Common barriers and enablers to the use of non-drug interventions for managing common chronic conditions in primary care: an overview of reviews.

BACKGROUND: Non-drug interventions are recommended for chronic condition prevention and management yet are underused in clinical practice. Understanding barriers and enablers to using non-drug interventions may help implement non-drug interventions in primary care. We aimed to conduct an overview of reviews to identify and summarise common barriers and enablers for using non-drug interventions for common chronic conditions in primary care. METHODS: We included qualitative and quantitative reviews that used systematic process or methods to examine barriers and enablers to using non-drug interventions for chronic condition prevention and management in primary care settings. We searched 5 electronic databases (PubMed, Cochrane Database of Systematic Reviews, EMBASE, PsycInfo and CINAHL) from inception to September 2022. Two authors independently screened reviews. One author extracted and deductively coded data to Consolidated Framework of Implementation Research (CFIR) (and where relevant, Theoretical Domains Framework [TDF]). A second author validated 10% of extracted data and coding. Data was synthesised thematically using CFIR and TDF. One author assessed the methodological quality of included reviews using a modified AMSTAR 2 tool, with 10% validated by a second author. We assessed overlap between primary studies in included reviews. RESULTS: From 5324 records, we included 25 reviews, with data predominately from patients. Overall, 130 subthemes (71 barrier and 59 enabler) were identified across 4 CFIR domains (Innovation, Outer Setting, Inner Setting, and Individuals), and all TDF domains. Common barrier and enabler subthemes were identified for CFIR constructs of Innovation Adaptability, Innovation Cost, Innovation Relative Advantage, Local Attitudes, External Pressure, Local Conditions, Relational Connections, Available Resources, and Access to Knowledge and Information. For TDF domains, important barrier and enabler subthemes were identified for Knowledge, Skills, Environmental Context and Resources, Beliefs about Consequences, Reinforcement, and Emotion. CONCLUSIONS: We synthesised reviews to provide new insight into common barriers and enablers for using non-drug interventions to prevent and manage chronic conditions in primary care. The factors identified can inform the development of generalisable implementation interventions to enhance uptake of multiple non-drug interventions simultaneously. TRIAL REGISTRATION: This study was registered in PROSPERO (CRD42022357583).

Long-Term Effect of Salt Substitution for Cardiovascular Outcomes : A Systematic Review and Meta-Analysis.

BACKGROUND: Salt substitution is a simple yet increasingly promising strategy to improve cardiovascular outcomes. PURPOSE: To evaluate the long-term effects of salt substitution on cardiovascular outcomes. DATA SOURCES: PubMed, EMBASE, Cochrane CENTRAL, and CINAHL searched from inception to 23 August 2023. Trial registries, citation analysis, and hand-search were also done. STUDY SELECTION: Randomized controlled trials (RCTs) comparing provision of or advice to use a salt substitute with no intervention or use of regular salt among adults for 6 months or longer in total study duration. DATA EXTRACTION: Two authors independently screened articles, extracted data, and assessed risk of bias. Primary outcomes include mortality, major cardiovascular events (MACE), and adverse events at 6 months or greater. Secondary and post hoc outcomes include blood pressure, cause-specific mortality, and urinary excretion at 6 months or greater. Random-effects meta-analyses were done and certainty of effect estimates were assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). DATA SYNTHESIS: Of the 16 included RCTs, 8 reported on primary outcomes. Most (n = 7 of 8) were done in China or Taiwan, 3 were done in residential facilities, and 7 included populations of older age (average 62 years) and/or with higher-than-average cardiovascular risk. In this population, salt substitute may reduce risk for all-cause mortality (6 RCTs; 27 710 participants; rate ratio [RR], 0.88 [95% CI, 0.82 to 0.93]; low certainty) and cardiovascular mortality (4 RCTs; 25 050 participants; RR, 0.83 [CI, 0.73 to 0.95]; low certainty). Salt substitute may result in a slight reduction in MACE (3 RCTs; 23 215 participants; RR, 0.85 [CI, 0.71 to 1.00]; very low certainty), with very low-certainty evidence of serious adverse events (6 RCTs; 27 995 participants; risk ratio, 1.04 [CI, 0.87 to 1.25]). LIMITATIONS: The evidence base is dominated by a single, large RCT. Most RCTs were from China or Taiwan and involved participants with higher-than-average cardiovascular risk; therefore, generalizability to other populations is very limited. CONCLUSION: Salt substitution may reduce all-cause or cardiovascular mortality, but the evidence for reducing cardiovascular events and for not increasing serious adverse events is uncertain, particularly for a Western population. The certainty of evidence is higher among populations at higher cardiovascular risk and/or following a Chinese diet. PRIMARY FUNDING SOURCE: National Health and Medical Research Council. (PROSPERO: CRD42022327566).

Clinical trials and their impact on policy during COVID-19: a review.

Background: Of over 8,000 recorded randomised trials addressing COVID-19, around 80% were of treatments, and 17% have reported results. Approximately 1% were adaptive or platform trials, with 25 having results available, across 29 journal articles and 10 preprint articles. Methods: We conducted an extensive literature review to address four questions about COVID-19 trials, particularly the role and impact of platform/adaptive trials and lessons learned. Results: The key findings were: Q1. Social value in conducting trials and uptake into policy? COVID-19 drug treatments varied substantially and changed considerably, with drugs found effective in definitive clinical trials replacing unproven drugs. Dexamethasone has likely saved ½-2 million lives, and was cost effective across a range of countries and populations, whereas the cost effectiveness of remdesivir is uncertain. Published economic and health system impacts of COVID-19 treatments were infrequent. Q2. Issues with adaptive trial designs. Of the 77 platform trials registered, 6 major platform trials, with approximately 50 treatment arms, recruited ~135,000 participants with funding over $100 million. Q3. Models of good practice. Streamlined set-up processes such as flexible and fast-track funding, ethics, and governance approvals are vital. To facilitate recruitment, simple and streamlined research processes, and pre-existing research networks to coordinate trial planning, design, conduct and practice change are crucial to success. Q4. Potential conflicts to avoid? When treating patients through trials, balancing individual and collective rights and allocating scarce resources between healthcare and research are challenging. Tensions occur between commercial and non-commercial sectors, and academic and public health interests, such as publication and funding driven indicators and the public good. Conclusion: There is a need to (i) reduce small, repetitive, single centre trials, (ii) increase coordination to ensure robust research conducted for treatments, and (iii) a wider adoption of adaptive/platform trial designs to respond to fast-evolving evidence landscape.

Comparing dietary strategies to manage cardiovascular risk in primary care: a narrative review of systematic reviews.

BACKGROUND: Nutrition care in general practice is crucial for cardiovascular disease (CVD) prevention and management, although comparison between dietary strategies is lacking. AIM: To compare the best available (most recent, relevant, and high-quality) evidence for six dietary strategies that are effective for primary prevention/absolute risk reduction of CVD. DESIGN AND SETTING: A pragmatic narrative review of systematic reviews of randomised trials focused on primary prevention of cardiovascular events. METHOD: Studies about: 1) adults without a history of cardiovascular events; 2) target dietary strategies postulated to reduce CVD risk; and 3) direct cardiovascular or all-cause mortality outcomes were included. Six dietary strategies were examined: energy deficit, Mediterranean-like diet, sodium reduction (salt reduction and substitution), the Dietary Approaches to Stop Hypertension (DASH) diet, alcohol reduction, and fish/fish oil consumption. Reviews were selected based on quality, recency, and relevance. Quality and certainty of evidence was assessed using GRADE. RESULTS: Twenty-five reviews met inclusion criteria; eight were selected as the highest quality, recent, and relevant. Three dietary strategies showed modest, significant reductions in cardiovascular events: energy deficit (relative risk reduction [RRR] 30%, 95% confidence interval [CI] = 13 to 43), Mediterranean-like diet (RRR 40%, 95% CI = 20 to 55), and salt substitution (RRR 30%, 95% CI = 7 to 48). Still, some caveats remain on the effectiveness of these dietary strategies. Salt reduction, DASH diet, and alcohol reduction showed small, significant reductions in blood pressure, but no reduction in cardiovascular events. Fish/fish oil consumption showed little or no effect; supplementation of fish oil alone showed small reductions in CVD events. CONCLUSION: For primary prevention, energy deficit, Mediterranean-like diets, and sodium substitution have modest evidence for risk reduction of CVD events. Strategies incorporated into clinical nutrition care should ensure guidance is person centred and tailored to clinical circumstances.

Attitudes, beliefs, behaviours and perspectives on barriers and enablers of Australian general practitioners towards non-drug interventions: a national survey.

BACKGROUND: Many guidelines recommend non-drug interventions (NDIs) for managing common conditions in primary care. However, compared with drug interventions, NDIs are less widely known, promoted and used. We aim to (1) examine general practitioners' (GPs') knowledge, attitudes and practices for NDIs, including their use of the Royal Australian College of General Practitioners (RACGP) Handbook of Non-Drug Interventions (HANDI), and (2) identify factors influencing their use of NDIs and HANDI. METHODS: We conducted a web-based cross-sectional survey of practicing GP members in Australia during October-November 2022. The survey contained five sections: characteristics of GP; knowledge and use of NDIs; attitudes towards NDIs; barriers and enablers to using HANDI; and suggestions of NDIs and ideas to improve the uptake of NDIs in primary care. RESULTS: Of the 366 GPs who completed the survey, 242 (66%) were female, and 248 (74%) were ≥45 years old. One in three GPs reported that they regularly ('always') recommend NDIs to their patients when appropriate (34%), whereas one-third of GPs were unaware of HANDI (39%). GPs identified several factors that improve the uptake of HANDI, including 'access and integration of HANDI in clinical practice', 'content and support to use in practice' and 'awareness and training'. CONCLUSIONS: While many GPs are aware of the effectiveness of NDIs and often endorse their use, obstacles still prevent widespread adoption in primary care. The results of this survey can serve as a foundation for developing implementation strategies to improve the uptake of effective evidence-based NDIs in primary care.

Comparison of Telephone and Video Telehealth Consultations: Systematic Review.

BACKGROUND: Telehealth has been used for health care delivery for decades, but the COVID-19 pandemic greatly accelerated the uptake of telehealth in many care settings globally. However, few studies have carried out a direct comparison among different telehealth modalities, with very few studies having compared the effectiveness of telephone and video telehealth modalities. OBJECTIVE: This study aimed to identify and synthesize randomized controlled trials (RCTs) comparing synchronous telehealth consultations delivered by telephone and those conducted by video with outcomes such as clinical effectiveness, patient safety, cost-effectiveness, and patient and clinician satisfaction with care. METHODS: PubMed (MEDLINE), Embase, and CENTRAL were searched via the Cochrane Library from inception until February 10, 2023, for RCTs without any language restriction. Forward and backward citation searches were conducted on included RCTs. The Cochrane Risk of Bias 2 tool was used to assess the quality of the studies. We included studies carried out in any health setting-involving all types of outpatient cohorts and all types of health care providers-that compared synchronous video consultations directly with telephone consultations and reported outcomes specified in the objective. We excluded studies of clinician-to-clinician telehealth consults, hospitalized patients, and asynchronous consultations. RESULTS: Sixteen RCTs-10 in the United States, 3 in the United Kingdom, 2 in Canada, and 1 in Australia involving 1719 participants-were included in the qualitative and quantitative analyses. Most of the telehealth interventions were for hospital-based outpatient follow-ups, monitoring, and rehabilitation (n=13). The 3 studies that were conducted in the community all focused on smoking cessation. In half of the studies, nurses delivered the care (n=8). Almost all included studies had high or unclear risk of bias, mainly due to bias in the randomization process and selection of reported results. The trials found no substantial differences between telephone and video telehealth consultations with regard to clinical effectiveness, patient satisfaction, and health care use (cost-effectiveness) outcomes. None of the studies reported on patient safety or adverse events. We did not find any study on telehealth interventions for diagnosis, initiating new treatment, or those conducted in a primary care setting. CONCLUSIONS: Based on a small set of diverse trials, we found no notable differences between telephone and video consultations for the management of patients with an established diagnosis. There is also a significant lack of telehealth research in primary care settings despite its high uptake.

Evaluating the use of clinical decision aids in an Australian emergency department: A cross-sectional survey.

OBJECTIVE: To identify healthcare professionals' knowledge, self-reported use, and documentation of clinical decision aids (CDAs) in a large ED in Australia, to identify behavioural determinants influencing the use of CDAs, and healthcare professionals preferences for integrating CDAs into the electronic medical record (EMR) system. METHODS: Healthcare professionals (doctors, nurses and physiotherapists) working in the ED at the Gold Coast Hospital, Queensland were invited to complete an online survey. Quantitative data were analysed using descriptive statistics, and where appropriate, mapped to the theoretical domains framework to identify potential barriers to the use of CDAs. Qualitative data were analysed using content analysis. RESULTS: Seventy-four healthcare professionals (34 medical officers, 31 nurses and nine physiotherapists) completed the survey. Healthcare professionals' knowledge and self-reported use of 21 validated CDAs was low but differed considerably across CDAs. Only 4 out of 21 CDAs were reported to be used 'sometimes' or 'always' by the majority of respondents (Ottawa Ankle Rule for ankle injury, Wells' criteria for pulmonary embolism, Wells' criteria for deep vein thrombosis and PERC rule for pulmonary embolism). Most respondents wanted to increase their use of valid and reliable CDAs and supported the integration of CDAs into the EMR to facilitate their use and support documentation. Potential barriers impacting the use of CDAs represented three theoretical domains of knowledge, social/professional role and identity, and social influences. CONCLUSIONS: CDAs are used variably by healthcare professionals and are inconsistently applied in the clinical encounter. Preferences of healthcare professionals need to be considered to allow the successful integration of CDAs into the EMR.

Telehealth versus face-to-face delivery of cognitive behavioural therapy for insomnia: A systematic review and meta-analysis of randomised controlled trials.

OBJECTIVE: This systematic review and meta-analysis compared the effectiveness of the delivery of care to patients with insomnia via telehealth to its delivery face-to-face. METHODS: We searched Medline, Embase, and Cochrane CENTRAL from inception to 11 January 2023, and conducted a citation analysis on 13 June 2023. No language restrictions were imposed. We included randomised controlled trials. Where feasible, mean differences were calculated; we used a random effects model. RESULTS: Four trials (239 patients) were included. There were no significant differences between telehealth and face-to-face for insomnia severity scores shortly post-intervention (MD 1.13, 95% CI -0.29-2.55) or at 3 months (mean difference (MD) 1.79, 95% CI -0.01-3.59). There were no differences in Short Form-36 physical and mental scores, Work and Social Adjustment scores, and sleep quality components. Depression scores did not differ post-intervention or at 3 months (MD 0.42, 95% CI -2.42-3.26). Functioning likewise did not differ post-intervention or at 3 months (standardised mean difference (SMD) 0.15, 95% CI -0.37-0.67, P = 0.58). Treatment satisfaction did not differ (one trial) or favoured the face-to-face group (one trial). CONCLUSIONS: Telehealth may be a viable alternative to the face-to-face provision of cognitive behavioural therapy for insomnia to patients with insomnia. However, the volume of the existing evidence is limited, therefore additional trials are needed, evaluating cognitive behavioural therapy for insomnia and other therapies for individuals for whom cognitive behavioural therapy for insomnia is not effective, and conducted with a wider range of populations, providers and settings.

Imaging the master regulator of the antioxidant response in non-small cell lung cancer with positron emission tomography.

Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. The cystine/glutamate antiporter, system xc-, is one of the >200 cytoprotective proteins controlled by NRF2, which can be non-invasively imaged by (S)-4-(3-18F-fluoropropyl)-l-glutamate ([18F]FSPG) positron emission tomography (PET). Through genetic and pharmacologic manipulation, we show that [18F]FSPG provides a sensitive and specific marker of NRF2 activation in advanced preclinical models of NSCLC. We validate imaging readouts with metabolomic measurements of system xc- activity and their coupling to intracellular glutathione concentration. A redox gene signature was measured in patients from the TRACERx 421 cohort, suggesting an opportunity for patient stratification prior to imaging. Furthermore, we reveal that system xc- is a metabolic vulnerability that can be therapeutically targeted for sustained tumour growth suppression in aggressive NSCLC. Our results establish [18F]FSPG as predictive marker of therapy resistance in NSCLC and provide the basis for the clinical evaluation of both imaging and therapeutic agents that target this important antioxidant pathway.

The chicken chorioallantoic membrane as a low-cost, high-throughput model for cancer imaging.

Mouse models are invaluable tools for radiotracer development and validation. They are, however, expensive, low throughput, and are constrained by animal welfare considerations. Here, we assessed the chicken chorioallantoic membrane (CAM) as an alternative to mice for preclinical cancer imaging studies. NCI-H460 FLuc cells grown in Matrigel on the CAM formed vascularized tumors of reproducible size without compromising embryo viability. By designing a simple method for vessel cannulation it was possible to perform dynamic PET imaging in ovo, producing high tumor-to-background signal for both 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) and (4S)-4-(3-18F-fluoropropyl)-L-glutamate (18F-FSPG). The pattern of 18F-FDG tumor uptake were similar in ovo and in vivo, although tumor-associated radioactivity was higher in the CAM-grown tumors over the 60 min imaging time course. Additionally, 18F-FSPG provided an early marker of both treatment response to external beam radiotherapy and target inhibition in ovo. Overall, the CAM provided a low-cost alternative to tumor xenograft mouse models which may broaden access to PET and SPECT imaging and have utility across multiple applications.

Imaging zinc trafficking in vivo by positron emission tomography with zinc-62.

Non-invasive imaging techniques to dynamically map whole-body trafficking of essential metals in vivo in health and diseases are needed. Despite 62Zn having appropriate physical properties for positron emission tomography (PET) imaging (half-life, 9.3 h; positron emission, 8.2%), its complex decay via 62Cu (half-life, 10 min; positron emission, 97%) has limited its use. We aimed to develop a method to extract 62Zn from a 62Zn/62Cu generator, and to investigate its use for in vivo imaging of zinc trafficking despite its complex decay. 62Zn prepared by proton irradiation of natural copper foil was used to construct a conventional 62Zn/62Cu generator. 62Zn was eluted using trisodium citrate and used for biological experiments, compared with 64Cu in similar buffer. PET/CT imaging and ex vivo tissue radioactivity measurements were performed following intravenous injection in healthy mice. [62Zn]Zn-citrate was readily eluted from the generator with citrate buffer. PET imaging with the eluate demonstrated biodistribution similar to previous observations with the shorter-lived 63Zn (half-life 38.5 min), with significant differences compared to [64Cu]Cu-citrate, notably in pancreas (>10-fold higher at 1 h post-injection). Between 4 and 24 h, 62Zn retention in liver, pancreas, and kidney declined over time, while brain uptake increased. Like 64Cu, 62Zn showed hepatobiliary excretion from liver to intestines, unaffected by fasting. Although it offers limited reliability of scanning before 1 h post-injection, 62Zn-PET allows investigation of zinc trafficking in vivo for >24 h and hence provides a useful new tool to investigate diseases where zinc homeostasis is disrupted in preclinical models and humans.

Overdiagnosis and overuse of diagnostic and screening tests in low-income and middle-income countries: a scoping review.

OBJECTIVE: Overdiagnosis and overuse of healthcare services harm individuals, take resources that could be used to address underuse, and threaten the sustainability of health systems. These problems are attracting increasing attention in low-income and middle-income countries (LMICs). Unaware of any review of relevant evidence, we conducted a scoping review of the evidence around overdiagnosis and overuse of diagnostic and screening tests in LMICs. DESIGN: Scoping review. METHODS: We searched PubMed, Embase, PsycINFO, Global Index Medicus for relevant studies published until 24 May 2021, with no restrictions on date or language. We categorised included studies by major focus (overdiagnosis, overuse of tests, or both) and main themes (presence or estimates of extent; drivers; consequences and solutions). RESULTS: We identified 2763 unique records and included 162 articles reporting on 154 studies across 55 countries, involving over 2.8 million participants and/or requests for tests. Almost half the studies focused on overdiagnosis (70; 45.5%), one-third on overuse of tests (61; 39.6%) and one-fifth on both (23; 14.9%). Common overdiagnosed conditions included malaria (61; 39.6%) and thyroid cancer (25; 16.2%), estimated to be >70% in China. Overused tests included imaging (n=25 studies) such as CT and MRI; laboratory investigations (n=18) such as serological tests and tumour markers; and procedures (n=14) such as colonoscopy. Drivers included fear of conflict with patients and expanding disease definitions. Common consequences included unnecessary treatments such as antimalarials, and wasted resources, with costs of malaria overdiagnosis estimated at US$86 million in Sudan in 1 year alone. Only 9% of studies discussed solutions, which included addressing inappropriately lowered diagnostic thresholds and reforming test-ordering processes. CONCLUSIONS: Overdiagnosis and overuse of tests are widespread in LMICs and generate significant harm and waste. Better understanding of the problems and robust evaluation of solutions is needed, informed by a new global alliance of researchers and policy-makers.

Patient and public involvement in the development of clinical practice guidelines: a scoping review.

OBJECTIVES: Organisations that develop clinical practice guidelines (CPGs) encourage involvement of patients and the publics in their development, however, there are no standard methodologies for doing so. To examine how CPGs report patient and public involvement (PPI), we conducted a scoping review of the evidence addressing the following four questions: (1) who are the patients and publics involved in developing the CPG?; (2) from where and how are the patients and publics recruited?; (3) at what stage in the CPG development process are the patients and publics involved? and (4) how do the patients and publics contribute their views? We also extracted data on the use of PPI reporting checklists by the included studies. DESIGN: We used the methodology developed by Arksey and O'Malley and refined by the Joanna Briggs Institute. We searched PubMed, Embase, CINAHL and PsycINFO, websites of national guideline bodies from the UK, Canada, Australia and the USA, and conducted a forward citation search. No language, date or participant demographics restrictions were applied. Data were synthesised narratively. RESULTS: We included 47 studies addressing 1 or more of the 4 questions. All included studies reported who the patient and publics involved (PPI members) were, and several studies reported PPI members from different groups. Patients were reported in 43/47 studies, advocates were reported in 22/47 studies, patients and advocates reported in 17/47 studies, and general public reported in 2/47 studies. Thirty-four studies reported from where the patients and publics were recruited, with patient groups being the most common (20/34). Stage of involvement was reported by 42/47 studies, most commonly at question identification (26/42) and draft review (18/42) stages. Forty-two studies reported how the patients contributed, most commonly via group meetings (18/42) or individual interviews. Ten studies cited or used a reporting checklist to report findings. CONCLUSIONS: Our scoping review has revealed knowledge gaps to inform future research in several ways: replication, terminology and inclusion. First, no standard approach to PPI in CPG development could be inferred from the research. Second, inconsistent terminology to describe patients and publics reduces clarity around which patients and publics have been involved in developing CPGs. Finally, the under-representation of research describing PPI in the development of screening, as opposed to treatment, CPGs warrants further attention.

Telehealth v. face-to-face provision of care to patients with depression: a systematic review and meta-analysis.

Ensuring continuity of care for patients with major depressive disorders poses multiple challenges. We conducted a systematic review and meta-analysis of randomised controlled trials comparing real-time telehealth to face-to-face therapy for individuals with depression. We searched Medline, Embase, and Cochrane Central (to November 2020), conducted a citation analysis (January 2021), and searched clinical trial registries (March 2021). We included randomised controlled trials comparing similar or identical care, delivered via real-time telehealth (phone, video) to face-to-face. Outcomes included: depression severity, quality of life, therapeutic alliance, and care satisfaction. Where data were sufficient, mean differences were calculated. Nine trials (1268 patients) were included. There were no differences between telehealth and face-to-face care for depression severity at post-treatment (SMD -0.04, 95% CI -0.21 to 0.13, p = 0.67) or at other time points, except at 9 months post-treatment (SMD -0.39, 95% CI -0.75 to -0.02, p = 0.04). One trial reported no differences in quality-of-life scores at 3- or 12-months post-treatment. One trial found no differences in therapeutic alliance at weeks 4 and 14 of treatment. There were no differences in treatment satisfaction between telehealth and face-to-face immediately post-treatment (SMD -0.14, 95% CI -0.56 to 0.28, p = 0.51) or at 3 or 12-months. Evidence suggests that for patients with depression or depression symptoms, the provision of care via telehealth may be a viable alternative to the provision of care face-to-face. However, additional trials are needed with longer follow-up, conducted in a wider range of settings, and with younger patients.

A prodrug strategy for the in vivo imaging of aldehyde dehydrogenase activity.

Therapy resistance is one of the biggest challenges facing clinical oncology. Despite a revolution in new anti-cancer drugs targeting multiple components of the tumour microenvironment, acquired or innate resistance frequently blunts the efficacy of these treatments. Non-invasive identification of drug-resistant tumours will enable modification of the patient treatment pathway through the selection of appropriate second-line treatments. Here, we have designed a prodrug radiotracer for the non-invasive imaging of aldehyde dehydrogenase 1A1 (ALDH1A1) activity. Elevated ALDH1A1 activity is a marker of drug-resistant cancer cells, modelled here with matched cisplatin-sensitive and -resistant human SKOV3 ovarian cancer cells. The aromatic aldehyde of our prodrug radiotracer was intracellularly liberated by esterase cleavage of the geminal diacetate and specifically trapped by ALDH through its conversion to the charged carboxylic acid. Through this mechanism of action, ALDH-specific retention of our prodrug radiotracer in the drug-resistant tumour cells was twice as high as the drug-sensitive cells. Acylal masking of the aldehyde afforded a modest protection from oxidation in the blood, which was substantially improved in carrier-added experiments. In vivo positron emission tomography imaging of tumour-bearing mice produced high tumour-to-background images and radiotracer uptake in high ALDH-expressing organs but was unable to differentiate between drug-sensitive and drug-resistant tumours. Alternative strategies to protect the labile aldehyde are currently under investigation.

Real-Time Telehealth Versus Face-to-Face Management for Patients With PTSD in Primary Care: A Systematic Review and Meta-Analysis.

Objective: We conducted a systematic review and meta-analysis of randomized controlled trials comparing real-time telehealth (video, phone) with face-to-face therapy delivery to individuals with posttraumatic stress disorder (PTSD), by primary or allied health care practitioners.Data Sources: We searched MEDLINE, Embase, CINAHL, and Cochrane Central (inception to November 18, 2020); conducted a citation analysis on included studies (January 7, 2021) in Web of Science; and searched ClinicalTrials.gov and WHO ICTRP (March 25, 2021). No language or publication date restrictions were used.Study Selection: From 4,651 individual records screened, 13 trials (27 references) met the inclusion criteria.Data Extraction: Data on PTSD severity, depression severity, quality of life, therapeutic alliance, and treatment satisfaction outcomes were extracted.Results: There were no differences between telehealth and face-to-face for PTSD severity (at 6 months: standardized mean difference [SMD] = -0.11; 95% CI, -0.28 to 0.06), depression severity (at 6 months: SMD = -0.02; 95% CI, -0.26 to 0.22; P = .87), therapeutic alliance (at 3 months: SMD = 0.04; 95% CI, -0.51 to 0.59; P = .90), or treatment satisfaction (at 3 months: mean difference = 3.09; 95% CI, -7.76 to 13.94; P = .58). One trial reported similar changes in quality of life in telehealth and face-to-face.Conclusions: Telehealth appears to be a viable alternative for care provision to patients with PTSD. Trials evaluating therapy provision by telephone, and in populations other than veterans, are warranted.

Telehealth Versus Face-to-face Psychotherapy for Less Common Mental Health Conditions: Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Mental disorders are a leading cause of distress and disability worldwide. To meet patient demand, there is a need for increased access to high-quality, evidence-based mental health care. Telehealth has become well established in the treatment of illnesses, including mental health conditions. OBJECTIVE: This study aims to conduct a robust evidence synthesis to assess whether there is evidence of differences between telehealth and face-to-face care for the management of less common mental and physical health conditions requiring psychotherapy. METHODS: In this systematic review, we included randomized controlled trials comparing telehealth (telephone, video, or both) versus the face-to-face delivery of psychotherapy for less common mental health conditions and physical health conditions requiring psychotherapy. The psychotherapy delivered had to be comparable between the telehealth and face-to-face groups, and it had to be delivered by general practitioners, primary care nurses, or allied health staff (such as psychologists and counselors). Patient (symptom severity, overall improvement in psychological symptoms, and function), process (working alliance and client satisfaction), and financial (cost) outcomes were included. RESULTS: A total of 12 randomized controlled trials were included, with 931 patients in aggregate; therapies included cognitive behavioral and family therapies delivered in populations encompassing addiction disorders, eating disorders, childhood mental health problems, and chronic conditions. Telehealth was delivered by video in 7 trials, by telephone in 3 trials, and by both in 1 trial, and the delivery mode was unclear in 1 trial. The risk of bias for the 12 trials was low or unclear for most domains, except for the lack of the blinding of participants, owing to the nature of the comparison. There were no significant differences in symptom severity between telehealth and face-to-face therapy immediately after treatment (standardized mean difference [SMD] 0.05, 95% CI -0.17 to 0.27) or at any other follow-up time point. Similarly, there were no significant differences immediately after treatment between telehealth and face-to-face care delivery on any of the other outcomes meta-analyzed, including overall improvement (SMD 0.00, 95% CI -0.40 to 0.39), function (SMD 0.13, 95% CI -0.16 to 0.42), working alliance client (SMD 0.11, 95% CI -0.34 to 0.57), working alliance therapist (SMD -0.16, 95% CI -0.91 to 0.59), and client satisfaction (SMD 0.12, 95% CI -0.30 to 0.53), or at any other time point (3, 6, and 12 months). CONCLUSIONS: With regard to effectively treating less common mental health conditions and physical conditions requiring psychological support, there is insufficient evidence of a difference between psychotherapy delivered via telehealth and the same therapy delivered face-to-face. However, there was no includable evidence in this review for some serious mental health conditions, such as schizophrenia and bipolar disorders, and further high-quality research is needed to determine whether telehealth is a viable, equivalent treatment option for these conditions.

Radiotracer stereochemistry affects substrate affinity and kinetics for improved imaging of system xC- in tumors.

Amino acid utilization is perturbed in cancer cells, which rewire their metabolism to support cell survival and proliferation. This metabolic reprogramming can be exploited for diagnostic purposes through positron emission tomography imaging of fluorine-18 labeled amino acids. Despite its promise, little is known regarding transporter-recognition of non-natural amino acid stereoisomers or their utility for cancer imaging. We report here the synthesis and in vivo characterization of a radiolabeled amino acid (R)-4-(3-18F-fluoropropyl)-ʟ-glutamate ([18F]FRPG) and compared its tumor imaging properties to the 4S-isomer, [18F]FSPG. Methods: [18F]FRPG and [18F]FSPG uptake was assessed in H460 lung cancer cells, with efflux measured 30 min after removal of exogenous activity. Specificity of [18F]FRPG for system xC- was further examined following transporter inhibition and blocking studies with system xC- substrates. [18F]FRPG and [18F]FSPG pharmacokinetics was next quantified in mice bearing subcutaneous A549, H460, VCAP and PC3 tumors, with mice bearing A549 tumors imaged by PET/CT. To better-understand differential tumor retention, radiometabolite analysis was performed on tissue and blood samples after imaging. Next, [18F]FRPG and [18F]FSPG retention in lipopolysaccharide-treated lungs were compared to an orthotopic H460 lung cancer model. Finally, the sensitivity of [18F]FRPG to manipulation of the redox environment was examined in cell and in vivo models. Results: [18F]FRPG was specifically transported across the plasma membrane by the cystine/glutamate antiporter system xC- and retained at high levels in multiple tumor models. Conversely, [18F]FRPG was rapidly extracted from the blood and cleared from tissues with low system xC- expression. Due to its favorable imaging properties, tumor-to-blood ratios ≥10 were achieved with [18F]FRPG, which were either equal to or greater than [18F]FSPG. In addition, [18F]FRPG retention in orthotopic lung tumors with high system xC- expression was 2.5-fold higher than inflamed tissue, allowing for clear tumor visualization. In vivo, [18F]FRPG and [18F]FSPG were metabolized to a single species, with [18F]FRPG showing a higher percentage of parent radiotracer in tumors compared to [18F]FSPG. [18F]FRPG was sensitive to redox manipulations and tumor retention was reduced following treatment with liposomal doxorubicin in mice bearing ovarian tumors. Conclusions: Given the fast clearance and low background retention of [18F]FRPG throughout the body, this radiotracer holds promise for the imaging of system xC- activity and treatment response monitoring in tumors of the thorax, abdomen, and head and neck. [18F]FRPG PET imaging provides a sensitive noninvasive measure of system xC- and excellent properties for cancer imaging.

The effectiveness of telehealth versus face-to face interventions for anxiety disorders: A systematic review and meta-analysis.

INTRODUCTION: Worldwide, it is estimated that 264 million people meet the diagnostic criteria for anxiety conditions. Effective treatment regimens consist of cognitive and behavioural therapies. During the COVID-19 pandemic, treatment delivery relied heavily on telemedicine technologies which enabled remote consultation with patients via phone or video platforms. We aim to identify, appraise and synthesise randomised controlled trials comparing telehealth to face-to-face delivery of care to individuals of any age or gender, diagnosed with anxiety disorders, and disorders with anxiety features. METHODS: To conduct this systematic review and meta-analysis, we searched three electronic databases, clinical trial registries and citing-cited references of included studies. RESULTS: A total of five small randomised controlled trials were includable; telehealth was conducted by video in three studies, and by telephone in two. The risk of bias for the 5 studies was low to moderate for most domains. Outcomes related to anxiety, depression symptom severity, obsessive-compulsive disorder, function, working alliance, and satisfaction were comparable between the two modes of delivery at each follow-up time point (immediately post-intervention, 3 months, 6 months and 12 months), with no significant differences reported (p > 0.05). None of the trials reported on the costs of telehealth compared to face-to-face care. DISCUSSION: For effectively treating anxiety and related conditions, interventions delivered by telehealth appear to be as effective as the same therapy delivered in-person. However, further high-quality trials are warranted to determine the effectiveness, acceptability, feasibility, and cost-effectiveness of telehealth interventions for the management of a wider range of anxiety disorders and treatments.

Latest Advances in Imaging Oxidative Stress in Cancer.

Oxidative stress is the imbalance of harmful reactive oxygen species (ROS) and the action of neutralizing antioxidant mechanisms. If left unchecked, the deleterious effects of oxidative stress result in damage to DNA, proteins, and membranes, ultimately leading to cell death. Tumors are highly proliferative and consequently generate high levels of mitochondrial ROS. To compensate for this and maintain redox homeostasis, cancer cells upregulate protective antioxidant pathways, which are further amplified in drug-resistant tumors. This review provides an overview of the latest molecular imaging techniques designed to image oxidative stress in cancer. New probes can now assess heterogeneous ROS and antioxidant production within tumors and across lesions. Together, the noninvasive imaging of these dynamic processes holds great promise for monitoring response to treatment and predicting drug resistance and may provide insight into the metastatic potential of tumors.