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PROTAC® (proteolysis-targeting chimera) molecules induce proximity between an E3 ligase and protein-of-interest (POI) to target the POI for ubiquitin-mediated degradation. Cooperative E3-PROTAC-POI complexes have potential to achieve neo-substrate selectivity beyond that established by POI binding to the ligand alone. Here, we extend the collection of ubiquitin ligases employable for cooperative ternary complex formation to include the C-degron E3 KLHDC2. Ligands were identified that engage the C-degron binding site in KLHDC2, subjected to structure-based improvement, and linked to JQ1 for BET-family neo-substrate recruitment. Consideration of the exit vector emanating from the ligand engaged in KLHDC2's U-shaped degron-binding pocket enabled generation of SJ46421, which drives formation of a remarkably cooperative, paralog-selective ternary complex with BRD3 BD2 . Meanwhile, screening pro-drug variants enabled surmounting cell permeability limitations imposed by acidic moieties resembling the KLHDC2-binding C-degron. Selectivity for BRD3 compared to other BET-family members is further manifested in ubiquitylation in vitro, and prodrug version SJ46420-mediated degradation in cells. Selectivity is also achieved for the ubiquitin ligase, overcoming E3 auto-inhibition to engage KLHDC2, but not the related KLHDC1, KLHDC3, or KLHDC10 E3s. In sum, our study establishes neo-substrate-specific targeted protein degradation via KLHDC2, and provides a framework for developing selective PROTAC protein degraders employing C-degron E3 ligases., (© 2024. The Author(s).)

Background: People with severe mental illness who experience co-occurring substance use experience poor outcome including suicide, violence, relapses and use of crisis services. They struggle to access care and treatment due to a lack of an integrated and co-ordinated approach which means that some people can fall between services. Despite these concerns, there is limited evidence as to what works for this population., Objectives: To undertake a realist evaluation of service models in order to identify and refine programme theories of what works under what contexts for this population., Design: Realist synthesis and evaluation using published literature and case study data., Setting: Mental health, substance use and related services that had some form of service provision in six locations in the United Kingdom (five in England and one in Northern Ireland)., Participants: People with lived experience of severe mental illness and co-occurring substance use, carers and staff who work in the specialist roles as well as staff in mental health and substance use services., Results: Eleven initial programme theories were generated by the evidence synthesis and in conjunction with stakeholders. These theories were refined through focus groups and interviews with 58 staff, 25 service users and 12 carers across the 6 case study areas. We identified three forms of service provision (network, consultancy and lead and link worker); however, all offered broadly similar interventions. Evidence was identified to support most of the 11 programme theories. Theories clustered around effective leadership, workforce development and collaborative integrated care pathways. Outcomes that are meaningful for service users and staff were identified, including the importance of engagement., Limitations: The requirement for online data collection (due to the COVID-19 pandemic) worked well for staff data but worked less well for service users and carers. Consequently, this may have reduced the involvement of those without access to information technology equipment., Conclusion: The realist evaluation co-occurring study provides details on how and in what circumstances integrated care can work better for people with co-occurring severe mental health and alcohol/drug conditions. This requires joined-up policy at government level and local integration of services. We have also identified the value of expert clinicians who can support the workforce in sustaining this programme of work. People with co-occurring severe mental health and alcohol/drug conditions have complex and multifaceted needs which require a comprehensive and long-term integrated approach. The shift to integrated health and social care is promising but will require local support (local expert leaders, network opportunities and clarity of roles)., Future Work: Further work should evaluate the effectiveness and cost-effectiveness of service models for this group., Study Registration: This study is registered as PROSPERO CRD42020168667., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128128) and is published in full in Health Technology Assessment ; Vol. 28, No. 67. See the NIHR Funding and Awards website for further award information.

Introduction: Frailty is a well-defined clinical syndrome in humans caused by accumulation of impairments which result in loss of reserve capacity and increased vulnerability to disability, dependence, and death. Dogs are of particular interest in studies of frailty due to the similarities they share with people in their environment, lifestyles, and age-related diseases., Materials and Methods: The aim of this study was to develop a frailty phenotype screening tool, based on previously validated measures in dogs, which could be easily applied in the clinical setting, and which was predictive of all-cause, short term (6-month) mortality. The study was conducted in two phases. In phase 1, a retrospective cohort of 51 dogs was used to identify and evaluate potential measures for the five domains of frailty. This information was then used to develop a simple frailty phenotype based on examination findings and owner directed questions. In phase 2 of the study, this phenotype was evaluated in a prospective cohort of 198 dogs aged 9 years or older from multiple different specialty and primary care services to determine how the phenotype performed across a diverse canine population., Results: The developed frailty phenotype was predictive of all-cause, short-term mortality independent of age, sex, or weight (hazard ratio = 4.71; 95% CI, 2.66-8.8). Of the covariates evaluated only breed was significant, with purebred dogs having 1.85 times higher mortality than mixed breed dogs (95% CI, 1.04-3.31). The frailty phenotype performed similarly across all hospital services from which patients were enrolled., Conclusion: Based on these findings, the defined frailty phenotype represents a valuable screening tool for early risk identification and intervention, and can aid in clinical decision making for owners and veterinarians. Additionally, it will promote further research into the understanding and treatment of frailty in dogs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Russell, Mondino, Fefer, Griffith, Saker, Gruen and Olby.)

We present genome sequences of 29 species of ducks from 8 genera. Illumina sequencing was performed on tissue from wild-collected museum specimens. The reads were assembled using a de novo method followed by a finishing step. The raw and assembled data are publicly available via Genbank.

Background: Epidermolysis bullosa (EB), characterized by skin fragility and blistering, often requires hospitalization. Training for inpatient management of EB is limited, with no unified recommendations available in North America., Objective: To develop consensus-derived best practices for hands-on inpatient management of EB in both the neonatal and postneonatal period., Methods: A modified Delphi method (expert-based input via 2 surveys and a final review) was implemented. Available guidelines from EB Clinical Research Consortium centers were analyzed to determine areas of focus and formulate statements to be voted on by EB Clinical Research Consortium members, experienced EB nurses, and select family members. Study participants evaluated statements using a Likert scale: statements with at least 70% agreement were accepted; statements with 30% or more disagreement were rejected., Results: Ten areas of focus were identified. Delphi participants included 15 dermatologists, 8 nurses, and 6 nonhealth care caregivers. Consensus was established on 103/119 neonatal statements and 105/122 postneonatal statements; no statements were rejected. Most recommendations applied to both age groups., Limitations: Recommendations may require adjustment based on individual patient's clinical context., Conclusion: Using the Delphi method, a consensus-derived resource for hospital-based health care professionals who manage patients with EB has been developed to improve the quality of inpatient care., Competing Interests: Conflicts of interest Dr Garcia-Romero has received the EBCRC grant and has been a speaker for Cerave Latinamerica and Carnot Mexico Laboratories. Dr Price’s’ conflicts of interest are Aegle (PI clinical trial), Rheacell (PI clinical trial) Krystal Biotech (consultant). Dr Perman has served as a consultant for Abeona. Dr Lucky has served as investigator for Krystal Pharma and Phoenicis. Dr McCuaig’s conflicts of interest are AbbVie, Bausch, Boehringer, Galderma, Incyte, J&J, Eli Lilly, Leo, Novartis, Oreal Pfizer, Sanofi, and Sun. Dr Gorell has served as a consultant for Krystal Biotech, Abeona Therapeutics, and Amryt Pharma. Dr Levy’s conflicts of interest are Abeona, Castle Creek, Krystal, and Rheacell. Dr Bruckner’s conflicts of interest are Abeona (consultant), Amryt (consultant and investigator), Castle Creek (consultant and investigator), Krystal Biotech (consultant), Phoenix Tissue Repair (investigator), Phoenicis (investigator), Rheacell (investigator), and TWi Bio (consultant). Dr Paller has been an investigator for AbbVie, Applied Pharma Research, Dermavant, Eli Lilly, Incyte, Janssen, Krystal, Regeneron, and UCB; a consultant for Aegerion Pharma, Azitra, BioCryst, Boehringer-Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen, Johnson & Johnson, Krystal, LEO Pharma, Novartis, Primus, Regeneron, Sanofi/Genzyme, Seanergy, TWI Biotechnology, and UCB; and on the data safety monitoring board for AbbVie, Abeona, Catawba, Galderma, and InMed., (Copyright © 2024 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: People who present to the emergency department with self-harm and co-occurring substance use problems often have difficulty accessing effective care. Aims: To develop a brief psychosocial intervention for this population, which would be suitable for testing in a future randomized controlled trial. Methods: A modified Delphi method was used. A 34-item, 3-round, online Delphi survey was informed by a literature review and stakeholder telephone discussions ( n = 17). Two panels consisting of people with lived experience (PWLE: n = 15) and people with occupational experience (PWOE: n = 21) participated in the survey. The threshold for consensus was a pooled agreement rate across the two panels of 80% or more. Results: Expert consensus was achieved for 22 items. The new intervention consists of weekly follow-up phone calls for up to 1 month, delivered by Liaison Psychiatry practitioners, in which both self-harm and substance use problems are explored and addressed, and patients are supported in accessing community services. Limitations: Some stakeholder ideas regarding intervention components could not be included as survey options due to anticipated difficulties with implementation. Conclusions: The key elements of a brief psychosocial intervention for self-harm and co-occurring substance use problems have been agreed. Feasibility testing is currently underway.

Age-related decline in mobility and cognition are associated with cellular senescence and NAD + depletion in dogs and people. A combination of a novel NAD + precursor and senolytic, LY-D6/2, was examined in this randomized controlled trial. Seventy dogs with mild to moderate cognitive impairment were enrolled and allocated into placebo, low or full dose groups. Primary outcomes were change in cognitive impairment measured with the owner-reported Canine Cognitive Dysfunction Rating (CCDR) scale and change in activity measured with physical activity monitors. Fifty-nine dogs completed evaluations at the 3-month primary endpoint, and 51 reached the 6-month secondary endpoint. There was a significant difference in CCDR score across treatment groups from baseline to the primary endpoint (p = 0.02) with the largest decrease in the full dose group. No difference was detected between groups using in house cognitive testing. There were no significant differences between groups in changes in measured activity. The proportion of dogs that improved in frailty and owner-reported activity levels and happiness was higher in the full dose group than other groups, however this difference was not significant. Adverse events occurred equally across groups. All groups showed improvement in cognition, frailty, and activity suggesting placebo effect and benefits of trial participation. We conclude that LY-D6/2 improves owner-assessed cognitive function over a 3-month period and may have broader, but more subtle effects on frailty, activity and happiness as reported by owners., (© 2024. The Author(s).)

Context: Clinical clerkships provide osteopathic medical students the opportunity to participate in the diagnosis and treatment of commonly encountered medical conditions. Appropriate management of these conditions may include pharmacotherapy and/or nonpharmacologic interventions, such as osteopathic manipulative treatment (OMT). Opportunities may exist to expand the utilization of OMT in the management of common conditions, particularly for geriatric patients, who are at increased risk for adverse outcomes from pharmacologic treatments., Objectives: This study aimed to assess the most common diagnoses and corresponding treatments logged by osteopathic medical students within an ambulatory geriatric population., Methods: Patient encounters logged electronically by osteopathic medical students were retrospectively reviewed to determine the most commonly reported diagnostic codes and their treatments. Logged interventions were filtered to include patients over the age of 65 years who were seen on family medicine rotations within an ambulatory setting. The top 10 diagnoses were sorted and assessed to determine the associated treatments, including medications, procedures, and OMT., Results: Between January 2018 and June 2020, a total of 11,185 primary diagnoses were logged pertaining to the defined patient population. The most frequently documented diagnoses were essential hypertension (n=1,420; 12.7 %), encounter for well examination (n=1,144; 10.2 %), type 2 diabetes mellitus (n=837; 7.5 %), hyperlipidemia (n=346; 3.1 %), chronic obstructive pulmonary disease (COPD; n=278; 2.5 %), osteoarthritis (OA; n=221; 2.0 %), low back pain (LBP; n=202; 1.8 %), pain in joint (n=187; 1.7 %), hypothyroidism (n=164; 1.5 %), and urinary tract infections (n=160; 1.4 %). Three of the top 10 logged diagnoses were musculoskeletal in nature (OA, LBP, and pain in joint). Pharmacotherapy was reported as the predominant treatment for musculoskeletal conditions, with OMT being logged as a treatment for 10.9 % (n=50) of those cases. The most commonly logged medication class in the management of patients with those musculoskeletal conditions was nonsteroidal anti-inflammatory drugs (NSAIDs; n=128; 27.9 %), while opioids were the second most frequently documented class of medications (n=65; 14.2 %)., Conclusions: Musculoskeletal complaints were commonly logged by osteopathic medical students within the studied population. Opioids were documented as a treatment for musculoskeletal conditions more frequently than OMT. As such, opportunities exist to expand the utilization of OMT during clinical clerkships and to decrease the frequency of prescribed medications for pain management., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)

Competing Interests: Declaration of Competing Interest None.

The hip capsule has been recognized as a vital structure in the stability and proper function of the hip. Preserving its integrity during arthroscopic surgery is one of the utmost important principles in hip preservation surgery. When capsular deficiency is present, capsular reconstruction may be indicated to restore stability and proper hip mechanics. In this technical note, we introduce a simple and reproducible shuttle method technique for hip capsular reconstruction using a dermal allograft., (© 2023 The Authors.)

Approximately 30-50% of people with serious mental illness have co-existing drug or alcohol problems (COSMHAD), associated with adverse health and social care outcomes. UK guidelines advocate both co-occurring needs being met within mental health services, but uncertainty remains about how to operationalise this to improve outcomes. Various unevaluated service configurations exist in the UK. A realist synthesis was done to identify, test, and refine programme theories of how context shapes the mechanisms through which UK service models for COSMHAD work, for whom, and in what circumstances. Structured and iterative realist searches of seven databases identified 5099 records. A two-stage screening process identified 132 papers. Three broad contextual factors shaped COSMHAD services across 11 programme theories: committed leadership, clear expectations regarding COSMHAD from mental health and substance use workforces, and clear care-coordination processes. These contextual factors led to increased staff empathy, confidence, legitimisation, and multidisciplinary ethos, which improved care coordination and increased the motivation of people with COSMHAD to work towards their goals. Our synthesis highlights that integrating COSMHAD care is complex, and both individual and cultural behavioural shifts in leadership, workforce, and service delivery are essential to ensure people with COSMHAD receive compassionate, trauma-informed care that meets their needs., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The geographic ranges in which species live is a function of many factors underlying ecological and evolutionary contingencies. Observing the geographic range of an individual species provides valuable information about these historical contingencies for a lineage, determining the distribution of many distantly related species in tandem provides information about large-scale constraints on evolutionary and ecological processes generally. We present a linear regression method that allows for the discrimination of various hypothetical biogeographical models for determining which landscape distributional pattern best matches data from the fossil record. The linear regression models used in the discrimination rely on geodesic distances between sampling sites (typically geologic formations) as the independent variable and three possible dependent variables: Dice/Sorensen similarity; Euclidean distance; and phylogenetic community dissimilarity. Both the similarity and distance measures are useful for full-community analyses without evolutionary information, whereas the phylogenetic community dissimilarity requires phylogenetic data. Importantly, the discrimination method uses linear regression residual error to provide relative measures of support for each biogeographical model tested, not absolute answers or p-values. When applied to a recently published dataset of Campanian pollen, we find evidence that supports two plant communities separated by a transitional zone of unknown size. A similar case study of ceratopsid dinosaurs using phylogenetic community dissimilarity provided no evidence of a biogeographical pattern, but this case study suffers from a lack of data to accurately discriminate and/or too much temporal mixing. Future research aiming to reconstruct the distribution of organisms across a landscape has a statistical-based method for determining what biogeographic distributional model best matches the available data., (© 2022 The Authors. The Anatomical Record published by Wiley Periodicals LLC on behalf of American Association for Anatomy.)

Background: Cognitive-behavioural therapy (CBT) has been shown to be an effective treatment for depression and anxiety. However, most research has focused on the sum scores of symptoms. Relatively little is known about how individual symptoms respond., Methods: Longitudinal models were used to explore how depression and generalised anxiety symptoms behave over the course of CBT in a retrospective, observational cohort of patients from primary care settings ( n = 5306). Logistic mixed models were used to examine the probability of being symptom-free across CBT appointments, using the 9-item Patient Health Questionnaire and the 7-item Generalised Anxiety Disorder scale as measures., Results: All symptoms improve across CBT treatment. The results suggest that low mood/hopelessness and guilt/worthlessness improved quickest relative to other depressive symptoms, with sleeping problems, appetite changes, and psychomotor retardation/agitation improving relatively slower. Uncontrollable worry and too much worry were the anxiety symptoms that improved fastest; irritability and restlessness improved the slowest., Conclusions: This research suggests there is a benefit to examining symptoms rather than sum scores alone. Investigations of symptoms provide the potential for precision psychiatry and may explain some of the heterogeneity observed in clinical outcomes when only sum scores are considered.

Background: Various effective psychotherapies exist for the treatment of depression; however, only approximately half of patients recover after treatment. In efforts to improve clinical outcomes, research has focused on personalised psychotherapy - an attempt to match patients to treatments they are most likely to respond to., Aim: The present research aimed to evaluate the benefit of a data-driven model to support clinical decision-making in differential treatment allocation to cognitive-behavioural therapy versus counselling for depression., Method: The present analysis used electronic healthcare records from primary care psychological therapy services for patients receiving cognitive-behavioural therapy ( n = 14 544) and counselling for depression ( n = 4725). A linear regression with baseline sociodemographic and clinical characteristics was used to differentially predict post-treatment Patient Health Questionnaire (PHQ-9) scores between the two treatments. The benefit of differential prescription was evaluated in a held-out validation sample., Results: On average, patients who received their model-indicated optimal treatment saw a greater improvement (by 1.78 PHQ-9 points). This translated into 4-10% more patients achieving clinically meaningful changes. However, for individual patients, the estimated differences in benefits of treatments were small and rarely met the threshold for minimal clinically important differences., Conclusion: Precision prescription of psychotherapy based on sociodemographic and clinical characteristics is unlikely to produce large benefits for individual patients. However, the benefits may be meaningful from an aggregate public health perspective when applied at scale.

Distributed virtual environments (DVEs) are challenging to create as the goals of consistency and responsiveness become contradictory under increasing latency. DVEs have been considered as both distributed transactional databases and force-reflection systems. Both are good approaches, but they do have drawbacks. Transactional systems do not support Level 3 (L3) collaboration: manipulating the same degree-of-freedom at the same time. Force-reflection requires a client-server architecture and stabilisation techniques. With Consensus Based Networking (CBN), we suggest DVEs be considered as a distributed data-fusion problem. Many simulations run in parallel and exchange their states, with remote states integrated with continous authority. Over time the exchanges average out local differences, performing a distribued-average of a consistent, shared state. CBN aims to build simulations that are highly responsive, but consistent enough for use cases such as the piano-movers problem. CBN's support for heterogeneous nodes can transparently couple different input methods, avoid the requirement of determinism, and provide more options for personal control over the shared experience. Our work is early, however we demonstrate many successes, including L3 collaboration in room-scale VR, 1000's of interacting objects, complex configurations such as stacking, and transparent coupling of haptic devices. These have been shown before, but each with a different technique; CBN supports them all within a single, unified system.

Electrophysiological oscillations in the brain have been shown to occur as multicycle events, with onset and offset dependent on behavioral and cognitive state. To provide a baseline for state-related and task-related events, we quantified oscillation features in resting-state recordings. We developed an open-source wavelet-based tool to detect and characterize such oscillation events (OEvents) and exemplify the use of this tool in both simulations and two invasively-recorded electrophysiology datasets: one from human, and one from nonhuman primate (NHP) auditory system. After removing incidentally occurring event-related potentials (ERPs), we used OEvents to quantify oscillation features. We identified ∼2 million oscillation events, classified within traditional frequency bands: δ, θ, α, β, low γ, γ, and high γ. Oscillation events of 1-44 cycles could be identified in at least one frequency band 90% of the time in human and NHP recordings. Individual oscillation events were characterized by nonconstant frequency and amplitude. This result necessarily contrasts with prior studies which assumed frequency constancy, but is consistent with evidence from event-associated oscillations. We measured oscillation event duration, frequency span, and waveform shape. Oscillations tended to exhibit multiple cycles per event, verifiable by comparing filtered to unfiltered waveforms. In addition to the clear intraevent rhythmicity, there was also evidence of interevent rhythmicity within bands, demonstrated by finding that coefficient of variation of interval distributions and Fano factor (FF) measures differed significantly from a Poisson distribution assumption. Overall, our study provides an easy-to-use tool to study oscillation events at the single-trial level or in ongoing recordings, and demonstrates that rhythmic, multicycle oscillation events dominate auditory cortical dynamics., (Copyright © 2022 Neymotin et al.)

Aging is associated with impairment in postural control in humans. While dogs are a powerful model for the study of aging, the associations between age and postural control in this species have not yet been elucidated. The aims of this work were to establish a reliable protocol to measure center of pressure excursions in standing dogs and to determine age-related changes in postural sway. Data were obtained from 40 healthy adult dogs (Group A) and 28 senior dogs (Group B) during seven trials (within one session of data collection) of quiet standing on a pressure sensitive walkway system. Velocity, acceleration, root mean square, 95% ellipse area, range and frequency revolve were recorded as measures of postural sway. In Group A, reliability was assessed with intraclass correlation, and the effect of morphometric variables was evaluated using linear regression. By means of stepwise linear regression we determined that root mean square overall and acceleration in the craniocaudal direction were the best variables able to discriminate between Group A and Group B. The relationship between these two center-of-pressure (COP) measures and the dogs' fractional lifespan was examined in both groups and the role of pain and proprioceptive deficits was evaluated in Group B. All measures except for frequency revolve showed good to excellent reliability. Weight, height and length were correlated with most of the measures. Fractional lifespan impacted postural control in Group B but not Group A. Joint pain and its interaction with proprioceptive deficits influence postural sway especially in the acceleration in the craniocaudal direction, while fractional lifespan was most important in the overall COP displacement. In conclusion, our study found that pressure sensitive walkway systems are a reliable tool to evaluate postural sway in dogs; and that postural sway is affected by morphometric parameters and increases with age and joint pain., Competing Interests: The authors have declared that no competing interests exist.

Herein we report the use of Chaperonin-Containing TCP-1 (CCT or TRiC) as a marker to detect circulating tumor cells (CTCs) that are shed from tumors during oncogenesis. Most detection methods used in liquid biopsy approaches for enumeration of CTCs from blood, employ epithelial markers like cytokeratin (CK). However, such markers provide little information on the potential of these shed tumor cells, which are normally short-lived, to seed metastatic sites. To identify a marker that could go beyond enumeration and provide actionable data on CTCs, we evaluated CCT. CCT is a protein-folding complex composed of eight subunits. Previously, we found that expression of the second subunit (CCT2 or CCTβ) inversely correlated with cancer patient survival and was essential for tumorigenesis in mice, driving tumor-promoting processes like proliferation and anchorage-independent growth. In this study, we examined CCT2 expression in cancer compared to normal tissues and found statistically significant increases in tumors. Because not all blood samples from cancer patients contain detectable CTCs, we used the approach of spiking a known number of cancer cells into blood from healthy donors to test a liquid biopsy approach using CCT2 to distinguish rare cancer cells from the large number of non-cancer cells in blood. Using a clinically validated method for capturing CTCs, we evaluated detection of intracellular CCT2 staining for visualization of breast cancer and small cell lung (SCLC) cancer cells. We demonstrated that CCT2 staining could be incorporated into a CTC capture and staining protocol, providing biologically relevant information to improve detection of cancer cells shed in blood. These results were confirmed with a pilot study of blood from SCLC patients. Our studies demonstrate that detection of CCT2 could identify rare cancer cells in blood and has application in liquid biopsy approaches to enhance the use of minimally invasive methods for cancer diagnosis., Competing Interests: We have read the journal’s policy and one of the authors of this manuscript (Dr. Annette Khaled) has the following competing interests: [shareholder in Seva Therapeutics, Inc.] This commercial entity holds a license to use intellectual property developed by the inventor (Dr. Khaled) and provided no funding and had no role in the design, preparation, or submission of this manuscript and did not employ any of the authors. This competing interest does not alter our adherence to PLOS ONE policies on sharing data and materials.

Excessive barking is a major source of noise pollution in dog kennels and negatively impacts welfare. Because resources are often limited, minimizing barking in the simplest and most easily implementable way is imperative. This pilot study implemented a Quiet Kennel Exercise (QKE) that utilized classical counterconditioning to change the dogs' negative emotional state (which can lead to barking) to a more positive emotional state. Therefore, barking motivation is reduced, so barking should decrease. This study aims to show proof of concept that decreasing barking through classical counterconditioning is effective. It was conducted in one ward of day-time boarding kennels at North Carolina State University College of Veterinary Medicine. Data was collected three times per day and included decibel readings, number of dogs present, and number of dogs barking during a 5-day initial baseline and 10-day intervention period. During baseline, people passing through the ward acted as they normally would. During intervention, passersby were asked to simply toss each dog a treat regardless of the dogs' behaviors in the kennel. Descriptive results show improvement in maximum level of barking after QKE, fewer dogs barking over time, dogs barking less each time, and the most improvement noted in the afternoon.

Substantial molecular and morphological character differences lead us to the description of a new species of the genus Pristimantis from the cloud forest of Cerro Chucantí, Maje Mountains, Darien Province, as well as from several other mountain ranges in eastern and central Panama. Pristimantisgretathunbergae sp. nov. is a sister species to the allopatric P.erythropleura-penelopus group from northern Colombia with a mtDNA sequence divergence of > 4.4% at 16S and > 14.6% at COI. Its closest congener in sympatry is P.cruentus that differs by a large sequence divergence of > 9.6% in 16S mtDNA and 19.0% at COI, and from which it differs also by ventral and groin coloration, unusually prominent black eyes, a contrasting light upper lip, commonly a single conical to spine-like tubercle on the upper eyelid, and a larger head. While the habitat continuity at most sites in eastern Panama is moderate, habitats in central Panama are severely fragmented. Cerro Chucantí and the surrounding Maje Mountains are highly threatened by rapid deforestation and replaced by plantations and cattle pastures. Thus, investigations on the ecology of the new species and its population status, especially at the type locality, are highly recommended. As a flagship species, this new frog can help to preserve the Chucantí cloud forest including several recently described species known only from this isolated area in eastern Panama., (Konrad Mebert, Macario González-Pinzón, Madian Miranda, Edgardo Griffith, Milan Vesely, P. Lennart Schmid, Abel Batista.)

Background: This implementation feasibility study was conducted to determine whether an evidence-based parent-implemented distance-learning intervention model for young children at high likelihood of having ASD could be implemented at fidelity by Part C community providers and by parents in low-resource communities., Methods: The study used a community-academic partnership model to adapt an evidence-based intervention tested in the current pilot trial involving randomization by agency in four states and enrollment of 35 coaches and 34 parent-family dyads. After baseline data were gathered, providers in the experimental group received 12-15 h of training while control providers received six webinars on early development. Providers delivered 6 months of intervention with children-families, concluding with data collection. Regression analyses were used to model outcomes of the coach behaviors, the parent fidelity ratings, and child outcomes., Results: A block design model-building approach was used to test the null model followed by the inclusion of group as a predictor, and finally the inclusion of the planned covariates. Model fit was examined using changes in R 2 and F-statistic. As hypothesized, results demonstrated significant gains in (1) experimental provider fidelity of coaching implementation compared to the control group; and (2) experimental parent fidelity of implementation compared to the control group. There were no significant differences between groups on child developmental scores., Conclusions: Even though the experimental parent group averaged less than 30 min of intervention weekly with providers in the 6 months, both providers and parents demonstrated statistically significant gains on the fidelity of implementation scores with moderate effect sizes compared to control groups. Since child changes in parent-mediated models are dependent upon the parents' ability to deliver the intervention, and since parent delivery is dependent upon providers who are coaching the parents, these results demonstrated that two of these three links of the chain were positively affected by the experimental implementation model. However, a lack of significant differences in child group gains suggests that further work is needed on this model. Factors to consider include the amount of contact with the provider, the amount of practice children experience, the amount of contact both providers and parents spend on training materials, and motivational strategies for parents, among others., Trial Registration: Registry of Efficacy and Effectiveness Studies: #4360, registered 1xx, October, 2020 - Retrospectively registered, https://sreereg.icpsr.umich.edu/sreereg/., (© 2022. The Author(s).)

Objectives: Fear of relapse (FOR) after experiencing psychosis has been found to predict actual relapse; however, potential mechanisms underlying this relationship have not been investigated. Negative appraisals of 'prodromal symptoms' are believed to play an important role in both psychosis and mental health anxiety (MHA). This study aimed to explore whether people in recovery from psychosis or anxiety disorders show an enduring tendency to negatively interpret ambiguous experiences both related and less related to their previous mental health difficulty relative to controls., Design: Cross-sectional between-groups questionnaire design., Methods: Participants self-reported as in recovery from psychosis (n = 33) or anxiety (n = 77) or without previous experience of mental health problems (n = 61) were recruited online or via NHS services. Interpretations of psychosis-like, anxiety-like, and external-control experiences were measured using the newly developed Experiences Interpretation Questionnaire (EIQ). MHA and FOR were measured using self-report questionnaires., Results: People in recovery from psychosis interpreted psychosis-like experiences significantly more negatively than the other groups. Negative interpretations of anxiety-like experiences were greater than controls but comparable between mental health groups. Contrary to predictions, FOR was not significantly different between the mental health groups. MHA and FOR did not significantly predict negative interpretations of psychosis-like items in the psychosis group, however, MHA predicted negative interpretations of anxiety-like items in the anxiety group. The EIQ subscales demonstrated good test-retest reliability., Conclusions: People in self-defined recovery from psychosis or anxiety are more likely to negatively interpret ambiguous experiences relating to their previous mental health difficulties. Clinical and future research implications are outlined., Practitioner Points: People in recovery from psychosis or anxiety appraise possible symptoms of their previous difficulties negatively/catastrophically (as indicating relapse) relative to those without prior MH problems. Clinicians should consider attending to how people in recovery appraise possible symptoms when encouraging early signs monitoring as part of relapse prevention. This may be important to ensure that self-monitoring leads to helpful responses rather than being counterproductive, with catastrophic interpretations leading to anxiety and thus increasing the risk of relapse. Interventions drawing on CBT principles to address catastrophic interpretations of possible symptoms may potentially be a useful addition to relapse prevention work; in psychosis this may also include symptoms of anxiety., (© 2021 The Authors. British Journal of Clinical Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)