Implementing a digital rare disease case-finding tool in UK primary care: a qualitative study of health professionals' experience.

BACKGROUND: Rare diseases affect millions of people globally, with a lifetime incidence of 1 in 17. They are complex, multisystem, severe disease, and patients experience a diagnostic delay averaging 5.6 years with associated misdiagnoses, inappropriate treatments, and anxiety. MendelScan is a digital case-finding tool that uses structured primary care data to identify patients at risk of being affected by one of a series of rare diseases. This qualitative study explored primary healthcare professionals' experiences of implementing this technology. AIM: To develop an understanding of primary healthcare professionals' experiences of implementing MendelScan with a focus on their perception of the technology and its implementation, challenges and opportunities. METHOD: A qualitative appraisal of implementing MendelScan using descriptive analysis of surveys and semi-structured interviews with professionals. RESULTS: A total of 11 professionals from the two project areas participated. Participants included GPs, nurses, a genetic counsellor, and healthcare managers.Participants reported that they received adequate support, the project increased confidence in integrating genetics in primary care, and that it may improve inequity in rare disease diagnosis. Professionals' reservations were related to knowledge, time commitments, primary care pressures, contacting patients, data sharing and confidentiality, and overcoming clinical resistance in sharing data with a non-NHS external body. CONCLUSION: This study provides a valuable insight into the experiences of primary care professionals using a novel tool to identify rare diseases. The potential of this tool is promising with benefits for skill development. Large-scale implementation faces challenges related to primary care capacity, data, and funding.

Effect of MDMA-assisted therapy on mood and anxiety symptoms in advanced-stage cancer (EMMAC): study protocol for a double-blind, randomised controlled trial.

BACKGROUND: Symptoms of anxiety and depression are common in patients with terminal illness and multiple challenges exist with timely and effective care in this population. Several centres have reported that one dose of the serotonergic psychedelic psilocybin, combined with therapeutic support, improves these symptoms for up to 6 months in this patient group. Drawing upon related therapeutic mechanisms, 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy may have the potential to achieve similar, positive mental health outcomes in this group. Preliminary evidence also supports the tolerability of MDMA-assisted therapy for anxiety and depression in advanced-stage cancer. METHODS: Up to 32 participants with advanced-stage cancer and associated depression and anxiety will be randomised in a 1:1 ratio into one of two blinded parallel treatment arms. The intervention group will receive 120 mg (+ 60 mg optional supplemental dose) MDMA-assisted therapy. The psychoactive control group will receive 20 mg oral (+ 10 mg optional supplemental dose) methylphenidate-assisted therapy. For each medication-assisted therapy session, participants will undergo two 90-min therapeutic support sessions in the week preceding, and one 90-min support session the day after the experimental session. A battery of measures (mood, anxiety, quality of life, mystical experience, spiritual wellbeing, attitudes towards death, personality traits, holistic health and wellbeing, connectedness, demoralisation, expectations, qualitative data and safety measures) will be assessed at baseline and through to the end of the protocol. Participants will be followed up until either 12 months post-randomisation or death, whichever occurs first. DISCUSSION: This study will examine the effect of MDMA-assisted therapy on symptoms of anxiety and depression in advanced-stage cancer. Potential therapeutic implications include establishing the safety and effectiveness of a novel treatment that may relieve mental suffering in patients with life-threatening illness. TRIAL REGISTRATION: Trial registered on Australian New Zealand Clinical Trials Registry. REGISTRATION NUMBER: ACTRN12619001334190p. Date registered: 30/09/2019. URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378153&showOriginal=true&isReview=true.

PAM trial protocol: a randomised feasibility study of psychedelic microdosing-assisted meaning-centred psychotherapy in advanced stage cancer patients.

BACKGROUND: An advanced cancer diagnosis can be associated with a significant profile of distress. Psychedelic compounds have shown clinically significant effects in the treatment of psychological distress in patients with advanced-stage cancer. Given the challenges of delivering timely and effective intervention in the advanced cancer context, it is possible that an alternative, more pragmatic, approach lies in psychedelic 'microdosing'. Microdosing refers to repeated administration of psychedelics in sub-hallucinogenic doses. The purpose of this study is to evaluate the feasibility of conducting a full-scale randomised controlled trial comparing psychedelic microdose-assisted-meaning-centred psychotherapy (PA-MCP) to standard meaning-centred psychotherapy (MCP) in New Zealand indigenous (Maori) and non-indigenous people with advanced cancer and symptoms of anxiety and/or depression. Although MCP is a well-established psychotherapeutic treatment in advanced cancer populations, the potential efficacy and effectiveness of this therapy when delivered alongside a standardised microdose regimen of a psychedelic compound have not been investigated. METHODS: Participants with advanced-stage cancer and symptoms of anxiety and/or depression (N = 40; 20 Maori, 20 non-Maori) will be randomised under double-blind conditions to receive 7 sessions of MCP alongside 13 doses of either an LSD microdose (4-20 µg) (PA-MCP) or inactive placebo (placebo-MCP). The feasibility, acceptability, and safety of this intervention and physiological and psychological measures will be recorded at baseline, at each session of MCP, and at a 1-month and 6-month follow-up. DISCUSSION: Our findings will evaluate the feasibility, acceptability, and safety of a larger randomised controlled trial and provide an initial indication of the potential benefits of psychedelic microdosing for psychological distress in advanced-stage indigenous and non-indigenous cancer patients. TRIAL REGISTRATION: NZCTR, ACTRN12623000478617. Registered 11 May 2023.  https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385810&isReview=true .

Atherosclerotic three-layer nanomatrix vascular sheets for high-throughput therapeutic evaluation.

In vitro atherosclerosis models are essential to evaluate therapeutics before in vivo and clinical studies, but significant limitations remain, such as the lack of three-layer vascular architecture and limited atherosclerotic features. Moreover, no scalable 3D atherosclerosis model is available for making high-throughput assays for therapeutic evaluation. Herein, we report an in vitro 3D three-layer nanomatrix vascular sheet with critical atherosclerosis multi-features (VSA), including endothelial dysfunction, monocyte recruitment, macrophages, extracellular matrix remodeling, smooth muscle cell phenotype transition, inflammatory cytokine secretion, foam cells, and calcification initiation. Notably, we present the creation of high-throughput functional assays with VSAs and the use of these assays for evaluating therapeutics for atherosclerosis treatment. The therapeutics include conventional drugs (statin and sirolimus), candidates for treating atherosclerosis (curcumin and colchicine), and potential gene therapy (miR-146a-loaded liposomes). The high efficiency and flexibility of the scalable VSA functional assays should facilitate drug discovery and development for atherosclerosis.

Power-controlled acoustofluidic manipulation of microparticles.

Recently, surface acoustic wave (SAW) based acoustofluidic separation of microparticles and cells has attracted increasing interest due to accuracy and biocompatibility. Precise control of the input power of acoustofluidic devices is essential for generating optimum acoustic radiation force to manipulate microparticles given their various parameters including size, density, compressibility, and moving velocity. In this work, an acoustophoretic system is developed by employing SAW based interdigital electrode devices. Power meters are applied to closely monitor the incident and reflected powers of the SAW device, which are associated with the separation efficiency. There exists a range of input powers to migrate the microparticles to the pressure node due to their random locations when entering the SAW field. Theoretical analysis is performed to predict a proper input power to separate mixtures of polystyrene microspheres, and the end lateral position of microspheres being acoustically separated. The separation efficiency of four sizes of microspheres, including 20 µm, 15 µm, 10 µm, and 5 µm, is calculated and compared with experimental results, which suggest the input power for separating the mixture of these microspheres. The study provides a practical guidance on operating SAW devices for bioparticle separation using the incident power as a control parameter.

Embedding genomics across the NHS: a primary care perspective.

Primary care remains the point of access to the NHS as well as having key roles in care coordination and prescribing. Therefore, embedding of genomic medicine in the NHS relies on successful implementation into the primary care landscape. Primary care is currently facing considerable challenges, including increasing numbers of patients and consultations per GP, multiple health conditions and polypharmacy, all contributing to increasing workload within a resource-constrained system. Although genomic medicine has enormous potential to benefit patients, its successful implementation demands alignment with existing skills and working practices, development of underpinning informatics infrastructure, integration into care pathways with consideration of commissioning and leadership. Here, we set out current initiatives and future strategies to support primary care colleagues in the delivery of genomic medicine, covering issues of workforce development and education, primary care leadership, and data and digital considerations.

Is it possible to implement a rare disease case-finding tool in primary care? A UK-based pilot study.

INTRODUCTION: This study implemented MendelScan, a primary care rare disease case-finding tool, into a UK National Health Service population. Rare disease diagnosis is challenging due to disease complexity and low physician awareness. The 2021 UK Rare Diseases Framework highlights as a key priority the need for faster diagnosis to improve clinical outcomes. METHODS AND RESULTS: A UK primary care locality with 68,705 patients was examined. MendelScan encodes diagnostic/screening criteria for multiple rare diseases, mapping clinical terms to appropriate SNOMED CT codes (UK primary care standardised clinical terminology) to create digital algorithms. These algorithms were applied to a pseudo-anonymised structured data extract of the electronic health records (EHR) in this locality to "flag" at-risk patients who may require further evaluation. All flagged patients then underwent internal clinical review (a doctor reviewing each EHR flagged by the algorithm, removing all cases with a clear diagnosis/diagnoses that explains the clinical features that led to the patient being flagged); for those that passed this review, a report was returned to their GP. 55 of 76 disease criteria flagged at least one patient. 227 (0.33%) of the total 68,705 of EHR were flagged; 18 EHR were already diagnosed with the disease (the highlighted EHR had a diagnostic code for the same RD it was screened for, e.g. Behcet's disease algorithm identifying an EHR with a SNOMED CT code Behcet's disease). 75/227 (33%) EHR passed our internal review. Thirty-six reports were returned to the GP. Feedback was available for 28/36 of the reports sent. GP categorised nine reports as "Reasonable possible diagnosis" (advance for investigation), six reports as "diagnosis has already been excluded", ten reports as "patient has a clear alternative aetiology", and three reports as "Other" (patient left study locality, unable to re-identify accurately). All the 9 cases considered as "reasonable possible diagnosis" had further evaluation. CONCLUSIONS: This pilot demonstrates that implementing such a tool is feasible at a population level. The case-finding tool identified credible cases which were subsequently referred for further investigation. Future work includes performance-based validation studies of diagnostic algorithms and the scalability of the tool.

Influence of Lumbar Mobilizations During the Nordic Hamstring Exercise on Hamstring Measures of Knee Flexor Strength, Failure Point, and Muscle Activity: A Randomized Crossover Trial.

OBJECTIVE: The aims of this study were to quantify the effects of spinal mobilization on force production, failure point, and muscle activity of the hamstrings during the Nordic hamstring exercise (NHE), and to explore individual differences in responses. METHODS: In a replicated randomized crossover trial, 24 asymptomatic, recreationally active men (age [mean ± standard deviation]: 27 ± 6 years; body mass: 82 ± 17 kg; height: 181 ± 8 cm) completed 2 standardized intervention trials (L4/5 zygapophyseal mobilizations) and 2 control trials. The failure point of the NHE was determined with 3D motion capture. Peak force, knee flexor torque, and electromyography (EMG) of the biceps femoris were measured. Data analyses were undertaken to quantify mean intervention response and explore any individual response heterogeneity. RESULTS: Mean (95% confidence interval) left-limb force was higher in intervention than in control trials by 18.7 (4.6-32) N. Similarly, right-limb force was higher by 22.0 (3.4-40.6) N, left peak torque by 0.14 (0.06-0.22) N • m, and right peak torque by 0.14 (0.05-0.23) N • m/kg. Downward force angle was decreased in intervention vs control trials by 4.1° (0.5°-7.6°) on the side of application. Both peak EMG activity (P = .002), and EMG at the downward force (right; P = .020) increased in the intervention condition by 16.8 (7.1-26.4) and 8.8 (1.5-16.1) mV, respectively. Mean downward acceleration angle changed by only 0.3° (-8.9° to 9.4°) in intervention vs control trials. A clear response heterogeneity was indicated only for right force (Participant × Intervention interaction: P = .044; response heterogeneity standard deviation = 34.5 [5.7-48.4] N). Individual response heterogeneity was small for all other outcomes. CONCLUSION: After spinal mobilization, immediate changes in bilateral hamstring force production and peak torque occurred during the NHE. The effect on the NHE failure point was unclear. Electromyographic activity increased on the ipsilateral side. Response heterogeneity was generally similar to the random trial-to-trial variability inherent in the measurement of the outcomes.

A 12-month continuous and intermittent high-impact exercise intervention and its effects on bone mineral density in early postmenopausal women: a feasibility randomized controlled trial.

BACKGROUND: Intermittent mechanical loading generates greater bone adaptations than continuous mechanical loading in rodents but has never been evaluated in humans. This study aimed to evaluate the feasibility of a continuous and intermittent countermovement jump (CMJ) intervention for attenuating early postmenopausal BMD loss. METHODS: 41 healthy early postmenopausal women (age=54.6±3.4 years) were randomly assigned to a continuous countermovement jumping group, an intermittent countermovement jumping group or a control group for 12 months. Adherence and dropout rates were recorded along with bone mineral density (BMD) at lumbar spine, femoral neck and trochanter sites at baseline, 6 months and 12 months. RESULTS: 28 participants completed the study. Dropout rate during the intervention (from the initiation of exercise) was 36% from continuous and 38% from intermittent countermovement jumping groups. For the participants that completed the intervention, adherence was 60.0±46.8% for continuous and 68.5±32.3% for intermittent countermovement jumping. The control group lost significant lumbar spine BMD (% difference=-2.7 [95%CI: -3.9 to -1.4]) and femoral neck BMD (% difference=-3.0% [95%CI: -5.1 to -0.8]). There was no statistically significant change in BMD for either countermovement jumping group. There was no statistically significant difference in BMD change between continuous or intermittent countermovement jumping groups when compared with the control group. CONCLUSIONS: Adherence and dropout rates were in line with previous similar interventions. To evaluate the effect of continuous and intermittent exercise on BMD, future studies should focus on maintaining participant engagement and adherence to the exercise intervention.

Validity and Reliability of the Apple Watch for Measuring Heart Rate During Exercise.

We examined the validity and reliability of the Apple Watch heart rate sensor during and in recovery from exercise. Twenty-one males completed treadmill exercise while wearing two Apple Watches (left and right wrists) and a Polar S810i monitor (criterion). Exercise involved 5-min bouts of walking, jogging, and running at speeds of 4 km.h -1 , 7 km.h -1 , and 10 km.h -1 , followed by 11 min of rest between bouts. At all exercise intensities the mean bias was trivial. There were very good correlations with the criterion during walking (L: r=0.97; R: r=0.97), but good (L: r=0.93; R: r=0.92) and poor/good (L: r=0.81; R: r=0.86) correlations during jogging and running. Standardised typical error of the estimate was small, moderate, and moderate to large. There were good correlations following walking, but poor correlations following jogging and running. The percentage of heart rates recorded reduced with increasing intensity but increased over time. Intra-device standardised typical errors decreased with intensity. Inter-device standardised typical errors were small to moderate with very good to nearly perfect intraclass correlations. The Apple Watch heart rate sensor has very good validity during walking but validity decreases with increasing intensity.