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Background: In internet-delivered cognitive behavioural therapy (ICBT) programs, beyond standardized core ICBT lessons, brief additional resources are sometimes available to clients to address comorbid concerns or offer additional information/strategies. These resources remain understudied in terms of how they are selected and perceived by clients, as well as their relationship to satisfaction and outcomes. Methods: Among clients (N = 793) enrolled in a 5-lesson transdiagnostic ICBT course, we examined client use and perceptions of 18 additional resources at 8 weeks in terms of whether clients found resources informative (yes/no) and or helpful (yes/no). Resources elaborated on cognitive strategies (managing beliefs, risk calculation) or on managing specific problems (agricultural stress, alcohol misuse, anger, assertiveness, chronic conditions, communication, grief, health anxiety, motivation, pain, panic, postpartum depression/anxiety, PTSD, sleep, workplace accomodations, worry). Clients also completed symptom measures and ICBT satisfaction questions at 8 weeks. Results: Approximately 50 % (n = 398) of clients rated the resources and, on average, clients reported that 3.35 (SD = 3.34) resources were informative and 2.35 (SD = 2.52) resources were helpful as measured by direct questions developed for this study. Higher pre-treatment PTSD and GAD scores were related to a greater number of resources perceived as informative and or helpful. Rating more resources as informative and or helpful had a weak but positive association with ICBT satisfaction and depression, anxiety, PTSD and insomnia change scores. Limitations of the study include that 31 % (n = 245) did not respond to questions about use of resources and 18.9 % (n = 150) said they did not review resources. Conclusions: There is considerable use of diverse additional resources in ICBT in routine care. Associations suggest that clients are using resources to personalize treatment to their needs and these resources are associated with treatment satisfaction and outcomes. The correlational associations between symptoms and perceived helpfulness of resources can help inform personalization algorithms to optimize ICBT delivery for clients. Further research on how to match clients with, encourage use of, and maximize benefits of resources would be beneficial.

Summary: Background: Ross River virus (RRV), Australia's most notifiable vector-borne disease transmitted through mosquito bites, has seen increased transmission due to rising temperatures. Quantifying the burden of RRV infection attributable to increasing temperatures (both current and future) is pivotal to inform prevention strategies in the context of climate change. Methods: As RRV-related deaths are rare in Australia, we utilised years lived with disability (YLDs) associated with RRV infection data from the Australian Institute of Health and Welfare (AIHW) Burden of Disease database between 2003 and 2018. We obtained relative risks per 1 °C temperature increase in RRV infection from a previous meta-analysis. Exposure distributions for each Köppen-Geiger climate zone were calculated separately and compared with the theoretical-minimum-risk exposure distribution to calculate RRV burden attributable to increasing temperatures during the baseline period (2003–2018), and projected future burdens for the 2030s and 2050s under two greenhouse gas emission scenarios (Representative Concentration Pathways, RCP 4.5 and RCP 8.5), two adaptation scenarios, and different population growth series. Findings: During the baseline period (2003–2018), increasing mean temperatures contributed to 35.8 (±0.5) YLDs (19.1%) of the observed RRV burden in Australia. The mean temperature attributable RRV burden varied across climate zones and jurisdictions. Under both RCP scenarios, the projected RRV burden is estimated to increase in the future despite adaptation scenarios. By the 2050s, without adaptation, the RRV burden could reach 45.8 YLDs under RCP4.5 and 51.1 YLDs under RCP8.5. Implementing a 10% adaptation strategy could reduce RRV burden to 41.8 and 46.4 YLDs, respectively. Interpretation: These findings provide scientific evidence for informing policy decisions and guiding resource allocation for mitigating the future RRV burden. The current findings underscore the need to develop location-specific adaptation strategies for climate-sensitive disease control and prevention. Funding: Australian Research Council Discovery Program.

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer associated with shorter survival and a higher likelihood of recurrence. In early TNBC, platinum chemotherapy has been shown to improve pathological complete response (pCR); however, its effect on long-term survival outcomes has not been fully elucidated. Methods: Randomised controlled trials examining neoadjuvant or adjuvant platinum chemotherapy for early TNBC were included. Primary outcomes were disease-free survival (DFS) and overall survival (OS). Secondary outcomes were pCR, treatment adherence, grade III or IV toxicity related to chemotherapy, and quality of life. Results: From 3972 records, we included 20 published studies. All studies reporting DFS and OS used carboplatin. Inclusion of platinum chemotherapy improved DFS (neoadjuvant: hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.53 to 0.75; adjuvant: HR 0.69, 95% CI 0.54 to 0.88) and OS (neoadjuvant: HR 0.69, 95% CI 0.55 to 0.86; adjuvant: 0.70, 95% CI 0.50 to 0.96). Our analysis confirmed platinum chemotherapy increased pCR rates (risk ratio (RR) 1.44, 95% CI 1.31 to 1.59). There were no differences seen in examined subgroups. Platinum chemotherapy was associated with reduced dose intensity and increased haematological toxicity. Conclusions: Platinum-based chemotherapy using carboplatin in the adjuvant or neoadjuvant setting improves long-term outcomes of DFS and OS in early TNBC, with no evidence of differences by subgroup. This was at the cost of more frequent chemotherapy delays and dose reductions, and greater haematological toxicity. These findings support the use of platinum-based chemotherapy for people with early TNBC.

Objectives: HIV and malaria coinfection impacts disease management and clinical outcomes. This study investigated hematologic abnormalities in malaria-asymptomatic people living with HIV (PLHIV) in regions with differing malaria transmission. Methods: Study participants were enrolled in the African Cohort Study: two sites in Kenya, one in Uganda, and one in Nigeria. Data was collected at enrollment and every 6 months. Logistic regression estimated odds ratios for associations between HIV/malaria status and anemia, thrombocytopenia, and leucopenia. Results: Samples from 1587 participants with one or more visits comprising 1471 (92.7%) from PLHIV and 116 (7.3%) without HIV were analyzed. Parasite point prevalence significantly differed across the study sites (P

Transdiagnostic Internet-delivered cognitive behaviour therapy (ICBT) for patients experiencing anxiety and depression can produce large improvements in symptoms. Comorbid insomnia is common among individuals seeking treatment for anxiety and depression, yet transdiagnostic ICBT rarely targets insomnia and many ICBT patients report that symptoms of insomnia remain after treatment. This trial explored the impact of including a brief intervention for insomnia alongside an existing transdiagnostic ICBT course that included brief weekly therapist assistance. Patients were randomly assigned to receive either the Standard transdiagnostic (n = 75) or a Sleep-Enhanced course (n = 142), which included information on sleep restriction and stimulus control. Intent-to-treat analyses using generalized estimating equation (GEE) showed significant, large reductions in all primary outcomes (insomnia: d = 0.96, 95 % CI [0.68, 1.24]; depression: d = 1.04, 95 % CI [0.76, 1.33]; and anxiety: d = 1.23, 95 % CI [0.94, 1.52]) from pre-treatment to post-treatment, with changes maintained at 3-months. Patients assigned to the Sleep-Enhanced course reported larger reductions in insomnia than patients in the Standard transdiagnostic course (Cohen's d = 0.31, 95 % CI [0.034, 0.60]) at post-treatment but no significant between-group differences in any of the primary outcomes were found at follow-up. Patient-reported adherence to sleep restriction guidelines (p = .03), but not stimulus control instructions (p = .84) was associated with greater reductions in insomnia symptoms during the course. Overall, patients who received the Sleep-Enhanced course were satisfied with the materials and most patients reported making sleep behaviour changes. The trial results demonstrate that including a brief intervention targeting insomnia can be beneficial for many patients who enroll in ICBT primarily for symptoms related to anxiety and depression.

Agriculture producers are less likely to seek or to receive mental health services compared to the general population. Additional research is needed to identify effective and accessible mental health interventions for this underserved population. This study used a mixed-methods approach and open trial design to examine the acceptability and effectiveness of therapist-assisted internet-delivered cognitive behaviour therapy (ICBT) supplemented with an additional agricultural resource for clients from agricultural backgrounds receiving ICBT in routine care. Clients (n = 34) participated in an online, five-lesson course that provided psychoeducation and strategies for dealing with symptoms of anxiety and depression, with weekly therapist assistance. Clients also received a tailored resource (developed with input from those with an agricultural background) providing culturally specific information and case stories pertinent to agricultural communities. Intent-to-treat analyses showed that the ICBT program was effective in reducing anxiety and depression symptoms among the agricultural population. Large within-group pre-to-post-treatment Cohen's effect sizes of d = 1.14, 95 % CI [0.41, 1.86] and d = 1.15, 95 % CI [0.42, 1.87] were found for depression and anxiety, respectively and comparable to the same program offered to the general population. Clients also experienced reductions in perceived stress and significant improvements in resiliency from pre- to post-treatment. Semi-structured interviews conducted at post-treatment with the agricultural clients (n = 31) on their experiences with ICBT identified four main themes: perceived strengths of ICBT and the tailored resource, suggestions to improve service delivery for agriculture producers, clients experienced internal and external challenges to participating in ICBT, and the positive impact of the course reached beyond the client. Very high satisfaction rates were found. These results provide support for the acceptability and effectiveness of ICBT with a tailored resource offered in routine care among agriculture producers.

Internet-delivered Cognitive-Behavioural Therapy (ICBT) aims to support people with mental health concerns using online treatment materials. Client stories (either real or a composite based on many clients) are often used in ICBT to facilitate learning. However, these stories remain understudied in terms of how they are perceived by clients, as well as their relationship to ICBT engagement, satisfaction, and outcomes. Among a sample of 324 clients enrolled in transdiagnostic ICBT targeting symptoms of depression and anxiety, we examined client perceptions of stories through mixed-method qualitative (open-ended) and quantitative (closed-ended) data collection. Specifically, 234 (72.22 %) clients responded to questions about stories at 4 weeks and 221 (68.21 %) responded to questions at 8 weeks. Most clients who responded to questions endorsed reviewing at least some stories (79.06 % at 4 weeks, 71.95 % at 8 weeks). Moreover, they rated stories positively in terms of being relatable, making clients feel less alone, increasing knowledge, providing ideas for how to use skills, and motivating clients to use skills. These perceptions of stories remained stable over the course of treatment. Stories were perceived more positively among those with lower symptom severity at 8 weeks as well as those who were more satisfied with ICBT at 8 weeks. Story perceptions at 4 weeks were predictive of decreased post-treatment anxiety symptom severity but not depression while controlling for baseline scores, age, and education. 26.49 % of clients at 4 weeks who reviewed stories and 33.33 % at 8 weeks provided suggestions about how to improve stories. In a qualitative analysis, we found 5 categories of suggestions including increasing the variety of issues and relatability of stories, ensuring the stories are realistic, refining the formatting, and making the stories shorter. Overall, this study provides insights into how client stories could be improved to play a more significant role in future ICBT programs.

Summary: Background: The dual impacts of a warming climate and population ageing lead to an increasing kidney disease prevalence, highlighting the importance of quantifying the burden of kidney disease (BoKD) attributable to high temperature, yet studies on this subject are limited. The study aims to quantify the BoKD attributable to high temperatures in Australia across all states and territories, and project future BoKD under climatic, population and adaptation scenarios. Methods: Data on disability-adjusted-life-years (DALYs) due to kidney disease, including years of life lost (YLL), and years lived with disability (YLD), were collected during 2003–2018 (baseline) across all states and territories in Australia. The temperature-response association was estimated using a meta-regression model. Future temperature projections were calculated using eight downscaled climate models to estimate changes in attributable BoKD centred around 2030s and 2050s, under two greenhouse gas emissions scenarios (RCP4.5 and RCP8.5), while considering changes in population size and age structure, and human adaptation to climate change. Findings: Over the baseline (2003–2018), high-temperature contributed to 2.7% (Standard Deviation: 0.4%) of the observed BoKD in Australia. The future population attributable fraction and the attributable BoKD, projected using RCP4.5 and RCP8.5, showed a gradually increasing trend when assuming no human adaptation. Future projections were most strongly influenced by the population change, with the high temperature-related BoKD increasing by 18.4–67.4% compared to the baseline under constant population and by 100.2–291.2% when accounting for changes in population size and age structure. However, when human adaptation was adopted (from no to partial to full), the high temperature-related BoKD became smaller. Interpretation: It is expected that increasing high temperature exposure will substantially contribute to higher BoKD across Australia, underscoring the urgent need for public health interventions to mitigate the negative health impacts of a warming climate on BoKD. Funding: Australian Research Council Discovery Program.

Virtual Reality technology has gained increased attention due to its capacity to provide immersive and interactive experiences to its users. Although increasing evidence has suggested that incorporating multisensory components in VR can promote the sense of presence and improve user performance, most of the current VR applications are limited to visual and auditory senses. In this article, a novel method of integrating thermal-related devices (heat lamps and fans) into Virtual Reality was developed. Automated interaction with the thermal-related devices was achieved using Arduino-based control module with its program embedded into the VR platform-Unity. The functions, hardware and software requirements of the multisensory Virtual Reality system as well as the step-by-step procedures are detailed to provide a reproducible workflow for future applications. • A practical workflow to integrate thermal apparatus into Virtual Reality. • Dynamic airflow and radiative heating incorporated into Virtual Reality. • Automated process to allow user interaction with the thermal components in Virtual Reality.

Public safety personnel (PSP) face high rates of mental health problems and many barriers to care. Initial outcomes of transdiagnostic internet-delivered cognitive behavioural therapy (ICBT) tailored for PSP are promising, but prior research has not evaluated outcomes of PTSD-specific ICBT among PSP or PSP's preferences for transdiagnostic or PTSD-specific ICBT. The current paper presents the initial outcomes (N = 150) of a mixed-methods observational study designed to (a) investigate preferences for transdiagnostic or PTSD-specific ICBT among PSP with elevated symptoms of PTSD and/or a primary concern with PTSD symptoms and (b) explore potential differences in client engagement, satisfaction, and symptom changes between the two forms of ICBT. PSP completed questionnaires before and after their preferred ICBT program. Mixed-methods analyses included generalized estimating equations, descriptive statistics, and inductive conventional qualitative content analysis. More clients (n = 85; 57 %) selected transdiagnostic ICBT than PTSD-specific ICBT (n = 65; 43 %), but the difference in the number of clients who selected each course was not statistically significant. Clients in both ICBT programs reported similar and favorable treatment satisfaction (e.g., 98 % would recommend the course to a friend), treatment engagement (i.e., 69 % accessed at least four of the five lessons), and pre-post improvement in symptoms (e.g., Hedges' g = 0.81 for reduction in PTSD symptom). Transdiagnostic ICBT resulted in greater reductions in symptoms of panic disorder than PTSD-specific ICBT. Qualitative analyses showed similarities across the ICBT programs in client feedback. The current study provides further evidence supporting the use and outcomes of ICBT for PSP in both transdiagnostic and disorder-specific formats. Implications for the literatures on PSP mental health and ICBT, as well as practical recommendations, are discussed.

Anxiety and depressive disorders are common, often chronic and result in significant disability and distress. The delivery of psychological interventions via the internet is now recognised to be a safe and effective way to treat these disorders. The predominant therapeutic model in clinical trials and in routine care has been cognitive-behavioural therapy (CBT), which helps patients identify and modify unhelpful thoughts and behaviours. However, other models of treatment for anxiety and depression, such as acceptance and commitment therapy (ACT), which uses the examination of both positive and negative experiences in the service of living a personally meaningful and values-based life, have been developed and tested, although most of these interventions are long and require more clinician support to ensure adherence and achieve positive outcomes. The aim of the present study was to examine the feasibility of a new brief, clinician supported transdiagnostic internet-delivered (iACT) program, designed to treat symptoms of both anxiety and depression and improve social function. A single-group open trial was conducted on 24 adults with long-term symptoms of anxiety and depression. The course is comprised of five online modules delivered over 8 weeks either self-guided or with support from a clinician. There was a high course completion rate (70 %) and a high level of satisfaction with the course (94 % satisfied or very satisfied). Significant clinical improvement in our primary outcome measures (within-group Cohen's d) of anxiety (d ≥ 0.62), depression (d ≥ 0.63), disability (d ≥ 0.43) and quality of life (d ≥ −0.57) were observed at posttreatment. Relatively little clinician time was required per participant (M = 30.6 min, SD = 5.7). The findings of the current study support the feasibility and potential of a transdiagnostic iACT treatment for adults experiencing long-term symptoms of anxiety and depression, including those patients who have not derived benefit from other treatments.

Babesia species are intraerythrocytic piroplasms that can result in disease characterized by hemolytic anemia and thrombocytopenia. Of the 5 species that are known to infect canids in the United States, Babesia conradae is most frequently diagnosed in California, and Babesia vogeli is prevalent in the US. Despite the recent re-emergence of B. conradae, the mechanism of transmission is not known. Coyotes (Canis latrans) have been a proposed reservoir of disease, and previous work has shown that dogs with known aggressive interactions with coyotes are at greater risk for infection. This study aimed to determine the prevalence of B. conradae in wild coyote populations in California to assess the viability of coyotes as a potential source of infection for domestic dogs. Four hundred and sixty-one splenic samples were obtained during post-mortem examination of coyote carcasses from Southern California, Fresno, and Hopland. Demographic data including age, sex, cause of death, and urbanity were collected for each coyote. DNA was extracted from samples and amplified using real-time PCR with primers specific for the B. conradae ITS-2 gene. The 18S gene was amplified and sequenced using conventional PCR primers specific to the Babesia genus from any coyotes positive for B. conradae. In total, 22 coyotes tested positive for B. conradae in Fresno (n = 15), Orange (n = 4), San Bernardino (n = 1), and Los Angeles counties (n = 1) with an overall prevalence of 4.8%. Coyotes from Fresno (P

Summary: Background: Studies have shown that dengue virus transmission increases in association with ambient temperature. We performed a systematic review and meta-analysis to assess the effect of both high temperatures and heatwave events on dengue transmission in different climate zones globally. Methods: A systematic literature search was conducted in PubMed, Scopus, Embase, and Web of Science from January 1990 to September 20, 2022. We included peer reviewed original observational studies using ecological time series, case crossover, or case series study designs reporting the association of high temperatures and heatwave with dengue and comparing risks over different exposures or time periods. Studies classified as case reports, clinical trials, non-human studies, conference abstracts, editorials, reviews, books, posters, commentaries; and studies that examined only seasonal effects were excluded. Effect estimates were extracted from published literature. A random effects meta-analysis was performed to pool the relative risks (RRs) of dengue infection per 1 °C increase in temperature, and further subgroup analyses were also conducted. The quality and strength of evidence were evaluated following the Navigation Guide systematic review methodology framework. The review protocol has been registered in the International Prospective Register of Systematic Reviews (PROSPERO). Findings: The study selection process yielded 6367 studies. A total of 106 studies covering more than four million dengue cases fulfilled the inclusion criteria; of these, 54 studies were eligible for meta-analysis. The overall pooled estimate showed a 13% increase in risk of dengue infection (RR = 1.13; 95% confidence interval (CI): 1.11–1.16, I2 = 98.0%) for each 1 °C increase in high temperatures. Subgroup analyses by climate zones suggested greater effects of temperature in tropical monsoon climate zone (RR = 1.29, 95% CI: 1.11–1.51) and humid subtropical climate zone (RR = 1.20, 95% CI: 1.15–1.25). Heatwave events showed association with an increased risk of dengue infection (RR = 1.08; 95% CI: 0.95–1.23, I2 = 88.9%), despite a wide confidence interval. The overall strength of evidence was found to be “sufficient” for high temperatures but “limited” for heatwaves. Our results showed that high temperatures increased the risk of dengue infection, albeit with varying risks across climate zones and different levels of national income. Interpretation: High temperatures increased the relative risk of dengue infection. Future studies on the association between temperature and dengue infection should consider local and regional climate, socio-demographic and environmental characteristics to explore vulnerability at local and regional levels for tailored prevention. Funding: Australian Research Council Discovery Program.

Introduction: As a high symptom burden chronic condition, endometriosis is associated with diminished quality of life (QoL) and psychological distress. The EndoSMS text message intervention was developed to inform and support individuals living with endometriosis. The primary aim of this study is to assess the acceptability, feasibility and preliminary efficacy of EndoSMS, to improve endometriosis-specific QoL and reduce psychological distress in a randomised controlled trial, compared with care as usual. We will additionally assess the impact of EndoSMS on self-efficacy for managing endometriosis. Methodology: A two-arm parallel pilot randomised controlled trial with waitlist control was conducted. Baseline assessments included QoL, psychological distress, self-efficacy, demographic and medical variables. Following baseline survey completion, participants were randomised to either the Intervention (EndoSMS: 3-months of text messaging) or Control condition. At 3-month follow-up, all participants completed an online survey reassessing outcomes, and Intervention participants provided quantitative and qualitative user feedback on EndoSMS. Results: Data collection commenced on 18 November 2021 and was completed on 30 March 2022. Descriptive statistics will be used to analyse feasibility and acceptability of the intervention. Preliminary efficacy analyses will be conducted using linear mixed models for QoL, psychological distress and self-efficacy outcomes. Subgroup analyses will also be conducted for typically underserved populations (e.g., rural/regional). Conclusion: This pilot will provide acceptability, feasibility and preliminary efficacy evidence for the impact of a supportive text messaging program for endometriosis. It will contribute to understanding how to optimally support individuals in living with and managing their endometriosis. Trial Registration: Australian New Zealand Clinical Trials Registry.

Mental disorders are associated with impairment to daily functioning, which affects both the individual and society. Despite this, most research on treatment outcome only report symptom change. Self-reported days out of role (DOR) is a simple measure of functional impairment used in many population studies. The current study sought to report on the degree of functional impairment measured by DOR in a clinical sample at assessment, the factors associated with this impairment, the predictors of functional improvement after treatment and the relationship between symptomatic and functional change. Using a prospective uncontrolled observational cohort study design with a sample of 17,813 patients accessing a digital mental health service (DMHS), we examined self-reported demographic, psychosocial and clinical data. Using a series of univariate regression models and multivariate classification algorithms, we found that baseline DOR was associated with age, employment and relationship status, symptom severity, symptom chronicity and with the presence of several psychosocial difficulties. Baseline DOR was best predicted by older age, disability payments, higher symptom severity and increasing number of endorsed psychosocial difficulties (R2 = 32.7 %). Forty-one per cent of the sample experienced a >50 % or greater reduction in DOR following treatment. Those who were separated, unemployed or on disability payments, or with severe and chronic depression, experienced the greatest reductions in DOR after treatment. Changes in functioning were independent of changes in symptoms, highlighting the importance of functional impairment as a treatment outcome. This study found that many of the patients who access DMHS have significant levels of functional impairment, a large proportion obtain functional improvement after treatment, and improvement in function after treatment was independent of improvement in symptoms.

Background: The safety of mental health care provided remotely via the internet, in particular, the probability of suicide after contact, is not known. Method: An observational cohort study of patients registered with the MindSpot Clinic an Australian national digital mental health service (DMHS), linked to the National Death Index. Measures included demographic information, the nature of contact, duration between last contact and death, scores on measures of psychological distress (K-10), depression (PHQ-9) and anxiety (GAD-7), and responses to questions about suicidal thoughts or plans for patients who died by suicide within two years of last contact with the service. Results: Sixty-four (0.11%) of 59,033 patients registered with the MindSpot Clinic between 1 January 2013 and 31 December 2016 died from suicide within two years of last contact. The mean time between last contact and death was 344 days. Fourteen patients died within 90 days of last contact, and 4 of 285 who were urgently referred for crisis service intervention at the time of contact or soon afterwards died within 2 years. Suicidal thoughts (OR: 2.59), a suicide plan (OR: 10.8), and a score of “3” to item 9 of the PHQ9 (OR: 16.4) were significantly associated with subsequent suicide. Patients who died by suicide were more likely to be male (OR: 3.2), middle-aged (35–45; OR: 2.3), separated or divorced (OR: 3.1), unemployed (OR: 3.1) or receiving disability benefits (OR: 5.1). Enrolling in an online treatment course was associated with reduced risk (OR: 0.38). Conclusions: Although DMHS provide services to patients with severe symptoms of depression, only a small proportion died by suicide, and only a small number of those referred for urgent care, which suggests that the safety protocols of the clinic are relatively effective.

Young adults are less likely to use traditional mental health services than adults. iCBT may be more youth friendly, but its access remains limited in several countries. This study aims to evaluate the feasibility of a minimally monitored transdiagnostic iCBT program translated from English to French and offered in Canada for the treatment of anxiety and depression among young adults. The impact of the program on resilience was also assessed. Twenty-five participants from community and university samples were included in the analyses in two separate single-group feasibility trials with a 3-month follow-up. Feasibility outcomes were attrition, adherence, treatment acceptability and treatment gains. Outcome measures included the Patient Health Questionnaire 9-item (PHQ-9), Generalized Anxiety Disorder 7-item (GAD-7) and Connor-Davidson Resilience Scale (CD-RISC). In Trial 1 (N = 10), recruiting among the general population proved to be challenging. Low adherence (20%) and high attrition (80%) rates were observed. Methodological changes to recruitment were made and a second trial was conducted among university students using incentives (N = 15). About half of the participants completed treatment (55%, n = 8/15), 12/15 provided post-treatment data and 8/15 provided 3-month follow-up data. All study completers (100%; n = 14) reported they would recommend the program. Mixed effects model analyses revealed significant and large pre-post treatment reductions on the PHQ-9 and GAD-7 (Cohen's d = 1.09 and 1.64 respectively) with treatment gains maintained at follow-up. Moderate improvements were found on the CD-RISC post-treatment with further gains at follow-up (ds = 0.55 and 1.10 respectively). These finding suggest that future research on this French-Canadian version of the Mood Mechanic Course is feasible with appropriate attention to recruitment. Translating existing iCBT interventions and using minimal monitoring may be an optimal first step to initiate the cross-cultural dissemination of iCBT while increasing access to treatments among young adults. Lessons learned are discussed.

In routine care, Internet-delivered Cognitive Behaviour Therapy (ICBT) is often delivered with therapist support via emails/phone calls, but the cost-effectiveness of varying amounts of therapist support or having therapists specialized in ICBT is not known. This study compared the cost-effectiveness of specialized therapists providing ICBT support once-weekly (1WS) versus providing support once-weekly supplemented with a one-business-day response to patient emails (1W/1BD-S). We further compared the cost-effectiveness of 1W support offered by therapists employed in a specialized clinic (1WS) versus community clinics where therapists primarily deliver face-to-face therapy (1WC). Patients were randomly allocated to groups: 1WS group (n = 216), 1W/1BD-S group (n = 233), and 1WC group (n = 226). At baseline, 12, 24 and 52-week follow-up, patients completed the Treatment Inventory of Costs in Patients with Psychiatric Disorders questionnaire (TiC-P) adapted for use in Canada to assess healthcare use and productivity losses. Additionally, to assess Quality Adjusted Life Years (QALYs) gained, patients completed the EQ-5D-5L at the same time periods. We quantified uncertainties by one-way and probabilistic sensitivity analysis and reported Incremental cost-effectiveness ratios (ICER), cost-effectiveness planes and acceptability curves. Cost-effectiveness over 52 weeks was CAD 3072/QALY for 1WC, CAD 3244/QALY for 1W/1BD-S, and CAD 3528/QALY for 1WS. Our model suggests that 1WS is the best strategy since the incremental cost per QALY is below the $50,000 threshold (ICER is CAD 42,328/QALY compared to the next most effective, 1WC). 1W/1BD-S is dominated by the other strategies. The cost-effectiveness acceptability curves suggest that the 1WS group has a higher probability for cost-effectiveness (38 %) than 1W/1BD-S (30 %) and 1WC (32 %) when the willingness to pay is $50,000 per QALY. These results have important implications for health policymakers deciding on delivery of ICBT for the treatment of anxiety and/depressive disorders.

Background: Research shows that alcohol and drug use among mental health clients is common and has the potential to negatively impact treatment outcomes. Internet-delivered cognitive behavior therapy (ICBT) as a treatment for anxiety and depression is on the rise, but little is known about the prevalence of alcohol and drug use among clients and how this use affects treatment completion and outcomes. Objective: The objective of the current study was to explore the prevalence of alcohol and drug use among clients in ICBT for depression and anxiety, and to investigate the impact of alcohol and drug use on treatment completion and symptom outcomes. Material and methods: Data was collected from 1155 clients who participated in two randomized ICBT trials for depression and anxiety, conducted in a routine care clinic. Thirty-five individuals reporting severe substance use when applying to the trials were excluded. Demographic variables, and alcohol and drug use were measured at screening, and measures of depression and anxiety were administered at pre- and post-treatment. Results: Four out of five clients reported having used alcohol in the past year, while one in five reported having used drugs in the past year. Around a third of clients had reported either problematic alcohol use, drug problems, or both. The analyses showed that drug problems, and combined alcohol and drug problems were negatively associated with treatment completion, but neither alcohol nor drug use had an impact on depression and anxiety outcomes. Conclusions: Alcohol and drug problems are likely to be present among a large proportion of patients using ICBT for anxiety and depression. This may not be a barrier to treatment benefit, at least when those with severe alcohol and drug problems have been excluded.

While internet-delivered cognitive behavioural therapy (ICBT) is effective, some patients suggest extended support post-treatment could improve care. In this randomized factorial trial, we examined the benefits of an 8-week therapist-assisted ICBT program offered with or without an optional 4-week extension of support (Factor 1) and with or without an optional booster lesson (Factor 2). Patients screened for ICBT for depression and/or anxiety were randomly assigned to the conditions (N = 434) and we examined the use of the extension and booster, differences between those who did or did not use extension or booster, and the impact of the extension or booster on outcomes, engagement, and satisfaction at 26-weeks post-enrollment. Therapists recorded time and observations with offering support during the extension and booster. In the extension group, 54.4% (n = 56) requested the extension, while in the booster group 50.9% (n = 56) accessed the booster, and in the combined group, 41.6% (n = 47) requested the extension and 51.3% (n = 58) accessed the booster. Those who requested the extension were older, and more likely to report medication and mental health service use and severe mental health-related disability at pre-treatment; they also reported putting less effort into ICBT and finding skills more difficult. The booster was more often used among those with lower symptom severity, and those who put more effort into and had more positive experiences with ICBT. As expected, those assigned to extension sent more messages to their therapist, and those assigned to booster logged in more often. Therapists also took more time to deliver ICBT with an extension (>18 min) or booster (>13 min) compared to the 8-week program, and perceived extension and booster as beneficial for some, but not all patients. Treatment satisfaction was high across conditions, and effect sizes were large from pre-treatment to 26-week follow-up on most measures. No significant group differences were found in this study. Lack of group differences, however, could reflect low use of the extension and booster. Results provide helpful information about the demand for extensions and boosters, and provide directions for future research.

Digital mental health services (DMHS) have proven effectiveness and play an important role within the broader mental health system by reducing barriers to evidence-based care. However, improved understanding of the factors associated with successful treatment uptake, treatment completion and positive clinical outcomes will facilitate efforts to maximise outcomes. Previous studies have demonstrated that patient age is positively associated, and initial symptom severity negatively associated with treatment uptake and treatment completion rates in both DMHS and other mental health services. The current study sought to extend these findings by examining the effect of other patient characteristics, in particular, self-reported psychosocial difficulties, using data from a large-scale national DMHS. Using a prospective uncontrolled observational cohort study design, we collected self-reported demographic, psychosocial and clinical data from 15,882 patients who accessed the MindSpot Clinic, Australia, between 1 January and 31 December 2019. Using a series of univariate regression models and multivariate classification algorithms we found that older age, higher educational attainment, and being in a relationship were all positively associated with uptake, completion and significant symptom improvement, while higher initial symptom severity was negatively associated with those outcomes. In addition, self-reported psychosocial difficulties had a significant negative impact on uptake, completion, and symptom improvement. Consistent with previous literature, the presence of these characteristics in isolation or in combination have a significant impact on treatment uptake, completion, and symptomatic improvement. Individual and multiple psychosocial difficulties are associated with reduced capacity to participate in treatment and hence an increased treatment burden. Identifying patients with lower capacity to complete treatment, modifications to treatments and the provision of supports to reduce treatment burden may promote greater engagement and completion of treatments offered by digital mental health services.

Summary: Background: Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials in COVID19 without characterisation of Pharmacokinetics /Pharmacodynamics including safety data. One such drug is nafamostat mesylate. Methods: We present the findings of a phase Ib/IIa open label, platform randomised controlled trial of intravenous nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), nafamostat or an alternative therapy. Nafamostat was administered as an intravenous infusion at a dose of 0.2 mg/kg/h for a maximum of seven days. The analysis population included those who received any dose of the trial drug and all patients randomised to SoC. The primary outcomes of our trial were the safety and tolerability of intravenous nafamostat as an add on therapy for patients hospitalised with COVID-19 pneumonitis. Findings: Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous nafamostat. 86% of nafamostat-treated patients experienced at least one AE compared to 57% of the SoC group. The nafamostat group were significantly more likely to experience at least one AE (posterior mean odds ratio 5.17, 95% credible interval (CI) 1.10 – 26.05) and developed significantly higher plasma creatinine levels (posterior mean difference 10.57 micromol/L, 95% CI 2.43–18.92). An average longer hospital stay was observed in nafamostat patients, alongside a lower rate of oxygen free days (rate ratio 0.55–95% CI 0.31–0.99, respectively). There were no other statistically significant differences in endpoints between nafamostat and SoC. PK data demonstrated that intravenous nafamostat was rapidly broken down to inactive metabolites. We observed no significant anticoagulant effects in thromboelastometry. Interpretation: In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous nafamostat, and there were additional adverse events. Funding: DEFINE was funded by LifeArc (an independent medical research charity) under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230).

Canadian public safety personnel (PSP) experience high rates of mental health problems and barriers to receiving care. Internet-delivered cognitive behavioural therapy (ICBT) may help reduce barriers to care; however, there is no literature involving qualitative analyses of client feedback to describe PSP experiences with ICBT. Identifying these experiences is important because it can inform future use of ICBT with this group that has unique needs. The current study was designed to explore how clients (N = 82) experienced ICBT that had been tailored to meet their needs; specifically, the study assessed their perceptions of program impacts, what clients found helpful, and client suggestions for improvements. The ICBT course included five core lessons, client stories, and nine initial additional resources, as well as flexible frequencies (optional, once weekly, or twice weekly) and durations (8 to 16 weeks) of therapist support. A qualitative reliability thematic analysis was used to analyze client communications and feedback. Responses to a Treatment Satisfaction Questionnaire administered at eight weeks post-enrollment were available for 57 clients. Client emails with therapists were also examined among all clients, including an additional 25 clients who did not complete the Treatment Satisfaction Questionnaire. Themes identified in the qualitative analyses were related to: reported impacts and hindering events, helpful and challenging course skills and content, helpful aspects of the course, and areas for improvement. Clients who completed the Treatment Satisfaction Questionnaire and those who did not reported beneficial impacts from the program, with the most commonly endorsed themes being skill development and normalizing mental health issues. Hindering events were experienced by both groups and included timeline challenges, technology challenges, and negative effects. Comments from both groups suggested that clients had more success than challenges when practicing the skills. Thought challenging was the skill most frequently identified as helpful. Clients described many aspects of the program as helpful with the most frequently endorsed themes being the course format and content, the flexible nature of the course, access to additional materials and case stories, and therapist assistance. Clients also provided suggestions for improving the course (e.g., case stories, additional resources, timelines audio and videos). Overall, client communications suggest that ICBT is accepted and perceived as beneficial among PSP. These results informed rapid improvements to the ICBT program tailored for PSP and may inform others seeking to provide digital mental health services to PSP.

While the efficacy of therapist-guided internet-delivered cognitive behaviour therapy (iCBT) for anxiety and depression is well-established, a significant proportion of clients show little to no improvement with this approach. Given that motivational interviewing (MI) is found to enhance face-to-face treatment of anxiety, the current trial examined potential benefits of a brief online MI intervention prior to therapist-guided iCBT. Clients applying to transdiagnostic therapist-guided iCBT in routine care were randomly assigned to receive iCBT with (n = 231) or without (n = 249) the online MI pre-treatment. Clients rated motivation at screening and pre-iCBT and anxiety and depression at pre- and post-treatment and at 13- and 25-week follow-up after enrollment. Clients in the MI plus iCBT group made more motivational statements in their emails and were enrolled in the course for a greater number of days compared to clients who received iCBT only, but did not demonstrate higher motivation after completing the MI intervention or have higher course completion. Clients in both groups, at screening and pre-iCBT, reported high levels of motivation. No statistically significant group differences were found in the rate of primary symptom change over time, with both groups reporting large reductions in anxiety and depression pre- to post-treatment (Hedges' g range = 0.96–1.11). During follow-up, clients in the iCBT only group reported additional small reductions in anxiety, whereas clients in the MI plus iCBT group did not. The MI plus iCBT group also showed small increases in depression during follow-up, whereas improvement was sustained for the iCBT only group. It is concluded that online MI does not appear to enhance client outcomes when motivation at pre-treatment is high.

Background: Mental health is an important public health issue globally. A potential link between heat exposure and mental health outcomes has been recognised in the scientific literature; however, the associations between heat exposure (both high ambient temperatures and heatwaves) and mental health-related mortality and morbidity vary between studies and locations. Objective: To fill gaps in knowledge, this systematic review aims to summarize the epidemiological evidence and investigate the quantitative effects of high ambient temperatures and heatwaves on mental health-related mortality and morbidity outcomes, while exploring sources of heterogeneity. Methods: A systematic search of peer-reviewed epidemiological studies on heat exposure and mental health outcomes published between January 1990 and November 2020 was conducted using five databases (PubMed, Embase, Scopus, Web of Science and PsycINFO). We included studies that examined the association between high ambient temperatures and/or heatwaves and mental health-related mortality and morbidity (e.g. hospital admissions and emergency department visits) in the general population. A range of mental health conditions were defined using ICD-10 classifications. We performed random effects meta-analysis to summarize the relative risks (RRs) in mental health outcomes per 1 °C increase in temperature, and under different heatwaves definitions. We further evaluated whether variables such as age, sex, socioeconomic status, and climate zone may explain the observed heterogeneity. Results: The keyword search yielded 4560 citations from which we identified 53 high temperatures/heatwaves studies that comprised over 1.7 million mental health-related mortality and 1.9 million morbidity cases in total. Our findings suggest associations between heat exposures and a range of mental health-related outcomes. Regarding high temperatures, our meta-analysis of study findings showed that for each 1 °C increase in temperature, the mental health-related mortality and morbidity increased with a RR of 1.022 (95%CI: 1.015–1.029) and 1.009 (95%CI: 1.007–1.015), respectively. The greatest mortality risk was attributed to substance-related mental disorders (RR, 1.046; 95%CI: 0.991–1.101), followed by organic mental disorders (RR, 1.033; 95%CI: 1.020–1.046). A 1 °C temperature rise was also associated with a significant increase in morbidity such as mood disorders, organic mental disorders, schizophrenia, neurotic and anxiety disorders. Findings suggest evidence of vulnerability for populations living in tropical and subtropical climate zones, and for people aged more than 65 years. There were significant moderate and high heterogeneities between effect estimates in overall mortality and morbidity categories, respectively. Lower heterogeneity was noted in some subgroups. The magnitude of the effect estimates for heatwaves varied depending on definitions used. The highest effect estimates for mental health-related morbidity was observed when heatwaves were defined as “mean temperature ≥90th percentile for ≥3 days” (RR, 1.753; 95%CI: 0.567–5.421), and a significant effect was also observed when the definition was “mean temperature ≥95th percentile for ≥3 days”, with a RR of 1.064 (95%CI: 1.006–1.123). Conclusions: Our findings support the hypothesis of a positive association between elevated ambient temperatures and/or heatwaves and adverse mental health outcomes. This problem will likely increase with a warming climate, especially in the context of climate change. Further high-quality studies are needed to identify modifying factors of heat impacts.

Summary: Liver disease is a major cause of premature death. Oxidative stress in the liver represents a key disease driver. Compounds, such as dimethyl fumarate (DMF), can activate the antioxidant response and are used clinically to treat disease. In this study, we tested the protective properties of DMF before or after paracetamol exposure. Following DMF administration, Nrf2 nuclear translocation was tracked at the single-cell level and target gene transactivation confirmed. Next, the protective properties of DMF were examined following paracetamol exposure. Transcriptomic and biochemical analysis revealed that DMF rescue was underpinned by reduced Nf-kB and TGF-β signaling and cell senescence. Following on from these studies, we employed a Zebrafish model to study paracetamol exposure in vivo. We combined a genetically modified Zebrafish model, expressing green fluorescent protein exclusively in the liver, with automated microscopy. Pre-treatment with DMF, prior to paracetamol exposure, led to reduced liver damage in Zebrafish demonstrating protective properties.

The mechanisms of failure of a composite sandwich structure subjected to a projectile impact have been investigated. The results reveal the complex interplay between the various damage dissipation mechanisms. The effects of modifying the matrix of the skins with polysiloxane core–shell rubber (CSR) nanoparticles and silica nanoparticles were investigated. Single cantilever beam specimens were tested to evaluate skin-core debonding. The addition of CSR nanoparticles to the matrix beyond 3 wt% causes a change in failure mechanism from sub-interface foam failure to interfacial failure when 6 and 9 wt% CSR are added. The sandwich structures were impacted with an aluminium projectile at 130 m/s. High speed cameras were used to obtain 3D digital image correlation of the back-face. Sectioning and imaging of the panels revealed damage in the form of front skin perforation and delamination, crushing and fracture of the core and back-face skin-core debonding. The impacted specimens also exhibited a transition in failure mechanism relating to rear face skin-core debonding between 3 and 6 wt%. Panels containing low amounts of CSR resulted in increased core cracking, while beyond the transition point, widespread rear face skin-core debonding was observed. At 3 wt% CSR, optimum back face deflection is achieved, and lower front skin delamination is experienced.

Background: The MindSpot Clinic provides services to Australians with anxiety and depression. Routine data collection means that MindSpot has been able to monitor trends in mental health symptoms and service use prior to and during the COVID-19 pandemic, and these have been reported in two earlier studies. This third study describes user characteristics and volumes in the first 8 months of COVID-19, including a comparison between users from states and territories with significantly different COVID-19 infection rates. Methods: We examined trends in demographics and symptoms for participants starting an online assessment during the COVID-19 pandemic, from March to October 2020. Participants from the state of Victoria (n = 4203), which experienced a significantly larger rate of COVID-19 infections relative to the rest of Australia, were compared to participants from the rest of Australia (n = 10,500). Results were also compared to a baseline “comparison period” prior to the COVID-19 pandemic. Results: A total of 14,703 people started a mental health assessment with MindSpot between 19th March and 28th October 2020. We observed two peaks in service demand, one in the early weeks of the pandemic, and the second in August–September when COVID-19 transmission was high in Victoria. Mean symptom scores on standardised measures of distress (K-10), depression (PHQ-9) and anxiety (GAD-7) were lower during this second peak in service demand, but there were significantly higher levels of concern about COVID-19 in participants from Victoria, and a higher proportion of Victorian respondents reported that they had made significant changes in response to the pandemic. Many respondents reported changes to their mental health, such as increased feelings of worry. Most respondents reported implementing strategies to help manage the psychological impact of COVID-19, such as maintaining social connections and limiting exposure to news or social media. Conclusions: We did not observe increased levels of clinical anxiety or depression on standardised symptom measures. However, there were increases in service demand, and increased levels of concern and difficulties related to COVID-19, particularly in Victoria. Encouragingly, a significant proportion of participants have implemented coping strategies. These results continue to suggest that the mental health impacts of COVID-19 represent a normal response to an abnormal situation rather than an emerging mental health crisis. This distinction is important as we develop individually appropriate and proportional mental health system responses.

Background: The POP Trial was a phase 1, open-label, rising-dose, randomised study that explored the safety and tolerability of calmangafodipir (superoxide dismutase mimetic) co-treatment with n-acetylcysteine (NAC) for paracetamol overdose. Methods: Patients were recruited at the Royal Infirmary of Edinburgh (8th June 2017-10th May 2018). Inclusion criterion: adults within 24 h of a paracetamol overdose that required NAC. Within each of 3 sequential cohorts, participants were randomly assigned, with concealed allocation, to NAC and a single intravenous calmangafodipir dose (n = 6) or NAC alone (n = 2). Calmangafodipir doses were 2, 5, or 10 μmol/kg. Participants, study and clinical teams were not blinded. The primary outcome was safety and tolerability. Secondary outcomes were alanine transaminase (ALT), international normalised ratio (INR), keratin-18, caspase-cleaved keratin-18 (ccK18), microRNA-122, and glutamate dehydrogenase (GLDH). (Clinicaltrials.gov:NCT03177395). Findings: All 24 participants received their allocated drug doses and were analysed. Primary endpoints: all participants experienced ≥1 adverse event (AE), most commonly gastrointestinal. Patients experiencing ≥1 serious adverse event (SAE): NAC alone, 2/6; NAC + calmangafodipir (2 μmol/kg), 4/6; NAC + calmangafodipir (5 μmol/kg), 2/6; NAC + calmangafodipir (10 μmol/kg), 3/6. No AEs or SAEs were probably or definitely calmangafodipir-related. Secondary safety outcomes demonstrated no differences between groups. With NAC alone, 2/6 had ALT > 100 U/L; with NAC + calmangafodipir, 0/18. No INR difference. Keratin-18 and ccK18 increased in the NAC alone group more than with calmangafodipir (baseline to 20 h fold change, NAC + calmangafodipir (5 μmol/kg) compared to NAC alone: 0.48 (95%CI 0.28–0.83)). microRNA-122 changes were similar to K18, GLDH was frequently undetected. Interpretation: Calmangafodipir was tolerated when combined with NAC and may reduce biomarkers of paracetamol toxicity.

Background: Acetylcysteine (NAC) is effective at preventing liver injury after paracetamol overdose. The Scottish and Newcastle Anti-emetic Pre-treatment for Paracetamol Poisoning (SNAP) Study demonstrated that a 12 h NAC regimen was associated with fewer adverse drug reactions compared with the standard 21 h regimen. Here, we describe the clinical effectiveness of the SNAP NAC regimen. Methods: The SNAP regimen, consisting of intravenous NAC 100 mg/kg over 2 h then 200 mg/kg over 10 h, was introduced to treat all paracetamol overdose patients at the Royal Infirmary of Edinburgh, the Royal Victoria Infirmary, Newcastle and St Thomas' Hospital, London. Patient data were prospectively and systematically collected before and after the change in treatment (total patients N = 3340, 21 h N = 1488, SNAP N = 1852). Health record linkage was used to determine patient outcome after hospital discharge. Findings: There was no difference in liver injury or liver synthetic dysfunction between regimens. Hepatotoxicity (peak ALT > 1000 U/L) occurred in 64 (4.3%) and 67 (3.6%) patients, respectively, in the 21 h and SNAP groups (absolute difference −0.7%, 95% CI −2.1 to 0.6). Multivariable logistic regression did not identify treatment regimen as an outcome-associated factor. No patients were readmitted to hospital with, or died from, liver failure within 30 days of discharge. Anti-histamine treatment (for NAC anaphylactoid drug reactions) was prescribed for 163 (11.0%) patients with the 21 h regimen and 37 (2.0%) patients with the SNAP regimen (absolute difference 9.0% (95% CI 7.3 to 10.7)). Interpretation: In clinical use the SNAP regimen has similar efficacy as standard therapy for preventing liver injury and produces fewer adverse reactions. Keywords: Acute liver failure, Paracetamol, NAC, Clinical practice, Drug-induced liver injury

Health anxiety is associated with significant personal distress and economic cost; as such, widely available and effective treatment options are crucial. Several studies suggest that Internet-delivered cognitive behavior therapy (ICBT) programs that specifically target health anxiety are efficacious for this condition. However, no known studies have examined the impact of transdiagnostic ICBT, which emphasizes the acquisition of broad coping skills applicable to a variety of mental health concerns, on symptoms of health anxiety. The current study sought to explore changes in health anxiety symptoms by utilizing data available from a previously published study of 8-week transdiagnostic ICBT. Specifically, changes in symptoms of health anxiety in response to a transdiagnostic ICBT program that targeted broad symptoms of depression and anxiety, were examined in a subsample of individuals who endorsed elevated symptom scores on the Short Health Anxiety Inventory at pre-treatment (n = 72). Following treatment, large reductions in health anxiety symptoms (Cohen's d = 0.91; 20% improvement), depression (Cohen's d = 0.85; reduction = 38%), generalized anxiety (Cohen's d = 1.21; reduction = 42%), and disability (Cohen's d = 0.90; reduction = 35%) were reported. Furthermore, results showed that transdiagnostic ICBT was rated as acceptable to people with high health anxiety symptoms. Despite elevated pre-treatment health anxiety scores, email correspondence between clients and their therapist revealed very few mentions of health anxiety. These findings provide preliminary evidence for transdiagnostic ICBT for symptoms of health anxiety and suggest further research is warranted. Keywords: Health anxiety, Internet-delivered, Transdiagnostic, Cognitive behavior therapy

Introduction: Thiazide diuretics are among the most widely used antihypertensive medications worldwide. Thiazide-induced hyponatremia (TIH) is 1 of their most clinically significant adverse effects. A priori TIH must result from excessive saliuresis and/or water reabsorption. We hypothesized that pathways regulating the thiazide-sensitive sodium-chloride cotransporter NCC and the water channel aquaporin-2 (AQP2) may be involved. Our aim was to assess whether patients with TIH would show evidence of altered NCC and AQP2 expression in urinary extracellular vesicles (UEVs), and also whether abnormalities of renal sodium reabsorption would be evident using endogenous lithium clearance (ELC). Methods: Blood and urine samples were donated by patients admitted to hospital with acute symptomatic TIH, after recovery to normonatremia, and also from normonatremic controls on and off thiazides. Urinary extracellular vesicles were isolated and target proteins evaluated by western blotting and by nanoparticle tracking analysis. Endogenous lithium clearance was assessed by inductively coupled plasma mass spectrometry. Results: Analysis of UEVs by western blotting showed that patients with acute TIH displayed reduced total NCC and increased phospho-NCC and AQP2 relative to appropriate control groups; smaller differences in NCC and AQP2 expression persisted after recovery from TIH. These findings were confirmed by nanoparticle tracking analysis. Renal ELC was lower in acute TIH compared to that in controls and convalescent case patients. Conclusion: Reduced NCC expression and increased AQP2 expression would be expected to result in saliuresis and water reabsorption in TIH patients. This study raises the possibility that UEV analysis may be of diagnostic utility in less clear-cut cases of thiazide-associated hyponatremia, and may help to identify patients at risk for TIH before thiazide initiation. Keywords: diuretic, hypertension, hyponatremia, sodium, thiazide, urinary extracellular vesicles

Abstract Objective: To determine if global warming has changed the balance of summer and winter deaths in Australia. Methods: Counts of summer and winter cause‐specific deaths of subjects aged 55 and over for the years 1968–2018 were entered into a Poisson time‐series regression. Analysis was stratified by states and territories of Australia, by sex, age and cause of death (respiratory, cardiovascular, and renal diseases). The warmest and coldest subsets of seasons were compared. Results: Warming over 51 years was associated with a long‐term increase in the ratio of summer to winter mortality from 0.73 in the summer of 1969 to 0.83 in the summer of 2018. The increase occurred faster in years that were warmer than average. Conclusions: Mortality in the warmest and coldest times of the year is converging as annual average temperatures rise. Implications for public health: If climate change continues, deaths in the hottest months will come to dominate the burden of mortality in Australia.

Summary: Vascular and kidney dysfunction commonly co-exist. There is a need for biomarkers of vascular health. Circulating microRNAs are biomarkers; miR-126 is endothelial cell-enriched. We measured circulating miR-126 in rats with nephrotoxic nephritis (NTN) and humans with acute endothelial and renal injury (vasculitis associated with autoantibodies to neutrophil cytoplasm antigens (ANCAs)). We compared these findings to those from patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) and explored the relationship between miR-126 and vascular dysfunction. In NTN, miR-126 was reduced. In ANCA vasculitis (N = 70), pre-treatment miR-126 was reduced compared to health (N = 60) (88-fold). miR-126 increased 3.4-fold post-treatment but remained lower than in health (∼26-fold). Argonaute 2-bound miR-126 increased with ANCA vasculitis treatment. miR-126 did not differ between CKD (N = 30) and health but its concentration correlated with endothelial dysfunction. miR-126 was reduced in ESRD (N = 15) (∼350 fold). miR-126 may be a marker of vascular inflammation and could aid decision-making.

Background: Extracellular microRNAs enter kidney cells and modify gene expression. We used a Dicer-hepatocyte-specific microRNA conditional-knock-out (Dicer-CKO) mouse to investigate microRNA transfer from liver to kidney. Methods: Dicerflox/flox mice were treated with a Cre recombinase-expressing adenovirus (AAV8) to selectively inhibit hepatocyte microRNA production (Dicer-CKO). Organ microRNA expression was measured in health and following paracetamol toxicity. The functional consequence of hepatic microRNA transfer was determined by measuring the expression and activity of cytochrome P450 2E1 (target of the hepatocellular miR-122), and by measuring the effect of serum extracellular vesicles (ECVs) on proximal tubular cell injury. In humans with liver injury we measured microRNA expression in urinary ECVs. A murine model of myocardial infarction was used as a non-hepatic model of microRNA release. Findings: Dicer-CKO mice demonstrated a decrease in kidney miR-122 in the absence of other microRNA changes. During hepatotoxicity, miR-122 increased in kidney tubular cells; this was abolished in Dicer-CKO mice. Depletion of hepatocyte microRNA increased kidney cytochrome P450 2E1 expression and activity. Serum ECVs from mice with hepatotoxicity increased proximal tubular cell miR-122 and prevented cisplatin toxicity. miR-122 increased in urinary ECVs during human hepatotoxicity. Transfer of microRNA was not restricted to liver injury –miR-499 was released following cardiac injury and correlated with an increase in the kidney. Interpretation: Physiological transfer of functional microRNA to the kidney is increased by liver injury and this signalling represents a new paradigm for understanding the relationship between liver injury and renal function. Funding: Kidney Research UK, Medical Research Scotland, Medical Research Council.

In routine care, internet-delivered cognitive behaviour therapy (iCBT) regularly includes therapist support delivered via secure email, but the optimal response time to emails is unknown. In this study, we compared the benefits of therapists providing support once-weekly versus therapists providing support once-weekly supplemented with a one-business-day response to all patient emails. This pragmatic randomized controlled trial included therapists employed by a specialized iCBT clinic or community mental health clinics, where providing iCBT is a secondary service. Patients with depression and/or anxiety who enrolled in transdiagnostic iCBT (5 core lessons over 8 weeks) were randomized to: 1) once-weekly support supplemented with a one-business-day response to patient emails by specialized therapists (n = 233); 2) once-weekly support also offered by specialized therapists (n = 216); or 3) once-weekly support offered by community clinic therapists (n = 226). Outcomes were measured at 8, 12, 24, and 52-weeks post-enrollment. Patient engagement and treatment experiences (e.g., treatment satisfaction, therapist alliance) were also assessed and a focus group was conducted with therapists. Supplementing once-weekly therapist support with a one-business-day response to patient emails resulted in therapists sending more emails to patients (M: 13 versus 9) and required more therapist time over treatment (M: 155 versus 109 min), but was not associated with improved outcomes, patient engagement or treatment experiences. All groups showed large improvements in symptoms of depression and anxiety maintained at 52-week follow-up, strong engagement and positive treatment experiences. Therapists viewed challenges of responding to patient emails within one-business-day to outweigh benefits. Contrary to expectations, supplementing once-weekly therapist support with a one-business-day response to all patient emails did not benefit patients and increased therapist time as well as therapist challenges when delivering iCBT in routine care.

Background: The MindSpot Clinic, funded by the Australian Government, is a national digital mental health service (DMHS) providing services to people experiencing anxiety and depression. We recently reported increased service use in the early weeks of the COVID-19 pandemic (19 March to 15 April 2020), and a small increase in anxiety symptoms. This follow-up paper examines trends in service use and symptoms, over 12 weeks from 19 March to 10 June 2020. Methods: Demographics, symptoms, and psychosocial stressors were compared for participants starting an online assessment over four time-periods: A baseline “Comparison period” prior to the COVID-19 pandemic (1 to 28 September 2019), “Weeks 1–4” of the COVID-19 pandemic in Australia (19 March–15 April 2020), “Weeks 5–8” (16 April–13 May 2020) and “Weeks 9–12” (14 May–10 June). Responses to questions about the impact of COVID-19 and strategies used by participants to improve their mental wellbeing are also reported. Results: A total of 5455 people started a mental health assessment with MindSpot from 19 March to 10 June 2020. The number of assessments per week rose steadily from 303 in week 1 to a peak of 578 in week 5. Symptoms of anxiety were highest in Weeks 1–4, declining steadily over subsequent weeks. Psychological distress and depression, as measured by the K-10 and PHQ-9 respectively, remained stable. Concern about COVID-19 was highest in the first week then steadily declined during the following weeks. The proportions of participants reporting changes to routine were consistent across the 12 weeks, and most participants reported adopting helpful strategies to improve their mental wellbeing. Conclusions: We observed an initial increase in service use, which reduced over the 12 weeks. The initial rise in anxiety symptoms returned to baseline. Reported concern about the effect of COVID-19 declined steadily over 12 weeks. Symptoms of psychological distress and depression measured by the K-10 and PHQ-9, and the proportion reporting suicidal thoughts and plans did not change, and to date we have not identified indications of a mental health crisis. However, the long-term effects of COVID-19 on the economy and large sections of society are yet to be fully realised, indicating the importance of ongoing monitoring and reporting of trends as indicators of the mental health of the nation.

With the growing demand for internet-delivered cognitive behavioural therapy (iCBT), this pragmatic factorial (2 × 2 × 2) randomized controlled trial evaluated strategies for facilitating iCBT engagement and outcomes in routine care. Specifically, the benefits to patients and therapists of using homework reflection questionnaires and offering patients twice-weekly therapist support were examined. Patients (n = 632) accepted into iCBT for depression and/or anxiety were randomly assigned to complete homework reflection questionnaires or not (factor 1), receive once- or twice-weekly support (factor 2), and to receive care from therapists employed in one of two settings (iCBT clinic or a community mental health clinic; factor 3). Outcomes were measured at pre-treatment, and 8, 12, and 24-weeks post-enrollment. Therapist time was tracked and a focus group was conducted to examine therapist experiences. No differences in patient outcomes were found between therapists employed in the two settings; as such, these two groups were combined for further analyses. In terms of engagement, homework reflection questionnaires were associated with fewer website log-ins and days accessing iCBT; twice-weekly support was associated with more patient emails sent to therapists. Despite engagement differences, homework reflection questionnaires and twice-weekly support did not significantly impact primary outcomes; all groups showed large improvements in depression and anxiety that were maintained at 24-week follow-up. Therapists perceived a number of benefits and challenges associated with responding to homework reflection questionnaires and offering twice-weekly support; most notably the strategies did not benefit all patients. Twice-weekly support was associated with increased therapist time and organizational challenges. It is concluded that neither completion of homework questionnaires nor offering twice-weekly support significantly improve iCBT in routine care.

Since the emergence of psychological interventions delivered via the Internet they have differed in numerous ways. The wealth of formats, methods, and technological solutions has led to increased availability and cost-effectiveness of clinical care, however, it has simultaneously generated a multitude of terms. With this paper, we first aim to establish whether a terminology issue exists in the field of Internet-delivered psychological interventions. If so, we aim to determine its implications for research, education, and practice. Furthermore, we intend to discuss solutions to mitigate the problem; in particular, we propose the concept of a common glossary. We invited 23 experts in the field of Internet-delivered interventions to respond to four questions, and employed the Delphi method to facilitate a discussion. We found that experts overwhelmingly agreed that there were terminological challenges, and that it had significant consequences for conducting research, treating patients, educating students, and informing the general public about Internet-delivered interventions. A cautious agreement has been reached that formulating a common glossary would be beneficial for the field to address the terminology issue. We end with recommendations for the possible formats of the glossary and means to disseminate it in a way that maximizes the probability of broad acceptance for a variety of stakeholders.

Depression and anxiety are common among people who have experienced an acute coronary event (e.g., heart attack). Multidisciplinary cardiac rehabilitation programs often focus on reducing risk factors associated with future cardiac events, however, mental health interventions are not routinely available. Given known difficulties with access to mental health treatment, the present study sought to explore the efficacy and acceptability of an Internet-delivered cognitive behavioural therapy program (Cardiac Wellbeing Course) among participants who experienced an acute coronary event. The five-lesson course was delivered over eight weeks and was provided with brief weekly contact, via telephone and secure email with a guide. Participants were randomized to the Cardiac Wellbeing Course (n = 25) or waiting-list control group (n = 28). Symptoms were assessed at pre-treatment, post-treatment, and four-week follow-up. Completion rates (84%) and satisfaction ratings (95%) were high. Statistically significant between-group improvements were observed for the treatment group on primary measures of general anxiety (Cohen's d = 1.62; 67% reduction), depression (Cohen's d = 1.09; 61% reduction), and physical activity levels (Cohen's d = 0.27; 70% increase). Statistically significant improvements were also observed on secondary measures of distress (Cohen's d = 0.98; 51% reduction), cardiac anxiety (Cohen's d = 0.92; 34% reduction), and mental-health quality of life (Cohen's d = 0.23; 24% improvement). The changes were maintained at four-week follow-up. The current findings add to the existing literature and highlight the potential of Internet-delivered cognitive behavioural therapy programs among participants who have experienced an acute coronary event.

Background: Trends in contact with a high volume national digital mental health service (DMHS), the MindSpot Clinic, provide a unique opportunity to assess the mental health effects of the COVID-19 pandemic. Methods: Three methods were used to assess changes in responses to COVID-19. First, website visits and call centre traffic were compared across two time periods: the “comparison period” (1 to 28 September 2019), and during the early weeks of the “COVID-19 pandemic” (19 March to 15 April 2020). Second, demographic and symptom data were compared across all patients who started an assessment during the comparison (n = 1650) and the COVID-19 period (n = 1668). Third, responses to questions about the impact of COVID-19 introduced to the assessment from 19 March 2020, and reports from treating therapists were examined. Results: There was an 89% increase in website visits and a 90% increase in telephone calls to the clinic in the early COVID-19 period compared to the comparison period. There was a higher proportion of females in the COVID-19 sample (76.9% vs. 72.9%), and a lower proportion reported being in employment (52.8% vs. 60.8%). There was a small but significant increase in the severity of anxiety symptoms, and an increase in the number of people reporting recent onset of anxiety and depression. However, there were no differences between groups in severity of symptoms of distress or depression. Most people (94%) reported concern about the impact of COVID-19, and 88% reported making changes in lifestyle. Older adults had higher levels of concern about COVID-19. Therapists reported that patients were concerned about how to access testing, manage quarantine, financial security and the effect of social isolation. Conclusions: COVID-19 has resulted in a significant increase in contact with an established DMHS, but we have not yet detected increases in baseline symptom severity. With the prospect of prolonged restriction of movement, DMHS such as MindSpot could play an important role in both providing clinical services and monitoring the mental health of the population.

With the growing use of ICBT in routine care clinics there is a need for literature on how to monitor and improve the quality of therapist behaviours in clinical practice. In this paper, we first provide background literature on Audit and Feedback (A&F), a common quality improvement technique, and then present a case study regarding the use of A&F to improve quality of therapist behaviours in emails sent to patients provided with ICBT in routine care. The A&F measure used was derived from previous research on therapist's email behaviours in ICBT. Fifteen undesirable therapist behaviours (e.g., Did Not Message, Unresponsive to Symptom Increase, Does Not Address Patient Concern) were audited in 1840 emails sent from eight therapists to 198 randomly selected patients, representing 18% of 1114 patients who started between one and five lessons of ICBT in the previous year and did not formally withdraw from treatment (n = 31 patients). The therapists who were audited were provided feedback four times over a one-year period from October 2018 to September 2019. Overall, in all audit periods, we found a low percentage of undesirable therapist behaviours (i.e., therapists displayed the behaviour in 12% or less of the total emails sent). For most therapist behaviours, we saw a trend towards improvement across the four audit cycles. Three therapist behaviours (i.e., Failure to Ask One Question to the Patient, Poor Instructions, Not Linking Email to Course Content) did not follow this pattern and were flagged for clinical discussion to determine why behaviours were elevated and whether these behaviours represented unrealistic expectations. The process was valuable for monitoring and improving therapist behaviours and highlights the need for future research on standards for therapist behaviours (e.g., which behaviours to focus on, setting acceptable levels of undesirable behaviour).

Background: There is growing interest in Internet-delivered cognitive behavioural therapy (ICBT) as an alternative to face-to-face therapy for anxiety and depression because it reduces barriers to accessing traditional treatment (e.g., travel distance, cost, stigma). Extensive research has demonstrated that ICBT is an effective treatment for anxiety and depression and that it produces effect sizes comparable to medication and face-to-face therapy. In routine practice, however, ICBT patients commonly receive simultaneous pharmacological treatment, and few studies have examined how medication affects patient outcomes. Objective: The objective of this study was to explore whether use of psychotropic medications predicts outcomes or adherence among patients receiving ICBT for depression and anxiety in a large community sample. Methods: This study used data from 1201 patients who received an 8-week course of ICBT for anxiety and depression that included weekly therapist support as part of routine care. Patients reported medication usage and completed measures of depression and anxiety before treatment, after treatment, and at three-month follow-up. Results: 60% of patients at pre-treatment reported regularly taking psychotropic medication. Common classes of medication reported included: (i) selective serotonin reuptake inhibitors (34%); (ii) anxiolytics (15%); (iii) serotonin and norepinephrine reuptake inhibitors (14%); (iv) antipsychotics (8%); and (v) norepinephrine-dopamine reuptake inhibitors (7%). At post-treatment and three-month follow-up, overall medication usage reduced slightly to 55%, with the greatest reduction seen in anxiolytics. Logistic regression revealed that none of the classes of medication commonly reported at pre-treatment were associated with study completion rates. A recursive partitioning algorithm found that usage of tetracyclic medication was related to smaller pre-to-post reductions in anxiety symptoms and did not identify any medication types that were related to differences in depressive symptom change. Patients on medication tended to report higher levels of anxiety symptoms at intake and experienced somewhat more modest symptom reductions than patients not taking medications; nevertheless, they still experienced large reductions in depression and anxiety over the course of treatment. Conclusions: These results show that medication usage is very common in a diverse community sample of patients seeking ICBT for anxiety and depression. Patients reporting medication usage at intake are likely to benefit from treatment approximately as much as patients not taking medication. These results support the continued referral of patients receiving psychotropic medication to ICBT programs for anxiety and depression. Program designers might also consider providing information about the common medications (SSRIs, SNRIs, anxiolytics) used by this population alongside CBT materials. Keywords: Internet, Cognitive behavior therapy, Anxiety, Depression, Pharmacotherapy

Clinical trials have demonstrated the efficacy of internet delivered cognitive behaviour therapy (ICBT) for anxiety and depression. However, relatively little is known about the context, operations, and outcomes of ICBT when administered as part of routine care. This paper describes the setting, relationship to existing health services, procedures for referral, assessment, treatment, patients and outcomes of ICBT clinics in Sweden, Denmark, Norway, Canada and Australia.All five clinics provide services free or at low cost to patients. All have systems of governance to monitor quality of care, patient safety, therapist performance and data security. All five clinics include initial assessments by clinicians and between 10 and 20 min of therapist support during each week. Published reports of outcomes all demonstrate large clinical improvement, low rates of deterioration, and high levels of patient satisfaction. Services that require a face to face assessment treat smaller numbers of patients and have fewer patients from remote locations.The paper shows that therapist-guided ICBT can be a valuable part of mental health services for anxiety and depression. Important components of successful ICBT services are rigorous governance to maintain a high standard of clinical care, and the measurement and reporting of outcomes. Keywords: Delivery, Description, Implementation, Internet-delivered cognitive behaviour therapy, Psychological treatment, Routine care, Depression, Anxiety, Disorders

Internet-delivered cognitive behaviour therapy (ICBT) is often provided with therapist assistance via asynchronous secure emails, but there is limited research on undesirable behaviours exhibited by therapists in their correspondence with patients. In this study, an ICBT-Undesirable Therapist Behaviour Scale (ICBT-UTBS) was developed and used to assess the nature, frequency, and correlates of undesirable therapist behaviours in routine practice. Thematic analysis was used to identify undesirable therapist behaviours in 720 emails sent to 91 randomly selected patients in the context of a previous clinical trial of transdiagnostic ICBT for depression and anxiety. The following undesirable behaviours were identified, albeit infrequently, in therapist emails: inadequate detail (6.4%), unaddressed content (4.0%), unsupportive tone (0.6%), missed correspondence (0.6%), inappropriate self-disclosure (0.6%), and unmanaged risk (0.3%). At least one undesirable behaviour was found in 10.7% of all emails coded. Moreover, 37.4% of patients received at least one email containing an undesirable therapist behaviour. Number of undesirable therapist behaviours was not correlated with patient engagement, working alliance, treatment satisfaction, or patient outcome variables. However, undesirable therapist behaviours were negatively correlated with patient gender and therapist characteristics (e.g., clinical setting, therapist profession). The results of the present study provide preliminary psychometric support for the ICBT-UTBS, a measure of ICBT treatment integrity. In the future, the ICBT-UTBS should be used in combination with the ICBT-Therapist Rating Scale (ICBT-TRS), a measure of desirable or recommended therapist behaviours, for training purposes and to monitor ICBT therapists in routine practice. Keywords: Undesirable therapist behaviours, Internet-delivered cognitive behaviour therapy, Therapist assistance, Treatment integrity, Scale development

Internet-delivered cognitive behaviour therapy (ICBT) is an efficacious form of treatment for anxiety and depression, yet it is still possible for clients to experience negative effects associated with treatment. In the ICBT literature, the term negative effects is broadly used to refer to all potentially adverse or unwanted events or experiences that are perceived as undesirable by the client and may or may not be associated with long-term symptoms or distress. Previous ICBT studies have asked clients to retrospectively describe negative effects at post-treatment; however, no research has examined the content of clients' emails to their therapist to see whether clients are reporting negative effects as they arise. In the current study, 96 clients (80 completers; 16 non-completers) were randomly selected from a published ICBT trial and directed content analysis was used to examine client emails for mention of negative effects. In addition, correlational analyses were used to examine the relationship between negative effects and: 1) demographic characteristics; 2) treatment engagement; 3) treatment satisfaction; 4) working alliance; and 5) symptom outcomes among completers. The results indicated that 61.5% of clients experienced at least one negative effect during treatment, although total number of negative effects was not significantly correlated with client demographic characteristics, lessons completed, working alliance, treatment satisfaction, or symptom outcomes. Among completers, technical difficulties, implementation problems, and negative emotional states were the most commonly reported negative effects, whereas dropout was the most commonly reported negative effect by non-completers. Negative effects that have been identified in previous research, such as symptom deterioration, novel symptoms, and severe adverse events, were not identified in client emails. The high incidence of negative effects in the current study suggests there may be value in systematically monitoring client emails for negative effects throughout treatment as a supplement to retrospective post-treatment reports. This will give therapists the opportunity to intervene as negative effects occur and potentially mitigate any impact they have on treatment outcomes. Future research, both qualitative and quantitative, is needed to gain a more nuanced understanding of negative effects associated with ICBT. Keywords: Internet-delivered cognitive behaviour therapy, Negative effects, Adverse effects