An eHealth model of care in the management of chronic disease: Chronic hepatitis C infection

© 2020 James John HaridyThe rising burden of chronic disease in the developed world has resulted in an increasing accumulation of patients requiring long-term specialist input in care, despite a relatively stagnant specialist capacity in tertiary hospital services. Newer models of care, incorporating specialist input whilst empowering and enabling community-based treatment in a more cost-effective primary care setting are desirable. This thesis details the adaptation, implementation and evaluation of a new model of care that is underpinned by digital technology, using the HealthElink system, in facilitating community and prison-based treatment of chronic hepatitis C virus (HCV). This approach involved establishing outcomes for current treatment models, preliminary system functionality testing and prospective implementation of the eHealth model of care in both community and prison settings throughout Australia. Chronic hepatitis C virus represents a model disease in which rapid treatment advances have allowed care to primarily shift from hospital to community-based treatment. The advent and availability of direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) in Australia in March 2016 represented a treatment revolution. In effect, HCV became the first chronic viral infection for which a safe, efficacious and permanent cure exists, affording the opportunity to facilitate global eradication programs. The World Health Organisation therefore issued a position paper, calling for the elimination of HCV as a major public health threat by 2030 and ending onward transmission through ‘treatment as prevention’ programs. Owing to the efficacy, ease and safety of DAA therapy, Australia became one of the first jurisdictions to allow any prescriber to use these lifesaving medications. Despite an estimated 80% of patients deemed suitable for treatment by a primary care practitioner, only 18% of prescriptions were from a GP in the first twelve-months. This formed the ideal opportunity to deploy and examine the eHealth model of care. This thesis is built upon the largest prospective clinical study of a novel shared eHealth model of care in Australia. Baseline studies in this thesis established the real-world outcomes of DAA treatment in Australia in the new era of treatment. Failure to test for HCV cure and loss to follow-up were higher than previously reported in controlled trials, particularly in community and prison settings compared to tertiary-based treatment. The eHealth model of care was usable, acceptable and more accurate in treatment selection than the current standard of care in preliminary functionality testing. A quasi-experimental, hybrid implementation-effectiveness study of the eHealth model in both community settings and prisons was undertaken showing similar clinical outcomes to the standard of care, with an improvement in guideline-based quality of care and efficiency. Uptake of the eHealth model was low by general practitioners, likely influenced in part by low HCV screening particularly in regional areas. Integrated hepatitis nurses exhibited high uptake of the system, contrasting with lower usability scores. The electronic patient portal exhibited low utilisation and may hold limited value in the current iteration due to both clinician and patient factors. The clinical decision support system was the most useful component of the eHealth model of care. Integration into existing electronic systems is seen as crucial to future electronic shared care models amongst clinicians. When applied to chronic hepatitis C, the eHealth model is usable and acceptable and demonstrates similar clinical outcomes to the current standard of care. Additional benefits in adherence to guideline-based care and efficiency of care were found. An integrated eHealth model of care for chronic disease, although currently nascent, holds potential to profoundly improve the delivery and quality of care

PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation

Objective: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. Methods: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. Results: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5'-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. Interpretation: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels.ANN NEUROL 2019;86:225-24

Global distribution of alveolar and cystic echinococcosis

Alveolar echinococcosis (AE) and cystic echinococcosis (CE) are severe helminthic zoonoses. Echinococcus multilocularis (causative agent of AE) is widely distributed in the northern hemisphere where it is typically maintained in a wild animal cycle including canids as definitive hosts and rodents as intermediate hosts. The species Echinococcus granulosus, Echinococcus ortleppi, Echinococcus canadensis and Echinococcus intermedius are the causative agents of CE with a worldwide distribution and a highly variable human disease burden in the different endemic areas depending upon human behavioural risk factors, the diversity and ecology of animal host assemblages and the genetic diversity within Echinococcus species which differ in their zoonotic potential and pathogenicity. Both AE and CE are regarded as neglected zoonoses, with a higher overall burden of disease for CE due to its global distribution and high regional prevalence, but a higher pathogenicity and case fatality rate for AE, especially in Asia. Over the past two decades, numerous studies have addressed the epidemiology and distribution of these Echinococcus species worldwide, resulting in better-defined boundaries of the endemic areas. This chapter presents the global distribution of Echinococcus species and human AE and CE in maps and summarizes the global data on host assemblages, transmission, prevalence in animal definitive hosts, incidence in people and molecular epidemiology

Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia.

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays