Substantial transmission of SARS-CoV-2 through casual contact in retail stores: Evidence from matched administrative microdata on card payments and testing.

This paper presents quasiexperimental evidence of Covid-19 transmission through casual contact between customers in retail stores. For a large sample of individuals in Denmark, we match card payment data, indicating exactly where and when each individual made purchases, with Covid-19 test data, indicating when each individual was tested and whether the test was positive. The resulting dataset identifies more than 100,000 instances where an infected individual made a purchase in a store and, in each instance, allows us to track the infection dynamics of other individuals who made purchases in the same store around the same time. We estimate transmissions by comparing the infection rate of exposed customers, who made a purchase within 5 min of an infected individual, and nonexposed customers, who made a purchase in the same store 16 to 30 min before. We find that exposure to an infected individual in a store increases the infection rate by around 0.12 percentage points (P < 0.001) between day 3 and day 7 after exposure. The estimates imply that transmissions in stores contributed around 0.04 to the reproduction number for the average infected individual and significantly more in the period where Omicron was the dominant variant.

Acceptability of a digital health application to empower persons with multiple sclerosis with moderate to severe disability: single-arm prospective pilot study.

BACKGROUND: Many persons with multiple sclerosis (pwMS) desire to learn how health behaviour changes (e.g., dietary adjustments, physical activity, improvements in stress management) might help them manage their disease. Previous research has shown that certain health behaviour changes can improve quality of life (QoL), fatigue and other MS outcomes. Digital health applications may be well suited to deliver relevant health behavioural interventions because of their accessibility and flexibility. The digital health application "levidex" was designed to facilitate health behaviour change by offering evidence-based patient information and cognitive-behavioural therapy techniques to pwMS. By doing so, levidex aims to improve QoL and MS symptoms such as fatigue and mental health. OBJECTIVES: A previous study reported on the development of levidex; this non-randomised pilot study examined the feasibility (practicability and acceptability) of levidex in pwMS with moderate to severe disability. Furthermore, the intervention's impact on empowerment, stress management, and relevant health behaviours (e.g., dietary behaviour, physical activity) was explored. METHODS: levidex was originally developed for newly diagnosed pwMS in the first year after diagnosis and eventually modified to offer access to pwMS with moderate to severe disability. Participants (n = 43) with an Expanded Disability Status Scale between 3.5 and 7.5 and a disease duration of more than one year were eligible to participate. The intervention was used over a period of six months with measurement time points at baseline, month 3 and month 6. RESULTS: Out of 38 participants who completed the six-month intervention period, 18 (47.4%) completed all 16 modules and 9 (23.7%) reached modules 13-16, the long-term maintenance part of levidex. Participants rated levidex positively in terms of practicability and acceptability and had only few points of criticism such as to include more physical exercise routine suggestions suitable for participants with severe impairment. Data on secondary endpoints showed no significant changes. CONCLUSION: This pilot study provided evidence for the practicability and acceptability of levidex, a digital health application designed to facilitate health behaviour change in pwMS with moderate to severe disability. Adequately powered randomised controlled studies with longer follow-up periods are needed to clarify the benefit of levidex in pwMS with moderate to severe disability. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) DRKS00032667 (14/09/2023); Retrospectively registered.

Mobile health interventions in multiple sclerosis: A systematic review.

BACKGROUND: Persons with multiple sclerosis (pwMS) might be particularly well suited to benefit from digital health applications because they are, on average, younger and less severely disabled than patients with many other chronic diseases. Many digital health applications for pwMS have been developed. OBJECTIVES: Analysis of the evidence of digital health applications to improve health outcomes from a patient perspective. METHODS: A systematic review was performed on all randomized controlled trials (RCTs) that have studied mobile health interventions for pwMS, that is, which can be applied with a smartphone, tablet, or laptop to improve patient-reported outcomes. RESULTS: Of the 1127 articles identified in the literature search, 13 RCTs fit the inclusion criteria. Two trials studied messaging systems, two depression interventions, one addressed MS fatigue, five cognition, and three mobility issues, of which two focused on spasticity management. One trial aimed to enhance physical activity. Most were pilot studies that cannot yield definitive conclusions regarding efficacy. One depression intervention and one fatigue intervention showed significant results across several outcomes. CONCLUSION: Several mobile self-guided digital health applications for pwMS have been tested in RCTs, and two interventions targeting depression and fatigue have demonstrated significant effects. Challenges remain regarding implementation into routine care.

Internet-delivered cognitive behavioural therapy programme to reduce depressive symptoms in patients with multiple sclerosis: a multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: Depression is three to four times more prevalent in patients with neurological and inflammatory disorders than in the general population. For example, in patients with multiple sclerosis, the 12-month prevalence of major depressive disorder is around 25% and it is associated with a lower quality of life, faster disease progression, and higher morbidity and mortality. Despite its clinical relevance, there are few treatment options for depression associated with multiple sclerosis and confirmatory trials are scarce. We aimed to evaluate the safety and efficacy of a multiple sclerosis-specific, internet-based cognitive behavioural therapy (iCBT) programme for the treatment of depressive symptoms associated with the disease. METHODS: This parallel-group, randomised, controlled, phase 3 trial of an iCBT programme to reduce depressive symptoms in patients with multiple sclerosis was carried out at five academic centres with large outpatient care units in Germany and the USA. Patients with a neurologist-confirmed diagnosis of multiple sclerosis and depressive symptoms were randomly assigned (1:1:1; automated assignment, concealed allocation, no stratification, no blocking) to receive treatment as usual plus one of two versions of the iCBT programme Amiria (stand-alone or therapist-guided) or to a control condition, in which participants received treatment as usual and were offered access to the iCBT programme after 6 months. Masking of participants to group assignment between active treatment and control was not possible, although raters were masked to group assignment. The predefined primary endpoint, which was analysed in the intention-to-treat population, was severity of depressive symptoms as measured by the Beck Depression Inventory-II (BDI-II) at week 12 after randomisation. This trial is registered at ClinicalTrials.gov, NCT02740361, and is complete. FINDINGS: Between May 3, 2017, and Nov 4, 2020, we screened 485 patients for eligibility. 279 participants were enrolled, of whom 101 were allocated to receive stand-alone iCBT, 85 to receive guided iCBT, and 93 to the control condition. The dropout rate at week 12 was 18% (50 participants). Both versions of the iCBT programme significantly reduced depressive symptoms compared with the control group (BDI-II between-group mean differences: control vs stand-alone iCBT 6·32 points [95% CI 3·37-9·27], p<0·0001, effect size d=0·97 [95% CI 0·64-1·30]; control vs guided iCBT 5·80 points [2·71-8·88], p<0·0001, effect size d=0·96 [0·62-1·30]). Clinically relevant worsening of depressive symptoms was observed in three participants in the control group, one in the stand-alone iCBT group, and none in the guided iCBT group. No occurrences of suicidality were observed during the trial and there were no deaths. INTERPRETATION: This trial provides evidence for the safety and efficacy of a multiple sclerosis-specific iCBT tool to reduce depressive symptoms in patients with the disease. This remote-access, scalable intervention increases the therapeutic options in this patient group and could help to overcome treatment barriers. FUNDING: National Multiple Sclerosis Society (USA).

Effectiveness of an Internet-Based Self-Guided Program to Treat Depression in a Sample of Brazilian Users: Randomized Controlled Trial.

BACKGROUND: Depression is undertreated in Brazil. Deprexis is a self-guided internet-based program used to treat depressive symptoms based on empirically supported integrative and cognitive behavioral therapy. Evidence from a meta-analysis supports Deprexis' efficacy in German-speaking countries and the United States, but no study has been conducted using this program in countries with low literacy rates and large social disparities. Furthermore, few studies have investigated whether internet-based interventions ameliorate the psychological processes that might underlie depressive symptomatology, such as low perceived self-efficacy. OBJECTIVE: The main objective of this study was to replicate in Brazil previously reported effects of Deprexis on depressive symptom reduction. Therefore, the main research question was whether Deprexis is effective in reducing depressive symptoms and the general psychological state in Brazilian users with moderate and severe depression in comparison with a control group that does not receive access to Deprexis. A secondary research question was whether the use of Deprexis affects perceptions of self-efficacy. METHODS: We interviewed 312 participants recruited over the internet and randomized 189 participants with moderate to severe depression (according to the Patient Health Questionnaire-9 and a semistructured interview) to an intervention condition (treatment as usual plus immediate access to Deprexis for 90 days, n=94) or to a control condition (treatment as usual and delayed access to Deprexis, after 8 weeks, n=95). RESULTS: Participants from the immediate access group logged in at Deprexis an average of 14.81 (SD 12.16) times. The intention-to-treat analysis using a linear mixed model showed that participants who received Deprexis improved significantly more than participants assigned to the delayed access control group on the primary depression self-assessment measure (Patient Health Questionnaire-9; Cohen d=0.80; P<.001) and secondary outcomes, such as general psychological state measure (Clinical Outcome in Routine Evaluation-Outcome Measurement; Cohen d=0.82; P<.001) and the perceived self-efficacy measure (Cohen d=0.63; P<.001). The intention-to-treat analyses showed that 21% (20/94) of the participants achieved remission compared with 7% (7/95) in the control group (P<.001). The deterioration rates were lower in the immediate access control group. The dropout rate was high, but no differences in demographic and clinical variables were found. Participants reported a medium to high level of satisfaction with Deprexis. CONCLUSIONS: These results replicate previous findings by showing that Deprexis can facilitate symptomatic improvement over 3 months in depressed samples of Brazilian users. From a public health perspective, this is important information to expand the reach of internet-based interventions for those who really need them, especially in countries with less access to mental health care. This extends previous research by showing significant effects on perceived self-efficacy. TRIAL REGISTRATION: Registro Brasileiro de Ensaios Clíncos (ReBec) RBR-6kk3bx UTN U1111-1212-8998; https://ensaiosclinicos.gov.br/rg/RBR-6kk3bx/. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1590/1516-4446-2019-0582.

An interactive web-based programme on relapse management for people with multiple sclerosis (POWER@MS2) - development, feasibility, and pilot testing of a complex intervention.

Introduction: Despite the lack of high-quality evidence regarding its long-term effectiveness, intravenous corticosteroid therapy is recommended as the standard treatment of acute multiple sclerosis relapses in Germany. High financial expenses and the equivalent effectiveness of oral corticosteroid therapy contrast with this trend. There is an urgent need to provide patients with evidence-based and comprehensible information on relapse management and to actively involve patients in relapse treatment decisions. Web-based decision support on relapse management could be an effective measure to empower people with multiple sclerosis making informed treatment decisions. Objectives: To develop a web-based programme on relapse management for people with multiple sclerosis and evaluate the feasibility and acceptability of the intervention. Methods: The study followed the first two phases of the UK Medical Research Council Framework for complex interventions. The first phase involved the development of an interactive web-based programme on relapse management. The second phase focused on the feasibility and pilot testing of the programme with people with multiple sclerosis and experts with a professional background in multiple sclerosis. Data was obtained using questionnaires with closed- and open-ended questions as well as qualitative semi-structured telephone interviews. Quantitative data was analyzed descriptively, whereas qualitative data was clustered by topic. Results: Feasibility of the intervention programme was tested with 10 people with multiple sclerosis and 10 experts. Feasibility testing indicated good practicability and acceptance of the content. After revision, the programme was piloted with seven people with multiple sclerosis and three experts. The results showed good acceptance in both groups. Based on the feedback, a final revision was performed. Conclusion: Feasibility and pilot testing indicated good user-friendliness, acceptance, and practicability of the programme. The programme is currently evaluated in a randomized controlled trial (Registration Number on ClinicalTrials.gov: NCT04233970). It is expected that the programme will have a positive impact on patients' relapse management and strengthen their autonomy and participation.

'That would have been the perfect thing after diagnosis': development of a digital lifestyle management application in multiple sclerosis.

Background: A multiple sclerosis (MS) diagnosis urges decision-making on immunotherapies, while persons with MS (PwMS) need to develop a coping concept in parallel. At this stage, PwMS ask how they themselves may contribute to controlling the disease. Evidence suggests that maintaining a healthy lifestyle (e.g. physical activity and stress management) is a key factor for healthy aging and preserving activity, while data on MS are complex. Objectives: Following the Medical Research Council framework, this study aimed to develop and investigate the feasibility of a new digital health application that conveys evidence-based patient information about lifestyle factors in MS and engages PwMS in relevant behaviour change techniques. Methods: Based on a digital health application promoting lifestyle management in breast cancer survivors, an MS-specific adaptation ('levidex') was developed. Feasibility was tested with 15 PwMS and eight MS experts. Subsequently, a six-week pilot study with eight PwMS was conducted. All participants provided feedback on practicability and acceptability via a questionnaire and took part in a semi-structured telephone interview. Levidex was revised after each test phase. Results: The final levidex tool includes 16 modules, 177 references and several other functions. Feasibility results showed that PwMS and MS experts perceived levidex as understandable (14 out of 15; 6 out of 8), trustworthy (15 out of 15; 8 out of 8), and relevant (10 out of 15; 8 out of 8). Interviews revealed potential for improvement regarding the length and complexity of some content. Piloting of the revised version confirmed good feasibility and high acceptance. Most participants felt inspired to initiate (7 out of 8) or had already implemented (5 out of 8) lifestyle changes after working with levidex. Conclusion: Results suggest that levidex is feasible and well-accepted by PwMS and MS experts. It might be a useful tool to support PwMS in adapting to their diagnosis and initiating health-promoting lifestyle changes.

The NEVERMIND e-health system in the treatment of depressive symptoms among patients with severe somatic conditions: A multicentre, pragmatic randomised controlled trial.

Background: This study assessed the effectiveness of the NEVERMIND e-health system, consisting of a smart shirt and a mobile application with lifestyle behavioural advice, mindfulness-based therapy, and cognitive behavioural therapy, in reducing depressive symptoms among patients diagnosed with severe somatic conditions. Our hypothesis was that the system would significantly decrease the level of depressive symptoms in the intervention group compared to the control group. Methods: This pragmatic, randomised controlled trial included 425 patients diagnosed with myocardial infarction, breast cancer, prostate cancer, kidney failure, or lower limb amputation. Participants were recruited from hospitals in Turin and Pisa (Italy), and Lisbon (Portugal), and were randomly assigned to either the NEVERMIND intervention or to the control group. Clinical interviews and structured questionnaires were administered at baseline, 12 weeks, and 24 weeks. The primary outcome was depressive symptoms at 12 weeks measured by the Beck Depression Inventory II (BDI-II). Intention-to-treat analyses included 425 participants, while the per-protocol analyses included 333 participants. This trial is registered in the German Clinical Trials Register, DRKS00013391. Findings: Patients were recruited between Dec 4, 2017, and Dec 31, 2019, with 213 assigned to the intervention and 212 to the control group. The sample had a mean age of 59·41 years (SD=10·70), with 44·24% women. Those who used the NEVERMIND system had statistically significant lower depressive symptoms at the 12-week follow-up (mean difference=-3·03, p<0·001; 95% CI -4·45 to -1·62) compared with controls, with a clinically relevant effect size (Cohen's d=0·39). Interpretation: The results of this study show that the NEVERMIND system is superior to standard care in reducing and preventing depressive symptoms among patients with the studied somatic conditions. Funding: The NEVERMIND project received funding from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement No. 689691.

Sociodemographic Characteristics Associated With an eHealth System Designed to Reduce Depressive Symptoms Among Patients With Breast or Prostate Cancer: Prospective Study.

BACKGROUND: eHealth interventions have become a topic of interest in the field of mental health owing to their increased coordination and integration of different elements of care, in treating and preventing mental ill health in patients with somatic illnesses. However, poor usability, learnability, and user engagement might affect the effectiveness of an eHealth intervention. Identifying different sociodemographic characteristics that might be associated with higher perceived usability can help improve the usability of eHealth interventions. OBJECTIVE: This study aimed to identify the sociodemographic characteristics that might be associated with the perceived usability of the NEVERMIND (Neurobehavioural Predictive and Personalised Modelling of Depressive Symptoms During Primary Somatic Diseases) eHealth system, comprising a mobile app and a sensorized shirt, in reducing comorbid depressive symptoms in patients with breast or prostate cancer. METHODS: The study included a total of 129 patients diagnosed with breast (n=80, 62%) or prostate (n=49, 38%) cancer, who received a fully automated mobile app and sensorized shirt (NEVERMIND system). Sociodemographic data on age, sex, marital status, education level, and employment status were collected at baseline. Usability outcomes included the System Usability Scale (SUS), a subjective measure that covers different aspects of system usability; the user version of the Mobile App Rating Scale (uMARS), a user experience questionnaire; and a usage index, an indicator calculated from the number of days patients used the NEVERMIND system during the study period. RESULTS: The analysis was based on 108 patients (n=68, 63%, patients with breast cancer and n=40, 37%, patients with prostate cancer) who used the NEVERMIND system for an average of 12 weeks and completed the study. The overall mean SUS score at 12 weeks was 73.4 (SD 12.5), which indicates that the NEVERMIND system has good usability, with no statistical differences among different sociodemographic characteristics. The global uMARS score was 3.8 (SD 0.3), and women rated the app higher than men (ß=.16; P=.03, 95% CI 0.02-0.3), after adjusting for other covariates. No other sociodemographic characteristics were associated with higher uMARS scores. There was a statistical difference in the use of the NEVERMIND system between women and men. Women had significantly lower use (ß=-0.13; P=.04, 95% CI -0.25 to -0.01), after adjusting for other covariates. CONCLUSIONS: The findings suggest that the NEVERMIND system has good usability according to the SUS and uMARS scores. There was a higher favorability of mobile apps among women than among men. However, men had significantly higher use of the NEVERMIND system. Despite the small sample size and low variability, there is an indication that the NEVERMIND system does not suffer from the digital divide, where certain sociodemographic characteristics are more associated with higher usability. TRIAL REGISTRATION: German Clinical Trials Register RKS00013391; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013391.

A Personalized, Interactive, Cognitive Behavioral Therapy-Based Digital Therapeutic (MODIA) for Adjunctive Treatment of Opioid Use Disorder: Development Study.

BACKGROUND: Opioid use disorder (OUD) is characterized by the inability to control opioid use despite attempts to stop use and negative consequences to oneself and others. The burden of opioid misuse and OUD is a national crisis in the United States with substantial public health, social, and economic implications. Although medication-assisted treatment (MAT) has demonstrated efficacy in the management of OUD, access to effective counseling and psychosocial support is a limiting factor and a significant problem for many patients and physicians. Digital therapeutics are an innovative class of interventions that help prevent, manage, or treat diseases by delivering therapy using software programs. These applications can circumvent barriers to uptake, improve treatment adherence, and enable broad delivery of evidence-based management strategies to meet service gaps. However, few digital therapeutics specifically targeting OUD are available, and additional options are needed. OBJECTIVE: To this end, we describe the development of the novel digital therapeutic MODIA. METHODS: MODIA was developed by an international, multidisciplinary team that aims to provide effective, accessible, and sustainable management for patients with OUD. Although MODIA is aligned with principles of cognitive behavioral therapy, it was not designed to present any 1 specific treatment and uses a broad range of evidence-based behavior change techniques drawn from cognitive behavioral therapy, mindfulness, acceptance and commitment therapy, and motivational interviewing. RESULTS: MODIA uses proprietary software that dynamically tailors content to the users' responses. The MODIA program comprises 24 modules or "chats" that patients are instructed to work through independently. Patient responses dictate subsequent content, creating a "simulated dialogue" experience between the patient and program. MODIA also includes brief motivational text messages that are sent regularly to prompt patients to use the program and help them transfer therapeutic techniques into their daily routines. Thus, MODIA offers individuals with OUD a custom-tailored, interactive digital psychotherapy intervention that maximizes the personal relevance and emotional impact of the interaction. CONCLUSIONS: As part of a clinician-supervised MAT program, MODIA will allow more patients to begin psychotherapy concurrently with opioid maintenance treatment. We expect access to MODIA will improve the OUD management experience and provide sustainable positive outcomes for patients.

SARS-CoV-2 variant prediction and antiviral drug design are enabled by RBD in vitro evolution.

SARS-CoV-2 variants of interest and concern will continue to emerge for the duration of the COVID-19 pandemic. To map mutations in the receptor-binding domain (RBD) of the spike protein that affect binding to angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, we applied in vitro evolution to affinity-mature the RBD. Multiple rounds of random mutagenic libraries of the RBD were sorted against decreasing concentrations of ACE2, resulting in the selection of higher affinity RBD binders. We found that mutations present in more transmissible viruses (S477N, E484K and N501Y) were preferentially selected in our high-throughput screen. Evolved RBD mutants include prominently the amino acid substitutions found in the RBDs of B.1.620, B.1.1.7 (Alpha), B1.351 (Beta) and P.1 (Gamma) variants. Moreover, the incidence of RBD mutations in the population as presented in the GISAID database (April 2021) is positively correlated with increased binding affinity to ACE2. Further in vitro evolution increased binding by 1,000-fold and identified mutations that may be more infectious if they evolve in the circulating viral population, for example, Q498R is epistatic to N501Y. We show that our high-affinity variant RBD-62 can be used as a drug to inhibit infection with SARS-CoV-2 and variants Alpha, Beta and Gamma in vitro. In a model of SARS-CoV-2 challenge in hamster, RBD-62 significantly reduced clinical disease when administered before or after infection. A 2.9 Å cryo-electron microscopy structure of the high-affinity complex of RBD-62 and ACE2, including all rapidly spreading mutations, provides a structural basis for future drug and vaccine development and for in silico evaluation of known antibodies.

Maintaining Outcomes of Internet-Delivered Cognitive-Behavioral Therapy for Depression: A Network Analysis of Follow-Up Effects.

Background: Depression is a highly prevalent mental disorder, but only a fraction of those affected receive evidence-based treatments. Recently, Internet-based interventions were introduced as an efficacious and cost-effective approach. However, even though depression is a heterogenous construct, effects of treatments have mostly been determined using aggregated symptom scores. This carries the risk of concealing important effects and working mechanisms of those treatments. Methods: In this study, we analyze outcome and long-term follow-up data from the EVIDENT study, a large (N = 1,013) randomized-controlled trial comparing an Internet intervention for depression (Deprexis) with care as usual. We use Network Intervention Analysis to examine the symptom-specific effects of the intervention. Using data from intermediary and long-term assessments that have been conducted over 36 months, we intend to reveal how the treatment effects unfold sequentially and are maintained. Results: Item-level analysis showed that scale-level effects can be explained by small item-level effects on most depressive symptoms at all points of assessment. Higher scores on these items at baseline predicted overall symptom reduction throughout the whole assessment period. Network intervention analysis offered insights into potential working mechanisms: while deprexis directly affected certain symptoms of depression (e.g., worthlessness and fatigue) and certain aspects of the quality of life (e.g., overall impairment through emotional problems), other domains were affected indirectly (e.g., depressed mood and concentration as well as activity level). The configuration of direct and indirect effects replicates previous findings from another study examining the same intervention. Conclusions: Internet interventions for depression are not only effective in the short term, but also exert long-term effects. Their effects are likely to affect only a small subset of problems. Patients reporting these problems are likely to benefit more from the intervention. Future studies on online interventions should examine symptom-specific effects as they potentially reveal the potential of treatment tailoring. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT02178631.

Dismantling, optimising, and personalising internet cognitive behavioural therapy for depression: a systematic review and component network meta-analysis using individual participant data.

BACKGROUND: Internet cognitive behavioural therapy (iCBT) is a viable delivery format of CBT for depression. However, iCBT programmes include training in a wide array of cognitive and behavioural skills via different delivery methods, and it remains unclear which of these components are more efficacious and for whom. METHODS: We did a systematic review and individual participant data component network meta-analysis (cNMA) of iCBT trials for depression. We searched PubMed, PsycINFO, Embase, and the Cochrane Library for randomised controlled trials (RCTs) published from database inception to Jan 1, 2019, that compared any form of iCBT against another or a control condition in the acute treatment of adults (aged ≥18 years) with depression. Studies with inpatients or patients with bipolar depression were excluded. We sought individual participant data from the original authors. When these data were unavailable, we used aggregate data. Two independent researchers identified the included components. The primary outcome was depression severity, expressed as incremental mean difference (iMD) in the Patient Health Questionnaire-9 (PHQ-9) scores when a component is added to a treatment. We developed a web app that estimates relative efficacies between any two combinations of components, given baseline patient characteristics. This study is registered in PROSPERO, CRD42018104683. FINDINGS: We identified 76 RCTs, including 48 trials contributing individual participant data (11 704 participants) and 28 trials with aggregate data (6474 participants). The participants' weighted mean age was 42·0 years and 12 406 (71%) of 17 521 reported were women. There was suggestive evidence that behavioural activation might be beneficial (iMD -1·83 [95% credible interval (CrI) -2·90 to -0·80]) and that relaxation might be harmful (1·20 [95% CrI 0·17 to 2·27]). Baseline severity emerged as the strongest prognostic factor for endpoint depression. Combining human and automated encouragement reduced dropouts from treatment (incremental odds ratio, 0·32 [95% CrI 0·13 to 0·93]). The risk of bias was low for the randomisation process, missing outcome data, or selection of reported results in most of the included studies, uncertain for deviation from intended interventions, and high for measurement of outcomes. There was moderate to high heterogeneity among the studies and their components. INTERPRETATION: The individual patient data cNMA revealed potentially helpful, less helpful, or harmful components and delivery formats for iCBT packages. iCBT packages aiming to be effective and efficient might choose to include beneficial components and exclude ones that are potentially detrimental. Our web app can facilitate shared decision making by therapist and patient in choosing their preferred iCBT package. FUNDING: Japan Society for the Promotion of Science.

Results of the Optimune trial: A randomized controlled trial evaluating a novel Internet intervention for breast cancer survivors.

INTRODUCTION: After the acute treatment phase, breast cancer patients often experience low quality of life and impaired mental health, which could potentially be improved by offering cognitive behavioural therapy (CBT) and addressing exercise and dietary habits. However, CBT and other behavioural interventions are rarely available beyond the acute treatment phase. Internet-based interventions could bridge such treatment gaps, given their flexibility and scalability. In this randomized controlled trial (RCT), we investigated the effects of such an intervention ("Optimune") over three months. METHODS: This RCT included 363 female breast cancer survivors (age range = 30-70), recruited from the community, who had completed the active treatment phase. Inclusion criteria were: breast cancer diagnosis less than 5 years ago and acute treatment completion at least 1 month ago. Participants were randomly assigned to (1) an intervention group (n = 181), in which they received care as usual (CAU) plus 12-month access to Optimune immediately after randomization, or (2) a control group (n = 182), in which they received CAU and Optimune after a delay of 3 months. Primary endpoints were quality of life (QoL), physical activity, and dietary habits at three months. We hypothesized that intervention group participants would report better QoL, more physical activity, and improved dietary habits after 3 months. RESULTS: Intention-to-treat (ITT) analyses revealed significant effects on QoL (d = 0.27, 95% CI: 0.07-0.48) and dietary habits (d = 0.36, 95% CI: 0.15-0.56), but the effect on physical exercise was not significant (d = 0.30; 95% CI: 0.10-0.51). DISCUSSION: These findings suggest the effectiveness of Optimune, a new CBT-based Internet intervention for breast cancer survivors, in facilitating improvements in quality of life and dietary habits. Efforts to disseminate this intervention more broadly may be warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03643640. Registered August 23rd 2018, https://clinicaltrials.gov/ct2/show/NCT03643640.

Do sociodemographic variables moderate effects of an internet intervention for mild to moderate depressive symptoms? An exploratory analysis of a randomised controlled trial (EVIDENT) including 1013 participants.

OBJECTIVE: To explore the moderating effects of sociodemographic variables on treatment benefits received from participating in an internet intervention for depression. DESIGN: Randomised, assessor-blind, controlled trial. SETTING: Online intervention, with participant recruitment using multiple settings, including inpatient and outpatient medical and psychological clinics, depression online forums, health insurance companies and the media (eg, newspaper, radio). PARTICIPANTS: The EVIDENT trial included 1013 participants with mild to moderate depressive symptoms. INTERVENTIONS: The intervention group subjects (n=509) received an online intervention (Deprexis) in addition to care as usual (CAU), while 504 participants received CAU alone. METHODS: To explore subgroup differences, moderating effects were investigated using linear regression models based on intention-to-treat analyses. Moderating effects included sex, age, educational attainment, employment status, relationship status and lifetime frequency of episodes. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was change in self-rated depression severity measured by the Patient Health Questionnaire-9 (PHQ-9), comparing baseline versus 12-week post-test assessment. Secondary outcome measures were the Hamilton Rating Scale for Depression and the Quick Inventory of Depressive Symptoms each at 12 weeks and at 6 and 12 months, and PHQ-9 at 6 and 12 months, respectively. In this article, we focus on the primary outcome measure only. RESULTS: Between-group differences were observed in post-test scores, indicating the effectiveness of Deprexis. While the effects of the intervention could be demonstrated across all subgroups, some showed larger between-group differences than others. However, after exploring the moderating effects based on linear regression models, none of the selected variables was found to be moderating treatment outcomes. CONCLUSIONS: Our findings suggest that Deprexis is equally beneficial to a wide range of people; that is, participant characteristics were not associated with treatment benefits. Therefore, participant recruitment into web-based psychotherapeutic interventions should be broad, while special attention may be paid to those currently under-represented in these interventions. TRIAL REGISTRATION NUMBER: NCT01636752.

Internet-Based Cognitive Behavioral Therapy for Depression: A Systematic Review and Individual Patient Data Network Meta-analysis.

Importance: Personalized treatment choices would increase the effectiveness of internet-based cognitive behavioral therapy (iCBT) for depression to the extent that patients differ in interventions that better suit them. Objective: To provide personalized estimates of short-term and long-term relative efficacy of guided and unguided iCBT for depression using patient-level information. Data Sources: We searched PubMed, Embase, PsycInfo, and Cochrane Library to identify randomized clinical trials (RCTs) published up to January 1, 2019. Study Selection: Eligible RCTs were those comparing guided or unguided iCBT against each other or against any control intervention in individuals with depression. Available individual patient data (IPD) was collected from all eligible studies. Depression symptom severity was assessed after treatment, 6 months, and 12 months after randomization. Data Extraction and Synthesis: We conducted a systematic review and IPD network meta-analysis and estimated relative treatment effect sizes across different patient characteristics through IPD network meta-regression. Main Outcomes and Measures: Patient Health Questionnaire-9 (PHQ-9) scores. Results: Of 42 eligible RCTs, 39 studies comprising 9751 participants with depression contributed IPD to the IPD network meta-analysis, of which 8107 IPD were synthesized. Overall, both guided and unguided iCBT were associated with more effectiveness as measured by PHQ-9 scores than control treatments over the short term and the long term. Guided iCBT was associated with more effectiveness than unguided iCBT (mean difference [MD] in posttreatment PHQ-9 scores, -0.8; 95% CI, -1.4 to -0.2), but we found no evidence of a difference at 6 or 12 months following randomization. Baseline depression was found to be the most important modifier of the relative association for efficacy of guided vs unguided iCBT. Differences between unguided and guided iCBT in people with baseline symptoms of subthreshold depression (PHQ-9 scores 5-9) were small, while guided iCBT was associated with overall better outcomes in patients with baseline PHQ-9 greater than 9. Conclusions and Relevance: In this network meta-analysis with IPD, guided iCBT was associated with more effectiveness than unguided iCBT for individuals with depression, benefits were more substantial in individuals with moderate to severe depression. Unguided iCBT was associated with similar effectiveness among individuals with symptoms of mild/subthreshold depression. Personalized treatment selection is entirely possible and necessary to ensure the best allocation of treatment resources for depression.

Who seeks Internet-based interventions for depression in Brazil? / Quem procura intervenções baseadas na Internet para a depressão no Brasil?

Specific psychological treatments for depressive disorders delivered on the Internet have shown effectiveness and presented advantages over face-to-face treatments (potentially less expensive, flexible schedules, available in remote areas). This paper aims to describe the characteristics of those who sought help from an online self-guided intervention for depression and to explore hypotheses about predictors of enrollment to the program. Based on a sample of 282 of individuals who filled in screening questionnaires, we verified that the respondents were mainly female, were on average 34.36 years old, were primarily recruited through Facebook, had been previously diagnosed by mental health professionals, presented moderate self-efficacy perception, and had moderately severe symptoms of depression. Respondents who reported comorbid conditions were more likely to attend enrollment interviews, and being in treatment or not did not influence attendance. Such characterization may provide strategies to reach more people and to optimize the design of interventions targeting help-seeking depressed individuals in Brazil.

Alguns tratamentos para a depressão baseados na Internet se mostraram efetivos e apresentaram vantagens em relação a tratamentos presenciais (potencialmente menos caros, com horários mais flexíveis e com disponibilidade em áreas remotas). Este artigo descreve as características de indivíduos que procuraram ajuda de uma intervenção autoguiada on-line e explora hipóteses sobre preditores de adesão ao programa. Baseado em uma amostra de 282 indivíduos que preencheram questionários de triagem, verificou-se que os participantes eram majoritariamente mulheres, tinham em média 34,36 anos, foram recrutados em sua maioria pelo Facebook, apresentaram diagnóstico psiquiátrico prévio feito por algum profissional de saúde mental, apresentaram percepção de autoeficácia moderada e sintomas depressivos moderadamente severos. Os respondentes que relataram condições comórbidas apresentaram mais chances de avançar para as entrevistas diagnósticas, e estar ou não em tratamento não influenciou a chegada às entrevistas. Estas descrições podem auxiliar na identificação de estratégias para se atingir mais indivíduos e para otimizar o desenho das intervenções on-line para brasileiros que as buscam.

Immediate and long-term effectiveness of adding an Internet intervention for depression to routine outpatient psychotherapy: Subgroup analysis of the EVIDENT trial.

OBJECTIVE: To examine immediate and long-term effectiveness of an adjunctive Internet intervention for depression in a large sample of patients undergoing routine psychotherapy. METHOD: The current study evaluated a subgroup of patients from the Evident trial, a randomized investigation of a 12-week minimally guided Internet intervention (Deprexis) for the treatment of mild to moderate depression. 340 adults (mean age = 43.3 years; 71.7 % female) of the original sample received routine outpatient psychotherapy during the trial period, resulting in a standard psychotherapy group (n = 174) and an augmented therapy group (n = 166). Outcomes were assessed at baseline, post-treatment and 6-month follow-up. RESULTS: Intention-to-treat analyses indicated that combined treatment led to a greater reduction in symptoms of depression (effect size d = 0.32; p = .002), improved therapeutic progress (d = 0.36; p = .003), and higher mental health-related quality of life (d = 0.34; p = .004). There was no intervention effect on physical health-related quality of life. The same pattern was found at 6-month follow-up, and adjunctive treatment also resulted in increased rates of clinical improvement. Treatment success was independent from therapeutic orientation of combined face-to-face therapy. CONCLUSION: Results indicate that the adjunctive use of the investigated intervention can produce additional and lasting effects in routine outpatient psychotherapy for mild to moderate levels of depression. The study adds to the ongoing evidence on augmented effects of blended treatment. Future studies should investigate different types of blends in diverse populations by means of change-sensitive assessment strategies.

Selecting optimal spectral bands for improved detection of autofluorescent biomarkers in multiphoton microscopy.

SIGNIFICANCE: In multiphoton microscopy, two-photon excited fluorescence (TPEF) spectra carry valuable information on morphological and functional biological features. For measuring these biomarkers, separation of different parts of the fluorescence spectrum into channels is typically achieved by the use of optical band pass filters. However, spectra from different biomarkers can be unknown or overlapping, creating a crosstalk in between the channels. Previously, establishing these channels relied on prior knowledge or heuristic testing. AIM: The presented method aims to provide spectral bands with optimal separation between groups of specimens expressing different biomarkers. APPROACH: We have developed a system capable of resolving TPEF with high spectral resolution for the characterization of biomarkers. In addition, an algorithm is created to simulate and optimize optical band pass filters for fluorescence detection channels. To demonstrate the potential improvements in cell and tissue classification using these optimized channels, we recorded spectrally resolved images of cancerous (HT29) and normal epithelial colon cells (FHC), cultivated in 2D layers and in 3D to form spheroids. To provide an example of an application, we relate the results with the widely used redox ratio. RESULTS: We show that in the case of two detection channels, our system and algorithm enable the selection of optimized band pass filters without the need of knowing involved fluorophores. An improvement of 31,5% in separating different 2D cell cultures is achieved, compared to using established spectral bands that assume NAD(P)H and FAD as main contributors of autofluorescence. The compromise is a reduced SNR in the images. CONCLUSIONS: We show that the presented method has the ability to improve imaging contrast and can be used to tailor a given label-free optical imaging system using optical band pass filters targeting a specific biomarker or application.

A comparison of the three year course between chronic depression and depression with multiple vs. few prior episodes.

This study tested the hypothesis that chronic depression (CD) is more similar to depression with multiple prior episodes (ME) than to depression with few prior episodes (FE). Data from participants (n = 1013) with mild to moderate depressive symptoms (Patient Health Questionnaire [PHQ-9] score 5 - 14) who took part in a randomized control trial of an internet intervention for depression (EVIDENT trial) were re-analyzed. The MINI-interview was conducted to diagnose CD (n = 376). If CD was not diagnosed, the self-reported number of depressive episodes was used to categorize participants as having episodic depression with up to five (FE, n = 422) or more than five (ME, n = 215) prior episodes. Over a three-year period, participants were assessed repeatedly regarding the course of depression (PHQ-9, QIDS), quality of life (SF-12) and therapeutic progress (FEP-2). At baseline, most scores were different between CD and FE but comparable between CD and ME. Time to remission did not differ between CD and ME but was longer in CD compared to FE. Results suggest that ME closely resembles CD and that CD differs from FE.