Technology-based Cognitive Behavioral Therapy Interventions.

Technology-delivered cognitive behavioral therapy (CBT) has enabled more people to access effective, affordable mental health care. This study provides an overview of the most common types of technology-delivered CBT, including Internet-delivered, smartphone app, and telehealth CBT, as well as their evidence for the treatment of a range of mental health conditions. We discuss gaps in the existing evidence and future directions in the field for the use of technology CBT interventions.

Multiple cis-regulatory elements control prox1a expression in distinct lymphatic vascular beds.

During embryonic development, lymphatic endothelial cell (LEC) precursors are distinguished from blood endothelial cells by the expression of Prospero-related homeobox 1 (Prox1), which is essential for lymphatic vasculature formation in mouse and zebrafish. Prox1 expression initiation precedes LEC sprouting and migration, serving as the marker of specified LECs. Despite its crucial role in lymphatic development, Prox1 upstream regulation in LECs remains to be uncovered. SOX18 and COUP-TFII are thought to regulate Prox1 in mice by binding its promoter region. However, the specific regulation of Prox1 expression in LECs remains to be studied in detail. Here, we used evolutionary conservation and chromatin accessibility to identify enhancers located in the proximity of zebrafish prox1a active in developing LECs. We confirmed the functional role of the identified sequences through CRISPR/Cas9 mutagenesis of a lymphatic valve enhancer. The deletion of this region results in impaired valve morphology and function. Overall, our results reveal an intricate control of prox1a expression through a collection of enhancers. Ray-finned fish-specific distal enhancers drive pan-lymphatic expression, whereas vertebrate-conserved proximal enhancers refine expression in functionally distinct subsets of lymphatic endothelium.

An assessment of nicotine pharmacokinetics and subjective effects of the pulze heated tobacco system compared with cigarettes.

Nicotine delivery and subjective effects are determinants of the ability of potentially less harmful tobacco products such as heated tobacco products (HTPs) to support adult smokers in switching away from cigarettes, and therefore to support tobacco harm reduction. This open-label, randomised, crossover, clinical study in 24 healthy adult smokers study assessed nicotine pharmacokinetics and subjective effects of the Pulze Heated Tobacco System (HTS; Pulze HTP device and three iD stick variants-Intense American Blend, Regular American Blend and Regular Menthol) compared with subjects' usual brand cigarettes (UBC). Cmax and AUCt were highest for UBC and significantly lower for each Pulze HTS variant. Cmax and AUCt were significantly higher for Intense American Blend compared with Regular American Blend, while AUCt was significantly higher for Intense American Blend compared with Regular Menthol. Median Tmax was lowest (i.e., nicotine delivery was fastest) for subjects' usual brand cigarettes and similar across the iD stick variants, although no between-product differences were statistically significant. All study products reduced urges to smoke; this effect was greatest for cigarettes although this was not statistically significant. Product evaluation scores for each Pulze HTS variant in the domains of 'satisfaction', 'psychological reward' and 'relief' were similar, and lower than those for UBC. These data demonstrate that the Pulze HTS effectively delivers nicotine and generates positive subjective effects, including satisfaction and reduced urge to smoke. This supports the conclusion that the Pulze HTS may be an acceptable alternative to cigarettes for adult smokers while having a lower abuse liability than cigarettes.

Twenty-eight day repeated exposure of human 3D bronchial epithelial model to heated tobacco aerosols indicates decreased toxicological responses compared to cigarette smoke.

Tobacco harm reduction (THR) involves providing adult smokers with potentially reduced harm modes of nicotine delivery as alternatives to smoking combustible cigarettes. Heated tobacco products (HTPs) form a category with THR potential due to their ability to deliver nicotine and flavours through heating, not burning, tobacco. By eliminating burning, heated tobacco does not produce smoke but an aerosol which contains fewer and lower levels of harmful chemicals compared to cigarette smoke. In this study we assessed the in vitro toxicological profiles of two prototype HTPs' aerosols compared to the 1R6F reference cigarette using the 3D human (bronchial) MucilAir™ model. To increase consumer relevance, whole aerosol/smoke exposures were delivered repeatedly across a 28 day period (16, 32, or 48 puffs per exposure). Cytotoxicity (LDH secretion), histology (Alcian Blue/H&E; Muc5AC; FoxJ1 staining), cilia active area and beat frequency and inflammatory marker (IL-6; IL-8; MMP-1; MMP-3; MMP-9; TNFα) levels were assessed. Diluted 1R6F smoke consistently induced greater and earlier effects compared to the prototype HTP aerosols across the endpoints, and in a puff dependent manner. Although some significant changes across the endpoints were induced by exposure to the HTPs, these were substantially less pronounced and less frequently observed, with apparent adaptive responses occurring over the experimental period. Furthermore, these differences between the two product categories were observed at a greater dilution (and generally lower nicotine delivery range) for 1R6F (1R6F smoke diluted 1/14, HTP aerosols diluted 1/2, with air). Overall, the findings demonstrate the THR potential of the prototype HTPs through demonstrated substantial reductions in toxicological outcomes in in vitro 3D human lung models.

Single-cell analysis of lymphatic endothelial cell fate specification and differentiation during zebrafish development.

During development, the lymphatic vasculature forms as a second network derived chiefly from blood vessels. The transdifferentiation of embryonic venous endothelial cells (VECs) into lymphatic endothelial cells (LECs) is a key step in this process. Specification, differentiation and maintenance of LEC fate are all driven by the transcription factor Prox1, yet the downstream mechanisms remain to be elucidated. We here present a single-cell transcriptomic atlas of lymphangiogenesis in zebrafish, revealing new markers and hallmarks of LEC differentiation over four developmental stages. We further profile single-cell transcriptomic and chromatin accessibility changes in zygotic prox1a mutants that are undergoing a LEC-VEC fate shift. Using maternal and zygotic prox1a/prox1b mutants, we determine the earliest transcriptomic changes directed by Prox1 during LEC specification. This work altogether reveals new downstream targets and regulatory regions of the genome controlled by Prox1 and presents evidence that Prox1 specifies LEC fate primarily by limiting blood vascular and haematopoietic fate. This extensive single-cell resource provides new mechanistic insights into the enigmatic role of Prox1 and the control of LEC differentiation in development.

Multiple endpoint in vitro toxicity assessment of a prototype heated tobacco product indicates substantially reduced effects compared to those of combustible cigarette.

This study aimed to compare the aerosol chemistry and in vitro toxicological profiles of two prototype Heated Tobacco Product (p-HTP) variants to the 1R6F Reference Cigarette. In the neutral red uptake screen the p-HTPs were 37-39-fold less potent than 1R6F, in the micronucleus assay, responses to the p-HTPs were 8-22-fold less, and in the Ames test mutagenicity was weak or removed compared to 1R6F. The cardiovascular scratch wound assay revealed 58-fold greater wound healing impairment following exposure to 1R6F smoke extracts than the p-HTPs. Furthermore, in seven cell stress-related high content screening endpoints (cell count, cytochrome c release, mitochondrial membrane potential, GSH depletion, NFkB translocation, phosphorylation of c-jun and phosphorylation of H2AX), at 4 and 24 h, responses were substantially greater to 1R6F smoke extracts at comparable nicotine levels. The reduced in vitro effects of the p-HTPs were attributed to substantial reductions (90-97%) in selected HPHCs measured compared to in 1R6F smoke. The multiple endpoint in vitro assessment approach provides greater mechanistic insight and the first reported toxicological characterisation of these p-HTPs in the literature. Overall, the findings contribute to the growing weight of evidence that HTPs may offer a reduced harm mode of nicotine delivery to adult smokers.

Co-occurring insomnia and anxiety: a randomized controlled trial of internet cognitive behavioral therapy for insomnia versus internet cognitive behavioral therapy for anxiety.

STUDY OBJECTIVES: Insomnia and anxiety are highly prevalent and frequently co-occur. Given limited therapeutic resources and time constraints, the aim of this study was to compare which treatment-internet cognitive behavioral therapy (CBT) for insomnia or internet CBT for anxiety-leads to the best outcomes in individuals with comorbid insomnia and anxiety. METHODS: 120 participants with comorbid insomnia and clinical anxiety (as defined by scores above the clinical cutoff on the insomnia severity index (ISI) and the generalized anxiety disorder 7-item scale (GAD-7)) were randomized to receive internet-based cognitive behavioral therapy (iCBT) for insomnia or iCBT for anxiety. The primary outcome measures were the ISI and the generalized anxiety disorder 7-item scale. Primary outcome measures were assessed before treatment, at mid-treatment, at post-treatment, and 3 months after treatment. Secondary outcome measures assessed depression symptoms, distress, and sleep diary parameters. RESULTS: Participants in both groups experienced large reductions in symptoms of insomnia, anxiety, depression, and distress, as well as improvements in sleep efficiency and total sleep time. Improvements were maintained at follow-up. Crucially, at the end of treatment, the insomnia treatment was more effective in reducing symptoms of insomnia than the anxiety treatment, and equally effective in reducing symptoms of anxiety. Treatment gains were maintained at 3-month follow-up, however, there were no differences between groups at that time point. CONCLUSIONS: These results suggest that in the common case of a patient presenting with comorbid insomnia and anxiety, treatment for insomnia may be the most efficient treatment strategy. TRIAL REGISTRATION: The trial was registered with the Australian and New Zealand Clinical Trials Registry, https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12618001141235. Trial ID: ACTRN12618001141235. Trial name: a comparison of internet-based CBT for insomnia versus internet-based CBT for anxiety in a comorbid sample.

Identifying and Characterizing Medical Advice-Seekers on a Social Media Forum for Buprenorphine Use.

Background: Online communities such as Reddit can provide social support for those recovering from opioid use disorder. However, it is unclear whether and how advice-seekers differ from other users. Our research addresses this gap by identifying key characteristics of r/suboxone users that predict advice-seeking behavior. Objective: The objective of this analysis is to identify and describe advice-seekers on Reddit for buprenorphine-naloxone use using text annotation, social network analysis, and statistical modeling techniques. Methods: We collected 5258 posts and their comments from Reddit between 2014 and 2019. Among 202 posts which met our inclusion criteria, we annotated each post to determine which were advice-seeking (n = 137) or not advice-seeking (n = 65). We also annotated each posting user's buprenorphine-naloxone use status (current versus formerly taking and, if currently taking, whether inducting or tapering versus other stages) and quantified their connectedness using social network analysis. To analyze the relationship between Reddit users' advice-seeking and their social connectivity and medication use status, we constructed four models which varied in their inclusion of explanatory variables for social connectedness and buprenorphine use status. Results: The stepwise model containing "total degree" (p = 0.002), "using: inducting/tapering" (p < 0.001), and "using: other" (p = 0.01) outperformed all other models. Reddit users with fewer connections and who are currently using buprenorphine-naloxone are more likely to seek advice than those who are well-connected and no longer using the medication, respectively. Importantly, advice-seeking behavior is most accurately predicted using a combination of network characteristics and medication use status, rather than either factor alone. Conclusions: Our findings provide insights for the clinical care of people recovering from opioid use disorder and the nature of online medical advice-seeking overall. Clinicians should be especially attentive (e.g., through frequent follow-up) to patients who are inducting or tapering buprenorphine-naloxone or signal limited social support.

Readiness of healthcare providers for e-hospitals: a cross-sectional analysis in China before the COVID-19 period.

OBJECTIVES: The growth and development of smartphones and eHealth technologies have enabled the potential for extended care hospitals (e-hospitals) in China in order to facilitate the success of a primary healthcare centre (PHC)-based integrated delivery model. Although the adoption of e-hospitals is essential, few studies have directed their research towards understanding the perspectives of healthcare providers. This study aims to identify the current readiness of healthcare providers to adopt e-hospital technologies, determine the factors influencing this adoption and describe the perceived facilitators and barriers in regard to working at e-hospitals. DESIGN: A cross-sectional study conducted in Sichuan, China, between June and September 2019. SETTINGS: Information was collected from healthcare providers who have more than 3 years of work experience from a tertiary hospital, secondary hospital, PHCs and private hospital. PARTICIPANTS: 2298 medical professionals were included in this study. OUTCOME MEASURE: This study included a self-administered questionnaire that was used to assess participants' sociodemographic characteristics, online medical practices, willingness to use e-hospitals and perceived facilitators/barriers to working at e-hospitals. Multivariate regression analysis was performed in order to evaluate the independent factors associated with e-hospital work. RESULTS: Overall, 86.3% had a positive response towards working at e-hospitals. Age (p<0.05), familiarity with e-hospitals (p<0.001) and prior work practices in online healthcare settings (p<0.001) were associated with participants' readiness to work at e-hospitals. Gender, education level, professional level, the tier of their affiliated hospital and workload were not statistically associated. Healthcare providers who had positive attitudes towards e-hospitals considered improved efficiency, patient satisfaction, communication among physicians, increased reputation and income, and alleviated workload to be advantages of adoption. The participants who were unwilling to work at e-hospitals perceived lack of time, insufficient authenticity/reliability and underdeveloped policies as potential barriers. CONCLUSION: Improving operative proficiency in electronic devices, accommodating to work schedules, increasing familiarity with e-hospitals and regulating practices will improve the readiness of healthcare providers to work at e-hospitals.

Stakeholder Perceptions About Group B Streptococcus Disease and Potential for Maternal Vaccination in Low- and Middle-Income Countries.

BACKGROUND: To inform the World Health Organization's full value of vaccine assessment for group B Streptococcus (GBS) vaccines, a rapid literature appraisal was conducted to inform the operationalization of maternal GBS vaccination. We found limited published information on stakeholder perceptions of the public health importance of GBS disease and vaccination, and we therefore undertook a multicountry survey. METHODS: An online survey was conducted in late 2019 to collect information on stakeholders' awareness of GBS disease and the priority accorded to vaccination. The survey was distributed by email to 395 representatives of national pediatric, gynecology, and obstetrics associations, national immunization technical advisory groups (NITAGs), national regulatory agencies, academia, and United Nations organizations. RESULTS: Among 101 survey respondents from 66 countries, 36% were pediatricians, 25% obstetricians/gynecologists, 21% immunization specialists, and 18% other public health specialists. More than half (58%) of respondents reported being familiar with GBS disease as a public health problem; familiarity decreased by country income level. Knowledge of GBS disease was greatest in the Americas (68%) and Europe (66%) and lowest in Asia (13%-38%). Perception of GBS disease as a public health problem was highest among pediatricians (71%) and lowest among public health policy makers and NITAG members (30%) across country groupings. Approximately half of respondents (49%) considered the introduction of a GBS vaccine as a priority. CONCLUSIONS: The information obtained will inform the appropriate packaging and presentation of information to address stakeholder perceptions and promote evidence-based decision making on GBS vaccination.

A comprehensive group-based cognitive behavioural treatment for blood-injection-injury phobia.

OBJECTIVES: A key feature of blood-injection-injury (BII) phobia is activation of disgust responses, in addition to fear. Yet, standard treatments have largely neglected addressing disgust responses. The disorder is further complicated by fainting in 75% of sufferers. Moreover, treatments have been traditionally delivered in an individual format, which may not be as efficient as group treatment. The aim of this study was to develop a group-based programme for BII phobia, with components targeting fear, disgust, and fainting, to determine feasibility and effectiveness of such an intervention. METHODS: Participants took part in an 8-session, group-based Cognitive Behavioural Therapy (CBT) programme for BII phobia (N = 40). The key outcome measure was the Multidimensional Blood/Injury Phobia Inventory, which assesses a range of phobic stimuli and responses (including fear, disgust, and fainting). RESULTS: There were significant improvements, with large effect sizes, across symptoms over the course of treatment. Participants with higher disgust sensitivity reported higher pre-treatment symptom severity and greater life interference than those with lower disgust scores. Despite this, neither pre-treatment disgust sensitivity nor fainting history impacted on treatment response. For the first time, however, we showed that greater reductions in disgust to BII stimuli were associated with greater overall symptom reductions, highlighting the importance of disgust in the treatment of this disorder, and potentially others. CONCLUSION: Despite the heterogeneous nature of BII phobia, this group-based, modified CBT intervention was effective in reducing a variety of phobic responses, including fear, disgust, and fainting. PRACTITIONER POINTS: Disgust is a key maintaining factor in blood-injection-injury phobia, which clinicians should consider in their assessment and treatment of this disorder. There is little in the existing literature to guide clinicians in this regard. This study examined a novel group treatment for blood-injection-injury phobia which included strategies to target disgust, in addition to traditional CBT strategies to address fear and fainting. The treatment was feasible and acceptable. Symptoms of fear, disgust, and fainting reduced significantly over treatment. Changes in disgust symptoms were associated with overall symptom changes, however a control group is needed to determine the effects of individual treatment components and to make more robust conclusions about the benefits of this enhanced approach.

Insights into vaccine hesitancy from systems thinking, Rwanda.

OBJECTIVE: To investigate vaccine hesitancy leading to underimmunization and a measles outbreak in Rwanda and to develop a conceptual, community-level model of behavioural factors. METHODS: Local immunization systems in two Rwandan communities (one recently experienced a measles outbreak) were explored using systems thinking, human-centred design and behavioural frameworks. Data were collected between 2018 and 2020 from: discussions with 11 vaccination service providers (i.e. hospital and health centre staff); interviews with 161 children's caregivers at health centres; and nine validation interviews with health centre staff. Factors influencing vaccine hesitancy were categorized using the 3Cs framework: confidence, complacency and convenience. A conceptual model of vaccine hesitancy mechanisms with feedback loops was developed. FINDINGS: A comparison of service providers' and caregivers' perspectives in both rural and peri-urban settings showed that similar factors strengthened vaccine uptake: (i) high trust in vaccines and service providers based on personal relationships with health centre staff; (ii) the connecting role of community health workers; and (iii) a strong sense of community. Factors identified as increasing vaccine hesitancy (e.g. service accessibility and inadequate follow-up) differed between service providers and caregivers and between settings. The conceptual model could be used to explain drivers of the recent measles outbreak and to guide interventions designed to increase vaccine uptake. CONCLUSION: The application of behavioural frameworks and systems thinking revealed vaccine hesitancy mechanisms in Rwandan communities that demonstrate the interrelationship between immunization services and caregivers' vaccination behaviour. Confidence-building social structures and context-dependent challenges that affect vaccine uptake were also identified.

The RNA helicase Ddx21 controls Vegfc-driven developmental lymphangiogenesis by balancing endothelial cell ribosome biogenesis and p53 function.

The development of a functional vasculature requires the coordinated control of cell fate, lineage differentiation and network growth. Cellular proliferation is spatiotemporally regulated in developing vessels, but how this is orchestrated in different lineages is unknown. Here, using a zebrafish genetic screen for lymphatic-deficient mutants, we uncover a mutant for the RNA helicase Ddx21. Ddx21 cell-autonomously regulates lymphatic vessel development. An established regulator of ribosomal RNA synthesis and ribosome biogenesis, Ddx21 is enriched in sprouting venous endothelial cells in response to Vegfc-Flt4 signalling. Ddx21 function is essential for Vegfc-Flt4-driven endothelial cell proliferation. In the absence of Ddx21, endothelial cells show reduced ribosome biogenesis, p53 and p21 upregulation and cell cycle arrest that blocks lymphangiogenesis. Thus, Ddx21 coordinates the lymphatic endothelial cell response to Vegfc-Flt4 signalling by balancing ribosome biogenesis and p53 function. This mechanism may be targetable in diseases of excessive lymphangiogenesis such as cancer metastasis or lymphatic malformation.

Use of a rapid human primary cell-based disease screening model, to compare next generation products to combustible cigarettes.

A growing number of public health bodies, regulators and governments around the world consider electronic vapor products a lower risk alternative to conventional cigarettes. Of critical importance are rapid new approach methodologies to enable the screening of next generation products (NGPs) also known as next generation tobacco and nicotine products. In this study, the activity of conventional cigarette (3R4F) smoke and a range of NGP aerosols (heated tobacco product, hybrid product and electronic vapor product) captured in phosphate buffered saline, were screened by exposing a panel of human cell-based model systems using Biologically Multiplexed Activity Profiling (BioMAP® Diversity PLUS® Panel, Eurofins Discovery). Following exposure, the biological activity for a wide range of biomarkers in the BioMAP panel were compared to determine the presence of toxicity signatures that are associated with specific clinical findings. NGP aerosols were found to be weakly active in the BioMAP Diversity PLUS Panel (≤3/148 biomarkers) whereas significant activity was observed for 3R4F (22/148 biomarkers). Toxicity associated biomarker signatures for 3R4F included immunosuppression, skin irritation and thrombosis, with no toxicity signatures seen for the NGPs. BioMAP profiling could effectively be used to differentiate between complex mixtures of cigarette smoke or NGP aerosol extracts in a panel of human primary cell-based assays. Clinical validation of these results will be critical for confirming the utility of BioMAP for screening NGPs for potential adverse human effects.

Live-imaging of endothelial Erk activity reveals dynamic and sequential signalling events during regenerative angiogenesis.

The formation of new blood vessel networks occurs via angiogenesis during development, tissue repair, and disease. Angiogenesis is regulated by intracellular endothelial signalling pathways, induced downstream of vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs). A major challenge in understanding angiogenesis is interpreting how signalling events occur dynamically within endothelial cell populations during sprouting, proliferation, and migration. Extracellular signal-regulated kinase (Erk) is a central downstream effector of Vegf-signalling and reports the signalling that drives angiogenesis. We generated a vascular Erk biosensor transgenic line in zebrafish using a kinase translocation reporter that allows live-imaging of Erk-signalling dynamics. We demonstrate the utility of this line to live-image Erk activity during physiologically relevant angiogenic events. Further, we reveal dynamic and sequential endothelial cell Erk-signalling events following blood vessel wounding. Initial signalling is dependent upon Ca2+ in the earliest responding endothelial cells, but is independent of Vegfr-signalling and local inflammation. The sustained regenerative response, however, involves a Vegfr-dependent mechanism that initiates concomitantly with the wound inflammatory response. This work reveals a highly dynamic sequence of signalling events in regenerative angiogenesis and validates a new resource for the study of vascular Erk-signalling in real-time.

Complete Genome Sequences of Microbacterium Bacteriophages Danno, Otwor, and Scumberland, Isolated in Clarksville, Tennessee.

This paper reports the genome sequences of bacteriophages isolated from soil samples using Microbacterium foliorum Phages Danno and Otwor (cluster EE) have genomes of 17,452 bp and 17,454 bp, respectively, and 25 predicted genes. The phage Scumberland (cluster EC) has a genome of 53,276 bp with 92 predicted genes.

Comorbid personality difficulties are not associated with poorer outcomes for online cognitive behaviour therapy for symptoms of anxiety and depression.

Little is known about the prevalence and impact on treatment of comorbid personality disorders for adults undertaking online cognitive behaviour therapy (internet-delivered or internet-based cognitive behaviour therapy (iCBT)) for anxiety and depressive disorders. This study explored how common comorbid personality difficulties were in a large sample of consecutive patients (N = 1 132) seeking iCBT for their symptoms of anxiety and depression in routine care settings. Patients completed the Standardized Assessment of Personality-abbreviated Scale Self-Report prior to commencing an iCBT programme, as well as completing assessments of anxiety and depression symptom severity and psychological distress pre-iCBT and post-iCBT. Consistent with previous studies, a high proportion of the sample (62.6%) reported experiencing comorbid personality difficulties. However, comorbid personality difficulties were not significantly associated with poorer treatment adherence or higher post-treatment symptom severity or psychological distress (controlling for baseline symptom severity, demographic characteristics and treatment variables). Current findings support an inclusive approach to iCBT provision where comorbid personality difficulties do not appear to be a contraindication for treatment. © 2021 John Wiley & Sons, Ltd.