CBT for difficult-to-treat depression: self-regulation model

BACKGROUND: Cognitive behavioural therapy (CBT) is an effective treatment for depression but a significant minority of clients do not complete therapy, do not respond to it, or subsequently relapse. Non-responders, and those at risk of relapse, are more likely to have adverse childhood experiences, early-onset depression, co-morbidities, interpersonal problems and heightened risk. This is a heterogeneous group of clients who are currently difficult to treat. AIM: The aim was to develop a CBT model of depression that will be effective for difficult-to-treat clients who have not responded to standard CBT. METHOD: The method was to unify theory, evidence and clinical strategies within the field of CBT to develop an integrated CBT model. Single case methods were used to develop the treatment components. RESULTS: A self-regulation model of depression has been developed. It proposes that depression is maintained by repeated interactions of self-identity disruption, impaired motivation, disengagement, rumination, intrusive memories and passive life goals. Depression is more difficult to treat when these processes become interlocked. Treatment based on the model builds self-regulation skills and restructures self-identity, rather than target negative beliefs. A bespoke therapy plan is formed out of ten treatment components, based on an individual case formulation. CONCLUSIONS: A self-regulation model of depression is proposed that integrates theory, evidence and practice within the field of CBT. It has been developed with difficult-to-treat cases as its primary purpose. A case example is described in a concurrent article (Barton et al., 2022) and further empirical tests are on-going

Species-Specific Effects on Ecosystem Functioning Can Be Altered by Interspecific Interactions

Biological assemblages are constantly undergoing change, with species being introduced, extirpated and experiencing shifts in their densities. Theory and experimentation suggest that the impacts of such change on ecosystem functioning should be predictable based on the biological traits of the species involved. However, interspecific interactions could alter how species affect functioning, with the strength and sign of interactions potentially depending on environmental context (e.g. homogenous vs. heterogeneous conditions) and the function considered. Here, we assessed how concurrent changes to the densities of two common marine benthic invertebrates, Corophium volutator and Hediste diversicolor, affected the ecological functions of organic matter consumption and benthic-pelagic nutrient flux. Complementary experiments were conducted within homogenous laboratory microcosms and naturally heterogeneous field plots. When the densities of the species were increased within microcosms, interspecific interactions enhanced effects on organic matter consumption and reduced effects on nutrient flux. Trait-based predictions of how each species would affect functioning were only consistently supported when the density of the other species was low. In field plots, increasing the density of either species had a positive effect on organic matter consumption (with no significant interspecific interactions) but no effect on nutrient flux. Our results indicate that species-specific effects on ecosystem functioning can be altered by interspecific interactions, which can be either facilitative (positive) or antagonistic (negative) depending on the function considered. The impacts of biodiversity change may therefore not be predictable based solely on the biological traits of the species involved. Possible explanations for why interactions were detected in microcosms but not in the field are discussed

High-threshold mechanosensitive ion channels blocked by a novel conopeptide mediate pressure-evoked pain

Little is known about the molecular basis of somatosensory mechanotransduction in mammals. We screened a library of peptide toxins for effects on mechanically activated currents in cultured dorsal root ganglion neurons. One conopeptide analogue, termed NMB-1 for noxious mechanosensation blocker 1, selectively inhibits (IC50 1 µM) sustained mechanically activated currents in a subset of sensory neurons. Biotinylated NMB-1 retains activity and binds selectively to peripherin-positive nociceptive sensory neurons. The selectivity of NMB-1 was confirmed by the fact that it has no inhibitory effects on voltage-gated sodium and calcium channels, or ligand-gated channels such as acid-sensing ion channels or TRPA1 channels. Conversely, the tarantula toxin, GsMTx-4, which inhibits stretch-activated ion channels, had no effects on mechanically activated currents in sensory neurons. In behavioral assays, NMB-1 inhibits responses only to high intensity, painful mechanical stimulation and has no effects on low intensity mechanical stimulation or thermosensation. Unexpectedly, NMB-1 was found to also be an inhibitor of rapid FM1-43 loading (a measure of mechanotransduction) in cochlear hair cells. These data demonstrate that pharmacologically distinct channels respond to distinct types of mechanical stimuli and suggest that mechanically activated sustained currents underlie noxious mechanosensation. NMB-1 thus provides a novel diagnostic tool for the molecular definition of channels involved in hearing and pressure-evoked pain

New first trimester crown-rump length's equations optimized by structured data collection from a French general population

--- Objectives --- Prior to foetal karyotyping, the likelihood of Down's syndrome is often determined combining maternal age, serum free beta-HCG, PAPP-A levels and embryonic measurements of crown-rump length and nuchal translucency for gestational ages between 11 and 13 weeks. It appeared important to get a precise knowledge of these scan parameters' normal values during the first trimester. This paper focused on crown-rump length. --- METHODS --- 402 pregnancies from in-vitro fertilization allowing a precise estimation of foetal ages (FA) were used to determine the best model that describes crown-rump length (CRL) as a function of FA. Scan measures by a single operator from 3846 spontaneous pregnancies representative of the general population from Northern France were used to build a mathematical model linking FA and CRL in a context as close as possible to normal scan screening used in Down's syndrome likelihood determination. We modeled both CRL as a function of FA and FA as a function of CRL. For this, we used a clear methodology and performed regressions with heteroskedastic corrections and robust regressions. The results were compared by cross-validation to retain the equations with the best predictive power. We also studied the errors between observed and predicted values. --- Results --- Data from 513 spontaneous pregnancies allowed to model CRL as a function of age of foetal age. The best model was a polynomial of degree 2. Datation with our equation that models spontaneous pregnancies from a general population was in quite agreement with objective datations obtained from 402 IVF pregnancies and thus support the validity of our model. The most precise measure of CRL was when the SD was minimal (1.83mm), for a CRL of 23.6 mm where our model predicted a 49.4 days of foetal age. Our study allowed to model the SD from 30 to 90 days of foetal age and offers the opportunity of using Zscores in the future to detect growth abnormalities. --- Conclusion --- With powerful statistical tools we report a good modeling of the first trimester embryonic growth in the general population allowing a better knowledge of the date of fertilization useful in the ultrasound screening of Down's syndrome. The optimal period to measure CRL and predict foetal age was 49.4 days (9 weeks of gestational age). Our results open the way to the detection of foetal growth abnormalities using CRL Zscores throughout the first trimester

Simulating stable carbon isotopes in the ocean component of the FAMOUS general circulation model with MOSES1 (XOAVI)

Ocean circulation and the marine carbon cycle can be indirectly inferred from stable and radiogenic carbon isotope ratios (δ13C and Δ14C, respectively), measured directly in the water column, or recorded in geological archives such as sedimentary microfossils and corals. However, interpreting these records is non-trivial because they reflect a complex interplay between physical and biogeochemical processes. By directly simulating multiple isotopic tracer fields within numerical models, we can improve our understanding of the processes that control large-scale isotope distributions and interpolate the spatiotemporal gaps in both modern and palaeo datasets. We have added the stable isotope 13C to the ocean component of the FAMOUS coupled atmosphere–ocean general circulation model, which is a valuable tool for simulating complex feedbacks between different Earth system processes on decadal to multi-millennial timescales. We tested three different biological fractionation parameterisations to account for the uncertainty associated with equilibrium fractionation during photosynthesis and used sensitivity experiments to quantify the effects of fractionation during air–sea gas exchange and primary productivity on the simulated δ13CDIC distributions. Following a 10 000-year pre-industrial spin-up, we simulated the Suess effect (the isotopic imprint of anthropogenic fossil fuel burning) to assess the performance of the model in replicating modern observations. Our implementation captures the large-scale structure and range of δ13CDIC observations in the surface ocean, but the simulated values are too high at all depths, which we infer is due to biases in the biological pump. In the first instance, the new 13C tracer will therefore be useful for recalibrating both the physical and biogeochemical components of FAMOUS

A 4% Geometric Distance to the Galaxy NGC4258 from Orbital Motions in a Nuclear Gas Disk

The water maser in the mildly active nucleus in the nearby galaxy NGC4258 traces a thin, nearly edge-on, subparsec-scale Keplerian disk. Using the technique of very long baseline interferometry, we have detected the proper motions of these masers as they sweep in front of the central black hole at an orbital velocity of about 1100 km/s. The average maser proper motion of 31.5 microarcseconds per year is used in conjunction with the observed acceleration of the masers to derive a purely geometric distance to the galaxy of 7.2 +- 0.3 Mpc. This is the most precise extragalactic distance measured to date, and, being independent of all other distance indicators, is likely to play an important role in calibrating the extragalactic distance scale.Comment: 11 pages, 3 figures. Accepted for publication in Natur

Tissue mimicking materials for imaging and therapy phantoms: a review

Tissue mimicking materials (TMMs), typically contained within phantoms, have been used for many decades in both imaging and therapeutic applications. This review investigates the specifications that are typically being used in development of the latest TMMs. The imaging modalities that have been investigated focus around CT, mammography, SPECT, PET, MRI and ultrasound. Therapeutic applications discussed within the review include radiotherapy, thermal therapy and surgical applications. A number of modalities were not reviewed including optical spectroscopy, optical imaging and planar x-rays. The emergence of image guided interventions and multimodality imaging have placed an increasing demand on the number of specifications on the latest TMMs. Material specification standards are available in some imaging areas such as ultrasound. It is recommended that this should be replicated for other imaging and therapeutic modalities. Materials used within phantoms have been reviewed for a series of imaging and therapeutic applications with the potential to become a testbed for cross-fertilization of materials across modalities. Deformation, texture, multimodality imaging and perfusion are common themes that are currently under development

Identification of inhibitors of the Schistosoma mansoni VKR2 kinase domain

Schistosomiasis is a neglected tropical disease caused by parasitic flatworms. Current treatment relies on just one partially effective drug, praziquantel (PZQ). Schistosoma mansoni Venus Kinase Receptors 1 and 2 (SmVKR1 and SmVKR2) are important for parasite growth and egg production, and are potential targets for combating schistosomiasis. VKRs consist of an extracellular Venus Flytrap Module (VFTM) linked via a transmembrane helix to a kinase domain. Here, we initiated a drug discovery effort to inhibit the activity of the SmVKR2 kinase domain (SmVKR2KD) by screening the GSK published kinase inhibitor set 2 (PKIS2). We identified several inhibitors, of which four were able to inhibit its enzymatic activity and induced phenotypic changes in ex vivoS. mansoni. Our crystal structure of the SmVKR2KD displays an active-like state that sheds light on the activation process of VKRs. Our data provide a basis for the further exploration of SmVKR2 as a possible drug target

Navigation of Distinct Euclidean Particles via Hierarchical Clustering

We present a centralized online (completely reactive) hybrid navigation algorithm for bringing a swarm of n perfectly sensed and actuated point particles in Euclidean d space (for arbitrary n and d) to an arbitrary goal configuration with the guarantee of no collisions along the way. Our construction entails a discrete abstraction of configurations using cluster hierarchies, and relies upon two prior recent constructions: (i) a family of hierarchy-preserving control policies and (ii) an abstract discrete dynamical system for navigating through the space of cluster hierarchies. Here, we relate the (combinatorial) topology of hierarchical clusters to the (continuous) topology of configurations by constructing “portals” — open sets of configurations supporting two adjacent hierarchies. The resulting online sequential composition of hierarchy-invariant swarming followed by discrete selection of a hierarchy “closer” to that of the destination along with its continuous instantiation via an appropriate portal configuration yields a computationally effective construction for the desired navigation policy