in very large image volumes of brain tissue that require fully automatic segmentation algorithms to identify cell boundaries. However, these algorithms require hundreds of corrections per cubic micron of tissue. Even though this task is time consuming, it is fairly easy for humans to perform corrections through splitting, merging, and adjusting segments during proofreading. In this paper we present the design and implementation of Mojo, a fully-featured single-user desktop application for proofreading, and Dojo, a multi-user web-based application for collaborative proofreading. We evaluate the accuracy and speed of Mojo, Dojo, and Raveler, a proofreading tool from Janelia Farm, through a quantitative user study. We designed a between-subjects experiment and asked non-experts to proofread neurons in a publicly available connectomics dataset. Our results show a significant improvement of corrections using web-based Dojo, when given the same amount of time. In addition, all participants using Dojo reported better usability. We discuss our findings and provide an analysis of requirements for designing visual proofreading software.

Validation study of a fast, accurate, and precise brain tumor volume measurement.

UNLABELLED: Precision and accuracy are sometimes sacrificed to ensure that medical image processing is rapid. To address this, our lab had developed a novel level set segmentation algorithm that is 16× faster and >96% accurate on realistic brain phantoms. METHODS: This study reports speed, precision and estimated accuracy of our algorithm when measuring MRIs of meningioma brain tumors and compares it to manual tracing and modified MacDonald (MM) ellipsoid criteria. A repeated-measures study allowed us to determine measurement precisions (MPs) - clinically relevant thresholds for statistically significant change. RESULTS: Speed: the level set, MM, and trace methods required 1:20, 1:35, and 9:35 (mm:ss) respectively on average to complete a volume measurement (p<0.05). Accuracy: the level set was not statistically different to the estimated true lesion volumes (p>0.05). Precision: the MM's within-operator and between-operator MPs were significantly higher (worse) than the other methods (p<0.05). The observed difference in MP between the level set and trace methods did not reach statistical significance (p>0.05). CONCLUSION: Our level set is faster on average than MM, yet has accuracy and precision comparable to manual tracing.

Neural process reconstruction from sparse user scribbles.

We present a novel semi-automatic method for segmenting neural processes in large, highly anisotropic EM (electron microscopy) image stacks. Our method takes advantage of sparse scribble annotations provided by the user to guide a 3D variational segmentation model, thereby allowing our method to globally optimally enforce 3D geometric constraints on the segmentation. Moreover, we leverage a novel algorithm for propagating segmentation constraints through the image stack via optimal volumetric pathways, thereby allowing our method to compute highly accurate 3D segmentations from very sparse user input. We evaluate our method by reconstructing 16 neural processes in a 1024 x 1024 x 50 nanometer-scale EM image stack of a mouse hippocampus. We demonstrate that, on average, our method is 68% more accurate than previous state-of-the-art semi-automatic methods.