Design Of Intervention Trials Research Articles

Preferences for genetic interventions for SCA and Huntington’s disease: results of a discrete choice experiment among patients

BackgroundAlthough genetic interventions are on the horizon for some polyglutamine expansion diseases, such as subtypes of spinocerebellar ataxia (SCA) and Huntington’s disease (HD), the patients’ preferences regarding these new therapies are unclear. This study aims to get insight into what extent different characteristics of genetic interventions affect the preferences of patients with SCA and HD with regard to these interventions.MethodsManifest and premanifest patients with SCA or HD were recruited online by platforms of patient associations. The respondents conducted a questionnaire that included a discrete choice experiment (DCE). The experimental design included 24 choice sets, but these were divided into three blocks of eight to reduce the number of tasks per respondent. Each choice set included two alternative treatments and consisted of four attributes (mode and frequency of administration, chance of a beneficial effect, risks, and follow-up), each with three or four different levels. The forced choice-elicitation format was used. Data were analyzed by using a multinominal logistic regression model.ResultsResponses of 216 participants were collected. The mode and frequency of administration of a genetic intervention, as well as the chance of a beneficial effect both influence the choice for a genetic intervention. Respondents less prefer repeated lumbar punctures compared to a single operation. As expected, a higher beneficial effect of treatment was preferred. Risks and follow-up did not influence the choice for a genetic intervention.ConclusionsThe results can be used for the design and implementation of future genetic interventional trials as well as of patient-centered care pathways for rare movement disorders such as SCA and HD.

Cardiovascular Precision Medicine and Remote Intervention Trial Rationale and Design

Background: It has recently been shown that excessive fluctuation in blood pressure readings for an individual over time is closely associated with poor outcomes, including increased risk of cardiovascular mortality, coronary heart disease and stroke. Fluctuations may be associated with inconsistent adherence to medical recommendations. This new marker of risk has not yet been incorporated into a monitoring and intervention strategy that seeks to reduce cardiovascular risk by identifying patients through an algorithm tied to their electronic health record (EHR). Methods: We describe the methods used in an innovative “proof of concept” trial using CP&R (Cardiovascular Precision Medicine and Remote Intervention). A blood pressure variability index is calculated for clinic patients via an EHR review. Consenting patients with excessive variability are offered a remote intervention aimed at improving adherence to medical recommendations. The outcomes include the ability to identify and engage the identified patients and the effects of the intervention on blood pressure variability using a pre–post comparison design without parallel controls. Conclusions: Our innovative approach uses a recently identified marker based on reviewing and manipulating EHR data tied to a remote intervention. This design reduces patient burden and supports equitable and targeted resource allocation, utilizing an objective criterion for behavioral risk. This study is registered under ClinicalTrials.gov Identifier: NCT05814562.

Current and Future Directions in Developing Effective Treatments for PRPH2-Associated Retinal Diseases: A Workshop Report.

A workshop of affected individuals and their families, clinicians, researchers, and industry representatives was convened in March 2023 to define the knowledge landscape of peripherin 2 (PRPH2) biology and identify challenges and opportunities towards developing PRPH2-associated inherited retinal disease (IRD) treatments. The results of an online survey and presentations from affected individuals and their family members revealed disease characteristics and impacts on daily living. Scientific sessions highlighted the significant heterogeneity in clinical presentation of PRPH2-related retinopathy; PRPH2's crucial function in rod and cone outer segment formation and maintenance; the usefulness of existing animal and cellular models for understanding disease pathophysiology; and possible therapeutic approaches for autosomal dominant PRPH2-associated IRDs, including gene-specific therapies and gene-agnostic approaches. Priority gaps identified by the workshop included having a more complete understanding of PRPH2's fundamental biology and factors contributing to PRPH2-related disease phenotypic diversity, establishing genotype-phenotype correlations, and creating additional models to probe the functional consequences of PRPH2 variants and to test therapies. Additionally, a natural history study involving a large number of participants is required to more fully characterize PRPH2-related disease progression, aiding in interventional clinical trial design. Because PRPH2-associated IRDs are rare, maximizing opportunities for communication and collaboration among stakeholders, such as that provided by the workshop, is crucial to overcome the challenges to developing effective treatments and improve the lives of affected individuals. Fostering communication among stakeholders to identify knowledge gaps, therapeutic challenges, and potential opportunities toward developing effective treatments for PRPH2-related IRDs.

Impact of Clinical Trial Design on Recruitment of Racial and Ethnic Minorities.

Knowledge related to how oncology treatment trial design influences enrollment of racial and ethnic minorities is limited. Rigorous identification of clinical trial design parameters that associate favorably with minority accrual provides educational opportunities for individuals interested in designing more representative treatment trials. We identified oncology trials with a minimum of 10 patients at an NCI-Designated Comprehensive Cancer Center from 2010 to 2021. We defined a study endpoint of racial and ethnic minority accrual greater than zero. Multivariable logistic regression was used to determine whether co-variables predicted our study endpoint. P-values of less than 0.05 were considered significant. A total of 352 cancer trials met eligibility criteria. These studies enrolled a total of 7981 patients with a total of 926 racial and ethnic minorities leading to a median enrollment of 10%. Trials open in community sites (yes versus no) were more likely to have a minority patient (OR, 2.21; 95% CI, 1.02-4.96) as well as pilot/phase I studies compared to phase II/III (OR, 3.19; 95% CI, 1.34-8.26). Trials incorporating immunotherapy (yes versus no) were less likely to have a minority patient (OR, 0.47; 95% CI, 0.23-0.94). Trials open in community sites as well as early phase treatment studies were more likely to accrue minority patients. However, studies including immunotherapy were less likely to accrue racial and ethnic minorities. Knowledge gained from our analysis may help individuals design oncology treatment trials that are representative of more diverse populations.

Meal timing and its role in obesity and associated diseases.

Meal timing emerges as a crucial factor influencing metabolic health that can be explained by the tight interaction between the endogenous circadian clock and metabolic homeostasis. Mistimed food intake, such as delayed or nighttime consumption, leads to desynchronization of the internal circadian clock and is associated with an increased risk for obesity and associated metabolic disturbances such as type 2 diabetes and cardiovascular diseases. Conversely, meal timing aligned with cellular rhythms can optimize the performance of tissues and organs. In this review, we provide an overview of the metabolic effects of meal timing and discuss the underlying mechanisms. Additionally, we explore factors influencing meal timing, including internal determinants such as chronotype and genetics, as well as external influences like social factors, cultural aspects, and work schedules. This review could contribute to defining meal-timing-based recommendations for public health initiatives and developing guidelines for effective lifestyle modifications targeting the prevention and treatment of obesity and associated metabolic diseases. Furthermore, it sheds light on crucial factors that must be considered in the design of future food timing intervention trials.

Abstract 6559: Clinical validity of post-surgery circulating tumor DNA testing in stage III colon cancer patients treated with adjuvant chemotherapy: The PROVENC3 study

Abstract Introduction: Surgery followed by adjuvant chemotherapy (ACT) is standard of care in stage III colon cancer. However, only 15-20% of patients benefit from ACT, as half of patients are cured by surgery, and 25-30% still experience a recurrence. Detection of circulating tumor DNA (ctDNA) after resection of the primary tumor is a strong prognostic biomarker in non-metastatic colon cancer and offers a promising approach to better stratify stage III colon cancer patients for ACT treatment decisions. Aim: The PROVENC3 study aims to determine the clinical validity of post-surgery ctDNA detection in patients with stage III colon cancer treated with ACT. Methods: Blood was collected pre-surgery, post-surgery and post-ACT for stage III colon cancer patients treated with ACT. Tumor-informed detection of ctDNA was performed through integrated whole genome sequencing (WGS) analyses of formalin-fixed paraffin-embedded tumor tissue DNA (80x), germline DNA (40x), and plasma cell-free DNA (30x). The primary outcome was time to recurrence (TTR). Results: Results from 209 patients (median follow up: 40 months) show that ctDNA-positive patients post-surgery (n=28) had a higher risk of developing a recurrence than ctDNA-negative patients (HR: 6.3, [95%CI: 3.5-11.3], P<10−8). 38% of patients with a recurrence within 3 years were ctDNA-positive post-surgery. Combination of post-surgery ctDNA status with established clinicopathological risk classification of low-risk (T1-3 and N1) and high-risk (T4 and/or N2) resulted in a 3-year cumulative recurrence risk of 82% for clinical high-risk ctDNA-positive patients compared to 7% for clinical low-risk ctDNA-negative patients (HR 28.9 [95%CI: 10.6-78.2]; P<10−10). Results from 170 patients with post-ACT blood available showed that post-ACT ctDNA-positive patients (n=24) were at a higher risk of developing a recurrence (HR 7.9 [95%CI: 3.5-15.9]; P<10−8) than ctDNA-negative patients. The patients experiencing a recurrence had higher aggregate ctDNA variant allele frequencies than patients not experiencing a recurrence post-surgery or post-ACT (P<0.001 and P<0.001, respectively). Conclusion: Post-surgery ctDNA detection by tumor-informed WGS is a strong prognostic biomarker in stage III colon cancer patients, and improves the current risk stratification. Importantly, the post-surgery ctDNA-positive patients who did not experience a recurrence were likely cured by ACT. These data enable the design of clinical practice-changing ctDNA-guided interventional trials in stage III colon cancer to personalize adjuvant treatment decisions. Citation Format: Carmen Rubio Alarcon, Andrew Georgiadis, Ingrid A. Franken, Haoyue Wang, Sietske C. van Nassau, Suzanna J. Schraa, Dave E. van der Kruijssen, Karlijn van Rooijen, Theodora C. Linders, Pien Delis-van Diemen, Maartje Alkemade, Anne Bolijn, Marianne Tijssen, Margriet Lemmens, Lana Meiqari, Steven L. Ketelaars, Adria Closa Mosquera, Miranda M. van Dongen, Mirthe Lanfermeijer, Birgit I. Lissenberg-Witte, Linda J. Bosch, Teunise Bisschop-Snetselaar, Bregje Adriaans, Amy Greer, David Riley, James R. White, Christopher Greco, Liam Cox, Jesse Fox, Kaitlin Victor, Catherine Leech, Samuel V. Angiuoli, Niels F. Kok, Cornelis J. Punt, Daan van den Broek, Miriam Koopman, Gerrit A. Meijer, Victor E. Velculescu, Jeanine M. Roodhart, Veerle M. Coupé, Mark Sausen, Geraldine R. Vink, Remond J. Fijneman. Clinical validity of post-surgery circulating tumor DNA testing in stage III colon cancer patients treated with adjuvant chemotherapy: The PROVENC3 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6559.

The MARECA (national study of management of breast cancer locoregional recurrence and oncological outcomes) study: protocol for a prospective, multicentre cohort study.

Despite a UK 5-year breast cancer survival rate of 86.6%, patients may develop breast cancer recurrence within the same breast after breast conserving surgery, as well as in the remaining skin or chest wall after mastectomy or in the ipsilateral lymph glands. These recurrences, collectively termed locoregional recurrence (LRR), occur in around 8% of patients within 10 years of their original diagnosis. Currently, there is a lack of robust information on the presentation and prevalence of LRR with no UK-specific clinical guidelines available for the optimal management of this patient group. Additionally, there is a need to identify patterns of LRR presentation and their progression, which will enable prognostic factors to be determined. This will subsequently enable the tailoring of treatment and improve patient outcome. The MARECA study is a prospective, multicentre cohort study recruiting patients diagnosed with breast cancer LRR +/- associated distant metastases. Over 50 UK breast units are participating in the study with the aim of recruiting at least 500 patients over a recruitment period of 24 months. The data collected will detail the tumour pathology, imaging results, surgical treatment, radiotherapy and systemic therapy of the primary and recurrent breast cancer. Study follow-up will be for up to 5 years following LRR diagnosis to determine subsequent oncological outcomes and evaluate potential prognostic factors. This study will address the current knowledge gap and identify subgroups of patients who have less successful treatment outcomes. The results will determine the current management of LRR and the prognosis of patients diagnosed with breast cancer LRR +/- distant metastases in the UK, with the aim of establishing best practice and informing future national guidelines. The results will direct future research and inform the design of additional interventional trials and translational studies.

Targeting Gut Microbiome With Prebiotic in Patients With CKD: The TarGut-CKD Study

IntroductionDisruption of gut microbiota underpins some of the metabolic alterations observed in chronic kidney disease (CKD). MethodsIn a non-randomized, open-label, 3-phase pilot trial, with repeated measures within each phase, we examined the efficacy of oligofructose-enriched inulin (p-inulin) in changing the gut microbiome and their metabolic products in 15 CKD patients. The stability of microbiome and metabolome was studied during the pre-treatment phase (8 weeks), a p-inulin treatment phase (12 weeks), and a post-treatment phase (8 weeks) of the study. ResultsStudy participants completed 373 of the 420 expected study visits (88.8%). Adherence to p-inulin was 83.4%. 16S rRNA sequencing was performed in 368 stool samples. A total of 1085 stool, urine, and plasma samples were subjected to untargeted metabolomic studies. P-inulin administration altered the composition of the gut microbiota significantly, with an increase in abundance of Bifidobacterium and Anaerostipes. Inter-subject variations in microbiome and metabolome were larger than intra-subject variation, indicating the stability of the gut microbiome within each phase of the study. Overall metabolite compositions assessed by beta diversity in urine and stool metabolic profiles were significantly different across study phases. Several specific metabolites in stool, urine and plasma were significant at FDR ≤ 0.1 over phase. Specifically, there was significant enrichment in microbial metabolites derived from saccharolysis. ConclusionResults from our study highlight the stability of the gut microbiome and the expansive effect of p-inulin on microbiome and host co-metabolism in CKD patients. Findings from this study will enable rigorous design of microbiome-based intervention trials.

Cannabidiol and Depression: Promise and Challenge in Building an Evidence Base

Background: Interest in the potential mental health effects of cannabidiol (CBD) has increased recently, with a surge in commercial and pharmaceutical development of CBD products and a concomitant rise in consumer use. However, despite the widespread and growing use of CBD products by adults and adolescents, the mental health effects of CBD remain largely unknown. Objective: The goals of this review are: 1) to briefly review the evidence base for the mental health effects of CBD, using depression as an exemplar, and 2) to systematically outline complementary study designs needed to test CBD effects, together with challenges and special considerations related to each design. Methods: This review integrates empirical findings related to CBD's effects on mental health outcomes with the literature on intervention trial design and current legal regulations pertaining to CBD. Conclusion: Complementary controlled and observational studies of CBD are necessary to substantiate claims of mental health benefits, including for clinical depression and in pediatric populations. Investigators must consider challenges and opportunities specific to CBD as an intervention, including legal regulations, commercial or pharmaceutical product choice, dosing and bioavailability, and safety.

Community and Healthcare Perspectives on Implementing Hypertension Interventions for a Multiethnic Safety-Net Population.

To synthesize community and healthcare informants' perspectives on contextual considerations and tailoring recommendations for high-quality, sustainable implementation of evidence-based practices (EBPs) for managing hypertension (HTN) in a multiethnic safety-net population. Structured focus-group discussions and semistructured qualitative interviews. High-quality, sustainable implementation of HTN-related EBPs can promote equitable care. Implementation challenges extend beyond individual patients to span multiple levels of context. Few studies have systematically engaged community and healthcare perspectives to inform the design of HTN intervention trials. A large safety-net healthcare system. We conducted four structured discussions with each of five race- or ethnicity-specific community action boards (CABs) to understand community members' HTN-related norms, assets, needs, and experiences across local healthcare systems. We interviewed 41 personnel with diverse roles in our partnered healthcare system to understand the system's HTN-related strengths and needs. We solicited EBP tailoring recommendations from both groups. We summarized the findings using rapid content analysis. Participants identified contextual considerations spanning seven themes: social determinants, healthcare engagement, clinical interaction, system operations, standardization, patient education, and partnerships and funding. They offered tailoring recommendations spanning nine themes: addressing complex contexts, addressing social needs, system operations, healthcare system training and resources, linguistic and cultural tailoring, behavioral engagement, relational engagement, illness-course engagement, and community partnerships. Engaging community and healthcare informants can ground implementation in the policy, community, healthcare system, clinical, and interpersonal contexts surrounding diverse patients at risk for disparities. Such grounding can reframe inequitable implementation as a multilevel social problem facing communities and healthcare systems, rather than individuals.

Digital Phenotyping for Monitoring and Disease Trajectory Prediction of Patients With Cancer: Protocol for a Prospective Observational Cohort Study.

Timely recognition of cancer progression and treatment complications is important for treatment guidance. Digital phenotyping is a promising method for precise and remote monitoring of patients in their natural environments by using passively generated data from sensors of personal wearable devices. Further studies are needed to better understand the potential clinical benefits of digital phenotyping approaches to optimize care of patients with cancer. We aim to evaluate whether passively generated data from smartphone sensors are feasible for remote monitoring of patients with cancer to predict their disease trajectories and patient-centered health outcomes. We will recruit 200 patients undergoing treatment for cancer. Patients will be followed up for 6 months. Passively generated data by sensors of personal smartphone devices (eg, accelerometer, gyroscope, GPS) will be continuously collected using the developed LAIMA smartphone app during follow-up. We will evaluate (1) mobility data by using an accelerometer (mean time of active period, mean time of exertional physical activity, distance covered per day, duration of inactive period), GPS (places of interest visited daily, hospital visits), and gyroscope sensors and (2) sociability indices (frequency of duration of phone calls, frequency and length of text messages, and internet browsing time). Every 2 weeks, patients will be asked to complete questionnaires pertaining to quality of life (European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire [EORTC QLQ-C30]), depression symptoms (Patient Health Questionnaire-9 [PHQ-9]), and anxiety symptoms (General Anxiety Disorder-7 [GAD-7]) that will be deployed via the LAIMA app. Clinic visits will take place at 1-3 months and 3-6 months of the study. Patients will be evaluated for disease progression, cancer and treatment complications, and functional status (Eastern Cooperative Oncology Group) by the study oncologist and will complete the questionnaire for evaluating quality of life (EORTC QLQ-C30), depression symptoms (PHQ-9), and anxiety symptoms (GAD-7). We will examine the associations among digital, clinical, and patient-reported health outcomes to develop prediction models with clinically meaningful outcomes. As of July 2023, we have reached the planned recruitment target, and patients are undergoing follow-up. Data collection is expected to be completed by September 2023. The final results should be available within 6 months after study completion. This study will provide in-depth insight into temporally and spatially precise trajectories of patients with cancer that will provide a novel digital health approach and will inform the design of future interventional clinical trials in oncology. Our findings will allow a better understanding of the potential clinical value of passively generated smartphone sensor data (digital phenotyping) for continuous and real-time monitoring of patients with cancer for treatment side effects, cancer complications, functional status, and patient-reported outcomes as well as prediction of disease progression or trajectories. PRR1-10.2196/49096.

Disease progression of spinocerebellar ataxia types 1, 2, 3 and 6 before and after ataxia onset.

Our aim was to study the evolution of ataxia and neurological symptoms before and after ataxia onset in the most common spinocerebellar ataxias (SCAs), SCA1, SCA2, SCA3 and SCA6. We therefore jointly analysed the data of the EUROSCA and RISCA studies, which recruited ataxic and non-ataxic mutation carriers. We used mixed effect models to analyse the evolution of Scale for the Rating and Assessment of Ataxia (SARA) scores, SCA Functional Index (SCAFI) and Inventory of Non-Ataxia Signs (INAS) counts. We applied multivariable modelling to identify factors associated with SARA progression. In the time interval 5 years prior to and after ataxia onset, we calculated sensitivity to change ratios (SCS) of SARA, SCAFI and INAS. 2740 visits of 677 participants were analysed. All measures showed non-linear progression that was best fitted by linear mixed models with linear, quadratic and cubic time effects. R2 values indicating quality of the fit ranged from 0.70 to 0.97. CAG repeat was associated with faster progression in SCA1, SCA2 and SCA3, but not SCA6. 5 years prior to and after ataxia onset, SARA had the highest SCS of all measures with a mean of 1.21 (95% CI: 1.20, 1.21) in SCA1, 0.94 (0.93, 0.94) in SCA2 and 1.23 (1.22, 1.23) in SCA3. Our data have important implications for the understanding of disease progression in SCA1, SCA2, SCA3 and SCA6 across the lifespan. Furthermore, our study provides information for the design of interventional trials, especially in pre-ataxic mutation carriers close to ataxia onset and patients in early disease stages.

Co-creation of a complex, multicomponent rehabilitation intervention and feasibility trial protocol for the PostUraL tachycardia Syndrome Exercise (PULSE) study

BackgroundThere is a dearth of research to support the treatment of people with postural tachycardia syndrome (PoTS). Despite expert consensus suggesting exercise is recommended for this patient group, there are no randomised control trials examining this rigorously. The aim was to co-create a feasibility trial protocol and a rehabilitation intervention for people living with PoTS.MethodsThe intervention and feasibility trial design were co-created as part of the PostUraL tachycardia Syndrome Exercise (PULSE) study. We used the ‘three co’s framework’ of co-define, co-design and co-refine. Recruitment included key national charities and National Health Service Trusts treating people living with PoTS in the UK. Eighteen patient and public involvement members attended the co-define session, and 16 co-creators with a mix of expertise attended the subsequent co-design and co-refine sessions. Seven intervention practitioners were trained in the rehabilitation intervention, providing feedback for further co-refinement.ResultsThe final co-created intervention comprises online physical activity, and lifestyle and behaviour change support sessions. It is based on functional movement activities using a patient-centred approach tailored to individual needs. Physical activity intensity is guided by individuals’ perception of effort rather than by objective measures. Recumbent bikes are provided for home use. Patients deemed randomisation to be acceptable because research in this area was considered important.ConclusionsAn innovative approach was used to co-create the PULSE intervention and feasibility trial protocol to meet the evidence-based and logistical needs of people living with PoTS, clinicians, service deliverers, third-sector organisations, academics and funders. This can be used as a successful example and template for future research internationally. People living with PoTS were recognised as experts and involved in every aspect of conceptualisation, design and refinement. This complex rehabilitation intervention is currently being tested in a randomised feasibility trial comparing the PULSE intervention with best-practice usual care for people living with PoTS.Trial registrationISRCTN45323485 was registered on April 7, 2020.

PROTECT Norge: Online assessment of potentially modifiable risk factors for dementia on cognitive performance in a Norwegian ageing cohort

AbstractBackgroundPROTECT Norge, a fully digital platform, aims to help determine the role of defined genetic, lifestyle and environmental factors on cognition, health and wellbeing in people 50+. Annual questionnaires on demographics, medical conditions and medication use, mental health and lifestyle are completed online. The current study aims to assess whether potentially modifiable risk factors for dementia as presented by the Lancet Commission by Livingston and colleagues (2020) are related to cognitive performance in cognitively healthy people aged 50 and above.MethodA total of 2349 participants completed the PROTECT Cognitive Test System, an online cognitive battery containing six tasks which assess visual episodic memory, spatial and working memory, verbal reasoning, visual attention and task switching. The following risk factors were included in our analysis: physical activity, alcohol use, smoking, social isolation, age, BMI, education, depression, high blood pressure, head trauma and hearing loss. Multiple hierarchical regression analysis was performed. Separate analyses were conducted with the average performance across three sessions for each of the six cognitive measures as the dependent variable. Independent variables were included into the model in a hierarchy based on known risk factors for dementia.ResultResults show that age was associated with reduced cognitive performance for all tasks (p<0.001). In addition, for the digit span test, the risk factors were found to influence the test score were: smoking and previously diagnosed stroke. For the paired associate learning task, the only additional significant risk factor appeared to be gender, with male gender associated with poorer performance. For the grammatical reasoning task, the risk factors associated with lower scores were lower education, older age and smoking. For the switching Stroop test, the risk factors of lower scores were older age, smoking and previously diagnosed depression. For Trail‐making B test, the risk factors of lower scores were age, stroke and the history of heart disease.ConclusionThese preliminary results may improve our understanding of potentially modifiable risk factors for dementia and could inform the design and delivery of interventional trials as a mean to protect cognition in later life and to prevent or slow progression of cognitive decline.

Intraoperative monitoring of cerebrovascular autoregulation in infants and toddlers receiving major elective surgery to determine the individually optimal blood pressure - a pilot study.

Inducing general anesthesia (GA) in children can considerably affect blood pressure, and the rate of severe critical events owing to this remains high. Cerebrovascular autoregulation (CAR) protects the brain against blood-flow-related injury. Impaired CAR may contribute to the risk of cerebral hypoxic-ischemic or hyperemic injury. However, blood pressure limits of autoregulation (LAR) in infants and children are unclear. In this pilot study CAR was monitored prospectively in 20 patients aged <4 years receiving elective surgery under GA. Cardiac- or neurosurgical procedures were excluded. The possibility of calculating the CAR index hemoglobin volume index (HVx), by correlating near-infrared-spectroscopy (NIRS)-derived relative cerebral tissue hemoglobin and invasive mean arterial blood pressure (MAP) was determined. Optimal MAP (MAPopt), LAR, and the proportion of time with a MAP outside LAR were determined. The mean patient age was 14 ± 10 months. MAPopt could be determined in 19 of 20 patients, with an average of 62 ± 12 mmHg. The required time for a first MAPopt depended on the extent of spontaneous MAP fluctuations. The actual MAP was outside the LAR in 30% ± 24% of the measuring time. MAPopt significantly differed among patients with similar demographics. The CAR range averaged 19 ± 6 mmHg. Using weight-adjusted blood pressure recommendations or regional cerebral tissue saturation, only a fraction of the phases with inadequate MAP could be identified. Non-invasive CAR monitoring using NIRS-derived HVx in infants, toddlers, and children receiving elective surgery under GA was reliable and provided robust data in this pilot study. Using a CAR-driven approach, individual MAPopt could be determined intraoperatively. The intensity of blood pressure fluctuations influences the initial measuring time. MAPopt may differ considerably from recommendations in the literature, and the MAP range within LAR in children may be smaller than that in adults. The necessity of manual artifact elimination represents a limitation. Larger prospective and multicenter cohort studies are necessary to confirm the feasibility of CAR-driven MAP management in children receiving major surgery under GA and to enable an interventional trial design using MAPopt as a target.

Symptom burden of people with progressive ataxia, and its wider impact on their friends and relatives: a cross-sectional study

Background: Progressive ataxias are complex disorders that result in a wide variety of symptoms. Whilst we currently have a relatively good understanding of the spectrum of symptoms associated with the various types of ataxia, and their progression over time, their impact on the person with ataxia is less well understood. In addition, little is known about how carers, friends and relatives are affected by them. This paper aims to provide information on the presence and impact of medical symptoms and day-to-day challenges on people with ataxia and their friends and relatives. Method: Data were extracted from a survey by Ataxia UK done for their members. The views of 366 people with ataxia and 52 friends and relatives are reported. Data were analysed for the entire group, as well as for the three most common ataxia types represented in the sample, Friedreich’s ataxia, inherited ataxia (excluding Friedreich’s ataxia), and cerebellar ataxia of unknown cause. Results: The survey confirmed the symptom patterns described in previous research, but further showed that the impact of these symptoms can vary across ataxia populations. Similar findings were observed for day-to-day challenges. Friends and relatives experienced similar challenges to people with ataxia, indicating that support provided has to consider those supporting people with ataxia as well as the patient. Respondents also highlighted limitations in terms of accessing support services, and not all services were able to cater fully to their specific needs. Conclusion: This study begins to provide information that can be used in further research to explore the needs of people with ataxia and their carers, friends, and relatives. Such research will support treatment trial design, ensuring patients’ needs are considered, help to tailor support services to their needs, and ensure health care professionals have the necessary skills to fully address them.

Risk stratification in primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic liver disorder commonly affecting young patients and associated with uncertain prognosis and elevated risk of end-stage liver disease and hepatobiliary cancer. Rate of progression in PSC is heterogeneous and accurately predicting the disease course is of paramount importance to clinical practice and interventional trial design. So far, efforts have brought to the development of models looking at short-to-middle-term outcome using composite models including clinical, laboratory, radiological and histological parameters with limited performance. In the era of whole genome sequencing and digital innovation, the time is ripe for the development of stratified medicine in PSC. Efforts should be directed toward developing well-phenotyped cohorts of patients with longitudinal follow-up across sustained periods of time, application of novel image-processing technology, and biomarker discovery using multiomics platforms.

Identification of an immune-related gene prognostic index for predicting prognosis, immunotherapeutic efficacy, and candidate drugs in amyotrophic lateral sclerosis.

Considering the great insufficiency in the survival prediction and therapy of amyotrophic lateral sclerosis (ALS), it is fundamental to determine an accurate survival prediction for both the clinical practices and the design of treatment trials. Therefore, there is a need for more accurate biomarkers that can be used to identify the subtype of ALS which carries a high risk of progression to guide further treatment. The transcriptome profiles and clinical parameters of a total of 561 ALS patients in this study were analyzed retrospectively by analysis of four public microarray datasets. Based on the results from a series of analyses using bioinformatics and machine learning, immune signatures are able to be used to predict overall survival (OS) and immunotherapeutic response in ALS patients. Apart from other comprehensive analyses, the decision tree and the nomogram, based on the immune signatures, were applied to guide individual risk stratification. In addition, molecular docking methodology was employed to screen potential small molecular to which the immune signatures might response. Immune was determined as a major risk factor contributing to OS among various biomarkers of ALS patients. As compared with traditional clinical features, the immune-related gene prognostic index (IRGPI) had a significantly higher capacity for survival prediction. The determination of risk stratification and assessment was optimized by integrating the decision tree and the nomogram. Moreover, the IRGPI may be used to guide preventative immunotherapy for patients at high risks for mortality. The administration of 2MIU IL2 injection in the short-term was likely to be beneficial for the prolongment of survival time, whose dosage should be reduced to 1MIU if the long-term therapy was required. Besides, a useful clinical application for the IRGPI was to screen potential compounds by the structure-based molecular docking methodology. Ultimately, the immune-derived signatures in ALS patients were favorable biomarkers for the prediction of survival probabilities and immunotherapeutic responses, and the promotion of drug development.

Phenotypic features of adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP): presenting symptoms and clinical course

AbstractBackgroundALSP is an underdiagnosed, rapidly progressive, fatal autosomal dominant neurodegenerative disease caused by CSF1R gene mutations that result in microglial dysfunction. There are no published prospective studies on the natural history of ALSP. As a result, descriptions of phenotypic features of ALSP are derived from small case series and single case reports. To better understand the phenotypic characteristics of ALSP, a systematic literature review of these published case reports was performed.MethodA comprehensive, systematic literature review of the clinical and genetic features of ALSP was conducted to identify published case studies (January 1, 1980, through April 30, 2021) from a MEDLINE search using prespecified selection criteria. The search identified 76 published reports with data extracted from 274 ALSP patients and is the most extensive case series of ALSP to date.ResultThe mean±SD age (years) of onset of symptoms was 43.1±11.3, survival time (years) 6.3±4.6, and age of death (years) 52.9±10.8. The most common initial symptoms consisted of cognitive impairment (n = 113, 41.2%), behavioral and psychiatric dysfunction (n = 70, 25.6%), extrapyramidal motor abnormalities (n = 28, 10.2%), pseudo‐bulbar affects (n = 13 4.7%) and speech difficulty (n = 11, 4.0%) and confirmed the phenotypic heterogeneity of ALSP at disease onset, a major contributor to ALSP misdiagnosis. Clinical features associated with disease progression involved cognitive impairment (n = 216, 78.8%), behavioral and psychiatric dysfunction (n = 175, 63.9%), extrapyramidal motor abnormalities (n = 147, 53.7%), and pyramidal motor abnormalities, (n = 136, 49.6%). Less frequent clinical findings (each &lt; 25% incidence) were pseudo‐bulbar symptoms, seizures and aphasia or speech difficulty.ConclusionThe findings of this systematic literature review are consistent with previous, smaller reports on the phenotype of ALSP. Since cognitive impairment, behavioral and psychiatric dysfunction, and pyramidal and extrapyramidal motor abnormalities were identified as the most frequent clinical features in this review, endpoints quantifying these symptoms should be considered in the design of future interventional trials of ALSP.

Incisional hernia prevention: risk–benefit from a patient perspective (INVITE) – protocol for a single-centre, mixed-methods, cross-sectional study aiming to determine if using prophylactic mesh in incisional hernia prevention is acceptable to patients

IntroductionIncisional hernia (IH) is a common complication of abdominal surgery affecting between 10% and 20% of patients and is associated with significant morbidity along with cost to the National Health...