Comparing the unified protocol for transdiagnostic treatment of emotional disorders to prolonged exposure for the treatment of PTSD: Design of a non-inferiority randomized controlled trial.

Background: Prolonged Exposure (PE), a trauma-focused therapy, is one of the most efficacious treatments available for PTSD. However, many people with PTSD do not lose their diagnosis following delivery of PE. The Unified Protocol (UP) for Transdiagnostic Treatment of Emotional Disorders is a non-trauma focused treatment that may offer an alternative treatment for PTSD. Methods: This paper describes the study protocol for IMPACT, an assessor-blinded randomized controlled trial that examines the non-inferiority of UP relative to PE for participants who meet DSM-5 criteria for current PTSD. One hundred and twenty adult participants with PTSD will be randomized to receive either 10 × 90-min sessions of UP or PE with a trained provider. The primary outcome is severity of PTSD symptoms assessed by the Clinician Administered PTSD Scale for DSM-5 (CAPS-5) at post-treatment. Discussion: While evidence-based treatments are available for PTSD, high levels of treatment dropout and non-response require new approaches to be tested. The UP is based on emotion regulation theory and is effective in treating anxiety and depressive disorders, however, there has been limited application to PTSD. This is the first rigorous study comparing UP to PE in a non-inferiority randomized controlled trial and may help improve clinical outcomes for those with PTSD. Trial registration: This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry, Trial ID (ACTRN12619000543189).

CTC-5: A novel digital pathology approach to characterise circulating tumour cell biodiversity.

Metastatic progression and tumor evolution complicates the clinical management of cancer patients. Circulating tumor cell (CTC) characterization is a growing discipline that aims to elucidate tumor metastasis and evolution processes. CTCs offer the clinical potential to monitor cancer patients for therapy response, disease relapse, and screen 'at risk' groups for the onset of malignancy. However, such clinical utility is currently limited to breast, prostate, and colorectal cancer patients. Further understanding of the basic CTC biology of other malignancies is required to progress them towards clinical utility. Unfortunately, such basic clinical research is often limited by restrictive characterization methods and high-cost barrier to entry for CTC isolation and imaging infrastructure. As experimental clinical results on applications of CTC are accumulating, it is becoming clear that a two-tier system of CTC isolation and characterization is required. The first tier is to facilitate basic research into CTC characterization. This basic research then informs a second tier specialised in clinical prognostic and diagnostic testing. This study presented in this manuscript describes the development and application of a low-cost, CTC isolation and characterization pipeline; CTC-5. This approach uses an established 'isolation by size' approach (ScreenCell Cyto) and combines histochemical morphology stains and multiparametric immunofluorescence on the same isolated CTCs. This enables capture and characterization of CTCs independent of biomarker-based pre-selection and accommodates both single CTCs and clusters of CTCs. Additionally, the developed open-source software is provided to facilitate the synchronization of microscopy data from multiple sources (https://github.com/CTC5/). This enables high parameter histochemical and immunofluorescent analysis of CTCs with existing microscopy infrastructure without investment in CTC specific imaging hardware. Our approach confirmed by the number of successful tests represents a potential major advance towards highly accessible low-cost technology aiming at the basic research tier of CTC isolation and characterization. The biomarker independent approach facilitates closing the gap between malignancies with poorly, and well-defined CTC phenotypes. As is currently the case for some of the most commonly occurring breast, prostate and colorectal cancers, such advances will ultimately benefit the patient, as early detection of relapse or onset of malignancy strongly correlates with their prognosis.

Quantifying virtual self-motion sensations induced by galvanic vestibular stimulation.

BACKGROUND: The vestibular system provides a comprehensive estimate of self-motion in 3D space. Widely used to artificially stimulate the vestibular system, binaural-bipolar square-wave Galvanic Vestibular Stimulation (GVS) elicits a virtual sensation of roll rotation. Postural responses to GVS have been clearly delineated, however quantifying the perceived virtual rotation vector has not been fully realised. OBJECTIVE: We aimed to quantify the perceived virtual roll rotation vector elicited by GVS using a psychophysical approach on a 3D turntable. METHODS: Participants were placed supine on the 3D turntable and rotated around the naso-occipital axis while supine and received square-wave binaural-bipolar GVS or sham stimulation. GVS amplitudes and intensities were systematically manipulated. The turntable motion profile consisted of a velocity step of 20°/s2 until the trial velocity between 0-20°/s was reached, followed by a 1°/s ramp until the end of the trial. In a psychophysical adaptive staircase procedure, we systematically varied the roll velocity to identify the exact velocity that cancelled the perceived roll sensation induced by GVS. RESULTS: Participants perceived a virtual roll rotation towards the cathode of approximately 2°/s velocity for 1 mA GVS and 6°/s velocity for 2.5 mA GVS. The observed values were stable across repetitions. CONCLUSIONS: Our results quantify for the first time the perceived virtual roll rotations induced by binaural-bipolar square-wave GVS. Importantly, estimates were based on perceptual judgements, in the absence of motor or postural responses and in a head orientation where the GVS-induced roll sensation did not interact with the perceived direction of gravity. This is an important step towards applications of GVS in different settings, including sensory substitution or Virtual Reality.

Visuo-vestibular conflicts within the roll plane modulate multisensory verticality perception.

The integration of visuo-vestibular information is crucial when interacting with the external environment. Under normal circumstances, vision and vestibular signals provide corroborating information, for example regarding the direction and speed of self-motion. However, conflicts in visuo-vestibular signalling, such as optic flow presented to a stationary observer, can change subsequent processing in either modality. While previous studies have demonstrated the impact of sensory conflict on unisensory visual or vestibular percepts, here we investigated whether visuo-vestibular conflicts impact sensitivity to multisensory percepts, specifically verticality. Participants were exposed to a visuo-vestibular conflicting or non-conflicting motion adaptor before completing a Vertical Detection Task. Sensitivity to vertical stimuli was reduced following visuo-vestibular conflict. No significant differences in criterion were found. Our findings suggest that visuo-vestibular conflicts not only modulate processing in unimodal channels, but also broader multisensory percepts, which may have implications for higher-level processing dependent on the integration of visual and vestibular signals.

The role of booster vaccination and ongoing viral evolution in seasonal circulation of SARS-CoV-2.

Periodic resurgences of COVID-19 in the coming years can be expected, while public health interventions may be able to reduce their intensity. We used a transmission model to assess how the use of booster doses and non-pharmaceutical interventions (NPIs) amid ongoing pathogen evolution might influence future transmission waves. We find that incidence is likely to increase as NPIs relax, with a second seasonally driven surge expected in autumn 2022. However, booster doses can greatly reduce the intensity of both waves and reduce cumulative deaths by 20% between 7 January 2022 and 7 January 2023. Reintroducing NPIs during the autumn as incidence begins to increase again could also be impactful. Combining boosters and NPIs results in a 30% decrease in cumulative deaths, with potential for greater impacts if variant-adapted boosters are used. Reintroducing these NPIs in autumn 2022 as transmission rates increase provides similar benefits to sustaining NPIs indefinitely (307 000 deaths with indefinite NPIs and boosters compared with 304 000 deaths with transient NPIs and boosters). If novel variants with increased transmissibility or immune escape emerge, deaths will be higher, but vaccination and NPIs are expected to remain effective tools to decrease both cumulative and peak health system burden, providing proportionally similar relative impacts.

Impact of ablation index settings on pulmonary vein reconnection.

PURPOSE: Ablation index (AI) is a radiofrequency lesion quality marker. The AI value that allows effective and safe pulmonary vein isolation (PVI) is still debated. We evaluated the incidence of acute and late PV reconnection (PVR) with different AI settings and its predictors. METHODS: The Ablation Index Registry is a multicenter study that included patients with paroxysmal/persistent atrial fibrillation (AF) who underwent first-time ablation. Each operator performed the ablation using his preferred ablation catheter (ThermoCool® SmartTouch or Surround Flow) and AI setting (380 posterior-500 anterior and 330 posterior-450 anterior). We divided the study population into two groups according to the AI setting used: group 1 (330-450) and group 2 (380-500). Incidence of acute PVR was validated within 30 min after PVI, whereas the incidence of late PVR was evaluated at repeat procedure. RESULTS: Overall, 490 patients were divided into groups 1 (258) and 2 (232). There was no significant difference in the procedural time, fluoroscopy time, and rate of the first-pass PVI between the two study groups. Acute PVR was observed in 5.6% PVs. The rate of acute PVR was slightly higher in group 2 (64/943, 6.8%, PVs) than in group 1 (48/1045, 4.6% PVs, p = 0.04). Thirty patients (6%) underwent a repeat procedure and late PVR was observed in 57/116 (49%) PVs (number of reconnected PV per patient of 1.9 ± 1.6). A similar rate of late PVR was found in the two study groups. No predictors of acute and late PVR were found. CONCLUSION: Ablation with a lower range of AI is highly effective and is not associated with a higher rate of acute and late PVR. No predictors of PV reconnection were found.

Health Science Students as PPE Coaches in the Emergency Department - a Pandemic Pilot Project.

PPE is an integral part of reducing transmission of COVID-19. We assessed a 5-week pilot project of utilising health science student volunteers as PPE coaches in the adult and paediatric emergency department (ED) during the pandemic. PPE coaches were provided with training, PPE checklist, area for written observations, and feedback surveys. Overall, correct PPE use improved over time. Coaches felt safe, that training was adequate, and part of the team. Factors that contributed to project effectiveness included institutional support, role clarification, and continuous feedback from staff. Our findings support the utilisation of students in IPC projects.

The art of coarse Stokes: Richardson extrapolation improves the accuracy and efficiency of the method of regularized stokeslets.

The method of regularized stokeslets is widely used in microscale biological fluid dynamics due to its ease of implementation, natural treatment of complex moving geometries, and removal of singular functions to integrate. The standard implementation of the method is subject to high computational cost due to the coupling of the linear system size to the numerical resolution required to resolve the rapidly varying regularized stokeslet kernel. Here, we show how Richardson extrapolation with coarse values of the regularization parameter is ideally suited to reduce the quadrature error, hence dramatically reducing the storage and solution costs without loss of accuracy. Numerical experiments on the resistance and mobility problems in Stokes flow support the analysis, confirming several orders of magnitude improvement in accuracy and/or efficiency.

Timing of continuous renal replacement therapy in severe acute kidney injury patients with fluid overload: A retrospective cohort study.

PURPOSE: We aimed to evaluate the association of early versus late initiation of Continuous renal replacement therapy (CRRT) with mortality in patients with fluid overload. METHODS: This was a retrospective cohort study of patients with fluid overload (FO) treated with CRRT due to severe acute kidney injury (AKI) between January 2015 and December 2017 in a mixed medical intensive care unit of a teaching hospital in Beijing, China. Patients were divided into early (≤15 h) and late (>15 h) groups based on the median time from ICU admission to CRRT initiation. The primary outcome was all-cause mortality at day 60. Multivariable Cox model analysis was used for analysis. RESULTS: The study patients were male predominant (84/150) with a mean age of 64.8 ± 16.7 years. The median FO value before CRRT initiation was 10.1% [6.2-16.1%]. The 60-day mortality rates in the early vs the late CRRT groups were 53.9% and 73%, respectively. On multivariable Cox modelling, the late initiation of CRRT was independently associated with an increased risk of death at 60 days (HR 1.75, 95% CI 1.11-2.74, p = 0.015). CONCLUSIONS: Early initiation of CRRT was independently associated with survival benefits in severe AKI patients with fluid overload.

What Maintains Flower Colour Variation within Populations?

Natural selection acts on phenotypic trait variation. Understanding the mechanisms that create and maintain trait variation is fundamental to understanding the breadth of diversity seen on Earth. Flower colour is among the most conspicuous and highly diverse traits in nature. Most flowering plant populations have uniform floral colours, but a minority exhibit within-population colour variation, either discrete (polymorphic) or continuous. Colour variation is commonly maintained by balancing selection through multiple pollinators, opposing selection regimes, or fluctuating selection. Variation can also be maintained by heterozygote advantage or frequency-dependent selection. Neutral processes, or a lack of selection, may maintain variation, although this remains largely untested. We suggest several prospective research directions that may provide insight into the evolutionary drivers of trait variation.

All the Colors of the Rainbow: Diversification of Flower Color and Intraspecific Color Variation in the Genus Iris.

Floral color plays a key role as visual signaling and is therefore of great importance in shaping plant-pollinator interactions. Iris (Iridaceae), a genus comprising over 300 species and named after the Greek goddess of the colorful rainbow, is famous for its dazzling palette of flower colors and patterns, which vary considerably both within and among species. Despite the large variation of flower color in Iris, little is known about the phylogenetic and ecological contexts of floral color. Here, we seek to resolve the evolution of flower color in the genus Iris in a macroevolutionary framework. We used a phylogenetic analysis to reconstruct the ancestral state of flower color and other pollination-related traits (e.g., the presence of nectar and mating system), and also tracked the evolution of color variation. We further explored weather floral trait transitions are better explained by environmental or pollinator-mediated selection. Our study revealed that the most recent common ancestor likely had monomorphic, purple flowers, with a crest and a spot on the fall. The flowers were likely insect-pollinated, nectar-rewarding, and self-compatible. The diversity of floral traits we see in modern irises, likely represents a trade-off between conflicting selection pressures. Whether shifts in these flower traits result from abiotic or biotic selective agents or are maintained by neutral processes without any selection remains an open question. Our analysis serves as a starting point for future work exploring the genetic and physiological mechanisms controlling flower coloration in the most color-diverse genus Iris.

Synthesis of mesoscale ordered two-dimensional π-conjugated polymers with semiconducting properties.

Two-dimensional materials with high charge carrier mobility and tunable band gaps have attracted intense research effort for their potential use in nanoelectronics. Two-dimensional π-conjugated polymers constitute a promising subclass because the band structure can be manipulated by varying the molecular building blocks while preserving key features such as Dirac cones and high charge mobility. The major barriers to the application of two-dimensional π-conjugated polymers have been the small domain size and high defect density attained in the syntheses explored so far. Here, we demonstrate the fabrication of mesoscale ordered two-dimensional π-conjugated polymer kagome lattices with semiconducting properties, Dirac cone structures and flat bands on Au(111). This material has been obtained by combining a rigid azatriangulene precursor and a hot dosing approach, which favours molecular diffusion and eliminates voids in the network. These results open opportunities for the synthesis of two-dimensional π-conjugated polymer Dirac cone materials and their integration into devices.

Pollinator visitation rate and effectiveness vary with flowering phenology.

PREMISE: Flowering time may influence pollination success and seed set through a variety of mechanisms, including seasonal changes in total pollinator visitation or the composition and effectiveness of pollinator visitors. METHODS: We investigated mechanisms by which changes in flowering phenology influence pollination and reproductive success of Mertensia ciliata (Boraginaceae). We manipulated flowering onset of potted plants and assessed the frequency and composition of pollinator visitors, as well as seed set. We tested whether floral visitors differed in their effectiveness as pollinators by measuring pollen receipt and seed set resulting from single visits to virgin flowers. RESULTS: Despite a five-fold decrease in pollinator visitation over four weeks, we detected no significant difference in seed set among plants blooming at different times. On a per-visit basis, each bumblebee transferred more conspecific pollen than did a solitary bee or a fly. The proportion of visits by bumblebees increased over the season, countering the decrease in visitation rate so that flowering time had little net effect on seed set. CONCLUSIONS: This work illustrates the need to consider pollinator effectiveness, along with changes in pollinator visitation and species composition to understand the mechanisms by which phenology affects levels of pollination.

Simulations of particle tracking in the oligociliated mouse node and implications for left-right symmetry-breaking mechanics.

The concept of internal anatomical asymmetry is familiar-usually in humans the heart is on the left and the liver is on the right; however, how does the developing embryo know to produce this consistent laterality? Symmetry-breaking initiates with left-right asymmetric cilia-driven fluid mechanics in a small fluid-filled structure called the ventral node in mice. However, the question of what converts this flow into left-right asymmetric development remains unanswered. A leading hypothesis is that flow transports morphogen-containing vesicles within the node, the absorption of which results in asymmetrical gene expression. To investigate how vesicle transport might result in the situs patterns observe in wild-type and mutant experiments, we extend the open-source Stokes flow package, NEAREST, to consider the hydrodynamic and Brownian motion of particles in a mouse model with flow driven by one, two and 112 beating cilia. Three models for morphogen-containing particle released are simulated to assess their compatibility with observed results in oligociliated and wild-type mouse embryos: uniformly random release, localized cilium stress-induced release and localized release from motile cilia themselves. Only the uniformly random release model appears consistent with the data, with neither localized release model resulting in significant transport in the oligociliated embryo. This article is part of the Theo Murphy meeting issue 'Unity and diversity of cilia in locomotion and transport'.

Competing barnacle species with a time dependent reproduction rate.

A simple competition model with time varying periodic coefficients, in which two species use different reproduction strategies, is explored in this paper. The two species considered comprise a native species which reproduces once a year over a short time period and an invasive species which is capable of reproducing throughout the entire year. A monotonicity property of the model is instrumental for its analysis. The model reveals that the time difference between the peak of reproduction for the two species is a critical factor in determining the outcome of competition between these species. The impact of climate change and an anthropogenic disturbance, comprising the creation of additional substrate, is also investigated using a modified model. The results of this paper describe how climate change will favour the invasive species by reducing the time period between the reproductive peaks of the two species and how the addition of new substrates is likely to endanger a small population of either of the two species, depending on the timing of the introduction of the substrates.

Temperature-induced molecular reorganization on Au(111) driven by oligomeric defects.

The formation of ordered molecular structures on surfaces is determined by the balance between molecule-molecule and molecule-substrate interactions. Whether the aggregation process is guided by non-covalent forces or on-surface reactions, a deeper understanding of these interactions is pivotal to formulating a priori predictions of the final structural features and the development of bottom-up fabrication protocols. Theoretical models of molecular systems corroborate the information gathered through experimental observations and help explain the thermodynamic factors that underpin on-surface phase transitions. Here, we report a scanning tunneling microscopy investigation of a tribromo-substituted heterotriangulene on the Au(111) surface, which initially forms an extended close-packed ordered structure stabilized by BrBr halogen bonds when deposited at room temperature. X-ray photoelectron spectroscopy reveals that annealing the self-assembled layer induces a fraction of the molecular precursors to partially dehalogenate that in turn leads to the formation of a less stable BrO non-covalent network which coexists with the short oligomers. Density functional theory (DFT) and Monte Carlo (MC) simulations illustrate how dimer moieties act as defects whose steric hindrance prevents the retention of the more stable configuration. A small number of dimers is sufficient to drive the molecular reorganization into a lower cohesive energy phase. Our study shows the importance of a combined DFT - MC approach to understand the evolution of molecular systems on substrates.

Rapid sperm capture: high-throughput flagellar waveform analysis.

STUDY QUESTION: Can flagellar analyses be scaled up to provide automated tracking of motile sperm, and does knowledge of the flagellar waveform provide new insight not provided by routine head tracking? SUMMARY ANSWER: High-throughput flagellar waveform tracking and analysis enable measurement of experimentally intractable quantities such as energy dissipation, disturbance of the surrounding medium and viscous stresses, which are not possible by tracking the sperm head alone. WHAT IS KNOWN ALREADY: The clinical gold standard for sperm motility analysis comprises a manual analysis by a trained professional, with existing automated sperm diagnostics [computer-aided sperm analysis (CASA)] relying on tracking the sperm head and extrapolating measures. It is not currently possible with either of these approaches to track the sperm flagellar waveform for large numbers of cells in order to unlock the potential wealth of information enclosed within. STUDY DESIGN, SIZE, DURATION: The software tool in this manuscript has been developed to enable high-throughput, repeatable, accurate and verifiable analysis of the sperm flagellar beat. PARTICIPANTS/MATERIALS, SETTING, METHODS: Using the software tool [Flagellar Analysis and Sperm Tracking (FAST)] described in this manuscript, we have analysed 176 experimental microscopy videos and have tracked the head and flagellum of 205 progressive cells in diluted semen (DSM), 119 progressive cells in a high-viscosity medium (HVM) and 42 stuck cells in a low-viscosity medium. Unscreened donors were recruited at Birmingham Women's and Children's NHS Foundation Trust after giving informed consent. MAIN RESULTS AND THE ROLE OF CHANCE: We describe fully automated tracking and analysis of flagellar movement for large cell numbers. The analysis is demonstrated on freely motile cells in low- and high-viscosity fluids and validated on published data of tethered cells undergoing pharmacological hyperactivation. Direct analysis of the flagellar beat reveals that the CASA measure 'beat cross frequency' does not measure beat frequency; attempting to fit a straight line between the two measures gives ${\mathrm{R}}^2$ values of 0.042 and 0.00054 for cells in DSM and HVM, respectively. A new measurement, track centroid speed, is validated as an accurate differentiator of progressive motility. Coupled with fluid mechanics codes, waveform data enable extraction of experimentally intractable quantities such as energy dissipation, disturbance of the surrounding medium and viscous stresses. We provide a powerful and accessible research tool, enabling connection of the mechanical activity of the sperm to its motility and effect on its environment. LARGE SCALE DATA: The FAST software package and all documentation can be downloaded from www.flagellarCapture.com. LIMITATIONS, REASONS FOR CAUTION: The FAST software package has only been tested for use with negative phase contrast microscopy. Other imaging modalities, with bright cells on a dark background, have not been tested but may work. FAST is not designed to analyse raw semen; it is specifically for precise analysis of flagellar kinematics, as that is the promising area for computer use. Flagellar capture will always require that cells are at a dilution where their paths do not frequently cross. WIDER IMPLICATIONS OF THE FINDINGS: Combining tracked flagella with mathematical modelling has the potential to reveal new mechanistic insight. By providing the capability as a free-to-use software package, we hope that this ability to accurately quantify the flagellar waveform in large populations of motile cells will enable an abundant array of diagnostic, toxicological and therapeutic possibilities, as well as creating new opportunities for assessing and treating male subfertility. STUDY FUNDING/COMPETING INTEREST(S): M.T.G., G.C., J.C.K-B. and D.J.S. gratefully acknowledge funding from the Engineering and Physical Sciences Research Council, Healthcare Technologies Challenge Award (Rapid Sperm Capture EP/N021096/1). J.C.K-B. is funded by a National Institute of Health Research (NIHR) and Health Education England, Senior Clinical Lectureship Grant: The role of the human sperm in healthy live birth (NIHRDH-HCS SCL-2014-05-001). This article presents independent research funded in part by the NIHR and Health Education England. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The data for experimental set (2) were funded through a Wellcome Trust-University of Birmingham Value in People Fellowship Bridging Award (E.H.O.).The authors declare no competing interests.

Non-identifiability of parameters for a class of shear-thinning rheological models, with implications for haematological fluid dynamics.

Choosing a suitable model and determining its associated parameters from fitting to experimental data is fundamental for many problems in biomechanics. Models of shear-thinning complex fluids, dating from the work of Bird, Carreau, Cross and Yasuda, have been applied in highly-cited computational studies of hemodynamics for several decades. In this manuscript we revisit these models, first to highlight a degree of uncertainty in the naming conventions in the literature, but more importantly to address the problem of inferring model parameters by fitting to rheology experiments. By refitting published data, and also by simulation, we find large, flat regions in likelihood surfaces that yield families of parameter sets which fit the data equally well. Despite having almost indistinguishable fits to experimental data these varying parameter sets can predict very different flow profiles, and as such these parameters cannot be used to draw conclusions about physical properties of the fluids, such as zero-shear viscosity or relaxation time of the fluid, or indeed flow behaviours. We verify that these features are not a consequence of the experimental data sets through simulations; by sampling points from the rheological models and adding a small amount of noise we create a synthetic data set which reveals that the problem of parameter identifiability is intrinsic to these models.