Fostering the international interoperability of clinical research networks to tackle undiagnosed and under-researched rare diseases.

Clinical research is an essential component to advance diagnosis and therapeutic development. In 2022, the International Rare Diseases Research Consortium (IRDiRC) and the European Joint Programme on Rare Diseases (EJP RD) brought together key stakeholders from across the globe to discuss common themes in clinical research networks (CRNs) for rare diseases. Various topics were raised during discussions including current state of CRNs, the need for new CRNs, multi-stakeholder perspectives on value of CRNs, and ways to collaborate on a global scale.

Demystifying gene(tic) therapies.

This article summarizes the discussion from a session entitled "Demystifying gene therapies" that was held at the joint RE(ACT) congress and IRDiRC conference, 14-15 March 2023 in Berlin, Germany. The focus of this session was to discuss the changing landscape of genetic therapies and whether current resources exist to provide adequate education to stakeholders, such as researchers, clinicians, patient advocates, legislators, as well as the patients and their families. The goal of this article is not to provide a comprehensive overview of the current landscape in genetic therapies, but rather to highlight resources that may be useful to help "demystify" the myriad of genetic therapeutic approaches.

"What you Say Matters": Review of Clinical Outcome of Advanced Medical Directives Between Cancer and Non-cancer Patients in a Chinese Culture Society.

Introduction: Advance medical directives (AMD) are statements made by individuals indicating the life-sustaining treatment that they would refuse in the future when they lost their mental capacity for medical decisions. While the proposal for the AMD legislation is ongoing locally in Hong Kong SAR, there are limited reviews on the clinical outcomes associated with it.

Objective: To provide a comprehensive review on clinical outcomes of signed AMD.

Targeting shared molecular etiologies to accelerate drug development for rare diseases.

Rare diseases affect over 400 million people worldwide and less than 5% of rare diseases have an approved treatment. Fortunately, the number of underlying disease etiologies is far less than the number of diseases, because many rare diseases share a common molecular etiology. Moreover, many of these shared molecular etiologies are therapeutically actionable.

Recommendations from the IRDiRC Working Group on methodologies to assess the impact of diagnoses and therapies on rare disease patients.

Rare disease patients face many challenges including diagnostic delay, misdiagnosis and lack of therapies. However, early access to diagnosis and therapies can modify the management and the progression of diseases, which in return positively impacts patients, families and health care systems. The International Rare Diseases Research Consortium set up the multi-stakeholder Working Group on developing methodologies to assess the impact of diagnoses and therapies on rare disease patients.

Developing an algorithm across integrated healthcare systems to identify a history of cancer using electronic medical records.

Objective: Tumor registries in integrated healthcare systems (IHCS) have high precision for identifying incident cancer but often miss recently diagnosed cancers or those diagnosed outside of the IHCS. We developed an algorithm using the electronic medical record (EMR) to identify people with a history of cancer not captured in the tumor registry to identify adults, aged 40-65 years, with no history of cancer.

Materials And Methods: The algorithm was developed at Kaiser Permanente Colorado, and then applied to 7 other IHCS.

The IDeaS initiative: pilot study to assess the impact of rare diseases on patients and healthcare systems.

Background: Rare diseases (RD) are a diverse collection of more than 7-10,000 different disorders, most of which affect a small number of people per disease. Because of their rarity and fragmentation of patients across thousands of different disorders, the medical needs of RD patients are not well recognized or quantified in healthcare systems (HCS).

Methodology: We performed a pilot IDeaS study, where we attempted to quantify the number of RD patients and the direct medical costs of 14 representative RD within 4 different HCS databases and performed a preliminary analysis of the diagnostic journey for selected RD patients.

Patterns and infection outcomes of bacterial colonization in patients with indwelling abdominal drains for malignant ascites.

Background: Indwelling abdominal drains for intermittent drainage is an effective treatment for refractory malignant ascites, bacterial colonization and subsequent drain-related infection is however a common concern. This study aimed to investigate the patterns of bacterial colonization and the subsequent infection outcomes in patients with indwelling abdominal drains.

Methods: All consecutive advanced cancer patients with newly inserted indwelling abdominal drains and who were under the service of the ascites clinic of our institution for intermittent drainage between January 2011 and March 2018 were screened for study eligibility.

Dealing With Death Taboo: Discussion of Do-Not-Resuscitate Directives With Chinese Patients With Noncancer Life-Limiting Illnesses.

Background: Noncancer patients with life-limiting diseases often receive more intensive level of care in their final days of life, with more cardiopulmonary resuscitation performed and less do-not-resuscitate (DNR) orders in place. Nevertheless, death is still often a taboo across Chinese culture, and ethnic disparities could negatively affect DNR directives completion rates.

Objectives: We aim to explore whether Chinese noncancer patients are willing to sign their own DNR directives in a palliative specialist clinic, under a multidisciplinary team approach.

Delivering Precision Oncology in a Community Cancer Program: Results From a Prospective Observational Study.

Introduction: Precision oncology (PO) is a growing treatment approach in the era of next-generation sequencing (NGS) and matched therapies. Effective delivery of PO in the community has not been extensively studied. Our program developed a virtual molecular tumor board (MTB) strategy to help guide PO care.

A porcine model of neurofibromatosis type 1 that mimics the human disease.

Loss of the NF1 tumor suppressor gene causes the autosomal dominant condition, neurofibromatosis type 1 (NF1). Children and adults with NF1 suffer from pathologies including benign and malignant tumors to cognitive deficits, seizures, growth abnormalities, and peripheral neuropathies. NF1 encodes neurofibromin, a Ras-GTPase activating protein, and NF1 mutations result in hyperactivated Ras signaling in patients.

Supportive & palliative interventions in motor neurone disease: what we know from current literature?

Although there is no cure for motor neurone disease (MND), the advent of supportive interventions including multidisciplinary care (MDC) has improved treatment interventions and enhanced quality of life (QOL) for MND patients and their carers. Our integrative review showed evidence-based MDC, respiratory management and disease-modifying therapy that have improved the outcomes of patients diagnosed with MND. Supportive approaches to nutritional maintenance and optimization of symptomatic treatments, including management of communication and neuropsychiatric issues, improve the QOL for MND patients.

Using a social robot to teach gestural recognition and production in children with autism spectrum disorders.

While it has been argued that children with autism spectrum disorders are responsive to robot-like toys, very little research has examined the impact of robot-based intervention on gesture use. These children have delayed gestural development. We used a social robot in two phases to teach them to recognize and produce eight pantomime gestures that expressed feelings and needs.

Plasma biomarkers for neuronal ceroid lipofuscinosis.

The neuronal ceroid lipofuscinoses (NCLs) are a group of neurodegenerative genetic diseases that primarily affect children and have no known cure. A unified clinical rating scale for the juvenile form of NCL has been developed, although it has not been validated in other subtypes and does not give a true measure of the pathophysiological changes occurring during disease progression. In the present study, we have identified candidate biomarkers in blood plasma of NCL disease using multiple proteomic approaches, with the aim of developing a panel of biomarkers that could serve as a metric for therapeutic response.

A novel porcine model of ataxia telangiectasia reproduces neurological features and motor deficits of human disease.

Ataxia telangiectasia (AT) is a progressive multisystem disorder caused by mutations in the AT-mutated (ATM) gene. AT is a neurodegenerative disease primarily characterized by cerebellar degeneration in children leading to motor impairment. The disease progresses with other clinical manifestations including oculocutaneous telangiectasia, immune disorders, increased susceptibly to cancer and respiratory infections.

How is your biobank handling disaster recovery efforts?

Recent years have seen a great many natural disasters-superstorms, droughts, earthquakes, among others-as well as, in the biobanking world, the constant threat of man-made disaster with everything from freezer malfunctions to theft. To help inform the increasingly important issue of protection from, and recovery after, disasters, Biopreservation and Biobanking put forth the question to our community of experts: How is your biobank handling disaster recovery efforts? Following is a selection of responses. Additionally, please see the Supplementary Information for contingency planning recommendations for biobanks and a threats assessment checklist from Intelsius ( supplementary material can be accessed from the online article at www.

Osmotic stress changes the expression and subcellular localization of the Batten disease protein CLN3.

Juvenile CLN3 disease (formerly known as juvenile neuronal ceroid lipofuscinosis) is a fatal childhood neurodegenerative disorder caused by mutations in the CLN3 gene. CLN3 encodes a putative lysosomal transmembrane protein with unknown function. Previous cell culture studies using CLN3-overexpressing vectors and/or anti-CLN3 antibodies with questionable specificity have also localized CLN3 in cellular structures other than lysosomes.

The role of nonsense-mediated decay in neuronal ceroid lipofuscinosis.

Neuronal ceroid lipofuscinosis (NCL), commonly referred to as Batten disease, is a group of autosomal recessive neurodegenerative diseases of childhood characterized by seizures, blindness, motor and cognitive decline and premature death. Currently, there are over 400 known mutations in 14 different genes, leading to five overlapping clinical variants of NCL. A large portion of these mutations lead to premature stop codons (PTCs) and are predicted to predispose mRNA transcripts to nonsense-mediated decay (NMD).

BTN1, the Saccharomyces cerevisiae homolog to the human Batten disease gene, is involved in phospholipid distribution.

BTN1, the yeast homolog to human CLN3 (which is defective in Batten disease), has been implicated in the regulation of vacuolar pH, potentially by modulating vacuolar-type H(+)-ATPase (V-ATPase) activity. However, we report that Btn1p and the V-ATPase complex do not physically interact, suggesting that any influence that Btn1p has on V-ATPase is indirect. Because membrane lipid environment plays a crucial role in the activity and function of membrane proteins, we investigated whether cells lacking BTN1 have altered membrane phospholipid content.

Immunosuppression alters disease severity in juvenile Batten disease mice.

Autoantibodies to brain proteins are present in Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease) patients and in the Cln3-/- mouse model of this disease, suggesting an autoimmune component to pathogenesis. Using genetic or pharmaceutical approaches to attenuate this immune response in Cln3-/- mice, we demonstrate decreased neuroinflammation, decreased deposition of immunoglobulin G in the brain and protection of vulnerable neuron populations. Moreover, immune suppression results in a significant improvement in motor performance providing for the first plausible therapeutic approach for juvenile Batten disease.

Molecular correlates of axonal and synaptic pathology in mouse models of Batten disease.

Neuronal ceroid lipofuscinoses (NCLs; Batten disease) are collectively the most frequent autosomal-recessive neurodegenerative disease of childhood, but the underlying cellular and molecular mechanisms remain unclear. Several lines of evidence have highlighted the important role that non-somatic compartments of neurons (axons and synapses) play in the instigation and progression of NCL pathogenesis. Here, we report a progressive breakdown of axons and synapses in the brains of two different mouse models of NCL: Ppt1(-/-) model of infantile NCL and Cln6(nclf) model of variant late-infantile NCL.

Transcript and in silico analysis of CLN3 in juvenile neuronal ceroid lipofuscinosis and associated mouse models.

Juvenile neuronal ceroid lipofuscinoses (JNCL), commonly known as Batten disease, is a progressive neurodegenerative disorder of childhood characterized by blindness, seizures, motor and cognitive decline, leading to death in early adulthood. Mutations within the CLN3 gene, which encodes a putative lysosomal protein of unknown function, are the underlying cause of JNCL. Over 85% of JNCL patients harbor a 1 kb deletion that is predicted to result in a truncated CLN3 protein and is presumed to be a null mutation.

Palliative care for patients with end-stage renal disease: experiences from Hong Kong.

As the number of patients with end-stage renal disease continues to grow in Hong Kong, many are opting to be managed conservatively without dialysis. A new service was initiated in Tuen Mun Hospital in 2004 aimed at offering palliative care to dying patients with renal failure. This paper presents retrospective data reflecting our dealings with patients who decided not to initiate or considered discontinuation of dialysis.

Enhanced GABA(A) receptor-mediated activity following activation of NMDA receptors in Cajal-Retzius cells in the developing mouse neocortex.

Cajal-Retzius (CR) cells are among the earliest generated population of neurons in the developing neocortex and have been implicated in regulating cortical lamination. In rodents, CR cells are transient, being present only up to 2-3 weeks after birth. Although previous electrophysiological studies have demonstrated the presence of NMDA and GABAA receptors in CR cells, little is known about the functional properties of these receptors.