Trials Of New Therapies Research Articles

Clinical trials of new therapies for mucopolysaccharidoses

Background: Mucopolysaccharidoses (MPS) are a group of rare genetic diseases with a metabolic background. Currently, there are no effective methods of treating MPS, and new ways of treating patients are constantly being sought.Aim of the study: The purpose of this article is to review the available literature on clinical trials of new treatments for mucopolysaccharidoses.Material and methods: The review of research literature published between 1999 and 2023 was conducted, with a specific focus on the last ten years. The literature for this article was selected from publications available online in databases such as Google Scholar or PubMed. Research was based on keywords like: mucopolysaccharidoses, clinical trials, gene therapy, MPS. Results: A total of 104 publications were considered in the study, including 95 scientific articles and 9 clinical trial reports (consisting of 1 FDA approval). Out of those 104 articles, 82 discussed potential future therapies for patients with MPS. Among them, as many as 51 focused on gene therapy.Conclusions: The only currently approved treatments for mucopolysaccharidoses are enzyme replacement therapy and hematopoietic stem cell transplantation, which are not suitable for all types of MPS and have their limitations. In addition, there is no single therapy for all types of MPS, as they are the result of mutations in different genes and result from the deficiency of different enzymes. Numerous preclinical and clinical studies are being conducted on therapies for mucopolysaccharidoses. These include therapies that allow manipulation of cellular pathways, substrate reduction, or gene therapy, which is the most promising form of treatment. Some of the studies have successfully passed the first and second research phases.

Neuroimaging to monitor worsening of multiple sclerosis: advances supported by the grant for multiple sclerosis innovation.

Key unmet needs in multiple sclerosis (MS) include detection of early pathology, disability worsening independent of relapses, and accurate monitoring of treatment response. Collaborative approaches to address these unmet needs have been driven in part by industry-academic networks and initiatives such as the Grant for Multiple Sclerosis Innovation (GMSI) and Multiple Sclerosis Leadership and Innovation Network (MS-LINK™) programs. We review the application of recent advances, supported by the GMSI and MS-LINK™ programs, in neuroimaging technology to quantify pathology related to central pathology and disease worsening, and potential for their translation into clinical practice/trials. GMSI-supported advances in neuroimaging methods and biomarkers include developments in magnetic resonance imaging, positron emission tomography, ocular imaging, and machine learning. However, longitudinal studies are required to facilitate translation of these measures to the clinic and to justify their inclusion as endpoints in clinical trials of new therapeutics for MS. Novel neuroimaging measures and other biomarkers, combined with artificial intelligence, may enable accurate prediction and monitoring of MS worsening in the clinic, and may also be used as endpoints in clinical trials of new therapies for MS targeting relapse-independent disease pathology.

Motivators and Barriers for People with Sickle Cell Disease Participating in Clinical Trials: Global Findings from the LISTEN Survey

Background: The success of clinical trials of new therapies for sickle cell disease (SCD) will depend on the recruitment and retention of a large and diverse group of people with SCD (PwS). Qualitative studies have reported barriers to participation in clinical trials, including the potential impact on health, unmanageable study demands, limited knowledge of trials, and lack of trust in healthcare(Patterson CA et al. J Pediatr Hematol Oncol 2015; Lee LH et al. Blood Adv 2021). The Learning and Insights into Sickle Cell Trial Experiences (LISTEN) Survey was developed to provide a robust and comprehensive understanding of the global barriers and motivators to participation in clinical trials for PwS. Aim: To present interim findings from the LISTEN Survey regarding participation and experiences of PwS in clinical trials, barriers and motivators to participation, and differences in responses from PwS compared with perspectives of healthcare professionals (HCPs) treating PwS. Methods: Between October 6, 2022 and June 22, 2023, a broad range of adults (≥18 years) with SCD and HCPs involved in the treatment and/or clinical research of SCD in 17 countries were asked to complete corresponding quantitative surveys. PwS were asked whether they had participated in a clinical trial and, if so, whether their experience had met their expectations. PwS were asked to rate on a 7-point scale (from not at all to extremely important) and rank (from most to least important) the importance of specified factors (grouped into five categories) when deciding whether to participate in a clinical trial for SCD. HCPs provided their perspectives on the importance of these factors to PwS. The results presented here include the total proportion of respondents who rated factors as extremely or very important and the proportion who ranked factors first or second. Results: Overall, 1028 PwS (57% female) with a median age (interquartile range) of 30 years (24-37) from 16 of the 17 countries and 361 HCPs (67% hematologists and/or SCD specialists) from 17 countries completed the survey. In total, 35% of PwS had been invited to participate in a clinical trial for SCD. In PwS who had taken part in a clinical trial (24%; n=249/1028), compared with their expectations, 36% reported a better experience, 36% the same as expected experience, 9% a worse experience, and 20% did not know what to expect. Extremely or very important factors that motivated PwS to participate in a clinical trial included the potential to better manage their symptoms (52%), the opportunity to try a new treatment that might work better (51%), and to increase their knowledge of SCD (51%; Figure 1). An important barrier to participation was the potential to experience different side effects (51%). In the trial information category, PwS ranked (first or second of five) safety measures (57%) and how the treatment works (49%) as the most important factors; these were considered to be significantly more important than who is leading (27%) or funding (24%) the trial; p<0.001 for all combinations. In the further considerations category, the majority of PwS ranked (first or second of five) speaking to other PwS involved in the trial (51%) and experts running the trial (50%) as the most important factors. HCPs overstated the potential practical barriers for PwS compared with responses from PwS, including missing school/work (50% vs 42%; p=0.009), the effort required to start the trial treatment (45% vs 32%; p<0.001), and travel requirements (52% vs 36%; p<0.001). HCPs understated the importance of wider clinical trial outcomes as motivators for PwS compared with responses from PwS, including supporting new treatment developments that may benefit them (41% vs 51%; p=0.001) or other PwS (38% vs 49%; p<0.001; Figure 2). Conclusions: Improving access and recruitment into clinical trials in SCD will require clear communication of the potential benefits to individuals and the wider SCD community, as well as potential safety and side effects. Findings from the LISTEN Survey highlight that those directly involved in the trial should deliver these messages, including other PwS who are involved in the trial. Given the disconnect between PwS and HCPs, shared decision-making may also improve understanding and increase participation in clinical trials. Further analyses of the survey results will be important to identify the differences in responses between regions, age groups, and other subpopulations.

North American Clinical Trials Network for Spinal Cord Injury Registry: Methodology and Analysis.

The North American Clinical Trials Network (NACTN) for Spinal Cord Injury (SCI) is a consortium of neurosurgery departments at university affiliated hospitals with medical, nursing, and rehabilitation personnel who are skilled in the assessment, evaluation, and management of SCI. NACTN was established with the goal of consistently advancing the quality of life of people with SCI through clinical trials of new therapies that provide robust evidence of safety and effectiveness. A prospective multi-center Registry was created to collect the natural course of the acute traumatic SCI patient from time of injury to 12 months follow-up. NACTN's network of hospitals enrolls a significant number of patients, defines and adheres to standard protocols, and provides the infrastructure and highly skilled personnel to conduct trials of therapy for SCI. Registry data have been used by academic institutions and by the biotechnology and pharmaceutical sectors to create comparison datasets for Phase I clinical trials of new therapies.

A new era for optic pathway glioma: A developmental brain tumor with life-long health consequences.

Optic pathway and hypothalamic glioma (OPHG) are low-grade brain tumors that arise from any part of the visual pathways frequently involving the hypothalamus. The tumors grow slowly and present with features driven by their precise anatomical site, their age at presentation and the stage of growth and development of the host neural and orbital bony tissues. Up to 50% of optic pathway glioma arise in association with Neurofibromatosis type 1 (NF1), which affects 1 in 3,000 births and is a cancer predisposition syndrome. As low-grade tumors, they almost never transform to malignant glioma yet they can threaten life when they present under two years of age. The main risks are to threaten vision loss by progressive tumor damage to optic pathways; furthermore, invasion of the hypothalamus can lead to diencephalic syndrome in infancy and hypopituitarism later in life. Progressive cognitive and behavioural dysfunction can occur, as part of NF1 syndromic features and in sporadic cases where large bulky tumors compress adjacent structures and disrupt neuro-hypothalamic pathways. Persistently progressive tumors require repeated treatments to attempt to control vision loss, other focal brain injury or endocrine dysfunction. In contrast tumors presenting later in childhood can be seen to spontaneously arrest in growth and subsequently progress after periods of stability. These patterns are influenced by NF status as well as stages of growth and development of host tissues. The past two decades has seen an expansion in our understanding and knowledge of the clinical and scientific features of these tumors, their modes of presentation, the need for careful visual and endocrine assessment. This influences the decision-making surrounding clinical management with surgery, radiotherapy, chemotherapy and most recently, the potential benefit of molecularly targeted drug therapy. This article, based upon the authors' clinical and research experience and the published literature will highlight advances in approach to diagnosis, the established role of vision loss as justification of treatments and the emerging evidence of endocrine and neurological consequences that need to be incorporated into judgements for case selection for therapy or observation. Consideration is given to the current state of biological evidence justifying current trials of new therapies, the genetic studies of the NF1 gene and the potential for new approaches to OPHG detection and treatment. The outstanding health system priorities from the perspective of children, their parents and health system commissioners or insurers are discussed.

GAED Medal Lecture 2022: Challenging the Dogma in Diabetic Neuropathy and Beyond

AbstractDogma, according to the Britannica Dictionary, is ”a belief or set of beliefs that is accepted by the members of a group without being questioned or doubted.” Thus, in 2001, the heretical idea that corneal confocal microscopy (CCM)—an ophthalmic instrument—could be used to assess neurological disease truly challenged the dogma. The repurposing of CCM to study diabetic neuropathy and other neurodegenerative diseases is a wonderful illustration of being in the right time and place and having honest and open conversations between very different medical disciplines to 'challenge the dogma.' The Gulf Association of Diabetes and Endocrinology (GAED) Medal Lecture in 2022 and the European Association for the Study of Diabetes (EASD) Camillo Golgi Prize in 2019 have enabled me to tell my personal story in relation to the past, present, and future of CCM as a clinical tool to diagnose and predict neurodegeneration and identify nerve regeneration in clinical trials of new therapies for peripheral and central neurodegenerative diseases.

Comparative validation of the knee inflammation MRI scoring system and the MRI osteoarthritis knee score for semi-quantitative assessment of bone marrow lesions and synovitis-effusion in osteoarthritis: an international multi-reader exercise.

Bone marrow lesions (BMLs) and synovitis on magnetic resonance imaging (MRI) are associated with symptoms and predict degeneration of articular cartilage in osteoarthritis (OA). Validated methods for their semiquantitative assessment on MRI are available, but they all have similar scoring designs and questionable sensitivity to change. New scoring methods with completely different designs need to be developed and compared to existing methods. To compare the performance of new web-based versions of the Knee Inflammation MRI Scoring System (KIMRISS) with the MRI OA Knee Score (MOAKS) for quantification of BMLs and synovitis-effusion (S-E). Retrospective follow-up cohort. We designed web-based overlays outlining regions in the knee that are scored for BML in MOAKS and KIMRISS. For KIMRISS, both BML and S-E are scored on consecutive sagittal slices. The performance of these methods was compared in an international reading exercise of 8 readers evaluating 60 pairs of scans conducted 1 year apart from cases recruited to the OA Initiative (OAI) cohort. Interobserver reliability for baseline status and baseline to 1 year change in BML and S-E was assessed by intra-class correlation coefficient (ICC) and smallest detectable change (SDC). Feasibility was assessed using the System Usability Scale (SUS). Mean change in BML and S-E was minimal over 1 year. Pre-specified targets for acceptable reliability (ICC ⩾ 0.80 and ⩾ 0.70 for status and change scores, respectively) were achieved more frequently for KIMRISS for both BML and synovitis. Mean (95% CI) ICC for change in BML was 0.88 (0.83-0.92) and 0.69 (0.60-0.78) for KIMRISS and MOAKS, respectively. KIMRISS mean SUS usability score was 85.7 and at the 95th centile of ranking for usability versus a score of 55.4 and 20th centile for MOAKS. KIMRISS had superior performance metrics to MOAKS for quantification of BML and S-E. Both methods should be further compared in trials of new therapies for OA.

Can novel CT-and MR-based neuroimaging biomarkers further improve the etiological diagnosis of lobar intra-cerebral hemorrhage?

Lobar hematomas represent around half of all supratentorial hemorrhages and have high mortality and morbidity. Their management depends on the underlying cause. Apart from local causes such as vascular malformation, which are rare and can usually be easily excluded thanks to imaging, the vast majority of lobar hematomas equally frequently result from either hypertensive arteriolopathy (HA) or cerebral amyloid angiopathy (CAA). Distinguishing between CAA and HA is important for prognostication (risk of recurrence nearly sevenfold higher in the former), for decision-making regarding, e.g., antithrombotic therapies (for other indications) and for clinical trials of new therapies. Currently, a non-invasive diagnosis of probable CAA can be made using the MR-based modified Boston criteria, which have excellent specificity but moderate sensitivity against histopathological reference, leading to the clinically largely irrelevant diagnosis of "possible CAA". Furthermore, the Boston criteria cannot be applied when both lobar and deep MRI hemorrhagic markers are present, a not uncommon situation. Here we propose to test whether new CT and MR-based imaging biomarkers, namely finger-like projections of the hematoma and adjacent subarachnoid hemorrhage on acute-stage CT or MRI, and remote punctate diffusion-weighted imaging ischemic lesions on acute or subacute-stage MRI, have the potential to improve the performance of the Boston criteria. Furthermore, we also propose to test whether clinical-radiological biomarkers may also allow a positive diagnosis of HA to be made in lobar hematomas, which, if feasible, would not only further reduce the prevalence of "possible CAA" but also permit a diagnosis of HA and/or CAA to be made in the presence of mixed deep and lobar MRI hemorrhagic markers.

A survey: Understanding the health and perspectives of people with CF not benefiting from CFTR modulators.

BackgroundWhile the advent of cystic fibrosis transmembrane conductance regulator (CFTR) modulator use has improved daily life and long‐term prognosis of CF for many with approved CFTR mutations, approximately 10% of people with CF (pwCF) have only symptomatic treatments available.MethodsBetween June 10 and July 1, 2021, Emily's Entourage distributed a 38‐question anonymous survey targeted at pwCF not benefitting from approved modulators via social media and email to pwCF and CF advocacy groups in and outside the United States regarding health status, impact of CF, unmet needs, and clinical research interest.ResultsThere were 431 survey respondents representing pwCF on five continents. The majority of pwCF had moderate lung disease (50.3%). Ineligibility based on CFTR mutation (64.1%) was the most frequently reported reason pwCF were not on modulators. PwCF reported the most impacted aspects of life were mental (66.7%) and physical (40.7%) health. Financial concerns and feelings of isolation were commonly reported. Witnessing improvements for peers with access to modulators was both uplifting and disheartening. The majority of pwCF would be interested in participating in future clinical research (77.6%), although some living outside of the United States cited lack of opportunity to participate in clinical trials as a barrier.ConclusionsPwCF who are ineligible, intolerant, or lack access to modulators have a high burden of disease impacting their physical and mental health. Although most are happy for those who are benefiting from modulators, they are eager for the opportunity to experience similar improvements for themselves, and willing to participate in clinical trials of new therapies.

A Question-and-Answer System to Extract Data From Free-Text Oncological Pathology Reports (CancerBERT Network): Development Study.

BackgroundInformation in pathology reports is critical for cancer care. Natural language processing (NLP) systems used to extract information from pathology reports are often narrow in scope or require extensive tuning. Consequently, there is growing interest in automated deep learning approaches. A powerful new NLP algorithm, bidirectional encoder representations from transformers (BERT), was published in late 2018. BERT set new performance standards on tasks as diverse as question answering, named entity recognition, speech recognition, and more.ObjectiveThe aim of this study is to develop a BERT-based system to automatically extract detailed tumor site and histology information from free-text oncological pathology reports.MethodsWe pursued three specific aims: extract accurate tumor site and histology descriptions from free-text pathology reports, accommodate the diverse terminology used to indicate the same pathology, and provide accurate standardized tumor site and histology codes for use by downstream applications. We first trained a base language model to comprehend the technical language in pathology reports. This involved unsupervised learning on a training corpus of 275,605 electronic pathology reports from 164,531 unique patients that included 121 million words. Next, we trained a question-and-answer (Q&A) model that connects a Q&A layer to the base pathology language model to answer pathology questions. Our Q&A system was designed to search for the answers to two predefined questions in each pathology report: What organ contains the tumor? and What is the kind of tumor or carcinoma? This involved supervised training on 8197 pathology reports, each with ground truth answers to these 2 questions determined by certified tumor registrars. The data set included 214 tumor sites and 193 histologies. The tumor site and histology phrases extracted by the Q&A model were used to predict International Classification of Diseases for Oncology, Third Edition (ICD-O-3), site and histology codes. This involved fine-tuning two additional BERT models: one to predict site codes and another to predict histology codes. Our final system includes a network of 3 BERT-based models. We call this CancerBERT network (caBERTnet). We evaluated caBERTnet using a sequestered test data set of 2050 pathology reports with ground truth answers determined by certified tumor registrars.ResultscaBERTnet’s accuracies for predicting group-level site and histology codes were 93.53% (1895/2026) and 97.6% (1993/2042), respectively. The top 5 accuracies for predicting fine-grained ICD-O-3 site and histology codes with 5 or more samples each in the training data set were 92.95% (1794/1930) and 96.01% (1853/1930), respectively.ConclusionsWe have developed an NLP system that outperforms existing algorithms at predicting ICD-O-3 codes across an extensive range of tumor sites and histologies. Our new system could help reduce treatment delays, increase enrollment in clinical trials of new therapies, and improve patient outcomes.

A Matter of Timing: Rudy Tanzi on Alzheimer's Disease

A Matter of Timing: Rudy Tanzi on Alzheimer's Disease

Assessment of Minimal/Measurable Residual Disease Testing in Acute Myeloid Leukaemia By Molecular Methods in an Interlaboratory Study

BackgroundMinimal/measurable residual disease (MRD) testing is increasingly utilised and accepted as standard of care to manage a range of different haematological malignancies. It's use as a surrogate outcome in clinical trials of new therapies is being explored, where it has the potential to accelerate drug assessment and approval. The phenotypic and genetic heterogeneity of acute myeloid leukaemia (AML) has limited the use of MRD in this context; however, the European LeukaemiaNet (ELN) MRD working group have recently published consensus guidelines to standardise both flow cytometric and molecular genetic MRD testing. To assess the accuracy of testing and concordance between laboratories, crucial to patient safety, external quality assessment (EQA)/proficiency testing (PT) is required.AimsTo determine the performance of molecular methods for measuring of MRD using the t(8;21)(q22:q22) RUNX1-RUNX1T1, inv(16)(p13q22) CBFB-MYH11, t(15;17)(q24.1;q21.2) PML-RARA and NPM1 Type A markers in an international interlaboratory study.MethodsA total of 12 batches of lyophilised EQA material were manufactured. These consisted of three batches of samples for each marker all containing 9x10^6 cells: an MRD ‘high’ sample; an MRD ‘low’ sample; and an MRD ‘negative’ sample. The t(8;21)(q22:q22) RUNX1-RUNX1T1 positive samples were manufactured using the KASUMI-1 cell line, the inv(16)(p13q22) CBFB-MYH11 positive samples using the ME-1 cell line; t(15;17)(q24.1;q21.2 PML-RARA positive samples using the NB4 cell line and the NPM1 Type A (NM_002520.6:c.860_863dup) positive samples using the OCI-AML3 cell line. MRD positive samples were diluted with HL60 cells to achieve the desired MRD level. MRD negative samples were manufactured using the HL60 cell line. The samples were shipped at ambient temperature to the 29 laboratories in 12 countries. Participants were asked to test the blinded samples with their in-house assay and report % normalised ratio of the relevant marker alongside additional methodological and technical data.ResultsFor t(8;21) RUNX1-RUNX1T1, all participants who returned results (n=23) classified the MRD ‘high’ and MRD ‘low’ samples as positive and the MRD ‘negative’ sample as negative. The robust mean log reduction between the MRD ‘high’ and MRD low sample was 2.7 (range 2.5-2.9). For inv(16) CBFB-MYH11, all participants who returned results (n=22) classified the MRD ‘high’ sample as positive, 21/22 (95.5%) classified the MRD ‘low’ sample as positive and 21/22 (95.5%) classified the MRD negative sample as negative. The robust mean log reduction between the MRD ‘high’ and MRD ‘low’ sample was 3.16 (range 2.8-4.2). For t(15;17) PML-RARA, all participants who returned results (n=22) classified the MRD ‘high’ sample as positive, 21/22 (95.5%) classified the MRD ‘low’ sample as positive and 21/22 (95.5%) classified the MRD negative sample as negative. The robust mean log reduction between the MRD ‘high’ and MRD ‘low’ sample was 2.1 (range 1.4-2.4). For NPM1, all participants who returned results (n=23) classified the MRD ‘high’ as positive, 21/23 (91.3%) classified the MRD ‘low’ sample as positive and, 17/23 (73.4%) classified the MRD negative sample as negative. The robust mean log reduction between the MRD ‘high’ and MRD ‘low’ sample was 3.8 (range 3.2-4.2).Summary/ConclusionThe majority of participants in this study were able to detect and accurately quantify MRD when assessing the t(8;21)(q22:q22) RUNX1-RUNX1T1, inv(16)(p13q22) CBFB-MYH11, t(15;17)(q24.1;q21.2) PML-RARA and NPM1 markers, at levels that would be expected within a clinical trial or standard of care setting. A high proportion of participants reported false positive results in the NPM1 marker negative sample. This would have significant consequences clinically, with NPM1 marker false-positivity potentially committing patients to unneeded additional chemotherapy and/or transplant with the attendant risk of morbidity and mortality which highlights the need for ongoing EQA in this area. UK NEQAS LI will work with laboratories advocating they undertake a root cause analysis process to identify the source(s) of error contributing to false positive NPM1 marker results and support their subsequent corrective actions; sharing any educational findings with all participants. [Display omitted] DisclosuresScott: Novartis: Research Funding; Biorad: Research Funding. Dillon: Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support, Educational Events; Amgen: Other: Research support (paid to institution); Astellas: Consultancy, Other: Educational Events , Speakers Bureau; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Session chair (paid to institution), Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: educational events; Jazz: Other: Education events; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees. Whitby: Roche: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Other: Teaching.

Headache in Children and Adolescents.

This article reviews the approach to a child or adolescent with headache, the criteria for common diagnoses, and the evidence base for treatments. The guidelines for acute and preventive treatment of migraine were updated in 2019. These guidelines summarize the available evidence and outline the questions that should be addressed in future research. The US Food and Drug Administration (FDA) approval of several new classes of drugs and devices to treat adult migraine in the past few years has resulted in ongoing or planned pediatric trials. Headache is a common symptom in children, and it is important to take a detailed history and perform a thorough physical examination to make the diagnosis. Nearly 1 in 10 children experience recurrent headaches due to migraine, which cause significant impairment in school performance and quality of life. The acute and preventive treatments that are currently available will help at least two-thirds of children with migraine, and several trials of new therapies offer hope for the future.

Tackling the Challenges of Product Development Through a Collaborative Rare Disease Network: The Foundation Fighting Blindness Consortium

The Foundation Fighting Blindness, a 501(c)(3) nonprofit organization, established an international consortium of inherited retinal disease specialists in 2016, with a mission to accelerate the development of treatments for rare, inherited retinal degenerations, such as retinitis pigmentosa, Stargardt disease, Leber congenital amaurosis, Usher syndrome, choroideremia, and achromatopsia. The Consortium accomplishes its mission by evaluating novel outcome measures, sharing standardized study protocols and datasets, and disseminating findings. Having established research infrastructure in the first 3 years, including 39 global research sites, the network is now poised to expand its infrastructure for trials of new therapies in partnership with industry. This model represents an innovative approach to overcome challenges of therapeutic development for rare diseases.

Repeatability and sensitivity to change of non-invasive end points in PAH: the RESPIRE study

End points that are repeatable and sensitive to change are important in pulmonary arterial hypertension (PAH) for clinical practice and trials of new therapies. In 42 patients with PAH, test–retest...

Molecular diagnosis of scabies using a novel probe-based polymerase chain reaction assay targeting high-copy number repetitive sequences in the Sarcoptes scabiei genome.

The suboptimal sensitivity and specificity of available diagnostic methods for scabies hampers clinical management, trials of new therapies and epidemiologic studies. Additionally, parasitologic diagnosis by microscopic examination of skin scrapings requires sample collection with a sharp scalpel blade, causing discomfort to patients and difficulty in children. Polymerase chain reaction (PCR)-based diagnostic assays, combined with non-invasive sampling methods, represent an attractive approach. In this study, we aimed to develop a real-time probe-based PCR test for scabies, test a non-invasive sampling method and evaluate its diagnostic performance in two clinical settings. High copy-number repetitive DNA elements were identified in draft Sarcoptes scabiei genome sequences and used as assay targets for diagnostic PCR. Two suitable repetitive DNA sequences, a 375 base pair microsatellite (SSR5) and a 606 base pair long tandem repeat (SSR6), were identified. Diagnostic sensitivity and specificity were tested using relevant positive and negative control materials and compared to a published assay targeting the mitochondrial cox1 gene. Both assays were positive at a 1:100 dilution of DNA from a single mite; no amplification was observed in DNA from samples from 19 patients with other skin conditions nor from house dust, sheep or dog mites, head and body lice or from six common skin bacterial and fungal species. Moderate sensitivity of the assays was achieved in a pilot study, detecting 5/7 (71.4% [95% CI: 29.0% - 96.3%]) of clinically diagnosed untreated scabies patients). Greater sensitivity was observed in samples collected by FLOQ swabs compared to skin scrapings. This newly developed qPCR assay, combined with the use of an alternative non-invasive swab sampling technique offers the possibility of enhanced diagnosis of scabies. Further studies will be required to better define the diagnostic performance of these tests.

KCNQ2-DEE: developmental or epileptic encephalopathy?

Objective KCNQ2‐associated developmental and epileptic encephalopathies (DEE) present with seizures and developmental impairments. The relation between seizures and functional impairments in affected children and the relation of a specific genetic variant to seizure control remains unknown.MethodsParents of children with documented KCNQ2 variants who participated in a structured, online natural history survey provided information about seizure history, functional mobility, hand use, communication function, and feeding independence. Bivariate analyses were performed with nonparametric methods and logistic regression was used for multivariable analyses.ResultsThirty‐nine children (20, 51% girls, median age 4.5 years, interquartile range (IQR) 1.9—19.3) had a median age of seizure onset of 1 day (IQR 1—3 days). The most common seizure types were bilateral tonic‐clonic (N = 72, 28%) and bilateral tonic (N = 13, 33%). Time since last seizure was <6 months (N = 18, 46%), 6–23 months (N = 11, 28%), and ≥24 months (N = 10 26%). Severe functional impairment was reported for mobility (62%), hand grasp (31%), feeding (59%), and communication (77%). Twenty‐eight (72%) were impaired in ≥2 domains. There were only weak and inconsistent associations between seizure recency and individual impairments or number of impairments after adjustment for other factors. The functional location of the variants within the Kv7.2 protein was not associated with seizure control.InterpretationSeizures in KCNQ2‐DEE are often well‐controlled, but children have severe impairments regardless. With the increased potential for precision therapies targeting the Kv7.2 channel or the KCNQ2 gene itself, identifying the most relevant and sensitive clinical endpoints will be critical to ensure successful trials of new therapies.

Balancing risks: making decisions for maternal treatment without data on fetal safety

Challenges arise when treatment to improve maternal health brings the possibility of risk to fetal health. The coronavirus disease 2019 (COVID-19) vaccine is the most recent, but hardly the only, example. Because pregnant patients are often specifically excluded from trials of new therapies, this is often the dilemma that patients and providers face when considering new treatments. In this study, we used the COVID-19 vaccine as an exemplar to question the broader issue of how society, in general, and obstetricians, in particular, should balance obligations to pregnant women’s right of access to new therapeutic agents with the physician’s desire to protect the fetus from potential risks. We will argue that in almost all circumstances (with few exceptions, as will also be discussed), maternal benefit and respect for autonomy create the uncertainty that absent safety data bring. Consequently, if pregnant women choose to try new interventions and treatments, such as the COVID-19 vaccination, they should be offered those new regimens and their decision supported. In addition, we will argue that the right solution to avoid the dilemma of absent data is to include pregnant individuals in clinical trials studying new treatments, drugs, and other therapies. We will also discuss the basis for our opinion, which are mainstream obstetrical ethics, precedents in law (supreme court ruling that forbids companies to exclude women from jobs that might pose a risk to the fetus), and historic events (thalidomide). The ethical framework includes the supposition that sacrifice to improve fetal outcome is a virtue and not a mandate. Denying a pregnant patient treatment because of threats to their life can create absurd and paradoxical consequences. Either requiring abortion or premature delivery before proceeding with treatments to optimize maternal health, or risking a patient’s own life and ability to parent a child by delaying treatment brings clear and significant risks to fetal and/or neonatal outcomes. With rare exceptions, properly and ethically balancing such consequential actions cannot be undertaken without considering the values and goals of the pregnant patient. Therefore, active participation of both the pregnant patient and their physician in shared decision making is needed.

Rare Kidney Disease in the Time of COVID: Update on Atypical Hemolytic Uremic Syndrome (aHUS)

Despite its rarity, atypical hemolytic uremic syndrome (aHUS) featured prominently in this year’s virtual Kidney Week – including the second reported case worldwide of aHUS due to COVID-19. Presenters explored the challenging diagnosis of aHUS, in which kidney damage is central, through successful cases and biomarker data. Optimisation of Canadian treatment standard, eculizumab, was also featured, along with trials of new therapies.

The Frontotemporal Dementia Prevention Initiative: Linking Together Genetic Frontotemporal Dementia Cohort Studies.

Around one-third of frontotemporal dementia (FTD) is autosomal dominant with the major genetic causes being mutations in MAPT, GRN and C9orf72. Studying familial forms of FTD can provide a window into the earliest stages of the illness, many years before symptoms start. Large cohort studies have been set up in recent years to better understand this presymptomatic phase, including the Genetic FTD Initiative (GENFI) and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (ARTFL/LEFFTDS) studies. Whilst these studies have focused on the investigation of a variety of aspects of genetic FTD, from understanding the molecular pathogenesis to developing biomarkers, they also have a common goal: finding a way to prevent FTD. Researchers from these cohort studies have therefore come together to form the FTD Prevention Initiative (FPI), which has the overarching aim of promoting clinical trials of new therapies to prevent FTD through creating an international database of participants eligible for trials and uniform standards for conducting such trials. This chapter outlines the work of the FPI so far and its future goals over the next few years.